Original Investigation

Human Genetics

, Volume 129, Issue 2, pp 129-139

Open Access This content is freely available online to anyone, anywhere at any time.

AKT1 polymorphisms are associated with risk for metabolic syndrome

  • Joseph M. DevaneyAffiliated withDepartment of Integrative Systems Biology, Research Center for Genetic Medicine, Children’s National Medical Center
  • , Heather Gordish-DressmanAffiliated withDepartment of Integrative Systems Biology, Research Center for Genetic Medicine, Children’s National Medical Center
  • , Brennan T. HarmonAffiliated withDepartment of Integrative Systems Biology, Research Center for Genetic Medicine, Children’s National Medical Center
  • , Margaret K. BradburyAffiliated withDepartment of Integrative Systems Biology, Research Center for Genetic Medicine, Children’s National Medical Center
  • , Stephanie A. DevaneyAffiliated withDepartment of Integrative Systems Biology, Research Center for Genetic Medicine, Children’s National Medical Center
  • , Tamara B. HarrisAffiliated withNational Institute of Aging, National Institutes of Health
  • , Paul D. ThompsonAffiliated withDivision of Cardiology, Henry Low Heart Center, Hartford Hospital
  • , Priscilla M. ClarksonAffiliated withDepartment of Kinesiology, University of Massachusetts
  • , Thomas B. PriceAffiliated withDivision of Cardiology, Henry Low Heart Center, Hartford HospitalDepartment of Diagnostic Radiology, Yale University School of Medicine
    • , Theodore J. AngelopoulosAffiliated withDepartment of Health Professions, Center for Lifestyle Medicine, University of Central Florida
    • , Paul M. GordonAffiliated withLaboratory for Physical Activity and Exercise Intervention Research, University of Michigan
    • , Niall M. MoynaAffiliated withDepartment of Sport Science and Health, Dublin City University
    • , Linda S. PescatelloAffiliated withSchool of Allied Health, University of Connecticut
    • , Paul S. VisichAffiliated withDepartment of Integrative Systems Biology, Research Center for Genetic Medicine, Children’s National Medical CenterHuman Performance Laboratory, Central Michigan University
    • , Robert F. ZoellerAffiliated withDepartment of Integrative Systems Biology, Research Center for Genetic Medicine, Children’s National Medical CenterDepartment of Exercise Science and Health Promotion, Florida Atlantic University
    • , Richard L. SeipAffiliated withDivision of Cardiology, Henry Low Heart Center, Hartford Hospital
    • , Jinwook SeoAffiliated withDepartment of Integrative Systems Biology, Research Center for Genetic Medicine, Children’s National Medical Center
    • , Bo Hyoung KimAffiliated withDepartment of Integrative Systems Biology, Research Center for Genetic Medicine, Children’s National Medical CenterINFINITT Technology
    • , Laura L. TosiAffiliated withDepartment of Integrative Systems Biology, Research Center for Genetic Medicine, Children’s National Medical CenterOrthopedic Surgery and Sports Medicine, Children’s National Medical Center
    • , Melissa GarciaAffiliated withNational Institute of Aging, National Institutes of Health
    • , Rongling LiAffiliated withDepartment of Integrative Systems Biology, Research Center for Genetic Medicine, Children’s National Medical CenterDepartment of Preventive Medicine, University of Tennessee
    • , Joseph M. ZmudaAffiliated withDepartment of Integrative Systems Biology, Research Center for Genetic Medicine, Children’s National Medical CenterDepartment of Epidemiology and Human Genetics, University of Pittsburgh
    • , Matthew J. DelmonicoAffiliated withDepartment of Integrative Systems Biology, Research Center for Genetic Medicine, Children’s National Medical CenterDepartment of Kinesiology, University of Rhode Island
    • , Robert S. LindsayAffiliated withDepartment of Integrative Systems Biology, Research Center for Genetic Medicine, Children’s National Medical CenterFaculty of Medicine, University of Glasgow
    • , Barbara V. HowardAffiliated withDepartment of Integrative Systems Biology, Research Center for Genetic Medicine, Children’s National Medical CenterMedStar Research Institute
    • , William E. KrausAffiliated withDepartment of Integrative Systems Biology, Research Center for Genetic Medicine, Children’s National Medical CenterDuke Center for Living, Duke University Medical Center
    • , Eric P. HoffmanAffiliated withDepartment of Integrative Systems Biology, Research Center for Genetic Medicine, Children’s National Medical Center Email author 

Abstract

Converging lines of evidence suggest that AKT1 is a major mediator of the responses to insulin, insulin-like growth factor 1 (IGF1), and glucose. AKT1 also plays a key role in the regulation of both muscle cell hypertrophy and atrophy. We hypothesized that AKT1 variants may play a role in the endophenotypes that make up metabolic syndrome. We studied a 12-kb region including the first exon of the AKT1 gene for association with metabolic syndrome-related phenotypes in four study populations [FAMUSS cohort (n = 574; age 23.7 ± 5.7 years), Strong Heart Study (SHS) (n = 2,134; age 55.5 ± 7.9 years), Dynamics of Health, Aging and Body Composition (Health ABC) (n = 3,075; age 73.6 ± 2.9 years), and Studies of a Targeted Risk Reduction Intervention through Defined Exercise (STRRIDE) (n = 175; age 40–65 years)]. We identified a three SNP haplotype that we call H1, which represents the ancestral alleles at the three loci and H2, which represents the derived alleles at the three loci. In young adult European Americans (FAMUSS), H1 was associated with higher fasting glucose levels in females. In middle age Native Americans (SHS), H1 carriers showed higher fasting insulin and HOMA in males, and higher BMI in females. In older African-American and European American subjects (Health ABC) H1 carriers showed a higher incidence of metabolic syndrome. Homozygotes for the H1 haplotype showed about twice the risk of metabolic syndrome in both males and females (p < 0.001). In middle-aged European Americans with insulin resistance (STRRIDE) studied by intravenous glucose tolerance test (IVGTT), H1 carriers showed increased insulin resistance due to the Sg component (p = 0.021). The 12-kb haplotype is a risk factor for metabolic syndrome and insulin resistance that needs to be explored in further populations.