Association of T2DM Genetic Variants in GDM
Based on the findings that GDM women are at high risk of T2DM and both GDM and T2DM share similar pathophysiologies, it is reasonable to assume that they might also share similar genetic risk factors. Soon after the initial reports of T2DM genome-wide association (GWA) studies [18-21], several studies investigated whether genetic variants that were identified through GWA studies of T2DM were also associated with the risk of GDM [22, 23]. Cho et al. [22] 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 × 10-6). 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 T2DM variants are compared among a control group (n = 632, men : women = 287 : 345), T2DM 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 T2DM and from T2DM to GDM. Lauenborg et al. [23] 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 T2DM GWA study, were also significantly associated with the risk of GDM in Koreans (p < 0.05) [25]. Recently, it was reported that TPH1 and HTR2B play a crucial role in regulating pancreatic β-cell mass during pregnancy in a mouse model and that their genetic alterations could result in GDM [17]. A total 6 genetic variants in HTR2B and 11 variants in TPH1 were identified and genotyped in Korean GDM women and control subjects [26]. 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 [26].