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

Ping An, Iva Miljkovic, Bharat Thyagarajan, Aldi T. Kraja, E. Warwick Daw, James S. Pankow, Elizabeth Selvin, W. H.Linda Kao, Nisa M. Maruthur, Micahel A. Nalls, Yongmei Liu, Tamara B. Harris, Joseph H. Lee, Ingrid B. Borecki, Kaare Christensen, John H. Eckfeldt, Richard Mayeux, Thomas T. Perls, Anne B. Newman, Michael A. Province

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


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 HbA 1c 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.

Original languageEnglish (US)
Pages (from-to)461-468
Number of pages8
JournalMetabolism: clinical and experimental
Issue number4
StatePublished - Apr 2014

Bibliographical note

Funding Information:
The Long Life Family Study (LLFS): The Long Life Family Study was supported by the National Institute on Aging (NIA) grants U01AG023712, U01AG023744, U01AG023746, U01AG023749, U01AG023755, U19AG023122, K24AG025727, R01AG032319 , the Glenn Medical Research Foundation , and the National Heart Lung Blood Institute (NHLBI, R21HL114237 ). The content is solely the responsibility of the authors, and does not necessarily represent the official views of the NIA or the National Institutes of Health (NIH). The Atherosclerosis Risk in Communities (ARIC) Study: The Atherosclerosis Risk in Communities Study was carried out as a collaborative study supported by the NHLBI contracts ( HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694 ; the National Human Genome Research Institute contract U01HG004402 ; and the NIH contract HHSN268200625226C . The authors thank the staff and participants of the ARIC Study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005 , a component of the NIH and NIH Roadmap for Medical Research . This research was supported in part by NIH/NIDDK grants R21DK080294 and K01DK076595 (E.S.) and K01067207 (W.H.L.K.). The Health, Aging, and Body Composition (Health ABC) Study: The Health, Aging, and Body Composition Study was supported by the NIA contracts N01AG62101, N01AG62103, and N01AG62106 , and in part by the Intramural Research Program of the NIH, NIA . The genome-wide association study was funded by the NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the NIH to the Johns Hopkins University, contract number HHSN268200782096C .


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


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