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Whole exome sequencing identifies variation in CYB5A and RNF10 associated with adiposity and type 2 diabetes.

ABSTRACT: OBJECTIVE:Few coding variants in genes associated with type 2 diabetes (T2D) have been identified, and the underlying physiologic mechanisms whereby susceptibility genes influence T2D risk are often unknown. The objective of this study was to identify coding variation that increases risk for T2D via an effect on a pre-diabetic trait. METHODS:Whole exome sequencing was done in 177 Pima Indians. Selected variants (N = 345) were genotyped in 555 subjects characterized for body fatness, glucose disposal rates during a clamp, acute insulin response to glucose, and 2-h plasma glucose concentrations during an OGTT, and were also genotyped in up to 5,880 subjects with longitudinal measures of BMI. Variants associated with quantitative traits were assessed for association with T2D in 7,667 subjects. RESULTS:rs7238987 in CYB5A associated with body fatness (P = 7.0 × 10(-6) ). This SNP and a novel SNP in RNF10 also associated with maximum recorded BMI (P = 6.2 × 10(-7) and P = 7.2 × 10(-4) ) and maximum childhood BMI z-score (P = 5.9 × 10(-4) and P = 8.5 × 10(-7) ). The BMI increasing alleles increased the risk for T2D (P = 0.01; OR = 1.13 [1.03-1.24] and 9.5 × 10(-3) ; OR = 1.49 [1.10-2.02]). CONCLUSIONS:CYB5A, which has a role in stearyl-CoA-desaturase activity, and RNF10, with an unknown role in weight regulating pathways, associated with adiposity and nominally increased the risk for T2D in American Indians.

SUBMITTER: Huang K

PROVIDER: S-EPMC3968243 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Whole exome sequencing identifies variation in CYB5A and RNF10 associated with adiposity and type 2 diabetes.

Huang Ke K Nair Anup K AK Muller Yunhua Li YL Piaggi Paolo P Bian Li L Del Rosario Melissa M Knowler William C WC Kobes Sayuko S Hanson Robert L RL Bogardus Clifton C Baier Leslie J LJ

Obesity (Silver Spring, Md.) 20131205 4

<h4>Objective</h4>Few coding variants in genes associated with type 2 diabetes (T2D) have been identified, and the underlying physiologic mechanisms whereby susceptibility genes influence T2D risk are often unknown. The objective of this study was to identify coding variation that increases risk for T2D via an effect on a pre-diabetic trait.<h4>Methods</h4>Whole exome sequencing was done in 177 Pima Indians. Selected variants (N = 345) were genotyped in 555 subjects characterized for body fatnes ...[more]

PMID: 24151200

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Project description:PurposeTo identify susceptibility genes associated with hereditary predisposition to uveal melanoma (UM) in patients with no detectable germline BAP1 alterations.DesignRetrospective case series from academic referral centers.ParticipantsCohort of 154 UM patients with high risk of hereditary cancer defined as patients with 1 or more of the following: (1) familial UM, (2) young age (<35 years) at diagnosis, (3) personal history of other primary cancers, and (4) family history of 2 or more primary cancers with no detectable mutation or deletion in BAP1 gene.MethodsWhole exome sequencing, a cancer gene panel, or both were carried out. Probands included 27 patients with familial UM, 1 patient with bilateral UM, 1 patient with congenital UM, and 125 UM patients with strong personal or family histories, or both, of cancer. Functional validation of variants was carried out by immunohistochemistry, reverse-transcriptase polymerase chain reaction, and genotyping.Main outcome measuresClinical characterization of UM patients with germline alterations in known cancer genes.ResultsWe identified actionable pathogenic variants in 8 known hereditary cancer predisposition genes (PALB2, MLH1, MSH6, CHEK2, SMARCE1, ATM, BRCA1, and CTNNA1) in 9 patients, including 3 of 27 patients (11%) with familial UM and 6 of 127 patients (4.7%) with a high risk for cancer. Two patients showed pathogenic variants in CHEK2 and PALB2, whereas variants in the other genes each occurred in 1 patient. Biallelic inactivation of PALB2 and MLH1 was observed in tumors from the respective patients. The frequencies of pathogenic variants in PALB2, MLH1, and SMARCE1 in UM patients were significantly higher than the observed frequencies in noncancer controls (PALB2: P = 0.02; odds ratio, 8.9; 95% confidence interval, 1.5-30.6; MLH1: P = 0.04; odds ratio, 25.4; 95% confidence interval, 1.2-143; SMARCE1: P = 0.001; odds ratio, 2047; 95% confidence interval, 52-4.5e15, respectively).ConclusionsThe study provided moderate evidence of gene and disease association of germline mutations in PALB2 and MLH1 with hereditary predisposition to UM. It also identified several other candidate susceptibility genes. The results suggest locus heterogeneity in predisposition to UM. Genetic testing for hereditary predisposition to cancer is warranted in UM patients with strong personal or family history of cancers, or both.

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Whole exome sequencing identifies variation in CYB5A and RNF10 associated with adiposity and type 2 diabetes.

Publications

Whole exome sequencing identifies variation in CYB5A and RNF10 associated with adiposity and type 2 diabetes.

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