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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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 House, Breeyear, Akhtari, Evans, Buse, Hempe, Doria, Mychaleckyi, Fonseca, Shi, Li, Liu, Kelly, Rotroff and Motsinger-Reif.)

Metformin is the first-line treatment for type 2 diabetes (T2D). Although widely prescribed, the glucose-lowering mechanism for metformin is incompletely understood. Here, we used a genome-wide association approach in a diverse group of individuals with T2D from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial to identify common and rare variants associated with HbA 1c response to metformin treatment and followed up these findings in four replication cohorts. Common variants in PRPF31 and CPA6 were associated with worse and better metformin response, respectively ( P < 5 × 10 -6 ), and meta-analysis in independent cohorts displayed similar associations with metformin response ( P = 1.2 × 10 -8 and P = 0.005, respectively). Previous studies have shown that PRPF31 (+/-) knockout mice have increased total body fat ( P = 1.78 × 10 -6 ) and increased fasted circulating glucose ( P = 5.73 × 10 -6 ). Furthermore, rare variants in STAT3 associated with worse metformin response ( q <0.1). STAT3 is a ubiquitously expressed pleiotropic transcriptional activator that participates in the regulation of metabolism and feeding behavior. Here, we provide novel evidence for associations of common and rare variants in PRPF31, CPA6, and STAT3 with metformin response that may provide insight into mechanisms important for metformin efficacy in T2D., (© 2018 by the American Diabetes Association.)

Individuals with type 2 diabetes (T2D) and dyslipidemia are at an increased risk of cardiovascular disease. Fibrates are a class of drugs prescribed to treat dyslipidemia, but variation in response has been observed. To evaluate common and rare genetic variants that impact lipid responses to fenofibrate in statin-treated patients with T2D, we examined lipid changes in response to fenofibrate therapy using a genomewide association study (GWAS). Associations were followed-up using gene expression studies in mice. Common variants in SMAD3 and IPO11 were marginally associated with lipid changes in black subjects (P < 5 × 10 -6 ). Rare variant and gene expression changes were assessed using a false discovery rate approach. AKR7A3 and HSD17B13 were associated with lipid changes in white subjects (q < 0.2). Mice fed fenofibrate displayed reductions in Hsd17b13 gene expression (q < 0.1). Associations of variants in SMAD3, IPO11, and HSD17B13, with gene expression changes in mice indicate that transforming growth factor-beta (TGF-β) and NRF2 signaling pathways may influence fenofibrate effects on dyslipidemia in patients with T2D., (© 2017 American Society for Clinical Pharmacology and Therapeutics.)