A Genome-Wide Association Study in American Indians Implicates DNER as a Susceptibility Locus for Type 2 Diabetes

Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, 1550 East Indian School Road, Phoenix, AZ, 85014.
Diabetes (Impact Factor: 8.1). 10/2013; 63(1). DOI: 10.2337/db13-0416
Source: PubMed


Most genetic variants associated with type 2 diabetes mellitus (T2DM) have been identified through genome-wide association studies (GWASs) in Europeans. The present study reports a GWAS for young-onset T2DM in American Indians. Participants were selected from a longitudinal study conducted in Pima Indians and included: 278 cases with diabetes with onset before 25 years of age, 295 nondiabetic controls ≥age 45 years and 267 siblings of cases or controls. Individuals were genotyped on a ∼1M single nucleotide polymorphism (SNP) array, resulting in 453,654 SNPs with minor allele frequency >0.05. SNPs were analyzed for association in cases and controls and a family-based association test was conducted. Tag SNPs (n=311) were selected for 499 SNPs associated with diabetes (p<0.0005 in case-control analyses or p<0.0003 in family-based analyses), and these SNPs were genotyped in up to 6834 additional Pima Indians to assess replication. Rs1861612 in DNER was associated with T2DM (odds ratio=1.29 per copy of the T allele, p=6.6x10(-8), which represents genome-wide significance accounting for the number of effectively independent SNPs analyzed). Transfection studies in murine pancreatic β-cells suggested that DNER regulates expression of notch signaling pathway genes. These studies implicate DNER as a susceptibility gene for T2DM in American Indians.

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Available from: Leslie J Baier, Jan 20, 2015
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    ABSTRACT: Aim/hypothesis: A recent genome-wide trans-ancestry meta-analysis identified seven new loci associated with type 2 diabetes. We assessed the replication of the seven lead single nucleotide polymorphisms (SNPs) and evaluated these loci for additional signals in American Indians. Methods: Seven SNPs were genotyped in 7,710 individuals from a longitudinally studied American Indian population, and associations with type 2 diabetes, BMI and related phenotypes were assessed. Previous genome-wide association study (GWAS) data from these individuals were used to screen for additional type 2 diabetes signals at these loci. A variant independent of the trans-ancestry meta-analysis was identified within LPP, and its replication was assessed in an additional 3,106 urban American Indians. Results: SNP rs6813195 near to TMEM154 was nominally associated with type 2 diabetes (p = 0.01, OR 1.12 [95% CI 1.03, 1.22]) and adiposity: the type 2 diabetes risk allele was associated with a lower percentage body fat (β = -1.451%, p = 4.8 × 10(-4)). Another SNP, rs3130501 near to POU5F1-TCF19, was associated with BMI (β = -0.012, p = 0.004), type 2 diabetes adjusted for BMI (p = 0.02, OR 1.11 [95% CI 1.02, 1.22]), 2 h glucose concentrations (β = 0.080 mmol/l, p = 0.02) and insulin resistance estimated by homeostatic model (β = 0.039, p = 0.009). The independent variant identified at the LPP locus in our American Indian GWAS for type 2 diabetes was replicated in the additional samples (all American Indian meta-analysis, p = 8.9 × 10(-6), OR 1.29 [95% CI 1.15, 1.45]). Conclusions/interpretation: For two of the seven newly identified variants, there was nominal evidence for association with type 2 diabetes and related traits in American Indians. Identification of an independent variant at the LPP locus suggests the existence of more than one type 2 diabetes signal at this locus.
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    ABSTRACT: The aim of the study was to investigate the association between single nucleotide polymorphisms (SNPs), rs1861612 of delta/notch-like Epidermal Growth Factor (EGF)-related receptor (DNER) and rs1884190 in the Delta-like 1 ligand (DLL1) gene and type 2 diabetes mellitus (T2DM) susceptibility in a Chinese Han population. DNER rs1861612 and DLL1 rs1884190 polymorphisms were genotyped in patients with T2DM and age- and sex-matched T2DM-free controls from a Chinese Han population. A total of 298 patients with T2DM and 500 controls were enrolled in this study. We found that TC and TT genotypes of rs1861612 and variant T were associated with a significantly increased risk of T2DM. In contrast, the AG and AA genotypes of rs1884190 were not significantly associated with the risk of T2DM, even after further stratification analysis based on age or sex. Our results showed that DNER rs1861612 C to T change and variant T genotype may contribute to T2DM in a Chinese Han population.
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