title: Genome-wide association study identifies common loci influencing circulating glycated hemoglobin (HbA1c) levels in non-diabetic subjects: the Long Life Family Study (LLFS).
abstract: OBJECTIVE
  Glycated hemoglobin (HbA1c) is a stable index of chronic glycemic status and hyperglycemia associated with progressive development of insulin resistance and frank diabetes. It is also associated with premature aging and increased mortality. To uncover novel loci for HbA1c that are associated with healthy aging, we conducted a genome-wide association study (GWAS) using non-diabetic participants in the Long Life Family Study (LLFS), a study with familial clustering of exceptional longevity in the US and Denmark.
  
  
  METHODS
  A total of 4088 non-diabetic subjects from the LLFS were used for GWAS discoveries, and a total of 8231 non-diabetic subjects from the Atherosclerosis Risk in Communities Study (ARIC, in the MAGIC Consortium) and the Health, Aging, and Body Composition Study (HABC) were used for GWAS replications. HbA1c was adjusted for age, sex, centers, 20 principal components, without and with BMI. A linear mixed effects model was used for association testing.
  
  
  RESULTS
  Two known loci at GCK rs730497 (or rs2908282) and HK1 rs17476364 were confirmed (p<5e-8). Of 25 suggestive (5e-8<p<1e-5) loci, one known (G6PC2 rs560887, replication p=5e-5) and one novel (OR10R3P/SPTA1- rs12041363, replication p=1e-17) loci were replicated (p<0.0019). Similar findings resulted when HbA1c was further adjusted for BMI. Further validations are crucial for the remaining suggestive loci including the emerged variant near OR10R3P/SPTA1.
  
  
  CONCLUSIONS
  The analysis reconfirmed two known GWAS loci (GCK, HK1) and identified 25 suggestive loci including one reconfirmed variant in G6PC2 and one replicated variant near OR10R3P/SPTA1. Future focused survey of sequence elements containing mainly functional and regulatory variants may yield additional findings.
authors.affiliation: Department of Genetics Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: anping@wustl.edu.
authors.forename: Ping
authors.initials: P
authors.lastname: An
authors.affiliation: University of Pittsburgh, Graduate School of Public Health, Department of Epidemiology, Center for Aging and Population Health, Pittsburgh, PA, USA.
authors.forename: Iva
authors.initials: I
authors.lastname: Miljkovic
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Bharat
authors.initials: B
authors.lastname: Thyagarajan
authors.affiliation: Department of Genetics Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Aldi T
authors.initials: AT
authors.lastname: Kraja
authors.affiliation: Department of Genetics Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: E Warwick
authors.initials: EW
authors.lastname: Daw
authors.affiliation: Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Pankow
authors.affiliation: Department of Epidemiology, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Selvin
authors.affiliation: Department of Epidemiology, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: W H Linda
authors.initials: WH
authors.lastname: Kao
authors.affiliation: Division of General Internal Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Nisa M
authors.initials: NM
authors.lastname: Maruthur
authors.affiliation: Laboratory of Neurogenetics, NIA/NIH, Bethesda, MD, USA.
authors.forename: Micahel A
authors.initials: MA
authors.lastname: Nalls
authors.affiliation: Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest University, Winston-Salem, NC, USA.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Laboratory of Epidemiology, Demography and Biometry, NIA/NIH, Bethesda, MD, USA.
authors.forename: Tamara B
authors.initials: TB
authors.lastname: Harris
authors.affiliation: Gertrude H. Sergievsky Center and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York City, NY, USA.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Genetics Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Ingrid B
authors.initials: IB
authors.lastname: Borecki
authors.affiliation: Danish Aging Research Center, Epidemiology, University of Southern Denmark, Odense, Denmark; Department of Clinical Biochemistry and Pharmacology and Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
authors.forename: Kaare
authors.initials: K
authors.lastname: Christensen
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Eckfeldt
authors.affiliation: Gertrude H. Sergievsky Center and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York City, NY, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Mayeux
authors.affiliation: Division of Geriatrics, Department of Medicine, Boston University Medical Center, Boston, MA, USA.
authors.forename: Thomas T
authors.initials: TT
authors.lastname: Perls
authors.affiliation: University of Pittsburgh, Graduate School of Public Health, Department of Epidemiology, Center for Aging and Population Health, Pittsburgh, PA, USA.
authors.forename: Anne B
authors.initials: AB
authors.lastname: Newman
authors.affiliation: Department of Genetics Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Province
mesh_terms: D000368:Aged; D015331:Cohort Studies; D003718:Denmark; D003920:Diabetes Mellitus / Q000097:blood; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006442:Glycated Hemoglobin / Q000378:metabolism*; D006801:Humans; D008136:Longevity; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D014481:United States
chemical_list: D006442:Glycated Hemoglobin; C517652:hemoglobin A1c protein, human
keywords: Genome-wide association study; Glucose; Insulin resistance and diabetes; Non-enzymatic glycation; Premature aging processes