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 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 journalArticle

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 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
Volume63
Issue number4
DOIs
StatePublished - 2014

Fingerprint

Genome-Wide Association Study
Glycosylated Hemoglobin A
Premature Aging
Glycemic Index
Denmark
Body Composition
Hyperglycemia
Cluster Analysis
Insulin Resistance
Atherosclerosis
Mortality
Health

Keywords

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

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Genome-wide association study identifies common loci influencing circulating glycated hemoglobin (HbA1c) levels in non-diabetic subjects : The Long Life Family Study (LLFS). / An, Ping; Miljkovic, Iva; Thyagarajan, Bharat; Kraja, Aldi T.; Daw, E. Warwick; Pankow, James S.; Selvin, Elizabeth; Kao, W. H Linda; Maruthur, Nisa; Nalls, Micahel A.; Liu, Yongmei; Harris, Tamara B.; Lee, Joseph H.; Borecki, Ingrid B.; Christensen, Kaare; Eckfeldt, John H.; Mayeux, Richard; Perls, Thomas T.; Newman, Anne B.; Province, Michael A.

In: Metabolism, Vol. 63, No. 4, 2014, p. 461-468.

Research output: Contribution to journalArticle

An, P, Miljkovic, I, Thyagarajan, B, Kraja, AT, Daw, EW, Pankow, JS, Selvin, E, Kao, WHL, Maruthur, N, Nalls, MA, Liu, Y, Harris, TB, Lee, JH, Borecki, IB, Christensen, K, Eckfeldt, JH, Mayeux, R, Perls, TT, Newman, AB & Province, MA 2014, 'Genome-wide association study identifies common loci influencing circulating glycated hemoglobin (HbA1c) levels in non-diabetic subjects: The Long Life Family Study (LLFS)', Metabolism, vol. 63, no. 4, pp. 461-468. https://doi.org/10.1016/j.metabol.2013.11.018
An, Ping ; Miljkovic, Iva ; Thyagarajan, Bharat ; Kraja, Aldi T. ; Daw, E. Warwick ; Pankow, James S. ; Selvin, Elizabeth ; Kao, W. H Linda ; Maruthur, Nisa ; Nalls, Micahel A. ; Liu, Yongmei ; Harris, Tamara B. ; Lee, Joseph H. ; Borecki, Ingrid B. ; Christensen, Kaare ; Eckfeldt, John H. ; Mayeux, Richard ; Perls, Thomas T. ; Newman, Anne B. ; Province, Michael A. / Genome-wide association study identifies common loci influencing circulating glycated hemoglobin (HbA1c) levels in non-diabetic subjects : The Long Life Family Study (LLFS). In: Metabolism. 2014 ; Vol. 63, No. 4. pp. 461-468.
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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 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 1c 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.",
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TY - JOUR

T1 - Genome-wide association study identifies common loci influencing circulating glycated hemoglobin (HbA1c) levels in non-diabetic subjects

T2 - The Long Life Family Study (LLFS)

AU - An, Ping

AU - Miljkovic, Iva

AU - Thyagarajan, Bharat

AU - Kraja, Aldi T.

AU - Daw, E. Warwick

AU - Pankow, James S.

AU - Selvin, Elizabeth

AU - Kao, W. H Linda

AU - Maruthur, Nisa

AU - Nalls, Micahel A.

AU - Liu, Yongmei

AU - Harris, Tamara B.

AU - Lee, Joseph H.

AU - Borecki, Ingrid B.

AU - Christensen, Kaare

AU - Eckfeldt, John H.

AU - Mayeux, Richard

AU - Perls, Thomas T.

AU - Newman, Anne B.

AU - Province, Michael A.

PY - 2014

Y1 - 2014

N2 - 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 1c 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.

AB - 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 1c 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.

KW - Genome-wide association study

KW - Glucose

KW - Insulin resistance and diabetes

KW - Non-enzymatic glycation

KW - Premature aging processes

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