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ORIGINAL RESEARCH article

Front. Endocrinol.
Sec. Diabetes: Molecular Mechanisms
Volume 15 - 2024 | doi: 10.3389/fendo.2024.1473329

Genome-wide association study identifies genetic determinants of hemoglobin glycation index with implications across sex and ethnicity

Provisionally accepted
John S. House John S. House 1Joseph H. Breeyear Joseph H. Breeyear 1Farida S. Akhtari Farida S. Akhtari 1Violet Evans Violet Evans 1John B. Buse John B. Buse 2James Hempe James Hempe 3Alessandro Doria Alessandro Doria 4Josyf C. Mychaleckyi Josyf C. Mychaleckyi 5Vivian Fonseca Vivian Fonseca 6Mengyao Shi Mengyao Shi 7Changwei Li Changwei Li 7Shuqian Liu Shuqian Liu 7Tanika N. Kelly Tanika N. Kelly 7,8Daniel Rotroff Daniel Rotroff 9Alison Motsinger-Reif Alison Motsinger-Reif 1*
  • 1 National Institute of Environmental Health Sciences (NIH), Durham, United States
  • 2 School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • 3 School of Medicine, Louisiana State University, New Orleans, Louisiana, United States
  • 4 Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, United States
  • 5 School of Medicine, University of Virginia, Charlottesville, Virginia, United States
  • 6 School of Medicine, Tulane University, New Orleans, Louisiana, United States
  • 7 Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, United States
  • 8 Translational Science Institute, School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana, United States
  • 9 Cleveland Clinic, Cleveland, Ohio, United States

The final, formatted version of the article will be published soon.

    We investigated genetic determinants of variation in the hemoglobin glycation index (HGI), an emerging biomarker for risk of diabetes complications. We conducted genome-wide association analyses in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial (N=7,913) and formally replicated top findings in the Atherosclerosis Risk in Communities (ARIC) study. In ACCORD, we identified single nucleotide polymorphisms (SNPs) associated with HGI, including a peak with the strongest association at intergenic SNP rs73407935 (7q11.22) (P=5.8e-10) with local replication in ARIC. In black individuals, the variant rs10739419 on chromosome 9 in the Whirlin (WHRN) gene formally replicated (meta-P=2.2e-9). SNP-based heritability of HGI was 0.39 (P < 1e-10). Many HGI-associated SNPs were distinct from those associated with fasting plasma glucose or HbA1c, lending further support for HGI as a distinct biomarker of diabetes complications. HGI had significant sex-specific associations with SNPs in or near GALNT11 in women and HECW2 in men. Lastly, in Hispanic participants, we observed genome-wide significant associations with variants near USF1 and NXNL2/SPIN1. The results of the first evaluation of the genetic etiology of HGI indicate it is highly heritable and point to heterogeneity by sex and race.

    Keywords: Hemoglobin glycation index, HGI, HbA1c, Accord, ARIC, GWAS, genome-wide association study Font: Italic Formatted: Font: Italic Font: Italic Formatted: Font: Italic for n=3, 741 Normal

    Received: 30 Jul 2024; Accepted: 03 Oct 2024.

    Copyright: © 2024 House, Breeyear, Akhtari, Evans, Buse, Hempe, Doria, Mychaleckyi, Fonseca, Shi, Li, Liu, Kelly, Rotroff and Motsinger-Reif. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Alison Motsinger-Reif, National Institute of Environmental Health Sciences (NIH), Durham, United States

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