rs689

Meta-genome-wide association study of 3,479 European participants with type 1 diabetes identified a locus on chromosome 1 (rs559047, p=4.13×10⁻⁸) and multiple variants in the MHC region (rs61211515, rs9260151, rs3135002) associated with C-peptide levels as a measure of beta cell function. These associations partly differ from known type 1 diabetes risk loci, suggesting distinct mechanisms for disease development versus progression.

This candidate gene study of 130 Danish children with type 1 diabetes examined associations between 20 diabetes-related SNPs and diabetic retinopathy progression over 16 years. The CTSH/rs3825932 variant was associated with reduced risk of progression to proliferative diabetic retinopathy (OR=0.20, p=2.4×10⁻³, p_adjust=0.048), while ERBB3/rs2292239 was associated with increased risk of two-step DR progression (OR=2.76, p=7.5×10⁻³, p_adjust=0.15). The CTSH association remained significant after multiple testing correction.

This functional study demonstrates that differential proinsulin expression from type 1 diabetes-predisposing and -protective haplotypes of the INS gene is controlled by splicing efficiency of intron 1, specifically through the variant rs689 (IVS1-6A/T). The adenine allele at rs689 weakens the 3' splice site and increases dependence on U2AF35 binding, leading to increased intron retention and reduced proinsulin expression in the predisposing haplotype.

This case-cohort study of 704 postmenopausal women examined 33 SNPs in IGF-I, insulin resistance, and related signaling pathway genes. Six SNPs in INS, IGF-I, and IGFBP3 genes and 11 SNPs in IRS1 and AKT1/2 genes were associated with colorectal cancer risk, with associations differing by obesity status, physical activity, and exogenous estrogen use. Approximately 30-50% of the SNP-cancer association was mediated or influenced by IGF-I/IR traits, suggesting gene-lifestyle interactions affect postmenopausal CRC risk.

This case-control study of 591 late-onset Finnish type 1 diabetes patients (ages 15-40) and 1,538 controls identified SNPs at the INS (rs689, OR=0.57, p=2.77×10⁻⁹), PTPN22 (rs2476601, OR=1.50, p=3.98×10⁻⁶), and IFIH1 (rs1990760, OR=0.81, p=0.0028) loci significantly associated with disease. Notably, IL2RA SNPs (rs11594656 and rs41295061) showed no disease association but had independent effects on age at diagnosis (HR=0.83 and 0.74, p=0.015 and 0.006 respectively), making IL2RA a major determinant of disease onset timing.

A candidate gene association study of 2,613 Gambian individuals examined six SNPs flanking the insulin gene (INS) VNTR in relation to birth size and early growth. Maternal transmission of the rs689 allele was associated with increased birth length (effect size 17.5 mm; P = 0.004), and the African-specific rs5506 allele with greater post-natal weight gain (effect size 0.19 z-score points/year; P = 0.005). These findings suggest polymorphic variation in the INS region contributes to fetal and early growth characteristics in this African population.

This minireview summarizes associations between forensic STR (short tandem repeat) markers and various diseases including cancer, schizophrenia, hypertension, Down syndrome, Edwards syndrome, and cardiovascular disorders. The paper reviews numerous studies demonstrating that specific STR alleles (e.g., THO1 allele 9.3 with hypertension and SIDS, D13S317 and D5S818 with schizophrenia) show significant associations with disease susceptibility, supporting the use of STR markers for early diagnosis and genetic screening.

This genome-wide association study (GWAS) in the GoKinD population identified sequence variants in the PLEKHH2 region associated with diabetic nephropathy in individuals with type 1 diabetes. Two SNPs (rs1368086 and rs725238) in the PLEKHH2 locus showed association at P < 0.001 in 112 cases and 148 controls with HLA DR3/4 diplotypes. rs11886047, located upstream of the PLEKHH2 promoter, showed significant association in transmission disequilibrium testing (P = 0.0307) in 246 case trios and case/control analysis (P = 0.00256) in 601 cases and 577 controls, with evidence of heterozygote disadvantage.

This Norwegian case-control and family study (1,331 cases, 1,625 controls, 421 trios) examined joint effects of HLA, INS, PTPN22, and CTLA4 on type 1 diabetes risk. The high-risk HLA genotype conferred OR=20.6 compared to neutral-risk HLA. The joint effect of HLA and PTPN22 showed significant negative deviation from multiplicativity (p=0.024), while other gene pairs followed multiplicative models. Combined high/intermediate-risk HLA with risk genotypes at all three non-HLA loci showed joint OR=61, though this genotype combination was rare in the population.

This study examined whether genetic markers (HLA-DQB1, PTPN22, INS VNTR, TCF7L2) could distinguish autoimmune from non-autoimmune diabetes in 1,642 young (15-34 years) and 1,619 middle-aged (40-59 years) Swedish diabetic patients. TCF7L2 rs7903146 CT/TT genotypes were significantly more common in young GADA-negative than GADA-positive patients (53% vs 43%; p=0.0004), suggesting TCF7L2 variants help differentiate type 2 diabetes from autoimmune diabetes in young but not middle-aged patients.

In 4,364 type 1 diabetes cases from Great Britain (10.8% positive for thyroid peroxidase autoantibodies [TPOAbs]), the CTLA4 rs3087243 G allele showed a stronger association with disease in TPOAb-positive cases (OR=1.49, 95% CI=1.29-1.72) compared to TPOAb-negative cases (OR=1.16, 95% CI=1.10-1.24, P=0.0004). The TPOAb-positive subgroup showed a marked female bias (1.97:1 female:male ratio) and represents a form of autoimmune polyendocrine syndrome where tolerance to both insulin-producing cells and thyroid tissue is impaired.

This review examines slowly progressive type 1 diabetes mellitus (SPIDDM), also known as latent autoimmune diabetes in adults (LADA), discussing its pathogenesis, diagnostic markers, and genetic associations. Key findings include T-cell-mediated insulitis and pseudoatrophic islets characteristic of type 1 diabetes, absence of amyloid deposition seen in type 2 diabetes, and identification of multiple genetic susceptibility loci including HLA haplotypes, PTPN22 rs2476601, INS rs689, CTLA4, TCF7L2 rs7903146, ZMIZ1 rs12571751, SH2B3 rs7310615, and PFKFB3 rs1983890. GAD autoantibodies and HLA genotypes are important risk factors for beta-cell failure progression.