Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Wellcome Sanger Institute
  • Massachusetts General Hospital
  • Harvard University
  • Boston University
  • Karolinska Institutet
  • University of Cambridge
  • University of Lausanne
  • Johns Hopkins University
  • University of Utah
  • University of California at Los Angeles
  • National University of Singapore
  • National Institutes of Health (NIH)
  • Imperial College London
  • London North West University Healthcare NHS Trust
  • Jilin University
  • Johns Hopkins Medicine
  • Vanderbilt University
  • Academia Sinica - Institute of Biomedical Sciences
  • University of Virginia
  • AstraZeneca
  • California Pacific Medical Center
  • Korea National Institute of Health
  • Vrije Universiteit Amsterdam (VU)
  • University of Chinese Academy of Sciences
  • University of Michigan, Ann Arbor
  • Queen Mary University of London
  • Heidelberg University 
  • Uppsala University
  • Lund University
  • Université de Lille
  • Singapore National Eye Center
  • Icahn School of Medicine at Mount Sinai
  • University of Oxford
  • Helmholtz Zentrum München - German Research Center for Environmental Health
  • German Center for Diabetes Research (DZD e.V.)
  • Data Tecnica International
  • University of Edinburgh
  • University of Groningen
  • National Research Council of Italy (CNR)
  • Keck School of Medicine at University of Southern California
  • National Center for Global Health and Medicine

Abstract

Background: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes. Methods & findings: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04–1.06, per HbA1c-raising allele, p = 3 × 10−29); whereas GS-E was not (OR = 1.00, 95% CI 0.99–1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66–0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38–0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55–0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants. Conclusions: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.

Details

Original languageEnglish
Article numbere1002383
JournalPLoS medicine
Volume14
Issue number9
Publication statusPublished - Sept 2017
Peer-reviewedYes

External IDs

PubMed 28898252

Keywords

Sustainable Development Goals

ASJC Scopus subject areas