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Analysis of SLC16A11 Variants in 12,811 American Indians: Genotype-Obesity Interaction for Type 2 Diabetes and an Association With RNASEK Expression.

ABSTRACT: Genetic variants in SLC16A11 were recently reported to be associated with type 2 diabetes in Mexican and other Latin American populations. The diabetes risk haplotype had a frequency of 50% in Native Americans from Mexico but was rare in Europeans and Africans. In the current study, we analyzed SLC16A11 in 12,811 North American Indians and found that the diabetes risk haplotype, tagged by the rs75493593 A allele, was nominally associated with type 2 diabetes (P = 0.001, odds ratio 1.11). However, there was a strong interaction with BMI (P = 5.1 × 10(-7)) such that the diabetes association was stronger in leaner individuals. rs75493593 was also strongly associated with BMI in individuals with type 2 diabetes (P = 3.4 × 10(-15)) but not in individuals without diabetes (P = 0.77). Longitudinal analyses suggest that this is due, in part, to an association of the A allele with greater weight loss following diabetes onset (P = 0.02). Analyses of global gene expression data from adipose tissue, skeletal muscle, and whole blood provide evidence that rs75493593 is associated with expression of the nearby RNASEK gene, suggesting that RNASEK expression may mediate the effect of genotype on diabetes.

SUBMITTER: Traurig M

PROVIDER: S-EPMC4747458 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Analysis of SLC16A11 Variants in 12,811 American Indians: Genotype-Obesity Interaction for Type 2 Diabetes and an Association With RNASEK Expression.

Traurig Michael M Hanson Robert L RL Marinelarena Alejandra A Kobes Sayuko S Piaggi Paolo P Cole Shelley S Curran Joanne E JE Blangero John J Göring Harald H Kumar Satish S Nelson Robert G RG Howard Barbara V BV Knowler William C WC Baier Leslie J LJ Bogardus Clifton C

Diabetes 20151020 2

Genetic variants in SLC16A11 were recently reported to be associated with type 2 diabetes in Mexican and other Latin American populations. The diabetes risk haplotype had a frequency of 50% in Native Americans from Mexico but was rare in Europeans and Africans. In the current study, we analyzed SLC16A11 in 12,811 North American Indians and found that the diabetes risk haplotype, tagged by the rs75493593 A allele, was nominally associated with type 2 diabetes (P = 0.001, odds ratio 1.11). However ...[more]

PMID: 26487785

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Project description:BACKGROUNDWe aimed to determine whether metabolic syndrome (MetS) affects longitudinal trajectories of diabetic complications, including neuropathy, cardiovascular autonomic neuropathy (CAN), and kidney disease in American Indians with type 2 diabetes.METHODSWe performed a prospective study where participants underwent annual metabolic phenotyping and outcome measurements. The updated National Cholesterol Education Program criteria were used to define MetS and its individual components, using BMI instead of waist circumference. Neuropathy was defined using the Michigan Neuropathy Screening Instrument index, CAN with the expiration/inspiration ratio, and kidney disease with glomerular filtration rate. Mixed-effects models were used to evaluate associations between MetS and these outcomes.RESULTSWe enrolled 141 participants: 73.1% female, a mean (±SD) age of 49.8 (12.3), and a diabetes duration of 19.6 years (9.7 years) who were followed for a mean of 3.1 years (1.7 years). MetS components were stable during follow-up except for declining obesity and cholesterol. Neuropathy (point estimate [PE]: 0.30, 95% CI: 0.24, 0.35) and kidney disease (PE: -14.2, 95% CI: -16.8, -11.4) worsened over time, but CAN did not (PE: -0.002, 95% CI: -0.006, 0.002). We found a significant interaction between the number of MetS components and time for neuropathy (PE: 0.05, 95% CI: 0.01-0.10) but not CAN (PE: -0.003, 95% CI: -0.007, 0.001) or kidney disease (PE: -0.69, 95% CI: -3.16, 1.76). Systolic blood pressure (SBP, unit = 10 mmHg) was associated with each complication: neuropathy (PE: 0.23, 95% CI: 0.07, 0.39), CAN (PE: -0.02, 95% CI: -0.03, -0.02), and kidney disease (PE: -10.2, 95% CI: -15.4, -5.1).CONCLUSIONIn participants with longstanding diabetes, neuropathy and kidney disease worsened during follow-up, despite stable to improving MetS components, suggesting that early metabolic intervention is necessary to prevent complications in such patients. Additionally, the number of MetS components was associated with an increased rate of neuropathy progression, and SBP was associated with each complication.FUNDINGThe following are funding sources: NIH T32NS0007222, NIH R24DK082841, NIH R21NS102924, NIH R01DK115687, the Intramural Program of the NIDDK, the NeuroNetwork for Emerging Therapies, the Robert and Katherine Jacobs Environmental Health Initiative, the Robert E. Nederlander Sr. Program for Alzheimer's Research, and the Sinai Medical Staff Foundation.TRIAL REGISTRATIONClinicalTrials.gov, NCT00340678.

Dataset Information

Analysis of SLC16A11 Variants in 12,811 American Indians: Genotype-Obesity Interaction for Type 2 Diabetes and an Association With RNASEK Expression.

Publications

Analysis of SLC16A11 Variants in 12,811 American Indians: Genotype-Obesity Interaction for Type 2 Diabetes and an Association With RNASEK Expression.

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