gestational diabetes mellitus ( gdm ) is defined as abnormal glucose tolerance that is first identified or diagnosed during pregnancy .
it is estimated that approximately 2% to 5% of all pregnancies in korean women are complicated by gdm .
the clinical significance of gdm is that it increases the risk of adverse pregnancy outcomes . in a recent large - scale multinational prospective study ,
increased maternal glucose concentration during pregnancy was significantly associated with increased neonatal birth weight , primary cesarean delivery , neonatal hypoglycemia , and increased placental c - peptide levels .
after parturition , about 15% of gdm women had persistent diabetes at an early postpartum period of 2 months .
women with a previous history of gdm are at increased risk of future development of type 2 diabetes mellitus ( t2 dm ) .
the risk of t2 dm is 3.5 times greater in women with a history of gdm compared to the general population in koreans .
in addition , offspring of gdm women are also at risk of developing obesity and t2 dm .
the incidence of gdm is expected to rise , as it will parallel the increasing rate of obesity and t2 dm .
furthermore , the recent recommendation from the international association of diabetes and pregnancy study group has lowered the diagnostic threshold of gdm and is expected to increase the incidence of gdm .
gdm women have an increased positive family history of t2 dm . compared to pregnant women with normal glucose tolerance ,
gdm women have a significantly greater parental history of t2 dm ( 13.2% vs. 30.1% , p < 0.001 ) .
in addition , both gdm women and their offspring are at increased risk of future development of t2 dm . the heritability estimate of t2 dm was reported to be quite high ( h = 0.69 ) in a recent study performed in europeans .
these findings are indirect evidence that gdm has familial tendency . however , there is no study that has specifically evaluated the heritability of gdm using familial clustering or twins
. it would be important to estimate the heritability of gdm and compare it with that of t2 dm in women .
during normal pregnancy , women experience increased adiposity and weight gain , which begin near mid - pregnancy and progress throughout the third trimester . in this period , insulin resistance ensues as a consequence of multiple factors , including increased production of placental growth hormone , estrogen , and tumor necrosis factor  [ 14 , 15 ] .
pregnant women with normal glucose tolerance can increase their -cell insulin secretion in response to this increased insulin resistance during pregnancy .
although the mechanism of increased -cell insulin secretion during pregnancy is not fully understood , it is reported that prolactin , which increases during pregnancy , can repress islet menin levels and stimulate -cell proliferation in mice .
in addition , recent reports suggest that -cell serotonin signaling is also a major determinant of -cell mass during pregnancy .
it has been suggested from several clinical studies that gdm women have limited insulin secretion capacity that can not compensate for the increased insulin resistance .
similar to gdm , t2 dm is also characterized by relative deficiency in insulin secretion in the face of increased insulin resistance .
various factors , including increased age , obesity , high - fat diet , and sedentary lifestyle , can induce insulin resistance , and those who do not have sufficient -cell insulin secretory capacity are more likely to develop t2 dm .
therefore , it is said that a large proportion of gdm women are experiencing future t2 dm in advance .
based on the findings that gdm women are at high risk of t2 dm and both gdm and t2 dm share similar pathophysiologies , it is reasonable to assume that they might also share similar genetic risk factors .
soon after the initial reports of t2 dm genome - wide association ( gwa ) studies [ 18 - 21 ] , several studies investigated whether genetic variants that were identified through gwa studies of t2 dm were also associated with the risk of gdm [ 22 , 23 ] .
genotyped variants in or near cdkal1 , cdkn2a/2b , fto , hhex , igf2bp2 , slc30a8 , tcf7l2 , kcnj11 , and pparg in 869 gdm women and 632 carefully selected nondiabetic control subjects .
they found that genetic variants in cdkal1 and cdkn2a/2b were highly associated with the risk of gdm ( p < 1  10 ) .
in addition , variants in hhex , igf2bp2 , slc30a8 , and tcf7l2 were all nominally associated with gdm ( p < 0.05 ) . among a total of 18 genetic variants studied , 9 reached a nominal significance level ( p < 0.05 ) . in fig .
1 , the risk allele frequency as well as the odds ratios of known t2 dm variants are compared among a control group ( n = 632 , men : women = 287 : 345 ) , t2 dm group ( n = 761 , men : women = 354 : 407 ) , and gdm group ( n = 869 ) in koreans [ 22 , 24 ] . for most of the variants ,
there was an increasing trend of risk allele frequencies from control to t2 dm and from t2 dm to gdm .
.   also found that variants in tcf7l2 , cdkal1 , and tcf2 were significantly associated with the risk of gdm in europeans , consisting of 283 gdm women and 2,446 glucose - tolerant control women .
variants in kcnq1 , which were first identified in an east asian t2 dm gwa study , were also significantly associated with the risk of gdm in koreans ( p < 0.05 ) .
recently , it was reported that tph1 and htr2b play a crucial role in regulating pancreatic -cell mass during pregnancy in a mouse model and that their genetic alterations could result in gdm .
a total 6 genetic variants in htr2b and 11 variants in tph1 were identified and genotyped in korean gdm women and control subjects .
although there were no significant associations of these variants with the risk of gdm , they were associated with measures of obesity and weight gain during pregnancy .
following these candidate approach studies was a two - staged gwa study that was performed in korean gdm women .
a total of 468 gdm women and 1,242 nondiabetic control women were genotyped using affymetrix genome - wide human snp array 5.0 .
variants that passed the prespecified p - value threshold in the stage 1 genome scan were further genotyped in 931 gdm women and 783 nondiabetic control women .
two variants , one located in an intron of cdkal1 ( rs7754840 ) and one near mtnr1b ( rs10830962 ) , were associated with a risk of gdm at a genome - wide significance level ( p = 6.65  10 and p = 2.49  10 , respectively ) .
although variants in mtnr1b have been previously reported to be associated with increased fasting glucose levels , the study was the first to report that mtnr1b variants are associated with gdm at a genome - wide significance level .
one of the limitations was that it was not sufficiently powered to find truly novel genetic variants that were only specific in gdm .
it should be noted that current gwa and gwa meta - analysis performed in t2 dm recruits more than 100,000 cases and controls .
one of the interesting findings was that genetic variants of t2 dm were enriched in gdm subjects . among
the 34 confirmed t2 dm genetic variants , 8 were associated with a risk of gdm .
in addition , when the -coefficients ( or odds ratio ) of the variants derived from the logistic regression were compared between gdm and t2 dm , there was a significant positive correlation of -coefficients between the two .
these findings suggest that gdm and t2 dm might share similar genetic backgrounds , at least in part .
gwa studies have opened a new era in diabetes research . our knowledge on the genetic predisposition of gdm as well as t2 dm
is expected to increase even faster as next - generation sequencing technology is applied to this field .
there should be even larger gwa studies on gdm , and gwa meta - analyses should be available . in this way , we could find variants that have smaller effect sizes but are more specific to gdm than t2 dm . in order to understand the genetic determinants of glucose and insulin concentration during pregnancy ,
a fast way is to see whether genetic variants that are known to affect glucose or insulin concentration in the normal population also affect glucose or insulin concentration during pregnancy .
in addition , a gwa study on glucose or insulin concentration during pregnancy should also be helpful .
in this way , we would be able to better understand the pathophysiology of gdm . by definition
, gdm encompasses women with pre - exiting t2 dm , maturity onset diabetes of the young ( mody ) , or even type 1 diabetes patients that were not diagnosed previously .
in particular , about 15% of gdm patients remain diabetic at early postpartum periods , and a significant portion of these subjects might fall into the category of mody .
the contribution of genetic variants known to cause mody , such as gck and hnf1a , in gdm has been reviewed in recent literature .
however , whole - exome sequencing will provide us with better bird 's eye view on the contribution of mody genes in gdm .
in addition , it might be able to find novel mody genes in those who have persistent diabetes after gdm pregnancy and also have a strong family history of diabetes .
one of the first steps in translating the genetic information into clinical practice would be to predict the future development of t2 dm in gdm women .
gdm women are at particularly high risk of developing t2 dm and require preventive measures and early screening of t2 dm .
genetic information might improve our prediction of t2 dm in women with a history of gdm .
this is an area of active research [ 31 , 32 ] , and we are looking forward to studies that use genotype risk scores in predicting t2 dm in gdm women
. a similar approach could also be applied in predicting gdm , as more genetic variants associated with gdm are expected to be revealed .
the functional consequences of the current common genetic variants identified through gwa studies of gdm are not well understood yet .
it is not known whether they are markers in linkage disequilibrium with nearby causal variants or whether they have unknown but relevant functional roles .
next - generation sequencing might give answers to these questions , but a huge number of samples and much effort will be required .
gdm women are at increased risk of developing t2 dm and have familial clustering of t2 dm . a common pathophysiology that is shared by gdm and t2 dm is impaired compensatory increase in insulin secretion to overcome the increased insulin resistance .
the gwa study of gdm enabled us to investigate the common genetic risk factors of gdm , and it revealed that gdm and t2 dm share similar genetic backgrounds , at least in part ( fig .
although this information has significantly improved our insight in the pathogenesis of gdm , there are more unanswered questions remaining that should be explicitly expressed . using the technology of next - generation sequencing
in addition , we hope that personalized genomic medicine could be available using the advances in the genetics of gdm and t2 dm .
 gestational diabetes mellitus ( gdm ) is a complex metabolic disorder of pregnancy that is suspected to have a strong genetic predisposition . 
 it is associated with poor perinatal outcome , and both gdm women and their offspring are at increased risk of future development of type 2 diabetes mellitus ( t2 dm ) . during the past several years 
 , there has been progress in finding the genetic risk factors of gdm in relation to t2 dm . 
 some of the genetic variants that were proven to be significantly associated with t2 dm are also genetic risk factors of gdm . recently , 
 a genome - wide association study of gdm was performed and reported that genetic variants in cdkal1 and mtnr1b were associated with gdm at a genome - wide significance level . 
 current investigations using next - generation sequencing will improve our insight into the pathophysiology of gdm . 
 it would be important to know whether genetic information revealed from these studies could improve our prediction of gdm and the future development of t2 dm . we hope further research on the genetics of gdm would ultimately lead us to personalized genomic medicine and improved patient care . 