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Metabolism. 2014 Apr;63(4):461-8. doi: 10.1016/j.metabol.2013.11.018. Epub 2013 Dec 4.

Genome-wide association study identifies common loci influencing circulating glycated hemoglobin (HbA1c) levels in non-diabetic subjects: the Long Life Family Study (LLFS).

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Department of Genetics Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, USA. Electronic address:
University of Pittsburgh, Graduate School of Public Health, Department of Epidemiology, Center for Aging and Population Health, Pittsburgh, PA, USA.
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
Department of Genetics Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, USA.
Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA.
Department of Epidemiology, Johns Hopkins University, Baltimore, MD, USA.
Division of General Internal Medicine, Johns Hopkins University, Baltimore, MD, USA.
Laboratory of Neurogenetics, NIA/NIH, Bethesda, MD, USA.
Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest University, Winston-Salem, NC, USA.
Laboratory of Epidemiology, Demography and Biometry, NIA/NIH, Bethesda, MD, USA.
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.
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.
Division of Geriatrics, Department of Medicine, Boston University Medical Center, Boston, MA, USA.



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.


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.


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.


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.


Genome-wide association study; Glucose; Insulin resistance and diabetes; Non-enzymatic glycation; Premature aging processes

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