rs10946398

Association analysis of 31 GWAS-confirmed type 2 diabetes SNPs in 3,089 Indian sib pairs (2,528 for quantitative traits, 561 for diabetes) identified significant associations with intermediate traits: CDKAL1 rs7756992, TCF7L2 rs7903146 and rs12255372 with fasting glucose (β=0.009-0.01, p≤0.01); ADAM30 rs2641348, NOTCH2 rs10923931, TCF-2/HNF1B rs757210, and CDKN2A/B rs10811661 with fasting insulin and HOMA-IR (β=±0.05-0.09, p≤0.05); and THADA rs7578597 with type 2 diabetes (OR 1.5, p=0.03).

The HERITAGE Family Study examined eight type 2 diabetes susceptibility variants in 481 sedentary individuals undergoing 20-week endurance training. PPARG rs1801282 (Pro12Ala) was the only significant finding: Ala carriers showed greater improvements in glucose tolerance (p=0.0008), glucose effectiveness (p=0.004), and disposition index (p=0.003) in response to exercise training, though no associations were found with other recently identified GWAS variants.

This association study of 4,213 Danish individuals examined 25 type 2 diabetes risk variants and their association with birthweight. The study found that type 2 diabetes risk alleles near ADCY5 (rs11708067, β = -33 g, p = 0.004), CDKAL1 (rs7756992, β = -22 g, p = 0.04), and HHEX-IDE (rs1111875, β = -16 g in meta-analysis, p = 8×10⁻⁵, n = 25,164) were associated with reduced birthweight, supporting the fetal insulin hypothesis. Meta-analyses confirmed these associations and showed no strong general effect on birthweight from the 25 common type 2 diabetes risk alleles combined.

This study tests the thrifty genotype hypothesis by examining 17 confirmed type 2 diabetes susceptibility loci and 13 obesity-susceptibility loci for signatures of positive selection. Using ancestral/derived allele analysis, integrated haplotype scores (iHS), and population differentiation (FST), the authors found limited evidence supporting the thrifty genotype hypothesis. Only rs7901695 at TCF7L2 showed notably elevated FST values (0.579 between JPT+CHB and YRI populations), and FTO showed the strongest selection signal among obesity loci (iHS=1.991).

The D.E.S.I.R. prospective cohort study (N=4,707) validated 22 SNPs from genome-wide association studies for type 2 diabetes effects on glucose homeostasis. Risk alleles in SLC30A8 (rs13266634, P=0.0003), NGN3 (rs10823406, P=0.01), and MMP26 (rs2499953, P=0.04) were associated with elevated fasting glucose, while CDKAL1 variants (rs7756992, P=0.003) showed reduced fasting insulin. However, associations with type 2 diabetes incidence were modest (HRs ranging 1.25-2.03), and only SLC30A8 remained significant after Bonferroni correction for HOMA-B.

This case-control association study in 864 Japanese type 2 diabetes patients and 864 controls confirmed that three SNPs in HHEX (rs5015480 OR=1.46, rs7923837 OR=1.40, rs1111875 OR=1.30) were significantly associated with type 2 diabetes across ethnic groups. SNPs in FTO, CDKAL1, CDKN2B, and SLC30A8 showed nominal associations, while several SNPs were associated with impaired pancreatic beta cell function measured by HOMA-beta index.