AUTHOR=House John S. , Breeyear Joseph H. , Akhtari Farida S. , Evans Violet , Buse John B. , Hempe James , Doria Alessandro , Mychaleckyi Josyf C. , Fonseca Vivian , Shi Mengyao , Li Changwei , Liu Shuqian , Kelly Tanika N. , Rotroff Daniel , Motsinger-Reif Alison A. 

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

JOURNAL=Frontiers in Endocrinology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1473329

DOI=10.3389/fendo.2024.1473329

ISSN=1664-2392

ABSTRACT=<sec><title>Introduction</title><p>We investigated the genetic determinants of variation in the hemoglobin glycation index (HGI), an emerging biomarker for the risk of diabetes complications.</p></sec><sec><title>Methods</title><p>We conducted a genome-wide association study (GWAS) for HGI in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial (<italic>N</italic> = 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.</p></sec><sec><title>Results</title><p>In ACCORD, we identified single nucleotide polymorphisms (SNPs) associated with HGI, including a peak with the strongest association at the intergenic SNP <italic>rs73407935</italic> (7q11.22) (<italic>P</italic> = 5.8e−10) with a local replication in ARIC. In black individuals, the variant <italic>rs10739419</italic> on chromosome 9 in the Whirlin (<italic>WHRN</italic>) gene formally replicated (meta-<italic>P</italic> = 2.2e−9). The SNP-based heritability of HGI was 0.39 (<italic>P</italic>&lt; 1e−10). HGI had significant sex-specific associations with SNPs in or near <italic>GALNT11</italic> in women and <italic>HECW2</italic> in men. Finally, in Hispanic participants, we observed genome-wide significant associations with variants near <italic>USF1</italic> and <italic>NXNL2/SPIN1</italic>.</p></sec><sec><title>Discussion</title><p>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.</p></sec>