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AMPK subunits harbor largely non-overlapping genetic determinants for body fat mass, glucose- and cholesterol metabolism.

CONTEXT: AMP-activated protein kinase (AMPK) is a heterotrimeric enzyme and central regulator of cellular energy metabolism. The impact of single nucleotide polymorphisms (SNPs) in all seven subunit genes on adiposity, glucose- and lipid metabolism has not been systematically studied yet.

OBJECTIVE: To analyze the associations of common SNPs in all AMPK genes, and of different scores thereof, with adiposity, insulin sensitivity, insulin secretion, blood glucose, total-, LDL- and HDL-cholesterol and triglycerides.

STUDY DESIGN AND METHODS: A cohort of 2789 non-diabetic subjects from the Tübingen Family study of type-2 diabetes, metabolically characterized by oral glucose tolerance test and genotyped by genome-wide SNP array was analyzed.

RESULTS: We identified largely non-overlapping SNP sets across four AMPK genes (PRKAA1, PRKAA2, PRKAG2, PRKAG3) associated with adiposity, insulin sensitivity, insulin secretion, blood glucose, total-/LDL-cholesterol or HDL-cholesterol, respectively. A genetic score of body-fat-increasing alleles revealed per-allele effect sizes on BMI of +0.22 kg/m² (p=2.3·10-7), insulin sensitivity of -0.12·1019 L²/mol² (p=9.9·10-6) and 2-h blood glucose of +0.02 mmol/L (p=0.0048). Similar effects on blood glucose were observed with scores of insulin-sensitivity-reducing, insulin-secretion-reducing and glucose-raising alleles, respectively. A genetic cholesterol score increased total- and LDL-cholesterol by 1.17 mg/dL per allele (p=0.0002 and p=3.2·10-5, respectively), and a genetic HDL score decreased HDL-cholesterol by 0.32 mg/dL per allele (p=9.1·10-6).

CONCLUSIONS: We describe largely non-overlapping genetic determinants in AMPK genes for diabetes-/atherosclerosis-related traits which reflect the metabolic pathways controlled by the enzyme. Formation of trait-specific genetic scores revealed additivity of allele effects, with body-fat-raising alleles reaching a marked effect size.

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