PuSH - Publication Server of Helmholtz Zentrum München: AMPK subunits harbor largely non-overlapping genetic determinants for body fat mass, glucose- and cholesterol metabolism.

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Randrianarisoa, E. ; Lehn-Stefan, A. ; Krier, J. ; Böhm, A. ; Heni, M. ; Hrabě de Angelis, M. ; Fritsche, A. ; Häring, H.-U. ; Stefan, N. ; Staiger, H.

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

J. Clin. Endocrinol. Metab. 105, 14-25:dgz020 (2020)

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Context: Adenosine monophosphate (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 7 AMPK subunit genes on adiposity, glucose metabolism, and lipid metabolism has not yet been systematically studied.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, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, total cholesterol, and triglycerides.Study Design and Methods: A cohort of 2789 nondiabetic participants from the Tubingen 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 6 largely nonoverlapping SNP sets across 4 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 body mass index (BMI) of +0.22 kg/m(2) (P = 2.3 x 10(-7)), insulin sensitivity of -0.12 x 10(19) L-2/mol(2) (P = 9.9 x 10(-6)) and 2-hour 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 x 10(-5), respectively), and a genetic HDL score decreased HDL cholesterol by 0.32 mg/dL per allele (P = 9.1 x 10(-6)).Conclusions: We describe largely nonoverlapping 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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