The type 2 diabetes genetic risk variant TCF7L2 rs7903146 is differentially associated with gestational diabetes: Differences between central and Mediterranean Europeans

Abstract

Background and aims: Single nucleotide polymorphisms (SNPs) within the transcription factor 7-like 2 (TCF7L2) gene are well known risk variants for type 2 diabetes. The best studied SNP is rs7903146, which is additionally associated with insulin secretion and BMI. Here we assess and compare the effect of this TCF7L2 risk variant on the development of gestational diabetes mellitus (GDM) in two populations of women of German and Greek origin. Materials and methods: We genotyped the C/T polymorphism of the TCF7L2 gene variant rs7903146 in 96 unrelated women with a history of GDM (Greek n=50, German n=46), and in 93 women with type 2 diabetes mellitus (DM2) (Greek n= 43, German n=50) and in 155 non-diabetic pregnant women (Greek n=80, German n=75) as controls. The prevalences of non-risk CC, and risk TT alleles in the three groups were compared for Greek and German patients, both in combined and in separate country specific analysis sets. Results: In the combined analysis sets of GDM vs non-diabetic pregnant women, the TT genotype of the TCF7L2 gene variant rs7903146 was significantly associated with an increased risk of GDM as compared to the non-risk CC allele [p=0.011; Odds Ratio (OR)=3.17; 95%CI=1.318-7.665]. This risk association was particularly strong and driven by the Greek cohort [p=0.043; OR=3.39; 95%CI=1.097-10.49], while a much weaker association was observed in the German cohort [p=0.13; OR=3.26; 95%CI=0,72-14,7]. The CT genotype was similarly represented in both GDM and non-diabetic pregnant women, with no significant difference between German and Greek cohorts [p=0.83]. No significant differences were detected between the GDM and DM2 groups when comparing the presence of TT and CC genotype [OR = 1; p=1; 95%CI= 0.45-2.5]. As control, we found an association between TT genotype and DM2 when comparing both control groups [p=0.029; OR= 2.96; 95% CI=1.19-7.34]. Conclusion: Our data suggest significant variability of GDM risk conferred by the TCF7L2 rs7903146 TT allele even within two European populations of primary Caucasian origin. This novel observation could imply a much higher influence of the genetic background within the same ethnicity on the TCF7L2 associated risk for GDM than previously thought.