Our research sought to understand how falls risk, cognitive function, and daily function are associated with health related quality of life (using the EuroQol-5D) and quality of life (using the ICECAP-O) among older adults with mobility impairments.The EQ-5D and ICECAP-O were administered at 12 months post first clinic attendance at the Vancouver Falls Prevention Clinic. We report descriptive statistics for all baseline characteristics collected at first clinic visit and primary outcomes of interest. Using multivariate stepwise linear regression, we assessed the construct validity of the EQ-5D and ICECAP-O using three dependent measures that are recognized indicators of “impaired mobility” – physiological falls risk, general balance and mobility, and cognitive status among older adults.We report data on 215 seniors who attended the Vancouver Falls Prevention Clinic and received their first clinic assessment. Patients had a mean age of 79.3 (6.2) years. After accounting for known covariates , the ICECAP-O domains explained a greater amount of variation in each of the three dependent measures compared with the EQ-5D domains.Both the EQ-5D and ICECAP-O demonstrate associations with falls risk and general balance and mobility; however, only the ICECAP-O was associated with cognitive status among older adults with mobility impairments.ClinicalTrials.gov Identifier: NCT01022866 Health related quality of life (HRQoL) is an important construct for healthy aging; it describes an individual’s overall health status. PreviouImpaired mobility is also significantly associated with quality of life (QoL) – a consOne key question remains unanswered: Are we adequately assessing HRQoL and QoL among older adults with mobility impairments? To address this question, we first need to ascertain the association between falls risk, cognitive function, and general balance and mobility, and health-related quality of life and quality of life among older adults with mobility impairments.Two examples of feasible measures as relevant tools for this population of older adults that evaluate HRQoL and QoL, respectively, include the EQ-5D and the ICECAP-0,12.The most widely used utility-based measure of HRQoL is the EQ-5D-14. The The Index of Capability for older adults (ICECAP-O) is a relatively new measure developed to provide a broader assessment of QoL among older adults,15. The •Attachment (love and friendship)•Security (thinking about the future without concern)•Role •Enjoyment (enjoyment and pleasure)•Control (independence)The value system for the ICECAP-O provides a single summary score, anchored at zero (‘no capability’) and 1.0 (‘full capability’), for each state described in terms of the five attributes.There remains a gap in our current knowledge regarding the understanding of the association of falls risk, cognitive function and general balance and mobility with HRQoL (assessed using the EQ-5D) and quality of life (assessed using the ICECAP-O) among older adults with mobility impairments. Hence, we aim to examine the association of the EQ-5D with the ICECAP-O with valid and reliable measures of physiological falls risk, general balance and mobility, and cognitive status among older adults with mobility impairments.http://www.fallsclinic.com) due to a fall from January 2009 through May 2011.We conducted a cross-sectional analysis of participants visiting the Vancouver Falls Prevention Clinic  score ≥ •had a Physiological Profile Assessment (PPA) score of•were expected to live ≥ 12 months;•were able to walk 3 metres; and•were able to provide written informed consentWe excluded those with a neurodegenerative disease  or dementia, patients who recently had a stroke, those with clinically significant peripheral neuropathy or severe musculoskeletal or joint disease, and anyone with a history indicative of carotid sinus sensitivity .Ethical approval was obtained from the Vancouver Coastal Health Research Institute and the University of British Columbia’s Clinical Research Ethics Board. All participants provided written informed consent.The data presented in this paper include baseline characteristics collected at participants’ first clinic assessment. The ICECAP-O and EQ-5D, were collected once at 12 months post first clinic assessment.As part of the clinical assessment in the Falls Prevention Clinic visit, a comprehensive set of questionnaires and clinical tests were administered. From these, we selected three measures as key indicators of “impaired mobility” -- physiological falls risk, general balance and mobility, and cognitive status among older adults. These measures were chosen based on the rationale that physiological functions such as vision, proprioception, strength, reaction time, and postural stability are significantly associated with falls risk-20. ImpaFor physiological falls risk, we used the PPA © . For theFor global cognitive function, we used the MMSE. A scoreInstrumental Activities of Daily Living (IADLs) Scale. Participants completed the Lawton and Brody[For assessing activities of daily living, we used the nd Brody InstrumeThe EQ-5D is a short five-item multiple choice questionnaire that measures an individual’s HRQoL and health status according to the following five domains: mobility, self-care, usual activities, pain and anxiety/depression. Each doWe assessed QoL using the ICECAP-O,15. The Descriptive statistics were used to characterize the study sample.To measure the association between the EQ-5D and the ICECAP-O global scores with the PPA, SPPB, and MMSE we estimated the Pearson correlation coefficients. We used Spearman correlation coefficients for the specific domains of the EQ-5D  & ICECAP-O  with the PPA, SPPB, MMSE and IADLs.We conducted three separate stepwise multivariate linear regression models with valid and reliable measures of falls risk, general balance and mobility and cognitive status as the dependent variables. An alpha level of 0.1 was used for the stepwise selection approach. All regression models were bootstrapped with 1000 replications to determine the consistency of each of the three final multivariate models. Within each of these three models, we adjusted for known covariates including age and sex. Our key independent variables of interest were the EQ-5D domains  and ICECAP-O domains . For all domains of the EQ-5D and the ICECAP-O, level 1 was used as the reference category. Level 1 for both instruments indicates no problems with the domain of interest. All statistical analyses were performed using STATA Version11.0.Descriptive statistics for all baseline clinical variables and primary outcomes are reported in Table2 = 0.474; p<0.01).Table2 = −0.177, p<0.05) was significantly correlated with the SPPB. The EQ-5D domain of self-care  was significantly correlated with IADLs. For the ICECAP-O, the domain ‘control’ was significantly associated with the PPA , the domains ‘role’ and ‘control’ were significantly associated with the SPPB , the domain ‘security’ was significantly associated with the MMSE  and the domains of role , enjoyment  and control  were significant associated with IADLs.None of the domains of the EQ-5D were significantly correlated with the PPA or MMSE (p>0.05). The EQ-5D domain of mobility , we found that the ICECAP-O domains of role (level 4), enjoyment (level 4) and control (levels 2 and 3) explained a statistically significant amount of variation in the PPA score (p < 0.05). Mobility (level 2), a domain of the EQ-5D explained a non-significant degree of variation in the PPA score. Depression (level 2) and Usual Activities (level 3) of the EQ-5D explained a statistically significant amount of variation in the PPA score (p < 0.05).After accounting for known covariates, we found that the ICECAP-O domains of security (levels 3 and 4) and control (level 4) explained a statistically significant amount of variation in the SPPB score (p < 0.05). Self-care (level 3), a domain of the EQ-5D explained a significant degree of variation in the SPPB score (p < 0.05).After accounting for known covariates, we found that the ICECAP-O domains of control (level 3), security  and role (level 4) explained a statistically significant amount of variation in the MMSE score (p < 0.05). None of the domains of the EQ-5D explained a significant degree of variation in the MMSE score.After accounting for known covariates , we found that the ICECAP-O domains of role (level 3), security (levels 4) and control (levels 3 and 4) explained a statistically significant amount of variation in IADLs (p < 0.05). Pain (level 2), a domain of the EQ-5D explained a non-significant degree of variation in IADLs. Self-care (level 2), a domain of the EQ-5D explained a statistically significant amount of variation in IADLs (p < 0.05).Our data suggest that the EQ-5D and ICECAP-O are significantly correlated. Of note, a greater number of domains of the ICECAP-O compared with the EQ-5D explain significant variation in the PPA, SPPB, MMSE and IADLs. Using three key indicators of “impaired mobility”, we demonstrated several distinct differences between select domains of the EQ-5D and the ICECAP-O. Specifically, role, enjoyment and control (ICECAP-O domains) explained a statistically significant amount of variation in falls risk. Depression and usual activities (EQ-5D domains) explained a statistically significant amount of variation in falls risk. Security and control (ICECAP-O domains) explained a statistically significant amount of variation in general balance and mobility. Self-care (EQ-5D domain) explained a significant degree of variation in general balance and mobility. Control, security and role (ICECAP-O domains) explained a statistically significant amount of variation in the cognitive status and in IADLs; whereas, similar findings were not observed for any of the EQ-5D domains. Hence, our findings suggest that among older adults with impaired mobility, both instruments provide valuable yet unique information.A key strength of this study is that it compares the construct validity of the ICECAP-O and the EQ-5D in a specific population of older adults with impaired mobility. Given that the ICECAP-O is a relatively new instrument, this study provides a population specific recommendation for use of the ICECAP-O in select samples. This comparison is also useful given that the EQ-5D is a widely used instrument. It also provides a benchmark from which future studies can compare the construct validity of these and other widely used instruments such as the Short Form -6D and HealWe recognize that the analyses in this paper are cross-sectional and are therefore unable to infer causation. Further, the small sample size may have limited our ability to detect a statistically significant difference. To address this limitation, we conducted 1000 bootstrap replications of the three stepwise linear regression models. Lastly, our study is population specific to older adults with mobility impairment and did not include individuals with significant cognitive impairment. Thus, we are not able to generalize our findings to such broader populations.To our knowledge, only one study has examined associations of the ICECAP-O in a population of older adults. This stThe study of older adults with mobility impairments is essential because injuries in this population are associated with increased morbidity, decreased functioning and increased healthcare resource utilization,28-30. OOur study suggests that both the EQ-5D and ICECAP-O demonstrate associations with falls risk and general balance and mobility; however, only the ICECAP-O was associated with cognitive status among older adults with mobility impairments.The authors declare that they have no competing interests.JCD was principal investigator for the evaluation of the association between quality of life, assessed by the EQ-5D and ICECAP-O, and falls risk, cognitive function and daily function and was responsible for design, data analysis and interpretation, and writing of manuscript. TLA was principal investigator for the study and was responsible for study concept and design, acquisition of data, data analysis and interpretation, writing and reviewing of the manuscript. RM and JR were responsible for data collection and critical review of manuscript. KK was responsible for study concept and critical review of the manuscript. SB was responsible for data analysis and interpretation, writing and reviewing of the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2318/12/65/prepub


Introduction. Fatigue is often present in older adults with no identified underlying cause. The accruing burden of oxidative stress and inflammation might be underlying factors of fatigue. We therefore hypothesized that leukocyte telomere length (LTL) is relatively short in older adults who experience fatigue. Materials and Methods. We assessed 439 older nondisabled Danish twins. LTL was measured using Southern blots of terminal restriction fragments. Fatigue was measured by the Mob-T Scale based on questions on whether the respondents felt fatigued after performing six mobility items. Results. LTL was significantly associated with fatigue (P = 0.023), showing an increase of 0.038 kb/fatigue score unit. Aging-related diseases and mental health did not explain the association, while lifestyle factors slightly attenuated the estimates. Conclusion. Our results support an association between LTL and fatigue. Further studies are required to confirm this finding and the link of LTL with oxidative stress/inflammation over the life course. Fatigue is a common complaint among older adults. While it is often a symptom of psychiatric or medical illness, for many older persons, it is not possible to identify the underlying cause. Studies during the last 15 years have consistently shown that fatigue in older adults is a strong predictor of functional limitations , and morCellular and organismal damages caused by an accruing burden of oxidative stress could be an underlying factor to fatigue. Increased oxidative stress can be caused by defective mitochondria as well as by chronic low-grade inflammation. Both these conditions are known to be associated with increasing age, and evidence suggests that oxidative stress and inflammation are associated with frailty .It is generally accepted that oxidative stress and inflammation are important contributors to the pathology of aging-related diseases such as cardiovascular disease , dementiPotentially, shortened LTL and the consequent cellular aging could thus be an underlying mechanism to fatigue.Woo et al.  found noThe Longitudinal Study of Aging Danish Twins (LSADT) began in 1995 with an assessment of same-sex twin pairs born in Denmark before 1920 . Since 1For this study, the population was restricted to the 439 individuals who were nondisabled, that is, who were able to rise from a chair or bed, walk indoors, get outdoors, walk outdoors in nice weather, walk outdoors in bad weather, and climb stairs without help. Further, we excluded persons who had answered the questionnaire by a proxy. These restrictions were applied as previous studies have shown fatigue to be related to onset of disability , functioFor further information on the participants, see The study has been approved by the local scientific-ethical Committee. All participants provided written informed consent.r = 0.88, P < 0.001).Leukocyte DNA was extracted using standard techniques. DNA quality was assessed by electrophoresis. LTL was measured using Southern blots of the terminal restriction fragments after digestion with HphI and MnlI restriction enzymes; for 377 of the nondisabled twins the terminal restriction fragments were also generated by HinfI and RsaI digestion . The HphSamples from the cotwins in each twin pair were resolved in adjacent lanes of the same gel. Running DNA digests from the two cotwins in adjacent lanes on the same gel diminished the methodological variation within twin-pairs. In between-pair analysis the “gel effect” was included as covariate.Each sample was measured in duplicate (performed on different gels) and the mean of the two samples was used. The interassay coefficient of variation was 2.5% for the HinfI/RsaI digest and 3.4% for the HphI/MnlI digest.http://dx.doi.org/10.1155/2014/403253).We present data from the HphI/MnlI digest, while results obtained with HinfI/RsaI digest can be found in the corresponding Supplementary (S) Material  rising from a chair or bed, (b) walking indoors, (c) getting outdoors, (d) walking outdoors in nice weather, (e) walking outdoors in bad weather, and (f) climbing stairs). Every activity was described relative to whether the respondents did or did not feel fatigued afterwards. The mobility-tiredness Scale (Mob-T) counts the number of activities managed without fatigue. The highest scale value thus describes no fatigue. The construct validity of the scale was tested by the Rasch model for item analysis, which showed that the scale had satisfactory homogeneity , 20. TheCovariates of lifestyle, mental health, and aging-related somatic diseases were included as potential confounding factors since previous studies have shown that they might be associated with fatigue and LTL , 23–29.Smoking status was divided in never, former, and current smokers. BMI was deduced from self-reported height and weight. Physical activity was scored on a five-point scale deducted from self-reported level and frequency of physical activity. The answers were scored as follows: 0: “no physical activity,” 1: “seldom low intensity physical activity,” 2: “frequent low intensity physical activity,” 3: “seldom high and frequent low intensity physical activity,” and 4: “frequent high intensity physical activity.”Cognitive performance was scored by a cognitive composite score. This was evaluated by a battery of five brief cognitive tests, which were selected to be sensitive to age-related changes. The tasks included a verbal fluency test, forward and backward digit span, and immediate and delayed recall of a 12-item list. The standard scores for each task were summed to give an overall score. Higher cognitive composite scores indicated better cognitive function .r > 0.50), a 17-item total scale score has been defined [Depression symptomatology was assessed using an adaptation of the depression section of the Cambridge Mental Disorders of the Elderly Examination (CAMDEX) . McGue a defined . AnalyseCardiovascular disease included angina pectoris, heart failure, hypertension, irregular heart rhythm, and myocardial infarction. For diabetes and cancer any positive history is regarded as being a positive outcome and no distinction is done between type and duration. Rheumatologic disease covers the presence of either of the following conditions: rheumatic arthritis, osteoarthritis, and/or gout.We applied a multiple regression modeling to test if fatigue was associated with LTL. A random intercept regression model was considered to account for nonindependence within pairs .Possible association was further studied using an intrapair twin design in which difference in LTL was regressed on the difference in fatigue. This design enables us to control for age, sex, zygosity, and gel effect, as well as for early common environment and genetic factors. MZ twins share 100% of their genes while DZ twins only share 50%. If an association is attenuated among MZ twins it suggests genetic confounding. If an association is attenuated among MZ and DZ twins it suggests early environmental confounding.P value of 0.05 was chosen as significance level for all tests and the statistical analyses were done using STATA 11.1 .A A total of 439 twins representing 257 twin pairs were studied. 145 (33%) were men, and 294 (67%) were women; 235 (53.5%) came from a dizygotic twin pair (DZ) and 204 (46.5%) from a monozygotic twin pair (MZ). Descriptive statistics of participants are presented in R = −0.25, P < 0.001), that is, the higher the age the more fatigued (lower score).Women were found to have longer LTL than men . The age-related attrition in this population was 0.020 kb per year. There was no significant difference in fatigue score between men and women. Fatigue was inversely correlated with age . However, likelihood ratio test indicated that the optimal model of the LTL-fatigue association includes only sex and age (model 2).Including all covariates, that is, sex, age, gel effect, zygosity, somatic diseases, mental health, and lifestyle resulted in slight attenuation of the association between LTL and fatigue , model 6The analyses were repeated in a subsample of the study population restricted to individuals below 80 years. The LTL-fatigue association was found to be stronger in this younger subpopulation.P = 0.054) within the pair  (data not shown).The association was attenuated when including lifestyle factors from Coef = 0.039 to Coef = 0.030 due to a small confounding effect of smoking and physical activity not seen in the regression analysis. Likelihood ratio test suggested the inclusion of smoking in the model. Also inclusion of depression symptoms provided a better fit of the data but hardly influenced the association . There were similar associations between the examined covariates and, respectively, LTL and fatigue (Table S2).P = 0.846).The association with fatigue was of lesser magnitude and no longer reached significance , neither for the younger subpopulation. Likelihood ratio test showed that the inclusion of lifestyle factors  as well as depression symptomatology had a better fit of data. Including these factors completely attenuated the association . The coexistence of fatigue and depression has previously been reported [Fatigue is a central symptom in many organic and psychiatric diseases. We have chosen to include four major aging-related diseases  as well as cognitive function as potential confounders since these have previously been suggested to be associated with LTL dynamics. However, we found no influence of either diseases or cognitive function on the LTL-fatigue association. Depression is a condition closely correlated with fatigue and is evidently associated with short LTL . Thus, wreported  and founreported , as has reported , necessiOf the included lifestyle factors, we found that only smoking had a slight effect on the association between LTL and fatigue. We have previously found that physical activity level was associated with LTL . In thisA study by Woo et al.  found noSome limitations and strengths should be considered when interpreting the results. The low coefficient of variation is a strength to our study, as well as the twin design. We have included lifestyle factors and major aging-related diseases as covariates; in future studies inclusion of medications could be of value since these could contribute to fatigue. Various tools to evaluate fatigue exist . Many scOverall, our findings indicate that LTL is associated with fatigue and that this cannot be explained by common lifestyle factors, aging-related diseases, or cognitive function. These findings largely agree with previous studies showing that fatigue is a strong indicator of adverse health outcomes in nondisabled older adults  and in mS-table 1-4 present data from the results obtained with HinfI/RsaI digest for which the inter-assay coefficient of variation was 3.4%.Click here for additional data file.


We have recently developed a non-invasive periodontal diagnostic tool that was validated in periodontitis patients without systemic disorders like coronary artery disease (CAD). The purpose of present study is to verify whether this optical instrument can also be used in periodontitis patients with CAD.2) to the overall spectrum. The balance between tissue oxygen delivery and utilization in periodontal tissues was then assessed.A total of 62 periodontitis patients with CAD were recruited along with a control group consisting of 59 age and gender matched periodontitis volunteers without systemic disorders. Using a portable optical near-infrared spectrometer, optical spectra were obtained, processed and evaluated from the two groups. A modified Beer-Lambert unmixing model that incorporates a nonparametric scattering loss function was used to determine the relative contribution of deoxygenated hemoglobin (Hb) and oxygenated hemoglobin . No statistical differences were found in tissue oxygen saturation between the CAD and control groups either in periodontal healthy or inflammatory sites.Tissue oxygen saturation was significantly decreased in the periodontitis sites (p < 0.01), compared to the healthy sites in those individuals with CAD. There was a trend towards increased concentration of Hb and decreased concentration of HbOThis study supports the hypothesis that optical spectroscopy can determine the periodontal inflammation in patients with certain systemic disorders like CAD. And the overall periodontal oxygenation profiles in CAD patients resemble those in non-CAD individuals either in healthy or inflammatory sites. Increasing evidence has indicated that periodontitis, an endemic infectious disease of the tissues surrounding the teeth, may negatively impact systemic health. Particularly striking is the association between periodontitis and the increased risk of vascular diseases  and diabetes mellitus ,2.Meta-analysis of data linking coronary artery diseases (CAD) and periodontitis suggests periodontitis is a significant risk factor for CAD in a dose-dependent manner, with relative risk ranging from 1.24 to 1.35 .In spite of epidemiological evidence of significant association between established periodontitis and cardiovascular disease, the search for answers to why patients with periodontal disease are at higher risk for cardiovascular disease continues. Like other chronic inflammatory diseases, periodontitis has been associated with increased systemic inflammation, potentially leading to an increased risk of atherogenesis and other systemic disorders like diabetes and CAD ,8.Alternatively the local hemodynamic changes in periodontitis patients might be affected by the impact of atherosclerosis which in turn may manifest different clinical appearance. The pathological conditions of arteriosclerosis, hypertension or impaired heart function, often co-existing among cardiovascular diseases, disturb the systemic circulation and hence may have an influence on the gum microcirculation -8. For iPeriodontal diseases are currently diagnosed almost entirely by their clinical manifestations, including attachment and bone loss, pocket formation, marginal bleeding, suppuration and bleeding on probing (BOP) . Althoug2), total tissue hemoglobin (tHb), deoxyhemoglobin (Hb) and oxygenated hemoglobin (HbO2)) in those patients.Recently, our research group has developed an optical device to improve the diagnosis of periodontal diseases. Although our previous data from multicenter studies ,16,17 haThe study was carried out at the Affiliated Hospital of Qingdao University  and the Second Affiliated Hospital of Harbin Medical University . A total of 62 CAD patients  with moderate to severe chronic periodontitis were recruited consecutively during the period of May to October 2012. Meanwhile, 59 systemically healthy patients  with gingivitis and or periodontitis were also recruited and assigned to the control group for a comparative study. The research protocol was approved by each of the Research Ethics Boards of Affiliated Hospital of Qingdao University, the Second Affiliated Hospital of Harbin Medical University and the National Research Council of Canada. Informed, written consent was obtained from each individual before collection of spectra. CAD were diagnosed based on patient’s medical history, clinical symptoms, physical examinations and diagnostic tests such as electrocardiography, echocardiography, coronary computed tomography angiography (CCTA) or invasive coronary angiography (ICA), according to the diagnosis criteria recommended by the American College of Cardiology Foundation and the American Heart Association .Periodontitis sites were defined as those with periodontal probing depth (PD) ≥ 5 mm, clinical attachment loss (CAL) ≥3 mm and bleeding on probing. Gingivitis sites were defined as those with PD < 3 mm and bleeding on probing. Healthy sites were defined as those with periodontal probing depths < 3 mm and no bleeding on probing . ExclusiSpectra were collected using a portable PDA512-ISA spectrograph interfaced to a customized bifurcated fiber optic probe designed for use in the oral cavity. The intraoral probe was described in detail previously . The out2 to the optical attenuation spectrum obtained from tissue was described in detail previously [2 to the spectrum by using the known absorption coefficients of Hb and HbO2 to fit the spectrum. The visible region between 510 and 620 nm of the measured tissue attenuation spectrum, Aλ, was modeled as a sum of two parametric terms, Hb and HbO2, that contribute to the spectrum and a nonparametric term m (λ) modeling a vector of covariates, primarily the Rayleigh and Mie scattering losses that contribute to the attenuation of measured light.The derivation of the relative contribution of Hb and HbOeviously . Briefly2 per unit photon pathlength were estimated by solving an equation using a noniterative partially linear method based on kernel smoothing, as first described by Speckman [2 and tHb, a measure of tissue perfusion, were derived from the predicted Hb and HbO2 relative concentrations as follows:The concentrations of Hb and HbOSpeckman . StO2 an2, StO2, and tHb, derived from optical spectral were analyzed separately using a one-way analysis of variance (ANOVA) to test the hypothesis that the indices from the three groups of sites  would differ significantly. The unequal Tukey HSD was used for the post-hoc pairwise comparisons of mean differences between the clinical groups. Pearson product moment correlation coefficients were calculated between the hemodynamic indices to summarize the linear association between the variables. Statistical calculations were performed with Statistica 7.1.The hemodynamic indices, Hb, HbOBased on the periodontal probing depth, clinical attachment loss and dental presence as shown in Table 2 obtained from the optical attenuation spectra of the healthy, gingivitis, and periodontitis sites of the CAD patients, respectively. Although the relative concentrations of Hb and HbO2 in the periodontal tissues of CAD patients were not significantly different among groups (p > 0.05), there was a trend towards increased mean concentration of Hb and decreased mean concentration of HbO2 from healthy to diseased sites.Figure 2 and tHb in CAD group, that is closely related to oxygenation and blood volume of the tissue, are presented in Figure 2 decreased from the healthy to the gingivitis (p = 0.07) or periodontitis (p = 0.002) status, while there was no significant difference between the gingivitis and periodontitis groups (p > 0.05). The profiles of tHb parameter, an indicator of tissue perfusion, did not differ among groups  or periodontitis (p < 0.01) status, and there was significant difference between the gingivitis and periodontitis groups (p < 0.05). However, no significant differences were found when we compared the StO2 in control and CAD groups in all three pairs, i.e., healthy, gingivitis and periodontitis (p > 0.05).The StOThe clinically-based diagnosis of periodontal diseases has been used for more than 50 years without significant improvements ,22. AlthHowever, in our previous studies we have intentionally excluded patients presenting risk factors or risk indicators  for periodontitis that may affect overall spectral outcome ,16,17,232 was significantly lower in the inflamed compare to the healthy gingival sites  of the carotid artery, as measured by B-mode ultrasound, is a measure of preclinical atherosclerosis that has been shown to be associated with CAD, both prevalent  and inciHowever, none has looked into whether the altered hemodynamic forces existing in atherosclerosis patient will directly affect the local tissue oxygenation of periodontitis patients with CAD due to the limitation of available techniques. To our best knowledge, current study was the first report to document the local inflammatory hemodynamic profile in CAD patients with periodontal disease. As demonstrated in Figure 2 in periodontitis than gingivitis sites in CAD patients, this difference was not statistically supported (P = 0.056)  similar to our previous reports [Nevertheless, it is important to note that some CAD-associated masking effects on periodontal inflammation could be observed by the optical spectra in the present study. For instance, although there was a trend towards lower level of StO) Figure . In cont reports ,17. Agai reports ,36.In summary, the current study suggests that pathologic conditions like CAD will not affect our newly established periodontal diagnostic tool when used on CAD patients with periodontitis. Alternatively due to the fact that tissue oxygen saturation is not measureable clinically, our data would indicate that optical spectroscopy can serve as a supplementary tool for monitoring local oxygenation and provide essential information about local inflammation even in patients with CAD. Furthermore, since periodontal hemodynamic indices such as tissue oxygenation and perfusion are not clinically measurable, the development and validation of sensitive and specific tools to reveal the characteristics of periodontal hemodynamics in CAD patients have direct and relevant clinical implications. It is important to point out that the practical implications of the optical spectroscopy reported herein may be beyond the diagnosis of periodontitis with CAD. It may potentially serve as an alternative biologically-based assessment of periodontal inflammation. Future studies are warranted to evaluate other risk factors or risk indicators (i.e. systemic disorder like diabetes mellitus and among smokers) for periodontitis that may affect overall spectral outcome. Prospective longitudinal studies are also warranted to test this tool in differentiating progressive from stable lesions in monitoring periodontal inflammation in connection to the long-term stability of periodontal tissue.In summary, our data demonstrated that the visible-infrared spectral device can be a sensitive means to monitor the local periodontal inflammation with or without other systemic disorders like CAD disease by assessing the periodontal hemodynamic profiles. This novel tool will also allow scientists to better explore the essential relationship between periodontal disease and CAD. Future parallel cohort studies with expanded subject size are warranted to establish a large data base to understand the influence of other systemic disorders on periodontal inflammations embedded in optical spectra.CAD: Coronary artery diseases; Hb: Deoxygenated hemoglobin; HbO2: Oxygenated hemoglobin; PD: Probing depth; CAL: Clinical attachment loss; StO2: Tissue oxygen saturation; tHb: Total tissue hemoglobin; CCTA: Coronary computed tomography angiography; ICA: Invasive coronary angiography; IMT: Intima-media wall thickness.The authors report no conflicts of interest related to this study.The original hypothesis was developed by CYZ and KZL. CYZ and CF identified and recruited suitable clinical cases. XMX, MQX and CF performed periodontal assessments and spectral data acquisitions. MQX and MGS performed the extrapolation of data from the IR spectra and the spectral data analysis. MQX and KZL drafted the manuscript. KZL and MGS obtained the funding. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6831/14/25/prepub


IRS2 rs1805097 (G>A) polymorphisms and the risk of colorectal and breast cancer. However, the results were inconsistent.Insulin receptor substrate-2 (IRS-2), a signaling adaptor protein, was involved in two cancer-related pathways (the phosphatidylinositol 3′-kinase (PI3K) and the extracellular signal-regulated kinase (ERK) pathways). Several studies have evaluated the association between heterogeneity = 0.97; heterozygote comparison: OR = 0.91, 95%CI 0.73–1.13, Pheterogeneity<0.01; dominant model: OR = 0.92, 95%CI 0.80–1.06, Pheterogeneity = 0.05; recessive model: OR = 1.02, 95%CI 0.91–1.14, Pheterogeneity = 0.60). In the subgroup analysis by ethnicity, control source and consistency of frequency with Hardy-Weinberg equilibrium (HWE), still no significant associations were observed. For breast cancer, also no obvious associations were found for all genetic models . We performed subgroup analyses by sample size and did not find an association.A meta-analysis of seven published case-control studies  were conducted to assess the strength of association using crude odd ratios (ORs) with 95% confidence intervals (CIs). For colorectal cancer, no obvious associations were found for all genetic models (homozygote comparison OR = 0.96, 95%CI 0.85–1.08, PIRS2 rs1805097polymorphism was not associated with colorectal and breast cancer risk.This meta-analysis indicated that  IRS1 and IRS2 genes in the liver of mice (L-DKO mice) prevented activation of hepatic Akt-Foxo1 phosphorylation and resulted in the development of diabetes Insulin receptor substrates (IRs) are signaling adaptor proteins consisting of six members (IRS-1-6) IRS1 plays a central role in cancer cell proliferation, in contrast, IRS2 is associated with cancer cell motility and metastasis IRS2 may be a driver oncogene in colorectal cancer and over-expressed IRS-2 activated the PI3 kinase pathway and increase cell adhesion In addition, researchers have found out IRS-1 and IRS-2 mediate mitogenic and antiapoptotic signaling via binding to receptor tyrosine kinases (RKTs) such as ligand-phosphorylated insulin-like growth factor I receptor (IGF-IR) or insulin receptor (IR) IRS1 gene and 1704 SNP in the IRS2 gene have been reported (http://www.ncbi.nlm.nih.gov/SNP), some of which have been shown as susceptible loci for several kinds of diseases, such as cancer and Type 2 diabetes mellitus (T2DM) IRS1 polymorphism rs1801278 (G>A) has been extensively investigated as a determinant of insulin resistance and a meta-analysis demonstrated that the A carriers significantly increased the risk of T2DM in those subjects whose mean age at diagnosis was less than 45 years IRS2 gene is located on chromosome 13q34 IRS2 polymorphism rs2289046(A>G), which is a 3′UTR SNP, has already been reported it is closely related to the onset of pancreatic, breast and colorectal cancer IRS2 rs1805097(G>A) polymorphism, a nonsynonymous SNP that was predicted to affect splicing, transcriptional regulation, and post-translational modification, is common [minor allele frequency (MAF)  = 0.30] (http://www.ncbi.nlm.nih.gov/SNP) and most frequently studied for the association with cancer risk, especially colorectal and breast cancer Until now, about 3644 single nucleotide polymorphisms (SNP) in the IRS2 rs1805097(G>A) polymorphism and the risk of colorectal and breast cancer in diverse populations, the results remain inconclusive, partially due to the relatively small sample size in each of the published studies IRS2 rs1805097 polymorphism on colorectal and breast cancer risk, a meta-analysis was performed.Although reported studies have focused on the association between the Insulin receptor substrate2 or IRS2’, ‘polymorphism or variation’, ‘cancer or carcinoma or tumor or adenocarcinoma or neoplasm’. We evaluated all associated publications to retrieve the most eligible literature. Their reference lists were searched manually to identify additional eligible studies. When overlapping data of the same patient population were included in more than one publication, only the most recent or complete study was included. The results were limited to papers published in English.A literature search of Pubmed and EMbase was performed independently by two authors , using the key words: ‘IRS2 rs1805097 polymorphism and colorectal and breast cancer risk, (3) sufficient published data for estimating the OR and their corresponding 95%CI. Exclusion criteria included: (1) comment and review, (2) duplication of the previous publications, (3) no usable data reported.The following criteria were used for inclusion of the identified articles: (1) case-control studies for human, (2) investigation of the Two investigators independently extracted data and reached consensus on all the items. For each eligible study, the following information was extracted: first author’s name, year of publication, ethnicity, cancer types, matching variables (age and sex), numbers of cases and controls, and genotype frequencies for cases and controls. Eligible studies were defined as population-based and hospital-based according to the control source. Different ethnicity descents were classified as Caucasian, Asian, and Mixed that included more than one ethnic descent. And when studies included subjects of more than one ethnicity and were able to separate, data were extracted separately for each ethnic group. We also classified a study as a large study if its total sample size was more than 1000, or it would be categorized as a small one.IRS2 rs1805097 polymorphism and the risk of colorectal and breast cancer. Pooled ORs were computed for four genetic models of comparison: homozygote (AA vs GG), heterozygote (AG vs GG ), dominant (AA/AG vs GG), and recessive (AA vs AG/GG). A statistical test for heterogeneity was performed based on the I2 test and Q test 2>50% or P≤0.10which indicated heterogeneity in the comparison models among studies, so the estimated pooled ORs for each study were calculated using a random effects model (the DerSimonian and Laird method) We used the PRISMA checklist as protocol of the meta-analysis and followed the guideline . HWE wasFunnel plotting, in which the standard error of the log OR in each study was plotted against its log OR, was used to assess potential publication bias. An asymmetric plot suggested a possible publication bias. Funnel plot asymmetry was further assessed by the method of Egger’s linear regression test All statistical tests were performed with the STATA software, version 12.0 .There were 94 articles identified by literature search from PubMed and EMBASE. The flow chart in IRS2 rs1805097 polymorphism and colorectal cancer risk was observed   ( = 0.60) . Obvious = 0.07) . In the Funnel plots and Egger’s test were performed to assess publication bias of the literature. The results of Egger’s test are shown in IRS2 gene polymorphism was not significantly associated with both colorectal and breast cancer risk. In subgroup analysis, no significant association was observed. To the best of our knowledge, the present meta-analysis is the first article to assess the role of IRS2 rs1805097 polymorphism in colorectal and breast cancer.Accumulating number of genetic association and genome-wide association studies (GWASs) have focused on the association between gene polymorphisms and cancer risk As one of the typical signaling adaptors, IRS-2 was involved in the phosphatidylinositol 3′ -kinase (PI3K) and the extracellular signal-regulated kinase (ERK) pathways, despite the fact it did not have intrinsic kinase activity and require upstream activators IRS2 gene by transversion of G to A was located close to two putative tyrosine phosphorylation sites at positions 1042 and 1072, and might change the tertiary structure and function of the protein IRS2 rs1805097 polymorphism to phenotypic features of insulin resistance, T2MD, polycystic ovary syndrome and several kinds of cancer has been intensively studied with controversial results. Several case-control studies found significant associations between IRS2 rs1805097 polymorphism and gastric, colon and endometrial cancer IRS2 variant genotypes may be tissue-specific. D’Alfonso et al. also found that the common IRS2 rs1805097 variant did not appear to affect the level of IRS-2 expression and the ability to bind the P85 regulatory subunit of PI3-kinase An amino acid substitution of Gly to Asp at codon 1057 in IRS2 rs1805097 polymorphism and colorectal and breast cancer risk might be determined. Thirdly, a more precise analysis could have been conducted, if individual data such as sex, body mass index, smoking and drinking status were available. Fourthly, besides a relatively high level of heterogeneity was detected in some comparisons, the influences of the individual data setting on the pooled ORs were significant in the subgroup of PB or mixed for colorectal cancer, which indicated the instability of the result. Therefore, the results should be interpreted with caution and confirmed from an additional analysis with more published studies in the furture. Fifthly, not all of studies are population-based. Owing to some types of unhealthy life styles or certain genotypes, controls in a hospital-based study might be susceptible to cancer. Therefore, controls selected from the healthy population were more representative for the general population, and might contribute more reliable results to a meta-analysis. Finally, gene-environment interactions should be considered in further studies if individual data of environmental exposure were available.Certain potential limitations existed in our meta-analysis. Firstly, the number of published studies in our meta-analysis was insufficient, and the studies with small samples might decrease statistical power to properly evaluate the association. Secondly, when regarding with the ethnicity, most of the included studies conducted on Caucasians. Thus, it would be important to have more studies and samples from other ethnicity so that more accurate conclusions about the relationship between the IRS2 rs1805097 polymorphism may not contribute to the colorectal and breast cancer risk. However, large-sample studies of different ethnic groups with well matched cases and controls are necessary to further clarify the role of IRS2 rs1805097 polymorphisms and these two types of cancer susceptibility in the future.In conclusion, this meta-analysis suggests that the Checklist S1The guidelines of the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement.(DOC)Click here for additional data file.


CAT) is a risk factor for primary angle closure glaucoma (PACG) in the Saudi population.To Investigate whether the g.4760C>T polymorphism in the promoter region of the catalase gene  utilizing Taq-Man® assay. The association between different genotypes and various clinical indices important for PACG was also investigated.p= 0.568). Interestingly, there was a trend of association between the type of the variant  and one important parameter for PACG, which is visual acuity. The visual acuity increase was; 0.62 (±0.74), 0.88 (±0.88) and 1.27 (±0.95) in patients carrying the “C/C”, “C/T” and “T/T” genotypes respectively, which was statistically significant in both ANOVA and pairwise individual T tests  when compared to controls.The distribution of different genotypes was comparable between both study groups. The genotype “C/C” was predominant among cafses; 94 (68.1%) and controls; 289 (71.7%). Heterozygous genotype “C/T”, was present in 41 (29.7%) of cases and 103 (25.6%) of controls, where the homozygous variant genotype was present in only 3 (2.2%) of cases and 11 (2.7%) of the controls. The distribution of variant allele was similar in both study groups (This variant is possibly associated with visual acuity in PACG patients and thus had the potential to be used as a parameter for assessing PACG severity. PLEKHA7 (P=5.33×10(−12)), rs3753841 in COL11A1 (P=9.22×10(−10)) and rs1015213 located between PCMTD1 and ST18 on chromosome 8q (P=3.29×10(−9)) were reported , while that for controls was 61.1 (±10.8) years, median 60 and range [40–93]. Comparing both age means, there were no statistically significant difference between cases and controls  and controls 125 (15.5%) compared to the wild type “C” allele [229 (83.0%)] and [681 (84.5%)] in cases and controls respectively, however, the alleles distribution had no statistically significant association with encountering the disease;   and controls; 289 (71.7%). The heterozygous variant genotype “C/T” was present in 41 (29.7%) of the cases and 103 (25.6%) of the controls, whereas the homozygous variant genotype “T/T” was only present in 3 (2.2%) and 11 (2.7%) in cases and controls respectively. There was no association between having the heterozygous genotype “C/T” and getting closed angle glaucoma; OR: 1.22 [95% CI: 0.773 - 1.197; % and conp = 0.336). A similar trend was observed in mean (±SD) duration between getting closed angle glaucoma and presentation to the hospital, intraocular pressure (IOP) and logMAR visual acuity. The visual acuity increase was; 0.62 (±0.74), 0.88 (±0.88) and 1.27 (±0.95) in “C/C”, “C/T” and “T/T” groups respectively, which was statistically significant in both ANOVA and pairwise individual T tests . More findings on other clinical indices at presentation which were not statistically significant are presented in Table Examining the likelihood of an association between genotypes and important glaucoma clinical indices, showed that, the mean (±SD) age at onset increased with change in genotype (homozygous variant is worse than heterozygous and heterozygous is worse than wildtype genotype); 49.0 ±22.7), 57.9 (±12.2) and 62.4 (±8.9) for “C/C”, “C/T” and “T/T” respectively. This increase was however, statistically insignificant in ANOVA . This indicates that neither the variant genotype nor the variant allele is a risk factor for PACG in this population. It’s possible that the link between mitochondrial abnormalities and/or oxidative stress and glaucoma are not linked through the catalase pathway and that other oxidative stress pathway(s) may be involved. In any case, the exact mechanism of how oxidative stress contributes to glaucoma pathogenesis remains speculative. Additionally, glaucomatous optic neuropathy implies loss of RGCs, including their axons, and a major tissue remodeling, especially in the optic nerve head. Mechanisms leading to glaucomatous optic neuropathy are not yet clearly understood. We previously investigated mitochondrial abnormalities in a group of patients with PACG and found absence of mitochondrial abnormalities in those patients [The results presented in Table patients . We suggpatients , in contpatients .p = 0. 022, 0.031 and 0.039 respectively). Other clinical indices listed in Table Interestingly, when we investigated the potential association between the presence of a certain genotype and different clinical indices, important for PACG, we found an interesting trend corresponding to various clinical indices and severity of the variant . The mean (±SD) age at onset increased with increase in variation severity (homozygous variant is worst than heterozygous and heterozygous is worst than wildtype), but statistically insignificant. On the other hand, the visual acuity increase was; 0.62 (±0.74), 0.88 (±0.88) and 1.27 (±0.95) in “C/C”, “C/T” and “T/T” groups respectively, which was statistically significant in both ANOVA and individual T tests (There are few limitations to this study: i) the study was conducted on the Saudi population only and thus need to be carried out in other populations to establish the link between this variant and various clinical indices; 2) at this point, modifiers for this catalase SNP leading to glaucoma are not known and thus we will not know for sure if this SNP alone can influence the disease severity; 3) We cannot exclude other SNPs at the same locus, which may be associated with POAG and 4) Considering the fact that the frequency of the homozygous (T/T) variants was low  it is also plausible that more individuals are needed for such case–control genetic association study.In summary, we showed a possible association of the catalase polymorphism (g.4760 C>T) with the visual acuity, which is an important clinical indices for PACG. Thus, this SNP can be potentially used as a marker for PACG severity.CAT: Catalase; c/d: Cup-to-disk ratio; IOP: Intraocular pressure; KAUH: King Abdulaziz University Hospital; LogMAR: Logarithm of the minimum angle of resolution; PACG: Primary angle closure glaucoma; POAG: Primary open angle glaucoma; PCR: Polymerase chair reaction; ROS: Reactive oxygen species; RGCs: Retinal ganglion Cells; SNP: Single nucleotide polymorphism; SOD: Superoxide dismutase; TM: Trabecular meshwork.The authors declare that they have no competing interests.KKA supervised the overall study, writing the manuscripts and analysis of the data; TAZ and TS carried out the technical work in the laboratory; AM statistical analysis of the data and writing the manuscripts; EAO and SAO patient's requirements and reviewing the files for clinical information. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2350/14/84/prepub


Associations between apolipoprotein E (apoE) gene polymorphisms and the risk of ESRD remained inconclusive. This study aimed to investigate the association between Databases including PubMed, Embase, Web of Science and the Cochrane Library were searched to find relevant studies. Meta-analysis method was used synthesize the eligible studies. P < 0.0001; I2 = 18%, P for heterogeneity = 0.24). The ε2ε3, ε2ε4, ε3ε3, ε3ε4, ε4ε4, ε3 and ε4 were not associated with the susceptibility of ESRD. In the subgroup analysis by ethnicity, there was a statistically significant association between ε2ε3 or ε2 allele and ESRD risk in East Asians , but not in Caucasians. E2 carriers had higher plasma apoE  than the (ε3 + ε4) carriers in patients with ESRD. The publication bias was not significant.Sixteen pertinent case-control studies which included 3510 cases and 13924 controls were analyzed. A signiﬁcant association was found between ε2 allele and the ESRD risk (odds ratio (OR) = 1.30, 95% conﬁdence interval (CI) 1.15–1.46, apoE gene might increase the risk of ESRD. E2 carriers expressed higher level of plasma apoE in patients with ESRD. More well-designed studies are needed to conﬁrm these associations in the future.The ε2 allele of  End-stage renal disease (ESRD) is a significant public health problem in the world. The etiology of ESRD is not clear yet. In addition to dyslipidemia, chronic glomerulonephritis, hypertension and diabetes, ESRD is a multifaceted disorder with inherited components playing an important role .apoE knockout mice represented hyperlipidemia, accelerated atherogenesis, and glomerulosclerosis-like lesion [Apolipoprotein E (apoE) is a component of lipoprotein, and is one of the key regulatory proteins in cholesterol and lipoprotein metabolism. It is also the structural protein of chylomicron (CM) remnants, low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), and high-density lipoprotein (HDL) . ApoE ace lesion . ApoE gee lesion . First, e lesion . Second,e lesion . ApoE mae lesion . PatientApoE gene locates at 19q13.2, which includes 4 exons and 3 introns. Gene polymorphism was determined by the different amino acid residues at 112 and 158 sites in exon 4. ApoE gene polymorphisms include three codominant alleles: ε2, ε3, ε4, which encode 3 protein isoforms  [ and E4) . It is c and E4)  found paapoE gene variants on the risk of ESRD.The results of the studies remained inconsistent. This meta-analysis was performed to investigate the precise role of Pubmed, EMBASE, Web of Science and the Cochrane library were all searched . The terms in electronic search included “apoE”, “apolipoprotein E”, “ESRD or end-stage renal disease”, “chronic renal failure”, “dialysis”, “polymorphism or mutation or variant”. In addition, Google Scholar was used to check the references of eligible trials to make sure all studies were included.apoE polymorphisms or ESRD; (2) study design based on sibling or family pairs; (3) neither genotype frequencies nor number reported; (4) reviews or case reports.Studies fulfilling the following selection criteria were included in this meta-analysis: (1) the outcome had to be ESRD; (2) using case-control design, and control group were unrelated people chosen randomly from the same geographic region; (3) genotype distributions should be available for estimating an odds ratio (OR) and 95% conﬁdence interval (CI) in both cases and controls. If one of the following existed, studies were excluded: (1) not relevant to Included studies were independently reviewed by two investigators. Relevant data was extracted into predesigned data collection forms. If there was any discrepancy, two investigators resolved it by discussion or a third author would assess the relevant studies. We collected the following data from each included trial: ﬁrst author’s name, year of publication, country, ethnicity, sample size, age, genotyping method, ESRD treatment, and genotype number in cases and controls.apoE polymorphisms and ESRD risk was measured by OR and 95% CI. When P value < 0.05, OR was considered statistically signiﬁcant. Continuous outcome data from included trials were analyzed using the mean difference (WMD) and 95% CI. The heterogeneity of identified studies was assessed by I2 and the Chi square-test based Cochrane Q-test. When P value > 0.10 for the Q test, it indicated a lack of heterogeneity among the studies. Then the ﬁxed-effects model was used to pool OR. Otherwise, OR was pooled in the random-effects model. The sources of the heterogeneity and ethnic-specific effect were evaluated by subgroup analyses performed by ethnicity. One-way sensitivity analysis was carried out to access the stability of the meta-analysis. We also excluded the studies not in Hardy-Weinberg equilibrium (HWE) to perform the sensitivity analysis. Cumulative meta-analysis was made by sequential random-effects pooling (starting with the earliest studies), in order to show the consequence of adding studies on the effect size. HWE in controls was tested by the Chi-square test [P values was used. Revman 5.1 software  and STATA 11.0 software  were used to perform all the statistical tests.The strength of the association between are test . The Begare test . When peapoE variants published from 1992 and 2008 were identiﬁed, among which seven studies were form Asia [A total of 16 clinical studies ,15,18-31orm Asia ,27,29,31orm Asia ,26,28,30orm Asia , four usorm Asia ,25-28,31orm Asia ,25.P values, the results about apoE gene polymorphism were considered to be statistically significant when P < 0.00018. A signiﬁcant association was found between ε2 allele and the ESRD risk  , but the P values did not reach the statistical criterion. Then in the results of subgroup analysis by ethnicity, there was a statistically significant association between ε2ε3 or ε2 allele and ESRD risk in East Asians [P < 0.0001, P for heterogeneity = 0.18; OR = 1.62, 95% CI 1.31–2.01, P < 0.0001, P for heterogeneity = 0.20, respectively)  [P value, the positive association still could not be excluded in Caucasians. More investigations about Caucasians should be performed in the future. The heterogeneity decreased a lot in the subgroup analysis 1-way sensitivity analysis was performed to evaluate the stability of the meta-analysis of ε2 allele .The eligible studies ,15,18-31 = 0.24) 2. The ε = 0.24) 3. Intert Asians -24,27,29ctively) 3. Howev = 0.81) ,28,30,312 allele 3. When 2 allele 4. The hP = 0.0002; I2 = 66%; P for heterogeneity = 0.03) than the (ε3 + ε4) carriers  phenotypes in patients with ESRD, we performed another meta-analysis. Ε2 carriers with ESRD had increased apoE expression  and Egger’s test (P = 0.352). The funnel plot was symmetrical  carriers. In conclusion, the ε2 allele might increase the risk of ESRD and express more apoE protein. Early screening of the ε2 allele might prevent the patients with CKD from progression into ESRD.In this meta-analysis, the association between the apoE polymorphism [Ε2 allele might affect the susceptibility of ESRD through the lipid and non-lipid mediated mechanisms. First, apoE is mainly secreted by the mesangial cells in kidney . Throughmorphism . ApoE2 wmorphism . The ε2 morphism . The perapoE allele frequencies were affected by different genetic backgrounds and geographical diversities; (2) different eating habits may lead to various types of lipid metabolism; (3) the primary kidney disease of ESRD was different, in which the apoE allele played different roles. Although the P value of ε2 on ESRD risk in Caucasians was 0.03, a positive association between ε2 and ESRD risk may exist. When studies in Caucasians got larger sample size, we might have sufficient statistical power to detect the slight effect.In the results of subgroup analysis by ethnicity, there was a significant association in East Asians, but not in Caucasians. The findings from races seemed different. The possible reasons included: (1)  Both cumulative meta-analysis and one-way sensitivity analysis got highly stable results which were in accordance with the primary result of ε2. Publication bias was little which made the results more reliable. In overall populations, moderate heterogeneity was observed for the ε2ε3, ε3ε3, ε3ε4, ε3 and ε4 polymorphisms. Subgroup analysis was used to find the sources of heterogeneity. In the subgroup analysis by ethnicity, the heterogeneity among the comparisons decreased effectively or disappeared. So the main source of heterogeneity might be from different populations. The sensitivity analysis based on studies in HWE ,24,26-31 There were some limitations of this meta-analysis. First of all, the number of available studies included in this meta-analysis was moderate. Only one study provided the apoE gene frequencies in different etiologies of ESRD , and theapoE gene might increase the risk of ESRD, and expressed more apoE protein. More well-designed studies are needed to prove these associations in the future.In conclusion, the ε2 allele of Figure S1PRISMA 2009 Flow Diagram.(TIF)Click here for additional data file.Table S1PRISMA 2009 Checklist.(DOC)Click here for additional data file.


PTPN22 +1858 C/T single nucleotide polymorphism (SNP) (rs 2476601), previously shown to be associated with several autoimmune diseases, in patients with psoriatic arthritis (PsA) in comparison with population based controls.The purpose of the present study was to investigate the frequency of the PTPN22 +1858 C/T). Allelic frequencies were determined and compared with 725 controls.A total of 291 patients  52.2 (± 13.1) years) with PsA were examined clinically, by standard laboratory tests and their DNA was genotyped for the SNP rs2476601  1.49; 95% confidence interval (CI) 1.10 to 2.02). A significantly higher proportion of carriers of the risk allele (T) had significantly more deformed joints (n ± SEM) .Carriage of the risk allele, PTPN22 gene, known to be associated with several autoimmune diseases, was associated with PsA. The finding of significantly more joints with deformities among carriers of the T variant could indicate a more aggressive phenotype of disease.In this study the +1858T allele of the  Psoriatic arthritis (PsA) is a heterogeneous inflammatory arthritis associated with psoriasis. The disease severity not only varies between patients but also within an individual patient over time. The disease expression can vary from a mild mono-oligoarthritis to severe erosive polyarthritis comparable with rheumatoid arthritis (RA) . In cont1) of 55 in different studies compared with 5 to 10 for patients with cutaneous psoriasis, has been reported in different studies [As with many other autoimmune diseases a number of genes have been suggested to be associated with PsA ,7. Epide studies ,8. Previ studies ,7.PTPN22) gene, located on chromosome 1p13, codes for a protein, Lyp, thought to function as a negative regulator of T-cells [PTPN22 gene, has previously been found associated with several autoimmune diseases, for example, diabetes type-I [PTPN22 +1858C/T and susceptibility to PsA have shown conflicting results [The protein tyrosine phosphatase non-receptor 22  of 52.2 (± 13.1) years) and 725 controls  55.6 (± 12.4). All patients and controls were from the same geographic area of northern Sweden and all controls were randomly selected from the Medical Biobank of Northern Sweden. PsA was diagnosed when a patient presented with an actual psoriasis, or a history of psoriasis, of the skin combined with inflammatory arthropathy defined as peripheral arthritis (out of 66/68 joint) of more than six weeks duration and/or radiologically assessed axial involvement based on radiological findings in the sacroiliac joints according to the New York criteria (≥2)  and/or sPTPN22 +1865C/T) allele by the TaqMan® assay using an ABI PRISM 7900HT Sequence Detection System and the SDS 2.1 software  according to the manufacturer's instructions.DNA from the patients and controls was extracted from ethylenediamine tetraacetic acid-treated whole blood using a standard technique and genotyped for the SNP rs2476601  and C-reactive protein  were analyzed using standard protocols by the authorized chemical laboratory at the University Hospital of Umeå. Rheumatoid factor (RF) was measured using the ORG 522 M Rheumatoid Factor IgM ELISA kit  with a cut-off value >20 IU/mL. The presence of anti-citrullinated protein/peptide antibodies (ACPA) was determined using the DIASTAT Anti-CCP ELISA kit FCCP200 from Axis-Shield Diagnostics Limited  and a cut off value >5 U/mL.P-values refer to a two-sided test and a P-value ≤0.05 was considered statistically significant. For multivariate analysis, logistic regression analysis was used. Power calculation was performed using EpiInfo. To estimate the number of patients and controls needed, frequency data from a previous study were used [Statistical calculations were performed using SPSS 16.0 . The Chi-square test was used for testing categorical data between groups. Odds ratio (OR) was calculated with 95% confidence interval (CI). All PTPN22 +1858C/T SNP among patients and controls were in agreement with the Hardy-Weinberg equilibrium. Using the minor allele frequency of 0.085, which was reported for the Toronto population in an article by Butt et al. [The genotype and allele distribution of the t et al. , the prePTPN22 +1858T variant (CT + TT) was significantly increased in patients with PsA compared with controls ) ) as well as when ACPA sero-positive patients were excluded ). Only 6 patients (2.1%) and 10 controls (1.3%) were homozygous for the T-allele . This subgroup is thus too small to allow appropriate statistical calculations.Carriage of the 2 = 10.56, P = 0.001, OR 2.58 (95% CI 1.44 to 4.62)). Furthermore, they had significantly more deformed joints at examination compared with non-carriers , and this association remained significant after multiple logistic regression analysis (P = 0.017). There was no association between dactylitis and deformed joints and, no other significant associations between the carriage of the risk allele, T, and other examined disease phenotypes, for example, number of swollen or tender joints at examination, axial disease, level of ESR or CRP, nail psoriasis or distal interphalangeal (DIP)-joint involvement (data not shown). Furthermore, there was no significant difference in the allelic distribution in patients with mono-oligoarthritic disease compared with those having a polyarthritic disease expression (data not shown).When analyzing the separate disease phenotypes, a significantly higher proportion of carriers of the risk allele, T, had, at some point, been diagnosed with dactylitis .PTPN22 gene, previously shown to be associated with several autoimmune diseases, was found to be associated with a diagnosis of PsA.In this study of clinically and laboratory well characterized patients with PsA, the +1858T allele of the PTPN22 +1858C/T polymorphism and PsA have produced conflicting results. In a study by Hinks et al., no association was found between PsA and PTPN22 +1858C/T in a patient population from the United Kingdom [PTPN22 +1858C/T in a German cohort of 375 patients with PsA when the patient group was considered as a whole; however, a significantly higher proportion of males carried the risk allele [PTPN22 +1858C/T and PsA was only found in the Toronto population [et al., but are in contrast with the others cited. This could indicate that association with PTPN22 exists in specific populations, as to date exemplified by the Toronto population by Butt et al. and the population from northern Sweden in the present study. Alternatively, as suggested by the Canadian authors, a false positive association is, of course, possible due to population stratification. It is also possible that further studies with increased sample sizes would detect significant associations among other populations. The association with the male gender observed within the German cohort [PTPN22+1858T varies considerably among different populations, for example, within Caucasian populations in Europe it varies from 2 to 3% in the south of Europe to >10% in Scandinavian countries [PTPN22 and PsA could have been that misdiagnosed patients were included in the study. Anyhow, when patients with positive RF and ACPA were excluded, the OR increased, indicating that the result was not caused by misdiagnosed patients.Previous association studies regarding  Kingdom . Likewisk allele . In a stpulation . In thatn cohort  was not n cohort , in the n cohort , in the n cohort . These dountries  it is imPTPN22 +1858 T, had significantly more joints with deformities. There was no association found with a polyarthritic disease pattern, thus the results of this study could indicate that carriage of the risk allele, T, is a risk factor for a more aggressive form of PsA, although not with a disease pattern having similarities to RA.Interestingly, our study revealed that carriers of the risk allele, A limitation of this study is that the number of patients studied does not allow proper stratification of the data, for example, the number of RF and ACPA sero-positive subjects is too small to allow appropriate calculation. Therefore, it was not possible to evaluate properly any likely association in these sub-groups.PTPN22 gene, previously shown to be associated with several autoimmune diseases, is also associated with PsA in patients from northern Sweden, a result that is consistent with previous data regarding a population from Toronto. Carriers of the T-allele also had significantly more joints with deformities compared with non-carriers of the T-allele, possibly indicating a more aggressive phenotype of disease.In conclusion, this study shows that the +1858T allele in the PTPN22: protein tyrosine phosphatase non-receptor 22; RA: rheumatoid arthritis; RF: rheumatoid factor; SNP: single nucleotide polymorphism.ACPA: anti-citrullinated protein/peptide antibodies; CI: confidence interval; DIP: distal interphalangeal; OR: odds ratio; PsA: psoriatic arthritis; The authors declare that they have no competing interests.KJ, the main investigator, carried out the genotyping together with MJ, performed laboratory and statistical analysis, and contributed to preparation of the manuscript. GMA is the principal investigator, who, together with SRD, is responsible for the samples from the Biobank, designed the investigation, and participated in the data collection, statistical analysis and drafting of the manuscript.


Previous studies did not draw a consistent conclusion about the effects of marine-derived n-3 polyunsaturated fatty acids (PUFAs) on fasting blood level of C-reactive protein (CRP), interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α).2. The effect of marine-derived n-3 PUFAs from dietary intake was only assessed in subjects with chronic non-autoimmune disease, and a significant lowering effect was observed on IL-6, but not on CRP and TNF-α.A comprehensive search of Web of Science, PubMed, Embase and Medline (from 1950 to 2013) and bibliographies of relevant articles was undertaken. Sixty-eight RCTs with a total of 4601 subjects were included in the meta-analysis. Marine-derived n-3 PUFAs supplementation showed a lowering effect on Marine-derived n-3 PUFAs supplementation had a significant lowering effect on TNF-α, IL-6 and CRP in three groups of subjects . A significant negative linear relationship between duration and effect size of marine-derived n-3 PUFAs supplementation on fasting blood levels of TNF-α and IL-6 in subjects with chronic non-autoimmune disease was observed, indicating that longer duration of supplementation could lead to a greater lowering effect. A similar linear relationship was also observed for IL-6 levels in healthy subjects. Restricted cubic spline analysis and subgroup analysis showed that the lowering effect of marine-derived n-3 PUFAs on CRP, IL-6 and TNF-α in subjects with chronic non-autoimmune disease became weakened when body mass index was greater than 30 kg/mMarine-derived n-3 PUFAs supplementation had a significant lowering effect on CRP, IL-6 and TNF-α level. The lowering effect was most effective in non-obese subjects and consecutive long-term supplementation was recommended. Previous studies have shown that inflammation plays an important role in numerous chronic diseases, such as cardiovascular disease (CVD), diabetes, obesity-related diseases, and auto-immune diseases  Intake of n-3 polyunsaturated fatty acids (PUFAs) has been shown to have numerous beneficial effects on CVD, diabetes, and obesity-related diseases The protocol of the study was shown in We searched Web of Science, Pubmed, Embase and Medline for the terms n-3 polyunsaturated fatty acid, omega-3 polyunsaturated fatty acid, ω-3 fatty acid, omega-3 fatty acid, polyunsaturated fatty acid, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or fish oil, combined with interleukin 6, interleukin, tumor necrosis factor, tumor necrosis factor alpha, TNF-α, cytokine, C-reactive protein, CRP, or inflammation. The search was restricted to studies published in any language from 1950 to 2013. For inclusion, studies had to fulfill the following criteria: had a randomized placebo controlled design; reported data on fasting blood levels of TNF-α, IL-6, or CRP; had a drop-out rate less than 30% ’s name, year of publication, sample size, age, BMI sex ratio  and healthy status of subjects, intervention methods, study design , daily dose of n-3 PUFAs, duration of follow-up, data of fasting blood level of TNF-α, IL-6 and CRP, baseline levels of CRP, IL-6 and TNF-α, and mean changes of phospholipid n-3 PUFAs in plasma/serum.Study selection and data extraction were undertaken independently by two investigators, with discrepancies resolved by consensus. The data collected included the first authorCochrane criteria was used to assess the quality of studies included in the present meta-analysis, including sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, incomplete outcome data and selective outcome reporting Our study included studies in subjects with chronic disease and studies in healthy subjects. Considering the difference of pathogenesis between chronic autoimmune disease, which is an inappropriate immune response against substances and tissues normally present in the body, and other chronic disease , two independent meta-analyses were conducted for the two types of chronic disease, respectively. Another independent meta-analysis was conducted for healthy subjects. We also separated studies using n-3 PUFAs from supplementation (seafood oils or highly purified n-3 PUFAs) as active treatment with those using n-3 PUFAs from dietary intake (fish intake), and included them into different meta-analyses.As suggested in the Cochrane handbook for Systematic Reviews of Interventions For studies with a parallel-group or factorial design, mean changes and corresponding SDs from baseline to endpoint were used in data analysis. If SDs of changes were not reported, they were imputed based on SDs at baseline and endpoint by the method in a previous study 2>50% indicated significant heterogeneity 2 were used as the cut-off points for BMI. For meta-analysis in subjects with chronic diseases, subgroup analysis was also conducted according to difference in types of diseases. Meta-regression was conducted to explore whether subgroup difference was significant, and whether there was significant linear relationship (P for coefficient <0.05) between effect size and continuous confounding variables ; the adjusted R2 indicated the percentage of between-study heterogeneity that could be explained by the confounding variables. If two or more confounding factors showed significant influence on the effect size (P for subgroup difference or coefficient <0.05), a joint test was conducted to explain heterogeneity caused by these confounding factors by including them into a single meta-regression model simultaneously 2 of the overall model indicated the percentage of between-study heterogeneity that could be explained by these confounding factors All data analyses were conducted in Stata/SE 11.0 software . Weighted mean difference (WMD) was considered as the effect size. A random-effect model was used to pool study-specific effect sizes, and a P value <0.05 was considered to be statistically significant. Percentages of changes in geometric means of CRP, IL-6 and TNF-α from baseline to endpoint were also calculated based on WMDs using the following methods: estimating the ratio of geometric mean at endpoint to that at baseline based on WMD according to one study by Higgins et al. Characteristics of included studies are shown in Incomplete outcome data (attrition bias) and blinding of participants and personnel (performance bias) were the major potential sources of bias . In many2 values were 85.7%, 90.0% and 85.3%, respectively. One study assessing the effect on CRP recruited both subjects with chronic non-autoimmune disease and subjects with chronic autoimmune disease A significant lowering effect of marine-derived n-3 PUFA supplementation on CRP and IL-6 was observed: the pooled effect sizes were −0.20   and −0.22 ; the overall percentages of changes (in geometric mean) in the two subgroups were −19.75%  and −18.13% (95% CI −24.42% to −10.42%), respectively; joint test for the two covariates  showed that their variation could help explain 45.37% heterogeneity. Duration, age and baseline level of IL-6 had a significant influence on the effect size on IL-6: significant lowering effect was observed only when studies had a longer duration (≥ median), or recruited older subjects (age ≥ median) , and the overall percentages of changes (in geometric mean) in the two subgroups were −30.23%  and −33.63% , respectively; the lowering effect on IL-6 was significantly greater in subjects with a higher baseline level (≥ median) than those with a lower one (< median) (P for subgroup difference was 0.049), and the overall percentages of changes (in geometric mean) in the two subgroups were −32.29%  and −12.19% , respectively; joint test for duration, age and baseline of IL-6  showed that their variation could help explain 46.56% heterogeneity. BMI of subjects had a significant influence on the effect size on TNF-α: significant lowering effect of marine-derived n-3 PUFAs on TNF-α was only observed in subjects with a BMI <30 kg/m2 , and its variation  could help explain 23.54% heterogeneity; the overall percentage of changes (in geometric mean) in this subgroup was −19.75% .Results of subgroup analysis were shown in Meta-regression was conducted to assess the potential linear relationship between effect size and continuous covariates , BMI, and daily dose of EPA, DHA and total n-3 PUFAs). No significant result was observed for CRP. A significant linear relationship was observed between effect size on IL-6 and duration as well as age, and the coefficients were −0.023   and −0.02; however, when BMI was greater than 30 kg/m2, the lowering effect tended to become weaker with the increase of BMI . No significant result was observed for CRP and TNF-α. We found a significant cubic relationship between BMI of subjects and effect size on IL-6 (P for linearity = 0.047): the lowering effect did not change significantly with BMI when BMI was less than 30 kg/me of BMI . No sign2 = 0.0%).Subjects of all included studies had a high risk of or had been diagnosed with cardiovascular disease. The pooled effect sizes for CRP and TNF-α were not significant  . A signiSubgroup analysis was conducted by the same methods used for marine-derived n-3 PUFAs supplementation  or cubic relationship (P for linearity >0.05) between effect size on CRP/IL-6 and continuous variables (as were mentioned in the results for marine-derived n-3 PUFAs supplementation). Meta-regression and restricted cubic spline analysis were not conducted for TNF-α, considering less than 10 studies (or comparisons) were included.One study (two independent comparisons) assessing the effect on CRP had a risk of bias in two categories 2 = 0.0%); one study recruited both subjects with chronic non-autoimmune disease and subjects with chronic autoimmune disease We observed a significant lowering effect of marine-derived n-3 PUFAs supplementation on fasting blood level of CRP; the pooled effect size was −0.54  , and the2 values were 21.6% and 0.0%, respectively). A marginally significant lowering effect on IL-6 was observed  (2 = 75.1%).A significant lowering effect on CRP and TNF-α was observed, and the pooled effect sizes were -0.18   and −0.1= 0.065) , and theResults of subgroup analysis for CRP and IL-6 were shown in Meta-regression was conducted to explore potential linear relationship between effect size and continuous confounding factors , and daily dose of EPA, DHA, and total n-3 PUFAs). A significant linear relationship was observed between effect size on CRP and daily dose of EPA, and the coefficient was −0.195  , indicatRestricted cubic spline analysis for IL-6 showed no significant cubic relationship between effect size on the two inflammatory factors and continuous confounding factors (as were mentioned in the paragraph above) (P for linearity >0.05). We found a significant cubic relationship between baseline of CRP and effect size on CRP (P for linearity = 0.021) : the lowData of mean changes for phospholipid EPA, DHA and total n-3 PUFAs were shown in The funnel plot for studies assessing the effect of marine-derived n-3 PUFAs supplementation on IL-6 in subjects with chronic non-autoimmune disease showed a slight asymmetry, indicating that considerable publication bias existed ; trim-anThe present meta-analysis provided consistent evidence that marine-derived n-3 PUFAs supplementation had a significant lowering effect on fasting blood levels of CRP, IL-6 and TNF-α in subjects with chronic non-autoimmune disease and healthy subjects. Marine-derived n-3 PUFAs supplementation had a significant lowering effect on fasting blood level of CRP and a marginally significant lowering effect on TNF-α in subjects with chronic autoimmune disease; no included studies assessed the effect on IL-6 in subjects with chronic autoimmune disease. The effect of marine-derived n-3 PUFAs from dietary intake on CRP, IL-6 and TNF-α was only assessed in subjects with chronic non-autoimmune disease, and significant lowering effect was only observed on IL-6, but not on CRP and TNF-α.The lowering effect of n-3 PUFAs on CRP, IL-6 and TNF-α has a biological basis. The mechanism may involve both nuclear factor кB (NF-кB) and peroxisome proliferator agonist receptors (PPAR). N-3 PUFAs has been found to be a natural ligand of PPAR By subgroup analysis, we found that fatty acid compositions of placebo had a significant influence on the effect size of marine-derived n-3 PUFAs supplementation on CRP in subjects with chronic non-autoimmune disease, the significant lowering effect of marine-derived n-3 PUFAs was observed when oils mainly comprised of linoleic acid (n-6 fatty acid) rather than oleic acid (monosaturated fatty acid) were used as placebo (p for subgroup difference <0.05). A similar result was also observed in healthy subjects: although the subgroup difference was not significant (p for subgroup difference >0.05), significant result was observed only in subgroup using oils mainly comprised of linoleic acid (n-6 fatty acid) rather than oleic acid (monounsaturated fatty acid). Reasons for this difference induced by placebo might be explained by the role different fatty acid play in the immune system. Previous studies have demonstrated that n-6 polyunsaturated fatty acid play an opposing role with n-3 polyunsaturated fatty acid in the process of inflammation By meta-regression, we observed a significant negative linear relationship between duration and effect size of marine-derived n-3 PUFAs supplementation on IL-6 and TNF-α in subjects with chronic non-autoimmune disease, indicating that longer duration of use could lead to a greater lowering effect. Similar linear relationship was also observed between duration and effect size of marine-derived n-3 PUFAs supplementation on IL-6 in healthy subjects. The relationship between duration and effect size was easy to understand if we take into consideration that changing fatty acid composition of cell membrane and tissues by n-3 PUFAs intake needs a relatively long term. One previous controlled study by Katan et al. assessed the effect of fish oil intake on changes of fatty acid composition in serum cholesteryl esters, erythrocyte membranes and adipose tissue during an 18-month follow-up 2. Although cubic relationships between BMI and the effect sizes of marine-derived n-3 PUFAs supplementation on the level of CRP and TNF-α in subjects with chronic non-autoimmune disease were not significant, subgroup analysis found a similar result: marine-derived n-3 PUFAs supplementation had a significant lowering effect on CRP and TNF-α in subjects with a BMI less than 30 kg/m2 but not in subjects with a BMI ≥30 kg/m2, and the subgroup difference was significant. One possible reason for the lack of correlation in obese subjects may be explained by the association between fatty acid composition in tissue and obesity. A previous study found that the total n-6 PUFAs and arachidonic acid in adipose tissues all increased with BMI in obese subjects We observed a significant cubic relationship between BMI of subjects and the effect size of marine-derived n-3 PUFAs supplementation on fasting blood level of IL-6 in subjects with chronic non-autoimmune disease in studies with a parallel group design. From the fitted curve, we found that the lowering effect of marine-derived n-3 PUFAs supplementation on IL-6 became weakened when BMI was greater than 30 kg/mA significant negative linear relationship between age and the effect size of marine-derived n-3 PUFAs supplementation on fasting blood level of IL-6 was observed in subjects with chronic non-autoimmune disease, indicating that the lowering effect was stronger in older subjects. Subgroup analysis also found a consistent result. One previous study by Rodrigo et al. also found that older subjects showed a better antioxidant response to n-3 PUFAs supplementation We also observed a significant negative linear relationship between daily dose of EPA and the effect size on fasting blood level of CRP in healthy subjects, indicating that higher dose of EPA might lead to a greater lowering effect on CRP. But similar relationship was not observed for daily dose of total n-3 PUFAs or DHA. This provided some evidence that EPA might be at least more effective than DHA on lowering fasting blood level CRP. We also observed a significant positive linear relationship between daily dose of DHA and the effect size on fasting blood level of IL-6 in healthy subjects. This result was consistent with the negative relationship between daily dose of EPA and the effect size on fasting blood level of CRP if we take into consideration that marine-derived n-3 PUFA supplementation (mainly fish oil) is mainly comprised of EPA and DHA, and that higher dose of DHA might lead to a lower proportion of EPA. One previous studies in mice showed that the lowering effect on cytokines production by thioglycollate-induced macrophages were only significant in the group fed by diet with the highest EPA/DHA ratio However, our present meta-analysis showed that changes of phospholipid EPA, DHA and total n-3 PUFAs in plasma/serum did not show any significant influence on their effect size concerning CRP, IL-6 and TNF-α. As mentioned in the fourth paragraph of discussion, EPA in serum cholesteryl esters, erythrocyte membrane and gluteal fat tissue plateaued after 4–8 weeks, 6 months and 12 months, respectively, and the content of EPA in abdominal fat tissue still remain a trend to increase after supplementation for 12 months ex vivo mononuclear cells before and after supplementation ex vivo mononuclear cells and fasting blood levels of cytokines in vivo. Another study used a crossover design to assess the effect of fish oil on fasting blood level of CRP, IL-6 and TNF-α One previous study reviewed the effect of marine-derived n-3 PUFAs on inflammatory markers in randomized controlled trials, and found that only few studies showed a significant lowering effect on CRP, IL-6 and TNF-α in healthy subjects, and that the lowering effect of marine-derived n-3 PUFAs was significant on CRP and IL-6 in subjects with a presence or high risk of cardiovascular disease Several strengths can be observed in the present study. Firstly, we conducted meta-analysis based on log-transformed data, and this transformation eliminated potential bias caused by skew of data in some included studies. Secondly, our present study showed that the effect of marine-derived n-3 PUFAs supplementation had a lowering effect on all the three inflammatory factors . Considering the up-regulation effect of TNF-α on IL-6 and up-regulation effect of IL-6 on CRP (discussed in the second paragraph of discussion), the similarity of results concerning CRP, IL-6 and TNF-α strengthened the persuasion of our study. In addition, the large number of included studies and large sample size also make our results more plausible.Our study also had several limitations. Firstly, a risk of bias was observed in several studies included in the present meta-analysis. But results from our sensitivity analysis showed that these biases did not have a significant influence on the pooled effect size. Secondly, a significant heterogeneity was observed in the three meta-analyses assessing the effect of marine-derived n-3 PUFAs supplementation on CRP, IL-6 and TNF-α in subjects with chronic non-autoimmune disease as well as the meta-analysis evaluating the effect of marine-derived n-3 PUFAs supplementation on IL-6 in healthy subjects. However, the sources of heterogeneity and their influence on the effect size were well explained by subgroup meta-analysis, meta-regression and restricted cubic spline analysis.Our findings provide a scientific guide for nutritional therapy of inflammation-related chronic diseases. Consecutive long-term supplementation of marine-derived n-3 PUFAs is recommended. Our present studies also suggest that marine-derived n-3 PUFAs supplementation can effectively prevent inflammation-related chronic diseases considering its significant lowering effect on CRP, IL-6 and TNF-α in healthy subjects. The anti-inflammatory effect tends to be the most effective in non-obese subjects.In conclusion, marine-derived n-3 PUFAs supplementation has a significant lowering effect on fasting blood level of TNF-α, IL-6 and CRP.Figure S1Judgements about each risk of bias item presented as percentages across all included studies.(PDF)Click here for additional data file.Figure S2Judgements about each risk of bias item for each included study. Red ball, high risk of bias; yellow ball, unclear risk of bias; green ball, no risk of bias.(PDF)Click here for additional data file.Figure S3Funnel plot for publication bias (n-3 PUFAs supplementation and IL-6 in chronic non-autoimmune disease). SE, standard error; WMD, weighted mean difference.(TIF)Click here for additional data file.Figure S4Funnel plot for publication bias (n-3 PUFAs supplementation and CRP in chronic non-autoimmune disease). SE, standard error; WMD, weighted mean difference.(TIF)Click here for additional data file.Figure S5Funnel plot for publication bias (n-3 PUFAs supplementation and TNF-α in chronic non-autoimmune disease). SE, standard error; WMD, weighted mean difference.(TIF)Click here for additional data file.Figure S6Funnel plot for publication bias (n-3 PUFAs from dietary intake and CRP in chronic non-autoimmune disease). SE, standard error; WMD, weighted mean difference.(TIF)Click here for additional data file.Figure S7Funnel plot for publication bias (n-3 PUFAs from dietary intake and IL-6 in chronic non-autoimmune disease). SE, standard error; WMD, weighted mean difference.(TIF)Click here for additional data file.Figure S8Funnel plot for publication bias . SE, standard error; WMD, weighted mean difference.(TIF)Click here for additional data file.Figure S9Funnel plot for publication bias . SE, standard error; WMD, weighted mean difference.(TIF)Click here for additional data file.Table S1Baseline of inflammatory markers (log-transformed) and mean changes of phospholipid n-3 PUFAs in plasma/serum.(DOC)Click here for additional data file.Checklist S1PRISMA checklist.(DOC)Click here for additional data file.Text S1Protocol for meta-analysis to assess the effect of marine-derived n-3 polyunsaturated fatty acids on CRP, IL-6 and TNF-α.(DOC)Click here for additional data file.