The burden of stroke is disproportionately high in the South Asian subcontinent with South Asian ethnicity conferring a greater risk of ischemic stroke than European ancestry regardless of country inhabited. While genes associated with stroke in European populations have been investigated, they remain largely unknown in South Asians. We conducted a comprehensive meta-analysis of known genetic polymorphisms associated with South Asian ischemic stroke, and compared effect size of the MTHFR C677T-stroke association with effect sizes predicted from homocysteine-stroke association. Electronic databases were searched up to August 2012 for published case control studies investigating genetic polymorphisms associated with ischemic stroke in South Asians. Pooled odds ratios (OR) for each gene-disease association were calculated using a random-effects model. We identified 26 studies (approximately 2529 stroke cases and 2881 controls) interrogating 33 independent genetic polymorphisms in 22 genes. Ten studies described MTHFR C677T (108 with TT genotype and 2018 with CC genotype) -homocysteine relationship and six studies (735 stroke cases and 713 controls) described homocysteine-ischemic stroke relationship. Risk association ORs were calculated for ACE I/D , PDE4D SNP 83 , PDE4D SNP 32  and IL10 G1082A . Significant association was observed between elevated plasma homocysteine levels and MTHFR/677 TT genotypes in healthy South Asians (Mean difference (ΔX) 5.18 µmol/L; 95% CI 2.03–8.34: p = 0.001). Our results demonstrate that the genetic etiology of ischemic stroke in South Asians is broadly similar to the risk conferred in Europeans, although the dataset is considerably smaller and warrants the same clinical considerations for risk profiling. South Asia comprising of India, Pakistan, Sri Lanka and Bangladesh, forms 20% of the world's populous and shoulders much of the global death burden from cardiovascular disease We undertook a comprehensive meta-analysis of all known genetic associations with ischemic stroke in South Asians and compare it to published results in different ethnic groups. We further sought to establish whether homocysteine, the putative biochemical intermediary of the MTHFR gene is associated with quantitative levels of risk ‘relevant articles’ option was utilized. The following index terms along with ‘and/or’ as a Boolean operator were used: “South Asia” “India” “Pakistan” “Sri Lanka” “Bangladesh” for ancestry and “stroke genetics” “gene polymorphism” “gene mutation” “stroke genes” for genetics and “stroke” “cerebrovascular disease” “ischemic stroke” “brain infarction” “brain ischemia” for clinical phenotype.We identified all published case-control studies evaluating any gene polymorphisms and ischemic stroke in South Asians residing in their native countries and diasporas around the world. Electronic searches were conducted using Medline, EMBASE and Google Scholar. All published manuscripts up until and including August 2012 as well as letters, previous meta-analyses and abstracts were included. The retrieved studies were examined thoroughly to assess their appropriateness for inclusion in our study. The references of all identified publications were manually reviewed for additional studies and the PUBMED Study inclusion criteria were: (1) studies in populations of South Asian descent defined as Indian, Pakistani, Sri Lankan or Bangladeshi; (2) case-control studies where ischemic stroke was analyzed as a dichotomous trait; (3) stroke was confirmed using brain imaging with sub-acute (within 10 days) CT or MRI, and; (4) genotype frequency for both cases and controls was reported. Studies were excluded if: (1) subjects were <18 years age; (2) the genotype frequency was not reported and could not be obtained from authors and (3) stroke other than ischemic.Data extracted from each study included: first author, journal, year of publication, stroke sub-type, and number of cases and controls for each genotype and SNP. Baseline characteristics for cases and controls were documented including mean age, gender, ethnicity and geographical location.v5.0 and Comprehensive Meta-Analysis (CMA) v2.0. To test for strength of association for each gene variant, a pooled odds ratio (OR) and 95% confidence interval (CI) was calculated using a random effects model 2 test for heterogeneity For each genetic variant for which data were available from at least two studies, a meta-analysis was carried out. Data was analyzed using Review Manager For MTHFR C677T gene variant which had an associated biomarker homocysteine, we performed a separate analysis that produced an estimate of expected risk based upon genotype–biomarker, and biomarker–stroke, association studies, using mendelian randomization and/or’ as Boolean operators were used for MTHFR: (MTHFR OR Methylenetetrahydrofolate reductase ) AND (gene OR genetic OR genotype OR polymorphism OR mutation), in combination with (MTHFR OR Methylenetetrahydrofolate reductase ) AND (homocysteine OR activity OR level); and 2) (MTHFR OR Methylenetetrahydrofolate reductase) AND (activity OR level) in conjunction with  and (South Asia or India or Pakistan or Sri Lanka or Bangladesh).Electronic searches were conducted using Medline, EMBASE and Google Scholar and all published manuscripts up until and including August 2012 were considered. The following index terms along with ‘The literature was searched for two types of studies: (Study 1) case-control studies reporting dichotomous and continuous data for plasma homocysteine levels in South Asians with ischemic stroke, and; (Study 2) studies linking plasma homocysteine levels with the MTHFR 677 wild type (CC) and homozygous mutant (TT) genotype in healthy South Asians. Control populations with genotype-homocysteine data from case-control studies on psoriasis, coronary artery disease and glaucoma were also included.Data extracted from each study included: first author, journal, year of publication, stroke sub-type, and total number of participants. Baseline characteristics for cases and controls were documented including mean age, gender, ethnicity and geographical location. In addition for Study 1, plasma homocysteine levels as means with standard deviations and median with ranges in ischemic stroke cases and controls, and; for Study 2, plasma homocysteine levels as means with standard deviations and median with ranges in MTHFR 677 wild type (CC) and homozygous mutant (TT) genotype in healthy South Asians.v5.0. A pooled mean difference (ΔX) with 95% confidence interval was calculated for MTHFR TT vs CC genotypes using a random effects model. Mean difference in homocysteine levels between ischemic stroke cases vs. controls were converted to ORs and 95% confidence interval using Comprehensive Meta-Analysis (CMA) v2.0. Assuming a log-linear relationship, this OR was scaled with the ΔX change in homocysteine levels conferred by the MTHFR TT genotype to give the expected OR The methodology for a literature based mendelian randomization for MTHFR and homocysteine is well described 2 test for heterogeneity was performed, with significance set at p<0.05. Funnel plots and Egger regression intercept p-value (two-tailed) were used to determine probability of publication bias.For each meta-analysis an IOur search strategy identified ∼4500 potentially relevant studies of which 26 met the inclusion criteria allowing interrogation of 33 independent genetic polymorphisms in 22 different genes across 2529 stroke cases and 2881 controls Relevant studies identified were; five for MTHFR C677T HET] = 0.06, I2 = 65%).The PDE4D SNP83 polymorphism was investigated in three studies covering Pakistan and North India HET] = 0.002, I2 = 90%).The homozygous ACE D/D polymorphism was investigated in a total of 2 studies covering India HET] = 0.12, I2 = 59%).The homozygous G1082A polymorphism was investigated in a total of 2 studies covering India in 1414 subjects  providing a pooled OR of 1.44  with a recessive random-effects model. There was no evidence of inter-study heterogeneity .The homozygous MTHFR C677T polymorphism was investigated in seven studies v2.0 software. We found 10 studies Seven studies 5.18 = 5.18 µmol/L mean difference in homocysteine levels between the MTHFR TT vs. CC genotypes in healthy individuals2.90 = Mean difference of 2.90 µmol/L associated with an OR of 1.68The above calculation revealed an expected OR of 2.52. A 95% confidence interval for the logged odds ratio of 0.92 (LN 2.52) was obtained as 1.96 standard errors on either side of the point estimate as previously described by Bland et al We present, to the best of our knowledge, the most comprehensive genetic meta-analysis of ischemic stroke in South Asians from India, Pakistan, Sri Lanka and Bangladesh. Our findings suggest three genes  to have statistically significant ORs for risk of ischemic stroke in a South Asian adult population and the totality of data supported MTHFR C677T as a further likely risk factor. The two most significant risk associations, PDE4D SNP 83 and ACE I/D identified in our meta-analysis, were previously described as genetic risk factors for stroke in other ethnic groups D allele is associated with hypertension in Asian Indians ACE gene plays an important role in vascular physiology and structural integrity. Our study finds a high risk of ACE/DD variant in South Asians  which accounts for a five-fold increase in the risk of overall ischemic stroke per copy of the risk allele of the ACE DD variant relative to Europeans  Interleukin 10 is an anti-inflammatory cytokine produced primarily by monocytes and type 2 T helper cells. We found IL10 to be associated with a 44% increase  in the risk of overall ischemic stroke per copy of the risk allele of the IL 10 G1082A variant. IL10 is involved in various cellular processes such as inhibition of pro-inflammatory cytokines, suppression of antigen-presenting capacity of antigen presenting cells (APC) and stimulation of B cell maturation. IL10 forms part of an inflammatory genetic profile and elevated levels of IL10 post stroke have been implicated in severe neurological impairment and major adverse clinical outcomes MTHFR C677T genotype is associated with hyperhomocystinemia among South Asians and Europeans vs T also showed a high difference in homocysteine levels, ΔX value of 5.18 µMol/L, for South Asians, compared to Europeans ΔX of ∼2.3 µMol/L Although the genetic association between disease and gene for MTHFR C677T was weak (p = 0.08), the totality of data supported such an association and with its previously documented strong association in Europeans HET] = 0.002, I2 = 90%). The small sample size meant large a confidence interval and less statistical reliability of data. Lack of stroke TOAST classification amongst the selected studies also hampered sub-group analysis which is essential due to the heterogeneous etiology of ischemic stroke sub-types. Fewer studies also limited our ability to take the genetic stratification of the South Asian population As with all meta-analyses, a number of limitations to interpreting our data need to be reported. Possible publication bias Another major limitation was the inability to calculate the F statistic to determine the strength of the genetic instrumental variable (IV). A mendelian randomization strategy on individual patient level data involves the assessment of a causal effect of a phenotype on an outcome by using genetic IV MTHFR and ACE, literature based meta-analysis of comparable (or greater) power and sample size have been able to identify these genetic risk variants to be associated with stroke PHACTR1 which suggests that detection of any new genetic risk variants will rest on proper stroke subtyping. Though the effect sizes for these genes are small, it is likely that they are true associations as compared to genes identified in smaller underpowered candidate gene based studies.In the current climate of GWAS studies and whole genome sequencing, the literature based meta-analysis has its own unique utility. Where large GWAS studies have failed to identify risk associations with gene variants such as Our work supports a genetic etiology of ischemic stroke in South Asians but the dataset is considerably smaller compared to those of European descent. We show no major differences in risk associations for previously studied stroke susceptibility genes between South Asians, Europeans and South East Asians. However it would be fallacious to assume a literal comparison between studies that are not statistically at power and hence there is a clear need for large prospective well powered GWAS studies in South Asians, as has been done in Europeans.Table S1Summary table of gene polymorphisms associated with risk of ischemic stroke in South Asians.(DOCX)Click here for additional data file.


Although caffeine supplementation improves performance, the ergogenic effect is variable. The cause(s) of this variability are unknown. A (C/A) single nucleotide polymorphism at intron 1 of the cytochrome P450 (CYP1A2) gene influences caffeine metabolism and clinical outcomes from caffeine ingestion. The purpose of this study was to determine if this polymorphism influences the ergogenic effect of caffeine supplementation.2max = 59.35 ± 9.72 ml·kg-1·min-1) participated in two computer-simulated 40-kilometer time trials on a cycle ergometer. Each test was performed one hour following ingestion of 6 mg·kg-1 of anhydrous caffeine or a placebo administered in double-blind fashion. DNA was obtained from whole blood samples and genotyped using restriction fragment length polymorphism-polymerase chain reaction. Participants were classified as AA homozygotes (N = 16) or C allele carriers (N = 19). The effects of treatment  and the treatment × genotype interaction were assessed using Repeated Measures Analysis of Variance.Thirty-five trained male cyclists  magnitude in AA homozygotes  as compared to C allele carriers .Caffeine supplementation reduced 40 kilometer time by a greater (Results suggest that individuals homozygous for the A allele of this polymorphism may have a larger ergogenic effect following caffeine ingestion. Jacobson et al. [Prior studies have established the ergogenic benefits of caffeine for both high-intensity short-duration performances -3, as wen et al.  observedn et al. . Thus, tCytochrome P450 is a hepatic enzyme that is a key component of caffeine metabolism. A (C/A) single nucleotide polymorphism at intron 1 of the cytochrome P450 gene influences the inducibility of this enzyme, with the C variant affecting a slower caffeine metabolism following caffeine ingestion in smokers . This po2max = 59.35 ± 9.72 ml·kg-1·min-1) were used for data analysis. Written informed consent was obtained from all participants prior to participation and the study and consent form were approved by the James Madison University Institutional Review Board. Habitual caffeine intake was self-reported by participants. Briefly, participants were asked for their average weekly intake of coffee, tea, soda, chocolate, and other caffeinated beverages. Typical milligram doses [-1), moderate (151-300 mg·day-1) and high (> 300 mg·day-1) caffeine intake.A total of 36 male recreationally competitive cyclists participated in the present study. One of these participants was excluded from the study post-hoc, as their cycling performance differed by more than two standard deviations from the mean value of the group. Therefore, 35 cyclists  was defined as the highest 1-minute oxygen value obtained during the test. Oxygen uptake (VO2) was monitored continuously via a Sensormedics Vmax  metabolic measurement system calibrated in advance of all tests. Heart rate was monitored throughout the test using a Polar Heart Rate Monitor .Cyclists began the test at a work rate of 150 W on an electrically braked cycle ergometer, with load increases of 20 W each minute until volitional exhaustion. Maximal oxygen uptake  randomly administered in double-blind fashion. Time trials were performed on an indoor cycle trainer  on a computer-simulated course. The course consisted of eight laps of a flat, five-kilometer loop. Cyclists were free to self-select the resistance by changing gears during the test and were allowed to track distance completed on the course via a video display. However, they were blinded to their time, speed, and power output during the trials. Water was available for the cyclists to ingest ad libitum. Oxygen uptake and respiratory exchange ratio (RER) were obtained and averaged over the last two minutes of each lap. Heart rate and Ratings of Perceived Exertion  were obtained at the end of each lap.ApaI  as per manufacturer's instructions. Digested and undigested PCR products were evaluated in parallel via electrophoresis in a 2% agarose gel stained with ethidium bromide, and DNA bands were visualized by UV light. The presence of a 920 bp fragment following ApaI digestion identified the A/A genotype, while the presence of 709 bp and 211 bp fragments following ApaI digestion identified the C/C genotype. Caffeine metabolism is similar between heterozygotes and CC homozygotes [Investigators were blinded to genotype until the subject completed the study. Furthermore, all genotyping was performed by an investigator not involved with the performance testing. DNA was obtained from whole blood samples via a QiaAmp mini-blood kit . Each blood sample was obtained prior to one of the cycling trials. Genotyping was performed using restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR), as previously described . Brieflyozygotes . Therefoozygotes , cyclist2max, caffeine intake) were compared between groups using independent t-tests. The frequency of low, moderate and high caffeine intake in the two genetic groups was compared using a Chi-Squared analysis. Potential differences in 40-km time, average VO2, HR, RER and RPE were assessed using repeated measures analysis of variance (RMANOVA) with treatment as a within-subjects factor and genotype as a between-subjects factor. For all RMANOVA procedures, post-hoc tests were performed using independent and dependent t-tests with a Bonferroni correction such that P < 0.025 was required for significance.Descriptive data  between the two groups for height, weight, age, VO2max, or caffeine intake. In AA homozygotes, 12 out of the 16 participants were categorized as having low caffeine intake, three as moderate and one as high. Sixteen out of the 19 C allele carriers had low intake, one had moderate intake, with two characterized as having high intake. There was no difference in the distribution of low, moderate and high caffeine use between the two groups (p = 0.44).Out of the 35 participants analyzed, 16 (46%) were homozygous for the A variant and 19 (54%) were C allele carriers. This distribution is very similar to previously reported studies -12,15. Dp < 0.001) main effect for Treatment (Caffeine < Placebo) and a significant (p = 0.005) Treatment × Genotype interaction, such that caffeine lowered average (mean ± SD) 40-km time in AA homozygotes  to a greater degree than the C allele carriers . Caffeine significantly decreased 40-km time in the AA homozygotes (p < 0.001), with a strong trend towards decreased 40-km time in C allele carriers (p = 0.04). Individual data for the 40-km times in both groups are displayed in Figure 2, RER and heart rate for the 40-km time trial are shown in Table 2 and HR, with both variables higher in the caffeinated condition versus placebo (p < 0.001). Furthermore, there was a main effect of Genotype for VO2, with C allele carriers exhibiting significantly higher average VO2 than AA homozygotes (p = 0.03). There were no significant main effects or interaction effects for RPE or RER.Figure The major finding of the present study is that caffeine affects 40-kilometer time trial performance in cyclists homozygous for the A variant to a greater degree than those who possess the C variant. Specifically, caffeine decreased 40-km time by an average of 3.8 minutes in the AA homozygotes as compared to 1.3 minutes in the C allele carriers. To our knowledge, this is the first study to implicate a specific polymorphism as a potential cause of the variation in the ergogenic effect of caffeine supplementation.Sachse et al.  observedp = 0.047) greater effect in AA homozygotes  compared to the C allele carriers . Caffeine resulted in at least a 1-minute improvement in 40 k time in all but one of the AA homozygotes; whereas only about half of C allele carriers responded to that extent  of this selective ergogenic effect are unknown and future studies should seek to establish the impact of this polymorphism on caffeine metabolism during exercise. While these findings elucidate a possible source of variance in the ergogenic effect of caffeine, other factors, including other genetic polymorphisms, may also influence caffeine responses during exercise.The authors declare that they have no competing interests.CJW planned the study, assisted with data collection and wrote the bulk of the manuscript. MJS helped with study design, data interpretation and manuscript preparation. MKB helped with study design, performed genotyping and manuscript preparation. DJB helped with study design and data collection. MM helped with data collection and manuscript preparation. NDL assisted with data collection, study design and manuscript preparation. Both WD and MH performed genotyping and manuscript preparation. All authors read and approved the final manuscript.


Interleukin (IL)-18, an important proinflammatory cytokine, plays a potential pathological role in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Studies on the relationship of IL-18 gene promoter rs1946518 (−607A/C) polymorphism, rs187238 (−137G/C) polymorphism with RA and SLE are inconclusive. The aim of this study was to get a more precise estimation of the relationship in Asian populations.Meta-analysis was conducted on the associations between the IL-18 (−607A/C and -137G/C) polymorphisms and RA and SLE, using; (1) allele contrast, (2) dominant, and (3) recessive models. A total of 11 studies were included in this study.For the relationship of IL-18 rs1946518 polymorphism with RA  and SLE , no significant association with RA and SLE risk can be found under all genetic models in Asian populations. However, significant associations were observed in Chinese population for both RA  and SLE  under additive model. For the relationship between IL-18 rs187238 polymorphism and RA or SLE, there was no significant association detected in all genetic models, even in Chinese population.This meta-analysis indicates that the IL-18-607A/C polymorphism may confer susceptibility to RA and SLE in Chinese population, but not all Asians. Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are prototypic autoimmune diseases resulting in inflammation and tissue damage. However the etiologies of RA and SLE are not completely clear, a strong genetic component has been supported by genetic and family studies ,2. Like IL-18, formerly called interferon (IFN)-γ-inducing factor, is an important proinflammatory cytokine belong to the IL-1 family that is produced by a wide range of immune cells, such as monocytes, activated macrophages and Kupffer cells .The imbaThe IL18 gene is located on chromosome 11q22.2–22.3 with six exons and five introns , and manWe conducted a computer-based searches of PubMed, EMBASE, Web of Science, China National Knowledge Infrastructure (CNKI),China Biological Medicine Database (CBMD) and Wanfang (Chinese) to identify all studies examining the association of IL-18 promoter rs1946518 and rs187238 polymorphisms with RA and SLE susceptibility with the last report up to April 2012.The following keywords and subject terms were used for searching:“systemic lupus erythematosus”, “SLE”, “rheumatoid arthritis”, “RA”,“IL-18”, “Interlukin-18”and “polymorphism”. References of retrieved articles were also scanned. The following criteria were used to identify the relevant published studies: (i) the diagnosis of RA and SLE was established using the ACR classification criteria for RA and SLE respectively -17; (ii)P<0.05). If the control groups were not in HWE, sensitivity analysis or subgroup analysis was performed to test the robustness of the findings. The odds ratio (OR) corresponding to the 95% confidence interval (95% CI) was used to assess the strength of association between the rs1946518 and rs187238 polymorphisms in the IL-18 gene and the risk of RA and SLE respectively. We performed meta-analyses using (1) allele contrast, (2) dominant, and (3) recessive models. The heterogeneity among studies was assessed using the Q- [2-statistics [P<0.10.If heterogeneity existed, the pooled OR was estimated by the random-effects model and the Dersimonian and Laird method[P values) were two-sided.The Hard-Weinberg Equilibrium (HWE) was measured by chi-squared test for the control groups of each study . After review of full texts of the remaining 28 articles, 17 articles were excluded for failing to meet the inclusion criteria . Thus, 11 studies were selected in our meta-analysis , and the subgroup analysis also failed to find any significant results.P =0.03, I2-residual = 27.30%, adj-R2 =80.06%) was a significant source of heterogeneity among studies and under the recessive model population  was the significant source of heterogeneity among studies. The other variables were not potentially significant sources of heterogeneity. For SLE, meta-regression failed to identify the sources of heterogeneity.Meta-regression was performed with population (Chinese and other), genotyping method (RFLP and other methods), sample size and HWE status to assess the heterogeneity among the studies. For RA and SLE, when analyzed the rs1946518 polymorphism, strong evidence for heterogeneity among studies was demonstrated under all genetic models. For RA, the regression analysis showed that under the additive model sample size .We used modified Egger's linear regression test to access publication bias of the rs1946518 and rs187238 polymorphisms in the IL-18 gene and RA and SLE risk respectively under all genetic models  site resulting in higher levels of the IL-18 production ,32. For Several limitations of this research should be considered. First, our literature searching was depended on English and Chinese, language bias might be existed. Second, our subjects were all Asians, so it was not suitable to other populations. Third, publication bias may still be present, distorting the meta-analysis. Fourth, we couldn’t calculate the linkage disequilibrium (LD) between SNPs, so we couldn’t exclude the potential likelihood that the significant association in Chinese population was only due to other real significant polymorphisms which were linkage with rs187238. Finally, the studies included were small, our results should be interpreted with caution.In conclusion, pooled results demonstrated no significant association between IL-18 polymorphisms and RA or SLE, but subgroup analysis detected a significant association between IL-18 rs1946518 (−607 A/C) polymorphism and both diseases within Chinese population.The authors declare that they have no competing interests.SC was in charge of collection of data and manuscript preparation. FJ, JR and JL were responsible for checking the data and performing the statistical analysis. WM participated in study design and critically revised the manuscript. All authors were responsible for drafting the manuscript, read and approved the final version.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2350/13/107/prepub


GJB2 gene is considered as a risk factor for the non-syndromic hearing loss (NSHL), and a significant difference in the frequency and distribution of the 235delC mutation has been described world widely.The 235delC mutation of GJB2” associated with “carrier frequency” was conducted to include all papers from January 1999 to June 2011. A total of 36 papers were included and there contained 13217 cases and 6521 controls derived from Oceania, American, Europe and Asian.A systematic review was performed by means of a meta-analysis to evaluate the influence of the 235delC mutation on the risk of NSHL. A literature search in electronic databases using keywords “235delC”, “OR = 7.9, 95%CI 4.77 ~ 13.11, P <0.00001). Meanwhile, heterogeneity of genetic effect was also observed due to the ethnic specificity and regional disparity. Therefore, the stratified meta-analysis was subsequently conducted and the results indicated that the 235delC mutation was significantly correlated with the risk of NHSL in the East Asian and South-east Asian populations , but not significantly in the Oceania and European populations .A remarkable heterogeneity between these studies was observed. The combined results of meta-analysis showed that the 235delC mutant increased the risk of NSHL (GJB2 gene increased the risk of NHSL in the East Asian and South-east Asian populations, but non-significantly associated with the NSHL susceptibility in Oceania and European populations, suggesting a significant ethnic specificity of this NSHL-associated mutation.The 235delC mutation of  Among them, DFNB1 was considered to be the main cause of prelingual deafness. As one of the DFNB1 locus-linked genes, GJB2 was the first to be indentified which encoded the gap junction protein connexin 26 (Cx26). To date, more than a hundred different mutations of this gene has been implicated in NSHL [GJB2 gene comprised 35delG, 167delT and 235delC with the varied incidence among populations [Hearing impairment is the most common sensory disorder, present in 1 of every 1000 newborns, about half of which could be attributed to genetic factors [GJB2 is the most frequently known mutation in some East Asian groups, with a carrier frequency of approximately 1% [The 235delC mutation of ately 1% ,5, whileately 1% ,7. In thGJB2, Connexin 26 (Cx26), mutation, variant, NSHL or NSHI (non-syndromic hearing impairment). All related citations were retrieved to find other relevant articles that were not initially identified. The entire literature search was performed by two independent researchers.The electronic databases including PubMed, InterScience, British Library Direct, Embase, Sciencedirect, Chinese Biomedical Literature, Chinese WanFang database and China National Knowledge Infrastructure were searched from January 1999 to June 2011, fulfilling all case-control studies holding information on the epidemiology study in molecular genetics of hearing loss. The following terms were used in search strategies: GJB2 with NSHL was examined based on case-control design; (2) the selected papers contained complete information and represented Odds Ratio (OR) and 95% Confidence Interval (95%CI) directly or indirectly; (3) for the same studied populations, only the papers newly published or providing the complete data were adopted. All collected papers were scored and categorized according to the Newcastle-Ottawa Scale (NOS) for assessing the quality of case-control studies [The reference lists of all traced articles were examined manually and screened for eligibility using the following criteria: (1) the association of the 235delC mutation of  studies . StudiesGJB2 gene and the NSHL susceptibility were selected for the following data analysis. The flow chart of review process was shown as Figure A total of 146 papers were obtained through the search of electronic databases. Among them, 36 papers associated with the 235delC mutation of GJB2 and hearing loss was evaluated for each group or continent. The statistical analysis was conducted using Review Manager 5.1 (RevMan) supplied by the Cochrane Collaboration . Heterogeneity among studies was assessed through Cochrane χ2 test and I2 statistic (P < 0.05 indicating the existence of between-study heterogeneity). Based on the test of heterogeneity, the combined meta-analysis and stratified meta-analysis were conducted respectively. The pooled OR was calculated using fixed or random effect model, along with the 95%CI to measure the strength of the genetic association. The publication bias was analyzed by STATA 11.0 and Begg’s test, and failsafe number (Nsf) was calculated . The statistical analysis was performed using Software SPSS . An online tool (http://ihg.gsf.de/cgi-bin/hw/hwa1.pl/) was applied to test whether the genetic type of control group was consistent with Hardy-Weinberg equilibrium (HWE) for each study.The mean value of carrier frequency of the 235delC mutation in the individual studies was calculated. The included populations were divided into two groups (Asian and non-Asian groups) according to the distribution of carriers. The relationship between the 235delC mutation of GJB2 allele, as shown in Table Among 36 included papers, there were 24 papers containing the information on the 235delC carrier frequencies of A total of 36 case-control studies comprising 13217 patients’ cases with NSHL and 6521 controls were included in meta-analysis . As shown in Figure OR and 95%CI values demonstrated that there was a higher prevalence of the 235delC mutation in the case group than in the control group. The publication bias was examined by use of funnel plot , which suggested that the publication bias had little effect on the result of meta-analysis and the conclusions obtained were confident.The 235delC mutation of 2 = 56.12, df = 30, P = 0.003<0.05, I2 = 47%), which indicated that the association of the 235delC mutation with the risk of NSHL was varied due to the ethnic specificity or regional disparity. To elucidate the prevalence of the 235delC mutation related to the NSHL susceptibility more precisely, the stratified meta-analysis was subsequently performed according to the regional studies. It was observed that a high prevalence of the 235delC mutation related to hearing loss was reported in Asian . As shown in Figure OR and 95%CI values demonstrated that the 235delC mutation of GJB2 gene was significantly associated with the risk of NSHL in Asian population. The visual inspection of funnel plot seemed to be symmetrical , which suggested that and the publication bias had little effect on the result of meta-analysis and the conclusions obtained were confident.Two studies were excluded due to undetectable 235delC mutations in patients’ cases or incomplete statistical data in controls. And a total of 22 papers compromising 9855 patients’ cases and 3634 controls were included in the stratified meta-analysis. The pooled 2 = 33.90, df = 21, P = 0.04<0.05, I2 = 38%), which demonstrated the presence of disparity in the prevalence of the 235delC mutation related to NSHL susceptibility among Asian populations suggesting the need of further stratified meta-analysis.Heterogeneity of genetic effect was still detected as shown in Figure OR = 12.05, 95%CI: 8.33 ~ 17.44, Z = 13.21, P <0.00001). As shown in Figure OR and 95%CI values demonstrated that the prevalence of the 235delC mutation was higher in the case group than in the control group. Publication bias was examined by use of funnel plot , which suggested that and the publication bias had little effect on the result of meta-analysis and the obtained conclusion was confident. In addition, no significant heterogeneity of genetic effect was found as shown in Figure 2 = 27.16, df = 18, P = 0.08>0.05, I2 = 34%).The overall effect on included studies in East Asian and Southeast Asian populations was evaluated, and a total of 19 papers were included, compromising 9275 patients’ cases and 2904 controls. The forest plot on the association of mutation carriers with the risk of NSHL was fulfilled using random effect model .Three case-control studies were excluded due to no 235delC mutation of GJB2 mutations and the NSHL susceptibility with ethnic specificity or certain genetic backgrounds of affected families. Meanwhile, the same type of single nucleotide polymorphisms (SNP) could show various contributions to the genetic models derived from different studies due to the ethnic specificity.The investigation on heterogeneity in genetic association were commonly leveled to the genetic effect and genetic model: the genetic effect focused on the difference in study method, potential interaction of gene-gene or gene-environment and linkage disequilibrium , while tGJB2 gene and the NSHL susceptibility. Results of stratified meta-analysis showed that the 235delC mutation was prominently associated with the risk of NSHL in East Asian and Southeast Asian populations, but not significantly in European and Oceania populations. The 235delC mutation of GJB2 gene trended to be consistent with recessive model in Chinese population, while heterogeneity of genetic effect was also detected in studies of GJB2 mutation reported in Europe and Oceania, which suggested that multiple models could possibly be present in European and American populations, due to a complex interaction between GJB2 mutations and environmental factors. A further research on the prevalence of the 235delC mutation of GJB2 gene related to the NSHL susceptibility, as well as the regional disparity and ethnic specificity will be essentially need.By increasing the sample size, meta-analysis based on case-control studies has the potential to evaluate the between-study heterogeneity and detect small effects in genetic association. In this study, the combined results of meta-analysis showed that the 235delC mutant increased the risk of NSHL, but significant between-study heterogeneity and genetic-effect heterogeneity were detected, indicating that the ethnic specificity and regional disparity contributed to the association between the 235delC mutation of GJB2 gene will be carried out in our future work.A systematic review was performed by means of a meta-analysis to evaluate the influence of the 235delC mutation on the NSHL susceptibility. The combined results of meta-analysis by pooling all relevant studies showed that the 235delC mutant increased the risk of NSHL. However, heterogeneity of genetic effect was observed due to the ethnic specificity and regional disparity. Therefore, stratified meta-analysis was conducted in different ethnic population group, and the results indicated that the 235delC mutation was prominently correlated with the risk of NHSL in the East Asian and South-east Asian populations, but non-significantly associated with the Oceania and European populations. Based on this study, a further research on the genetic mechanism of the NSHL susceptibility related to the 235delC mutation of The authors declare that they have no competing interests.JY and YJL carried out the literature search and screening, performed the meta-analysis and drafted the manuscript. QJW participated in the design of the study and the statistical analysis. GQX and XC conceived of the design of the study and helped to draft the manuscript. All authors read and approved the final manuscript.


Emerging evidence suggests that single nucleotide polymorphisms (SNPs) in microRNA-coding genes may participate in the pathogenesis of lung cancer by altering the expression of tumor-related microRNAs. Several studies were investigated in recent years to evaluate the association between hsa-miR-196a2 rs11614913 polymorphism and increased/decreased lung cancer risk. In the present study, we performed a meta-analysis to systematically summarize the possible association.We performed a meta-analysis of 4 case-control studies that included 2219 lung-cancer cases and 2232 cancer-free controls. We evaluated the strength of the association using odds ratios (ORs) with 95% confidence intervals (CIs). In the overall analysis, it was found that the rs11614913 polymorphism significantly elevated the risk of lung cancer (CC versus (vs.) TT OR = 1.26, 95% CI 1.07–1.49, P = 0.007; CC/CT vs. TT: OR = 1.13, 95% CI 0.98–1.29, P = 0.007; C vs. T: OR = 1.12, 95% CI 1.03–1.22, P = 0.008). In the subgroup analysis by ethnicity, statistically significantly increased cancer risk was found among Asians . For Europeans, a significant association with lung cancer risk was found in recessive model . No publication bias was found in this study.Our meta-analysis suggests that the rs11614913 polymorphism is significant associated with the increased risk of lung cancer, especially in Asians. Besides, the C allele of rs11614913 polymorphism may contribute to increased lung cancer risk. Lung cancer is the leading cause of cancer related deaths worldwide and the incidence rate has significantly increased in the last decades. More than one million deaths are reported worldwide every year, and the five-year survival rate is less than 15% MicroRNAs (miRNAs) are small non-coding, single-stranded RNA molecules of ∼ 22 nucleotides that form base-pairs with target messenger RNA (mRNAs), leading to negatively regulate their translational stability and efficiency http://www.ncbi.nlm.nih.gov/projects/SNP) as possible biomarker, which was associated with multiple kind of cancers, such as lung cancer Single nucleotide polymorphisms (SNPs) or mutations occurring in the miRNA gene region may have effects on the function of miRNAs through altering miRNAs expression and/or maturation, consequently contributing to cancer susceptibility We carried out a systematic search using PubMed, Excerpta Medica Database (EMBASE), ISI Web of Science, Cochrane Central Register of Controlled Trials, ScienceDirect, Wiley Online Library, Chinese Biomedical Literature Database (CBM) and Chinese National Knowledge Infrastructure (CNKI) databases with the last search updated on August 31, 2012. The following search terms were analyzed: “microRNA OR mir OR miRNA”, “lung cancer OR tumour OR tumor OR neoplasm OR carcinoma”, “gene OR allele OR polymorphism OR variation”, and “196a2 OR rs11614913”. Searching was investigated without restriction on publication date and language. We evaluated all potentially associated publications to retrieve the most eligible studies. Reference lists were searched manually to further identify additional eligible literatures.The following inclusion criteria were analyzed in selecting studies for the current meta-analysis: (1) evaluation of hsa-miR-196a2 rs11614913 polymorphism and lung cancers; (2) use an independent case-control design studies for human; (3) describing useful allele and genotype frequencies for estimating an odds ratios (ORs) and 95% confidence intervals (95% CIs); (4) only full-text manuscripts were included. The major exclusion criteria were: (1) duplication of the previous publications; (2) abstract, comment, and review; (3) no sufficient data were reported.Three investigators  extracted all data independently, complied with the inclusion criteria listed above. Discrepancies were adjudicated by other investigators (Wang and Liu) until consensus was achieved on all items. The following items were collected from each eligible publication: the first author’s name, year of publication, country origin, ethnicity, numbers of cases and controls, allele and genotype frequencies for cases and controls, and genotyping method. Different ethnic descents were categorized as Asian and Caucasian.2 index 2 index >50% for Q-test indicated the existence of notable heterogeneity among the studies We performed the PRISMA checklist as protocol of the meta-analysis and followed the guideline  [46]. ThA total of 72 articles were retrieved by literature search from the PubMed, EMBASE, ISI Web of Science, Cochrane Central Register of Controlled Trials, ScienceDirect, Wiley Online Library, CBM and CNKI databases, using different combinations of key terms. As shown in 2 = 49.59, P<0.01). Previous studies reported the parallel observations There was a distinct variation in the allele frequency of the hsa-miR-196a2 rs11614913C>T polymorphism among the controls across different ethnicities. The C allele frequency of rs11614913C>T polymorphism ranged from 45.27% to 68.60% across Asian and Caucasian controls. In Caucasians controls, the C allele frequency was 68.60%, which was higher than that in Asian controls . As shown in Previous studies suggest that miRNAs participate in crucial biological processes and is considered as a key factor in the oncogenesis. Much research effort has been directed toward understanding the role of SNPs present in precursor and mature miRNA and their influences on gene function or expression, cancer susceptibility, and progression of various diseases. The identification of SNPs is important to help predict individual and population risk and understand the pathogenesis of cancer. Many studies demonstrated that the hsa-miR-196a2 rs11614913 SNP was significantly associated with the susceptibility of various cancers such as lung cancer Several previous meta-analyses have been carried out to reveal the potential associations of the hsa-miR-196a2 rs11614913 polymorphism with overall cancer susceptibility. Xu et al. Some advantages can be highlighted in the current study. Firstly, our study shed light on the association between hsa-miR-196a2 polymorphism and increased risk of lung cancer systematically and comprehensively. Secondly, according to our selection criteria, all included studies in our meta-analysis had acceptable quality and the numbers of cases and controls were collected from all included studies, which significantly increased the statistical power. Thirdly, no evidence of publication bias was observed, indicating that the whole pooled results may be unbiased. Fourthly, our study suggested that functional polymorphism of hsa-miR-196a2 could be conducted and replicate these observations, therefore it could be beneficial to detect novel mechanism to forecast the risk of lung cancer. However, some limitations of this study should be noticed in our meta-analysis at the same time. First, lack of the original data of the including studies limited our further evaluation of the potential interactions, because genetic factors, tumor biological characteristics and their interactions with environmental factors may modulate lung cancer risk. A more precise analysis with an adjustment estimate could be conducted if individual data were available. Second, in this meta-analysis, only published studies were included, ongoing studies and unpublished data were not sought, which may have biased our results. Third, the included case-control studies were carried out from Asians (Chinese and Korean populations) and Caucasians . Therefore, results from this meta-analysis may be applicable only to these ethnic populations.In conclusion, despite the limitation, our meta-analysis suggested that the hsa-miR-196a2 rs11614913 polymorphism may contribute to genetic susceptibility for increased lung cancer risk, especially in Asian populations. The rs11614913 polymorphism could be considerably acted as a candidate biomarker for lung cancer screening, diagnosis and therapy in the future. To confirm our findings, further well-designed studies with large sample size in diverse ethnic populations should be performed to validate the association.Table S1PRISMA 2009 Checklist.(DOC)Click here for additional data file.


Chlamydia (C.) infections are associated with age-related macular degeneration (AMD) and to assess if this association is influenced by the complement factor H (CFH) Y402H or the high temperature requirement A serine peptidase 1 (HTRA1) rs11200638 risk genotypes.To evaluate whether CFH Y402H variant genotype status . Plasma from all patients and controls was tested for C. pneumoniae, C. trachomatis, and C. psittaci IgG seropositivity using a micro-immunofluorescent assay to establish previous infection status. Assays were conducted blind to risk genotypes and the results analyzed using univariate and multivariate (logistic regression) analysis.One hundred ninety-nine AMD patients with early and late forms of the disease and 100 unaffected controls, at least 50 years old were included in the study. Patients in the AMD and control groups were selected based on known C. pneumoniae was most prevalent , followed by C. trachomatis  and C. psittaci . No association was found between each of the three Chlamydia species IgG seropositivity and AMD status or severity (early/late). There was also no significant association between Chlamydia species IgG seropositivity and AMD status or severity, in patients carrying at least one CFH Y402H risk allele (C) or HTRA1 rs11200638 risk allele (A), with univariate or logistic regression analysis.IgG seropositivity to Chlamydia infection status does not appear to be associated with AMD status or severity. The presence of CFH Y402H and HTRA1 rs11200638 risk genotypes does not alter this negative association. Visual impairment and blindness). Environmental and genetic factors play a role in AMD pathogenesis [CFH) [C3) [HTRA1) [CFB) [CFHR1+CFHR3) [CFH Y402H  risk allele (C) in AMD. This increased the risk of AMD significantly  with an estimated population risk of 59% [Age-related macular degeneration (AMD) is the leading cause of severe visual impairment in developed countries ,2, affecogenesis -8. Howevis [CFH) -12, compFH) [C3) , high te [HTRA1) , complem1) [CFB) , and com1+CFHR3) ,17. A prk of 59% .CFH Y402H with AMD is intriguing as the CFH protein is involved in regulating the alternative complement pathway. By binding to C3b, the CFH protein accelerates the decay of the alternative pathway convertase C3bBb, and acts as a cofactor for complement factor I, another C3b inhibitor [Chlamydia species [Chlamydia infection in the presence of abnormal CFH protein production may lead to enhanced alternative complement pathway activation in the retina, therefore increasing an individual’s risk of developing AMD.The association of nhibitor ,20. Acti species -23. ThisChlamydiae include three species that can infect humans: Chlamydia (C.) pneumoniae, C. trachomatis, and C. psittaci. Chlamydiae are obligate intracellular parasites, due to their reliance on host metabolism. They are found in the environment as non-active stable small cells known as elementary bodies (EB). These cells are able to bind to and enter host epithelial cells, forming larger intracellular reticulate bodies (RB). The RB then multiply, deriving energy from host metabolic processes, to form a cytoplasmic inclusion. This inclusion can then release new EBs from the host cell to infect other cells. Typically, Chlamydiae remain in the host on a subclinical level on a prolonged basis [The ed basis .C. pneumoniae causes respiratory tract infections in humans, including pneumonia, bronchitis, pharyngitis, and sinusitis. C. pneumoniae is transmitted airborne, human to human. It is extremely prevalent, with 30%–50% of the population carrying C. pneumoniae antibodies worldwide. Only one species of C. pneumoniae has been described. Chronic infection with C. pneumoniae has been associated with AMD and other degenerative diseases  [pneumoniae with CFH polymorphisms in AMD has not been consistently replicated [clerosis -29, cardclerosis , and mulclerosis ). The asendix 1) -44. In aplicated ,42,45.C. trachomatis can cause a range of diseases in humans, including trachoma, inclusion conjunctivitis, non-gonococcal urethritis, salpingitis, cervicitis, and lymphogranuloma venereum. C. trachomatis is transmitted person to person, including by sexual contact and from mother to baby during delivery. At least 15 antigen-specific species (“serovars”) of C. trachomatis have been described, including B, Ba, C-K, and L1-L3 [C. trachomatis in a general European population aged 15–40 is around 3% [C. trachomatis is endemic in poorer countries, where it is a leading cause of blindness through trachoma. Only one study has investigated the association between C. trachomatis and AMD but found no association [CFH genotype and C. trachomatis in AMD.nd L1-L3 . The preround 3% , but canround 3% . C. tracociation . No studC. psittaci are birds, especially parrots and parakeets. C. psittaci can be transmitted via bird excretions to humans, causing a disease known as psittacosis, which primarily causes atypical pneumonia. At least four serovars of C. psittaci have been described [C. psittaci prevalence in the general population is the least common of the Chlamydia species, but is typically more common in bird handlers [C. psittaci and AMD.The natural hosts for escribed . C. psithandlers . No studChlamydia species  with the CFH Y402H AMD risk variant in AMD. We also investigated the association of the Chlamydia species with another genetic variant strongly associated with AMD, the HTRA1 gene  [Chlamydia.In this study, we investigated the association of all three 38, G→A) . The funPatients were selected from a preexisting database of AMD and control patients. Selection was restricted to those of Caucasian origin, at least 50 years old, and with confirmed genotyping [AMD status was determined according to the Age-Related Eye Disease Study (AREDS) grading system using clinical examination, stereoscopic fundus photographs, and fluorescein angiography (Topcon TRC50IX) . AREDS gCFH Y402H genotype status. In the AMD and control groups, one third of patients carried the homozygous (CC) risk CFH Y402H genotype, one third the heterozygous (CT) genotype, and the remaining one third the wild-type (TT) genotype. This was done to facilitate comparisons between genotypes. DNA was previously extracted using the salting-out method [CFH Y402H [HTRA1 rs11200638 genotype status were determined using TaqMan allelic discrimination assay probe kits on an Applied Biosystems 3730 Genetic Analyzer .Patients were selected based on AMD and t method , and stoFH Y402H  and HTRAChlamydia serology testing. These samples were previously obtained by collecting 10 ml of peripheral blood in lithium heparin tubes. These were then centrifuged within a few hours at 1,300 xg for 10 min, and the supernatant stored at −80 °C until analysis. Defrosted plasma samples were tested for the presence of Chlamydia IgG antibodies toward C. pneumoniae, C. trachomatis, and C. psittaci using a micro-immunofluorescent (MIF) assay kit . MIF is considered the laboratory gold standard for serological testing [Chlamydia infection and although titers do decrease after infection, the rate of decline is minimal.Stored plasma samples were used for  testing . The IgGChlamydia species  of C. trachomatis), diluted in 3% yolk sac (to provide background contrast). The fourth spot was composed of yolk sac alone and acted as a control. Each plasma sample was diluted 1:16 with phosphate buffered saline , and 25 µl added to each well. The slide was covered and incubated at room temperature for 60 min. The slide was then washed with PBS for 10 min to remove unbound plasma antibodies, dipped in distilled water, and then air-dried. Twenty-five µl of fluorescein-labeled anti-IgG antibody was then added to each well. The slide was covered and re-incubated at room temperature for 30 min. The slide was then washed twice (as before). “Mounting medium” (supplied with the kit) was then added to the slide, and wells viewed using a fluorescence microscope at 400× magnification. Positive reactions appeared green, indicating fluorescent EBs on a background of yolk sac . All assays were performed blind to patient AMD CFH/HTRA1 genotype status.The sensitivity and specificity of this test for detecting 2 test (and Fisher Exact test when appropriate) for categorical data. Continuous data was analyzed using the Student t test. Multivariate analysis was performed using binary logistic regression to assess whether covariates  could predict AMD status or severity. The level of statistical significance in the study was defined as p<0.05. When Chlamydia species were compared, a p value of <0.0167 was used to determine statistical significance, taking into account the Bonferroni correction for multiple testing. All statistical analyses were performed using SPSS .One hundred and ninety-nine patients with early and late AMD, and 100 controls without AMD were selected. Univariate analysis of differences between the AMD and control groups were performed using the χC. pneumoniae infection was common (69.2%), whereas C. trachomatis and C. psittaci were less prevalent . There was no difference in age between seropositive and seronegative patients, for C. pneumoniae  and C. trachomatis , although patients seropositive for C. psittaci were older . There was also no difference in age between patients with early versus late AMD  or the presence or absence of the risk allele  to explore any association with Chlamydia seropositivity status and AMD. There was no association with Chlamydia species seropositivity and AMD status or severity in this group  and CFH Y402H genotype (CC versus CT versus TT), C. pneumoniae IgG status was not predictive of AMD status (p=0.842) or AMD severity (p=0.078). The outcome was similar when the presence of the CFH Y402H risk allele (C: present versus absent) was used as a covariate instead of the CFH genotype.Multivariate logistic regression analysis was then performed to identify covariates that could predict AMD status or severity. C. pneumoniae IgG status, age, gender, BMI, CFH Y402H genotype, HTRA1 rs11200638 genotype), logistic regression analysis indicated predictors for AMD status included increased BMI , increased age , female gender , and HTRA1 rs11200638 homozygous (AA) status . Again, C. pneumoniae IgG+ve status (p=0.768) was not a predictor of AMD status.Controlling for multiple variables  were predictors of AMD severity. The only positive association in this model was CFH Y402H heterozygous (CT) status, associated with late AMD .We then performed logistic regression to predict whether these same covariates .In this study, there was no association with C. pneumoniae status with CFH genotype on AMD status. Shen et al. looked at 148 AMD patients and 162 controls, and found an association between C. pneumoniae and AMD , but not when a CFH risk genetic variant was taken into account. However, important differences exist between this study and ours. AMD patients were included if they had late AMD only (geographic atrophy/CNV), C. pneumoniae status was determined with PCR to identify C. pneumonia DNA in peripheral blood cells, and the rs380390 CFH single nucleotide polymorphism was selected as the risk CFH genotype. Furthermore, there was no comparison between AMD subtypes based on severity [C. pneumoniae seropositivity status. They found no association between C. pneumoniae seropositivity and AMD, or between C. pneumonia and the CFH Y402H genotype. This study did not perform further analysis of C. pneumoniae together with CFH genotype status in AMD due to insufficient numbers [C. pneumoniae IgG levels, as measured with ELISA, were at the upper tertile (42.5%) compared to the lower tertile (20.8%). They also found an additive risk of AMD progression in patients with the CFH Y402H risk allele (C) and upper tertile of C. pneumoniae titers  compared to those with T allele and lowest C. pneumoniae titer [Only one previous study has reported a similar retrospective case-control study to ours, examining the association of severity . Haas et numbers . Baird eChlamydia species and AMD, which may be a reflection of the lower prevalence in the developed world. Kayalagu et al. performed a small case-control study looking at serum levels of C. trachomatis heat shock protein in 25 patients with AMD and 13 controls, and found no association [C. psittaci and AMD. Although our study found no association between C. psittaci seropositivity and AMD, the low prevalence highlights the difficulty of studying this microorganism.Far less has been reported on the association of the other two ociation . Our stuChlamydia infection in this study group was higher for all three species compared to published data. This finding may reflect false positives from the MIF assay, or may indicate Chlamydia species prevalence rates are population-specific. PCR does have a higher specificity and sensitivity as a test for Chlamydia species, but was not chosen due to its reliance on the presence of Chlamydia DNA in the peripheral blood. Serological tests enable any previous infection to be detected, which was our aim. Serological techniques include complement fixation, indirect immunofluorescent assays, and ELISAs. The MIF test was chosen since it is considered the “gold standard” of Chlamydia serology testing [Chlamydia antibodies means cross-reactivity does not happen often with MIF but can occur especially between C. psittaci and C. pneumonia due to certain antigenic similarities [The prevalence of previous  testing . Drawbac testing . The uselarities ,56.Chlamydia infection status did not appear to be associated with AMD status or with severity in this study. The presence of CFH Y402H or HTRA1 risk genotypes did not alter this negative association. The negative association reported here is consistent with some previous reports but ideally should be replicated in a larger AMD cohort.In summary,


Genetic and environmental factors are important for the development of nonalcoholic fatty liver disease (NAFLD). Adiponectin is a white and brown adipose tissue hormone, and have been found to play essential roles in the regulation of energy homoeostasis. Recent reports have identified a possible role of adiponectin in NAFLD via PPARγ pathway.The present study was designed to find out the impact of adiponectin rs1501299 (276G/T) and rs266729 (-11377C/G) gene polymorphisms in NAFLD.Eighty-three patients with diagnosis of NAFLD, and 93 healthy subjects were included in the study. Tetra ARMS-PCR was designed to detect single nucleotide polymorphisms.A significant difference was found between NAFLD and control group regarding the rs266729 polymorphism . The rs266729 polymorphism increased the risk of NAFLD in codominant  and dominant  inheritance tested models. The G allele increased the risk of NAFLD  in comparison with C allele. No significant difference was found between the groups concerning adiponectin rs1501299 gene polymorphism .adiponectin rs266729 polymorphism might be a candidate gene, which determines the susceptibility to NAFLD. Larger studies are necessary to confirm these findings in various populations. Nonalcoholic fatty liver disease (NAFLD) is one of the most common forms of chronic liver diseases worldwide . NAFLD iThe gene coding for adiponectin, is officially named ADIPOQ, located on chromosome 3q27, and consists of 3 exons and 2 introns, spanning a total of 16 kb of genomic sequence. Adiponectin contains 244 amino acids, a signal peptide, a collagen-like domain at its N-terminus and a globular domain at its C-terminus, which shares sequence similarities with collagens X and VIII, as well as the complement factor C1q , 31. TheThe present study was aimed to evaluate the possible association between two adiponectin variants, 276 G/T (rs1501299) and –11377 C/G (rs266729), and susceptibility to NAFLD in a southeast Iranian population.This case-control study was conducted in the Departments of Internal Medicine and Biochemistry at Zahedan University of Medical Sciences. The study groups consisted of 83 patients with NAFLD , and 93 healthy participants . The study design and the enrolment procedure have been previously described in detail , 16. NAFIn this study we designed a Tetra amplification refractory mutation system polymerase chain reaction (T-ARMS-PCR) for detection of polymorphisms of adiponectin. This method is simple, rapid and sensitive for the detection of single nucleotide polymorphism , 44. TheStatistical analysis was performed using commercial software . Genotype and allelic frequencies were compared between the groups by chi-squared test. Logistic regression analysis was applied to estimate odds ratio (OR) and 95% confidence intervals (CI) of genetic risk in NAFLD. A p value less than 0.05 was considered statistically significant.2 = 7.35, P = 0.025). The adiponectin rs266729 polymorphism increased the risk of NAFLD in codominant and dominant tested inheritance models . The minor allele frequency (MAF)  of rs266729 polymorphism in NAFLD and controls were 0.356 and 0.253, respectively. A significant difference was found between the groups concerning allele frequency . The rs266729 G allele increased the risk of NAFLD in comparison with C allele . The adiponectin rs266729 polymorphism in controls was in HWE  but in cases was out of HWE .The genotype and allele frequencies of adiponectin -11377C/G (rs266729) gene polymorphisms are shown in 2 = 0.72, P = 0.697). The adiponectin rs1501299 polymorphism was not associated with NAFLD in codominant, dominant, and recessive tested inheritance models . The rs1501299 polymorphism in cases and controls were in HWE .As shown in e models . The MAFIn the current study, we investigated the possible association between adiponectin gene polymorphisms and NAFLD in a sample of Iranian population in the southeast of Iran. We found that rs266729 -11377 G/C) polymorphism increased the risk of NAFLD while there was no association between rs1501299 (+276 G/T) polymorphism and NAFLD in the population. Recently, a growing number of studies have evaluated the impact of adiponectin gene polymorphisms on NAFLD in different populations , 39. Gup377 G/C p


The correlation between xeroderma pigmentosum group D (XPD) polymorphisms (Lys751Gln and Asp312Asn) and clinical outcomes of non-small cell lung cancer (NSCLC) patients, who received platinum-based chemotherapy (Pt-chemotherapy), is still inconclusive. This meta-analysis was aimed to systematically review published evidence and ascertain the exact role of XPD polymorphisms.Databases of MEDLINE and EMBASE were searched up to April 2013 to identify eligible studies. A rigorous quality assessment of eligible studies was conducted according the Newcastle-Ottawa Quality Assessment Scales. The relationship between XPD polymorphisms and response to Pt-chemotherapy and survival was analyzed.A total of 22 eligible studies were included and analyzed in this meta-analysis. The overall analysis suggested that the XPD Lys751Gln polymorphism was not associated with response to Pt-chemotherapy or survival. However, the XPD 312Asn allele was significantly associated with poor response to Pt-chemotherapy compared with the Asp312 allele . Additionally, the variant genotype of XPD Asp312Asn polymorphism was associated with favorable survival in Caucasian  but unfavorable survival in Asian .These results suggest that XPD Asp312Asn polymorphism may function as a predictive biomarker on platinum-based chemotherapy in NSCLC and further studies are warranted. Lung cancer is the leading cause of cancer related death worldwide The cytotoxicity effect of platinum compounds, such as cisplatin and carboplatin, is due to the formation of platinum-DNA adducts that leads to bulky distortion of DNA, destabilization of the double helix, inhibition of DNA replication, transcription and ultimately death of tumor cells. It has been hypothesized that suboptimal DNA repair capacity may lead to decreasing removal of platinum-DNA adducts, and eventually favorable clinical outcomes Nucleotide excision repair (NER) is the major pathway for the removal of bulky DNA adducts Thus, by identifying all eligible studies, we performed this meta-analysis to re-evaluate the relationship between XPD polymorphisms (Lys751Gln and Asp312Asn) and clinical outcome  in NSCLC patients treated with Pt-CP.This meta-analysis was conducted and reported in accordance with the PRISMA guidelines for systematic reviews and meta-analyses  NSCLC patients; 2) patients treated with Pt-CP; 3) reporting relationship between XPD polymorphisms and response or survival; 4) available data for quantitative synthesis, namely genotype distribution data for response and hazard ratio (HR) and 95% confidence intervals (CIs) for overall survival (OS). Studies without available data were excluded. For multi-reports from the same center, only the most recent one was included. All searching records were screened by two authors (Qiu and Yang), with discrepancies solved by discussion with another author (Yin).Response to Pt-chemotherapy and overall survival were the primary outcomes in this meta-analysis. Response to chemotherapy was assessed with RECIST criteria Data of eligible studies were extracted by two authors (Qiu and Yang) independently in duplicate with a pre-designed data collection form. The two authors reached consensus on each item. The following data was collected, name of first author, year of publication, country, ethnicity, chemotherapy regimens,number of patients, TNM stages, age, percentage of male, SNPs investigated, genotype distribution data among responders and non-responders and HR and corresponding 95% CIs of OS. For OS, we collected HR and CIs of each comparison. Ethnicity descents were simply categorized as Asian or Caucasian. The two authors reached consensus on each item.Methodological quality of included studies was assessed with the Newcastle-Ottawa scale (NOS) for cohort studies Pooled odds ratio and 95% CIs were calculated to estimate the association strength of XPD polymorphisms with overall response rate. The 95% CIs were utilized for statistical significance test and a 95% CI without 1 suggested significant difference. For ORR, 5 genetic comparison models were analyzed . The genotype distribution data was directly used to estimate the pooled ORs and 95% CIs of ORR. For OS, HRs and CIs retrieved from each study were calculated to estimate the pooled HRs and 95% CIs. Also, the 95% CIs pooled HRs were used for statistical test. Pooled HRs for homozygote comparison, heterozygote comparison and dominant model were calculated.Heterogeneity was measured by chi-square based Q test, and p<0.10 indicated the existence of significant heterogeneity All statistical analyses were carried out with STATA software . All p values are two-side.Overall, 1367 records were identified by a primary search of databases and reference lists. After screening of titles and abstracts, a total of 39 full-text articles were retrieved for further evaluate the eligibility. Finally, 22 eligible studies were identified and included in this meta-analysis according to our inclusion and exclusion criteria Baseline characteristics of eligible studies were shown in All included studies were assessed with the NOS quality scale, and the detail quality score could be found in (heterogeneity = 0.064). There was no significant association of XPD Lys751Gln polymorphism with response in the sub-group of GP chemotherapy. No evidence of publication bias was detected.Fourteen studies, including 2241 NSCLC patients, were pooled to estimate the association strength of Lys751Gln polymorphism with response. In overall analysis, the Lys751Gln polymorphism was not associated with response rate in any of the 5 comparison models . Sub-groheterogeneity = 0.017; heterogeneity = 0.630; heterogeneity = 0.194; A total of 9 studies with 1145 individuals were included the analysis for Asp312Asn polymorphism and response. As showed in heterogeneity = 0.288) or dominant model . In sub-group analyses, we did not observe any significant association among Asian or Caucasian. The Lys751Gln polymorphism was not associated with OS of patients with GP chemotherapy. No evidence of publication bias was detected.OS and XPD Lys751Gln polymorphism was reported in 10 studies. By pooling all eligible studies, the Lys751Gln polymorphism was not associated OS in heterozygote comparison  was observed. The XPD Asp312Asn polymorphism was associated with favorable OS in Caucasian population but unfavorable OS in Asian population.It has been well documented that platinum agents block DNA replication and lead to tumor cell death by forming DNA-platinum adducts. DNA repair capability is a key factor that modulates sensitivity to platinum. The XPD gene encodes an ATP-dependent 5′–3′ helicase, a subunit of the basal transcription factor IIH (TFIIH) complex that is required for separation of the double helix during NER. Evidence has suggested that XPD overexpression leads to cisplatin resistance In the present meta-analysis, we showed that the XPD 312Gln allele was associated with poor response to Pt-chemotherapy. Our results were in consistence with a recent meta-analysis The strength of the present analysis lies in inclusion of 22 eligible studies. To minimize bias, we excluded studies that include patients receiving surgery or radiotherapy. Publication bias was not detected in our meta-analysis. However, limitation of this meta-analysis should also be noted. First, all data analyzed were directly extracted from original articles, and the data reported by each study differed significantly. No sufficient data were available to perform further stratified analyses, such as smoking, gender, chemotherapy regimens, performance status and follow up. Second, the number of studies included in each subgroup was small, especially for sub-group analysis of XPD polymorphisms and OS. Third, toxicity is an important issue of Pt-chemotherapy. Due to the fact that few studies have reported the correlation between XPD polymorphisms and toxicity, we did not analyze toxicity profiles.To summary, in the present meta-analysis we found that XPD Lys751Gln polymorphism was not associated with clinical outcomes of Pt-chemotherapy in NSCLC, while the XPD Asp312Asn polymorphism could predict poor response to Pt-chemotherapy, favorable survival in Caucasian but unfavorable survival in Asian population. Further studies with large sample size are warranted to validate these conclusions.Table S1PRISMA checklist.(DOC)Click here for additional data file.Table S2Quality assessment of eligible studies with Newcastle-Ottawa Scale.(DOCX)Click here for additional data file.


Human telomeres, tandem repeats of TTAGGG nucleotides at the ends of chromosomes, are essential for maintaining genomic integrity and stability. Results of previous epidemiologic studies about the association of telomere length with risk of colorectal cancer (CRC) have been conflicting.A case-control study was conducted in a Han population in Wuhan, central China. The relative telomere length (RTL) was measured in peripheral blood leukocytes (PBLs) using quantitative real-time polymerase chain reaction (PCR) in 628 CRC cases and 1,256 age and sex frequency matched cancer-free controls. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using unconditional logistic regression models to evaluate the association between RTL and CRC risk.Ptrend = 0.045; OR per quartile = 1.12, 95%CI: 1.03–1.23, Ptrend = 0.012). In stratified analyses, significant association between shorter RTL and increased CRC risk was found in females, individuals younger than 60 years old, never smokers and never drinkers.Using median RTL in the controls as the cutoff, individuals with shorter RTL were associated with a significantly increased risk of CRC . When participants were further categorized into 3 and 4 groups according to the tertile and quartile RTL values of controls, significant relationships were still observed between shorter RTL and increased CRC risk (OR per tertile = 1.13, 95%CI: 1.00–1.28, This study suggested that short telomere length in PBLs was significantly associated with an increased risk of CRC in Chinese Han population. Further validation in large prospective studies and investigation of the biologic mechanisms are warranted. Human telomeres are tandem repeats of TTAGGG nucleotides that cap the ends of the eukaryotic chromosome armsRb and/or p53 signal pathways will be triggered to initiate cellular senescence or apoptosisWhen telomeres shorten to a critical length, they become dysfunctional, and Several epidemiological studies have evaluated the relationship between telomere length and risk of cancers, but the results are inconsistent. Some investigations have demonstrated that shorter telomere length in PBLs is associated with increased risk of several cancers including lung, bladder, gastric, esophageal, ovarian, head and neck and renal cancerTERC. Studies above were all restricted to Europeans. Cui and colleaguesAbout CRC, results from previous studies have been conflicting. Three studiesThe study population consisted of 628 newly diagnosed CRC cases and 1256 cancer-free controls. Subject recruitment and data and specimen collection methods have been described previously36B4 on chromosome 12). The real-time PCR was conducted on an ABI 7900HT Sequence Detection System (Applied Biosystems). The PCR reaction mixture (10 µL) for the telomere or 36B4 amplification consisted of 1 X SYBR Green Master Mix (Toyobo), 300 nmol/L each telomere or 36B4 specific primers, and 5 ng genomic DNA. The thermal cycling conditions for both telomere and 36B4 were 95°C for 10 minutes to activate Taq-polymerase followed by 40 cycles of denaturation at 95°C for 15 seconds and annealing-extension at 60°C for 1 minute. The primer sequences for both PCR reactions have been previously publishedCt) values and the R2 correlation for each standard curve was ≥0.98. If the result was out of the acceptable range, then the run was repeated for the same sample. For testing intra- and inter-plate variation, the coefficients of variation (CVs) for the T/S ratio of the reference DNA at the 5 ng point were calculated. And the intra- and inter-plate CVs were 4.6% and 8.9%, respectively.Genomic DNA was isolated from participants' PBLs using the Relax Gene Blood DNA System DP319-02  according to the manufacturer's protocol. The RTL of each DNA sample was measured using a unified real-time quantitative PCR protocol originally described by Cawthont-test for continuous variables. RTL data were natural log-transformed so that these data were approximately normally distributed. RTL was analyzed as categorical variable based on the cut-off points at the median, tertile, and quartile value among controls. ORs and 95% CIs were calculated using unconditional logistic regression models to estimate the association between RTL and CRC risk. By treating the level of telomere length as a continuous variable, tests for trend were calculated. Adjusted analyses included terms for age, sex, smoking status and alcohol use. Stratified analyses were conducted to evaluate potential interactions between demographic factors and RTL on CRC risk. The power of our sample size was calculated to be 0.87 to detect a trend in ORs with decreasing quartiles of RTL assuming an OR of 1.4 comparing the lowest and highest quartiles, at an alpha of 0.05. All statistical analyses were performed using SPSS software 12.0  and all P values were tested two-tailed with a significant level at 0.05.The differences in the distribution of baseline characteristics between cases and controls were compared using the chi-square test for categorical variables, and the Student's P = 0.952). More smokers and drinkers were observed in cases than in controls (P<0.001).The baseline characteristics of the study participants were shown in Ptrend = 0.045). When the third (longest) tertile was used as the reference group, the adjusted OR for the second and first group were 1.66 (95%CI: 1.30–2.11) and 1.32 (95%CI: 1.03–1.69), respectively. Similarly, when participants were further categorized into 4 groups according to quartile values of RTL in controls, we also observed a significant relationship . When the fourth (longest) quartile was used as the reference group, the adjusted ORs for the third, second, and first quartiles were 1.77 (95%CI: 1.32–2.38), 2.05 (95% CI: 1.54–2.74), and 1.47 (95%CI: 1.09–1.99), respectively.We estimated the association between RTL and the risk of CRC by unconditional logistic regression analysis, through treating RTL as a categorical variable based on a cut off value of median, tertile and quartile distribution in controls. As shown in Stratified analyses were conducted to evaluate the potential modulating effect of each host variables. We found a significant association between shorter RTL and increased CRC risk in females  and individuals younger than 60 years old , but not in males and participants older than 60 years old . SignifiIn the current study, we investigated the association between telomere length in PBLs and the risk of CRC. We found that short telomere length was significantly associated with an increased risk of CRC in Chinese Han population. Further stratified analyses revealed that the association was significant in women, individuals younger than 60 years old, never smokers and never drinkers.Mixed findings have been identified from the numerous studies that have extensively investigated the relationship between altered telomere length and cancer risk, and the association appears to be cancer type-dependentAbout the association between leukocyte telomere length and CRC risk, results of previous studies were conflicting. Pooley and colleaguesp53TERT on activation by inflammatory stimuli potentially linked to short telomere lengthSignificant association between short telomere length and increased CRC risk observed in our study is biologically plausible. Various experiments and genetic studies support such a hypothesis that telomere attrition leads to the manifestation and dissemination of malignanciesSome limitations in this study need to be addressed. First, the sample size of our study for some stratified analyses remains relatively small, resulting in the relatively inadequate statistical power. Second, although we only included newly diagnosed CRC patients before any treatments, which may reduce the possible influence of disease status and treatment on telomere length, we could not completely get over the inherited limitation of “reverse causation” in a retrospective case-control study. Third, telomere length was only measured in leukocytes from peripheral blood and not in colorectal tumor tissues; however, leukocyte telomere length has been demonstrated to be correlating highly with that in cells from other tissuesIn conclusion, this study suggested that short telomere length in PBLs was significantly associated with an increased risk of CRC in Chinese Han population. Further validation in large prospective studies and investigation of the biologic mechanisms are warranted.


IL28B polymorphisms were shown to be strongly associated with the response to interferon therapy in chronic hepatitis C (CHC) and spontaneous viral clearance. However, little is known about how these polymorphisms affect the natural course of the disease. Thus, we conducted the present meta-analysis to assess the impact of IL28B polymorphisms on disease progression.A literature search was conducted using MEDLINE, EMBASE, and the Cochrane Library. Integrated odds ratios (OR) were calculated with a fixed-effects or random-effects model based on heterogeneity analyses.We identified 28 studies that included 10,024 patients. The pooled results indicated that the rs12979860 genotype CC was significantly associated , and that the rs8099917 genotype TT tended to be  associated, with an increased possibility of severe fibrosis. Both rs12979860 CC  and rs8099917 TT  were significantly associated with a higher possibility of severe inflammation activity. Rs8099917 TT was also significantly associated with a lower possibility of severe steatosis , whereas rs12979860 CC was not associated with hepatic steatosis .IL28B polymorphisms appeared to modify the natural course of disease in patients with CHC. Disease progression seems to be promoted in patients with the rs12979860 CC and rs8099917 TT genotypes. Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC) Currently, patients with CHC are treated with a combination of peg-interferon (peg-IFN) and ribavirin Polymorphisms of genes involved in innate immunity are likely to influence the strength and nature of this defense system Thus, we conducted the present meta-analysis to integrate the results of eligible studies and provide statistically reliable evidence of the role of IL28B polymorphisms in patients with CHC.IL28B, IL28, IL-28B, interleukin-28B, interleukin 28B, rs12979860, and rs8099917. The search was limited to the English language.An electronic search was conducted in MEDLINE, EMBASE, and the Cochrane Library for articles published prior to 30 April, 2012. Search terms included A study was included in the current analysis if it satisfied the following criteria: (1) It evaluated the associations between IL28B polymorphisms (rs12979860 or rs8099917) and liver fibrosis, inflammation activity, or steatosis. We also included studies that evaluated fibrosis or inflammation activity using the aminotransferase platelet ratio index or ALT. (2) It provided sufficient published data for estimating odds ratios (OR) with 95% confidence intervals (CIs). In case of multiple studies based on the same population, we selected the study with the largest number of participants. A study was excluded if (1) it dealt only with co-infection of HCV and human immunodeficiency virus, (2) it dealt only with patients with a specific condition such as a comorbid disease  or status after liver transplantation, or (3) it only used a recessive hereditary model .Two authors (M.S. and M.K.) independently screened titles and abstracts for potential eligibility and full texts for final eligibility. Disagreements were resolved by consultation with a third author (R.T.). The following information was extracted or calculated from each study: first author, year of publication, country of origin, ethnicity, sex, HCV genotype, and background liver information  for each genotype. The analysis was based on the dominant model .In some studies, mild or severe fibrosis or inflammation activity was not defined. To compare results among studies on these outcomes, we defined Ishak level F4 to F6; METAVIR, Ludwig Batts, and Inuyama level F3 to F4; and Knodell histology activity index as severe fibrosis. We also defined METAVIR A2 to A3 as severe inflammation activity.2 statistics interpreted as the proportion of total variation contributed by between-study variation 2<50% and P>0.05), the ORs and 95% CIs were calculated by the fixed-effects model. Otherwise, the random-effects model was adopted. When significant heterogeneity was observed, we performed a meta-regression analysis to investigate relationships between the effect of IL28B polymorphisms on liver fibrosis, inflammation activity, or steatosis; and continuous variables  to explore the possible reason for heterogeneity between studies The association of liver fibrosis, inflammation activity, or steatosis with the IL28B genotype in patients with CHC was assessed by summary ORs and corresponding 95% CIs. Heterogeneity among studies was examined with I2 = 25%, P = 0.147); thus, the fixed-effects model was applied. The pooled results indicated that IL28B rs12979860 genotype CC was associated with an increased possibility of severe fibrosis  , and IL28B rs8099917 genotype TT tended to be associated with a higher possibility of severe fibrosis; however, the difference did not reach statistical significance   and rs8099917 . For rs12979860, fixed-effect model analyses showed a higher probability of severe fibrosis in genotype CC   . For rs8= 0.076) . Egger's= 0.010) , and for= 0.010) . Egger's2 = 35%, P = 0.204) for rs12979860. In the fixed-effects model, the pooled results indicated that IL28B rs12979860 genotype CC was associated with a higher possibility of severe inflammation activity  , and IL28B rs8099917 genotype TT was also associated with a higher possibility of severe inflammation activity  ; thus, the random-effect model was applied. The pooled results indicated that IL28B rs12979860 genotype was not associated with inflammatory activity  . In the fixed-effects model, genotype TT tended to be associated with a higher possibility of severe inflammation activity  (The between-study heterogeneity was not significant (I= 0.015) . For rs8= 0.002) . Egger's= 0.108) . For rs8= 0.079) . Egger's2 = 86%, P<0.001) and rs8099917 ; thus, we applied the random-effects model for this outcome. The pooled results indicated that IL28B rs12979860 genotype CC was not associated with hepatic steatosis   and rs8099917 . For rs12979860, fixed-effect model analyses showed that rs12979860 genotype CC was significantly associated with a higher possibility of severe steatosis  (Significant heterogeneities were found for rs12979860 (I= 0.901) , whereas= 0.901) . Egger's= 0.901) . Finally= 0.032) , whereas= 0.032) . Egger'sIn the present study, we evaluated the association between IL28B polymorphisms and the background liver disease  in patients with CHC. The rs12979860 CC genotype was significantly associated with a higher probability of severe fibrosis , and theThe rs12979860 CC and rs8099917 TT genotypes were also associated with a higher possibility of severe inflammation activity. Genetic variations near the IL28B gene were originally reported as strong predictors of a sustained viral response IL28B polymorphisms were also shown to be associated with lipid metabolism According to the meta-regression analysis, the effect of rs8099917 polymorphisms on steatosis became smaller with the increase in the male proportion , suggestThe rs738409 genotype within the patatin-like phospholipase domain containing 3 locus was also reported to be associated with hepatic steatosis in patients with CHC In the present study, we included studies that did not report the associations between IL28B genotypes and background liver diseases as study outcomes, but provided raw data that allowed us to calculate the OR for each outcome, which may have minimized potential publication bias. In fact, no publication bias was observed in the present study. The Human Genome Epidemiology Network highlighted the necessity of meta-analysis before evidence for a particular association can be regarded as strong A potential limitation of this study is inter-study variability in the outcome measure and the definition of “severe” among studies, where some discrepancies among studies exist. The studies without a pathological diagnosis, using laboratory data as surrogates, were also included. These studies may have diminished the accuracy of our research results concerning liver disease severity.In conclusion, the present study highlighted the impact of IL28B polymorphisms on liver fibrosis, inflammation activity, and steatosis in patients with CHC. Disease progression appeared to be promoted in patients with rs12979860 CC or rs8099917 TT genotypes. The current findings may provide clinically important information in the follow-up of patients with CHC.Checklist S1PRISMA 2009 Checklist.(DOC)Click here for additional data file.