rs13266634

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 literature review of 70 studies examining single nucleotide polymorphisms (SNPs) associated with obesity in Mexican populations published 2011-2021. The authors identified SNPs with differential behavior in Mexican compared to Caucasian populations, including rs17782313 (MC4R), rs6548238 (TMEM18), rs6265 (BDNF), rs7498665 (SH2B1), and notably rs6232 (PCSK1) associated with early-onset obesity in Mexican youth. The review emphasizes ethnicity-dependent genetic effects on BMI heritability (40-70%) and highlights genes involved in cholesterol metabolism and adipokine signaling pathways.

This case-control study of 314 Euro-Brazilian pregnant women (134 with gestational diabetes, 180 controls) investigated the association of two polymorphisms with gestational diabetes: rs7799039 in the LEP gene and rs13266634 in the SLC30A8 gene. Neither polymorphism showed a statistically significant association with gestational diabetes (LEP rs7799039 p=0.627, SLC30A8 rs13266634 p=0.522), and genotype frequencies did not differ between groups.

This systematic study screened 18 T2D-associated SNPs and 5 environmental factors (trans-β-carotene, cis-β-carotene, γ-tocopherol, heptachlor epoxide, PCB170) for gene-environment interactions using NHANES data (1999-2000, 2001-2002). The strongest interaction was between rs13266634 (SLC30A8) and trans-β-carotene: in subjects with low trans-β-carotene levels, the per-risk-allele OR was 1.8 (95% CI 1.3-2.6), 40% higher than the marginal effect, and this interaction withstood Bonferroni correction (p = 0.006, FDR 1.5%). Four interactions total achieved FDR < 20%, suggesting that nutrient levels modify genetic risk for T2D.

Of 40 SNPs previously associated with type 2 diabetes, 19 (48%) introduce or remove CpG sites. In 84 human pancreatic islet donors, all 16 analyzed CpG-SNPs showed statistically significant differential DNA methylation (p≤2.3×10⁻⁵). Several CpG-SNPs including rs391300 (SRR), rs5945326 (DUSP9), rs11708067 (ADCY5), rs5015480 (HHEX), rs13266634 (SLC30A8), rs1801214 (WFS1), rs564398 (CDKN2A), and rs2237895 (KCNQ1) were associated with differential gene expression, alternative splicing, or hormone secretion, suggesting DNA methylation-mediated mechanisms linking genetic variants to type 2 diabetes pathogenesis.

This genome-wide association study identifies genetic loci associated with zinc transporter 8 autoantibodies (ZnT8A) positivity in 2,239 type 1 diabetes cases. The FCRL3 locus on chromosome 1 (rs7522061 T>C, p=1.13×10⁻¹⁶, OR=1.82) and HLA class I region (rs9258750 A>G, p=2.06×10⁻⁹) show strong associations with ZnT8A. The SLC30A8 rs13266634 (R325W) shows epitope-specific associations: strong association with ZnT8WA (p=9.26×10⁻²⁷) and negative association with ZnT8RA (p=7.20×10⁻¹⁷). Notably, these ZnT8A-associated loci do not alter type 1 diabetes risk, indicating ZnT8A is a downstream biomarker rather than primary pathogenic factor.

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).

A case-control study of 837 schizophrenic patients and 1,109 controls in a Han Chinese population found no significant association between the SLC30A8 rs13266634 (R325W, C/T) polymorphism and schizophrenia risk (χ² = 1.95, p = 0.38 for genotype; χ² = 0.47, p = 0.50 for allele frequencies), nor with any schizophrenia clinical symptoms. This null finding suggests that despite rs13266634 being a robust type 2 diabetes risk variant across multiple GWAS, it does not contribute to the genetic basis of the schizophrenia-T2DM comorbidity.

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 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 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.

This association study examined SLC30A8 rs13266634 (R325W) polymorphism in 3,007 Diabetes Prevention Program participants. The C risk allele was significantly associated with higher fasting proinsulin levels at baseline (p=0.002) in a dose-dependent manner, suggesting impaired insulin processing. However, after 1 year of lifestyle, metformin, or troglitazone intervention, proinsulin levels decreased significantly in all treatment groups and were no longer associated with SLC30A8 genotype (p=0.86), indicating that insulin-sensitizing interventions overcome the genetic effect.

This study maps conformational autoantibody epitopes in ZnT8 (Slc30A8), a major autoantigen in type 1 diabetes. Using 112 sera from newly diabetic subjects, the authors identified a third major epitope (m-REKK) requiring residues R332, E333, K336, and K340, with 39.3% of subjects ZnT8-autoantibody positive, of which 38.6% also recognized the mouse probe. The work confirms rs13266634 (Q325R polymorphism) as a major determinant affecting autoantibody recognition patterns.

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 GWAS of fasting glucose in the ARIC study examined 5,782-8,372 individuals across four longitudinal visits and identified five genomic regions significantly associated with fasting glucose (p < 5×10⁻⁸): GCKR, G6PC2, GCK, SLC30A8, and MTNR1B. The study demonstrated that averaging fasting glucose measures across visits improved statistical power and detected additional signals (GCKR rs780094, SLC30A8 rs13266634) not visible in single-visit analyses. Analysis of candidate SNPs revealed significant interactions with diabetes status: associations with fasting glucose were stronger in non-diabetic individuals than in those with prevalent diabetes for multiple SNPs including rs10830963 (MTNR1B), rs560887 (G6PC2), rs4607517 (GCK), and rs780094 (GCKR).

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 case-control study examined two SLC30A8 polymorphisms in 443 Chinese type 2 diabetes patients and 229 healthy controls. rs13266634 risk C allele was more frequent in T2DM patients (P<0.05). In 48 patients treated with repaglinide, rs13266634 CT+TT genotypes showed better response with reduced fasting (P<0.05) and postprandial insulin (P<0.01) levels, while rs16889462 GA genotype showed enhanced efficacy on fasting glucose, postprandial glucose, and HbA1c (P<0.01, P<0.01, P<0.05 respectively).

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 prospective study of 1,633 children with a first-degree family history of type 1 diabetes shows that autoantibodies to zinc transporter 8 (ZnT8A) are highly predictive of diabetes development, with 59% of ZnT8A-positive children progressing to diabetes within 5 years. The SLC30A8 rs13266634 (R325W) SNP strongly influences ZnT8A specificity and diabetes risk: ZnT8A-positive children with homozygous CC or TT genotypes had 59% risk vs 22% for heterozygous CT carriers (p=0.01).

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).

In 1,412 non-diabetic German participants, carriers of higher cumulative loads of type 2 diabetes risk alleles (rs7903146 in TCF7L2, rs7754840 in CDKAL1, rs7923837 in HHEX, rs13266634 in SLC30A8) showed significantly accelerated age-dependent decline in insulin secretion and impaired proinsulin conversion. Individuals with 5-8 risk alleles exhibited a ~13-18% reduction in insulin secretion compared to carriers of ≤3 alleles, with effects particularly pronounced in obese participants.

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 study demonstrates that the SLC30A8 rs13266634 (Arg325Trp) polymorphism is a key determinant of ZnT8 autoantibody specificity in Japanese type 1 diabetes patients. Among 44 ZnT8 autoantibody-positive patients, 73% of TT homozygotes had CW-specific autoantibodies (p<0.0001) while 42% of CC homozygotes had CR-specific autoantibodies. Notably, rs13266634 showed no association with type 1 diabetes susceptibility in this population.

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 study of 846 non-diabetic European offspring of type 2 diabetes patients demonstrates that homozygous carriers of the major risk C allele of SLC30A8 rs13266634 (encoding Arg325Trp) show a 19% reduction in first-phase insulin release during intravenous glucose tolerance testing (IVGTT), but no difference in oral glucose tolerance or insulin sensitivity. The findings suggest that SLC30A8 variation contributes to pancreatic beta cell dysfunction in type 2 diabetes pathogenesis.

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 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.

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.

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.