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

Front Endocrinol (Lausanne). 2024 Oct 28:15:1473329. doi: 10.3389/fendo.2024.1473329. eCollection 2024.

Abstract

Introduction: We investigated the genetic determinants of variation in the hemoglobin glycation index (HGI), an emerging biomarker for the risk of diabetes complications.

Methods: We conducted a genome-wide association study (GWAS) for HGI in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial (N = 7,913) using linear regression and additive genotype encoding on variants with minor allele frequency greater than 3%. We conducted replication analyses of top findings in the Atherosclerosis Risk in Communities (ARIC) study with inverse variance-weighted meta-analysis. We followed up with stratified GWAS analyses by sex and self-reported race.

Results: In ACCORD, we identified single nucleotide polymorphisms (SNPs) associated with HGI, including a peak with the strongest association at the intergenic SNP rs73407935 (7q11.22) (P = 5.8e-10) with a 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). The SNP-based heritability of HGI was 0.39 (P< 1e-10). HGI had significant sex-specific associations with SNPs in or near GALNT11 in women and HECW2 in men. Finally, in Hispanic participants, we observed genome-wide significant associations with variants near USF1 and NXNL2/SPIN1.

Discussion: 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. The results of this first evaluation of the genetic etiology of HGI indicate that it is highly heritable and point to heterogeneity by sex and race.

Keywords: ACCORD; ARIC; GWAS; HGI; HbA1c; genome-wide association study; hemoglobin glycation index.

MeSH terms

  • Aged
  • Biomarkers / blood
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism
  • Ethnicity / genetics
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study*
  • Genotype
  • Glycated Hemoglobin* / analysis
  • Glycated Hemoglobin* / genetics
  • Glycated Hemoglobin* / metabolism
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Sex Factors

Substances

  • Glycated Hemoglobin
  • Biomarkers

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This research was supported in part by the Intramural Research Program of the National Institute of Environmental Health Sciences.