Elko Randrianarisoa 1,2 , Angela Lehn-Stefan 1,2 , Johannes Krier 1,2 , Anja Böhm 1,2,3 , Martin Heni 1,2,3 , Martin Hrabě De Angelis 2,4,5 , Andreas Fritsche 1,2,3 , Hans-Ulrich Häring 1,2,3 , Norbert Stefan 1,2,3 , Harald Staiger 1,2,6 Show Affiliations »
Abstract
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 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 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/m2 (P = 2.3 × 10-7), insulin sensitivity of -0.12 × 1019 L2/mol2 (P = 9.9 × 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 × 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 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. (J Clin Endocrinol Metab XX: 0-0, 2019). © Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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 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 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/m2 (P = 2.3 × 10-7), insulin sensitivity of -0.12 × 1019 L2/mol2 (P = 9.9 × 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 × 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 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. (J Clin Endocrinol Metab XX: 0-0, 2019). © Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Entities: Chemical
Disease
Gene
Keywords:
energy metabolism; genetics; glucose metabolism; lipid metabolism; type 2 diabetes
Year: 2020
PMID： 31512724 DOI： 10.1210/clinem/dgz020
Source DB: PubMed Journal: J Clin Endocrinol Metab ISSN： 0021-972X Impact factor: 5.958