rs4402960

This association study examined 43 diabetes-related SNPs in relation to diastolic dysfunction and cardiovascular disease across two Swedish cohorts. HNF1B rs757210 (T-allele) was the main finding, associated with prevalent diastolic dysfunction in both the discovery cohort (MPP-RES; OR 1.21, P=0.024) and replication cohort (VARA; OR 1.38, P=0.042), and with increased risk of incident CVD (HR 1.05, P=0.042) but not CHF over 30+ years of follow-up.

A case-control study of 674 GDM patients and 690 controls combined with a meta-analysis found that the G allele of rs10830963 and T allele of rs1387153 in MTNR1B are significantly associated with increased risk of gestational diabetes mellitus (GDM). Meta-analysis of 6 studies showed rs10830963 G allele increased GDM risk in co-dominant model (OR 1.62, 95% CI 1.34-1.94) and rs1387153 T allele increased risk in co-dominant model (OR 1.53, 95% CI 1.26-1.86).

This case-control study investigated 25 T2DM-associated SNPs in a multi-ethnic Hawaiian cohort (291 GDM cases, 734 controls) and found ethnicity-specific associations with gestational diabetes. Key findings in Filipinos included rs1113132 (EXT2, OR=1.52, p=0.028), rs1111875 (HHEX, OR=1.5, p=0.047), rs2237892 (KCNQ1, OR=0.49, p<0.001), rs10830963 (MTNR1B, OR=0.63, p=0.025), and rs13266634 (SLC30A8, OR=0.58, p=0.011). In Japanese women, rs4402960 (IGFBP2, OR=0.5, p=0.031) and rs2237892 (KCNQ1, OR=0.5, p=0.03) were significant. Pacific Islanders showed associations with rs10830963 (MTNR1B, OR=0.52, p=0.037) and rs13266634 (SLC30A8, OR=2.43, p=0.03). No SNPs showed consistent associations across all three ethnic groups.

This case-control study analyzed 7 SNPs in 6 genes previously associated with type 2 diabetes (T2DM) in 235 kidney transplant patients medicated with tacrolimus to determine their effect on new-onset diabetes after transplantation (NODAT). While no individual SNP showed significant association with NODAT, patients carrying >7 of the 14 'diabetogenic' alleles had significantly higher NODAT risk (OR 2.17, 95% CI 1.18–3.99, p=0.015), particularly for late-onset NODAT (OR 1.37 per allele, 95% CI 1.05–1.78, p=0.017).

This association study identified rs10811661 near CDKN2A/B on chromosome 9p21, a type 2 diabetes risk SNP, as significantly associated with diabetic nephropathy in 2,963 type 1 diabetes patients (OR 1.33, p=0.00045). The association was replicated in meta-analysis across four cohorts (n>5,000; OR 1.15, p=0.011) and was particularly strong for end-stage renal disease (OR 1.35, p=0.00038). The SNP was also associated with severe retinopathy but not cardiovascular disease.

Population-based study of 6,733 non-diabetic Finnish men examining associations between 19 confirmed type 2 diabetes risk loci and tissue-specific insulin resistance indices. Type 2 diabetes risk SNPs in KCNJ11 (rs5219) and HHEX (rs1111875) showed significant associations with lower liver insulin resistance (p<0.0013 and p=5.4×10⁻⁵, respectively), while the Pro12 allele of PPARG2 (rs1801282) was significantly associated with higher adipocyte insulin resistance (p=6.2×10⁻⁵).

This functional study used New Zealand obese mice fed high-fat (HF) or carbohydrate-free high-fat (CHF) diets to identify candidate genes and pathways involved in diet-induced type 2 diabetes. Laser capture microdissection of pancreatic islets revealed 2,109 differentially expressed genes; 39 of these correlated with human genome-wide association studies (DGI and WTCCC), including validated hits such as IGF2BP2 and TSPAN8. The most significant finding was upregulation of oxidative phosphorylation genes in response to HF diet, implicating glucose-induced oxidative stress in beta cell failure.

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).

This case-control study in 869 Korean women with gestational diabetes mellitus (GDM) and 632 non-diabetic controls examined whether type 2 diabetes-associated genetic variants discovered in recent GWAS are also associated with GDM. Multiple variants showed significant associations with GDM, including rs7756992 and rs7754840 in CDKAL1 (OR 1.55, p=4.17×10⁻⁹), rs10811661 in CDKN2A-CDKN2B (OR 1.49, p=1.05×10⁻⁷), variants in HHEX, rs4402960 in IGF2BP2 (OR 1.18, p=0.03), rs13266634 in SLC30A8 (OR 1.24, p=0.005), and rs7903146 in TCF7L2 (OR 1.58, p=0.038).

This case-control and family-based association study tested whether 18 type 2 diabetes susceptibility loci are associated with type 1 diabetes in 7,606 type 1 diabetic cases and 8,218 controls. Only PPARG (rs1801282/Pro12Ala, OR=0.91, p=0.004) and HHEX-IDE (rs1111875, OR=0.94, p=0.003) showed evidence of association with type 1 diabetes. The authors conclude that type 1 and type 2 diabetes do not share a common genetic background, supporting the view that type 1 diabetes is primarily an autoimmune disease.

This prospective study of 16,143 individuals from the Malmö Preventive Project (mean follow-up 23 years) investigated whether genetic variants in 26 genes previously associated with type 2 diabetes or metabolic syndrome components could predict future development of metabolic syndrome. Polymorphisms in TCF7L2 (rs7903146, OR 1.10, p=0.00097), FTO (rs9939609, OR 1.08, p=0.0065), WFS1 (rs10010131, OR 1.07, p=0.0078), and IGF2BP2 (rs4402960, OR 1.07, p=0.021) predicted metabolic syndrome development, with TCF7L2, WFS1, and IGF2BP2 acting through hyperglycemia and FTO through obesity. A composite genotype score of 17 polymorphisms predicted metabolic syndrome risk (OR 1.04, p<0.00001), with carriers of ≥19 risk alleles having 51% increased risk compared to carriers of ≤12 alleles.

This replication study tested newly identified type 2 diabetes susceptibility loci in a Norwegian population-based cohort of 1,638 type 2 diabetes patients and 1,858 controls. The authors confirmed associations for rs10811661 near CDKN2B (OR 1.20, p=0.004), rs9939609 in FTO (OR 1.14, p=0.006), and rs13266634 in SLC30A8 (OR 1.20, p=3.9×10⁻⁴). They found borderline association for rs4402960 in IGFBP2 (OR 1.10, p=0.074) but no support for SNPs near FLJ39370 and PKN2.

This comprehensive review article traces the evolution of pharmacogenetics from single-gene analysis to whole-genome approaches. It discusses validated pharmacogenetic biomarkers with clinical impact including CYP2D6, CYP2C9, CYP2C19, TPMT, DPD, VKORC1, UGT1A1, and ADRB1/ADRB2, providing examples of how genetic variants affect drug metabolism and response. The paper emphasizes the importance of integrating pharmacogenetic information into clinical practice and drug development.

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 candidate gene study of 1,065 German participants investigated seven type 2 diabetes-associated SNPs and their relationship with proinsulin processing. Risk alleles in TCF7L2 (rs7903146), CDKAL1 (rs7754840), and SLC30A8 (rs13266634) significantly impaired proinsulin to insulin conversion (p<0.05), while variants in HHEX showed impaired insulin secretion without affecting proinsulin conversion, demonstrating that these two aspects of beta cell dysfunction are independently regulated.

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.