The hemoglobin glycation index (HGI) is the difference between observed HbA1c and predicted HbA1c from FPG using linear regression. HGI is an important biomarker of clinical management/drug treatment outcomes and can identify individuals at high risk for multiple adverse events and outcomes before the appearance of clinical symptoms. Here, we sought to test if variation in HGI has genetic determinants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial using a genome-wide association approach (N = 7913) . We subsequently replicated the top hits (P < 1e-5) in the Atherosclerosis Risk in Communities Study (ARIC; N = 3741) . An intergenic SNP rs73407935 (7q11.22) was associated with HGI (P = 5.8e-10) with the locus replicating in ARIC. Further, multiple variants at suggestive genome-wide significance in discovery (P < 5e-6) replicated in ARIC including variants near or in ASAH1 (P = 2.4e-6) , a region previously associated with risk of CAD in T2D, LRRC4C (P = 2.4e-6) , SHLD1 (P = 3.7e-6) and FAM22B (P = 2.5e-6) . The top 2 replicated SNPs in FAM22B are characterized eQTLs for expression of multiple genes in cells from pancreas, brain, and the immune system, including TRAF4, PROCA1, and RPL23A. Many SNPs associated with HGI were distinct from those associated with FPG or HbA1c. In ACCORD, sex-specific HGI associations with SNPs in or near GALNT11 in females (P = 5e-9) and HECW2 (P = 1.5e-8) in males were observed. Further, analysis of 544 Hispanics revealed associations of a strong eQTL variant near USF1 (rs2516837; P = 1.5e-09) and SNPs near NXNL2/SPIN1 (rs141006133; P = 6.9e-9) with HGI. This work represents the first evaluation of the genetic etiology of HGI. We identified and replicated variants that merit further study in the development of precision medicine for treatment of T2D. The results of the stratified analyses highlight the potential importance of heterogeneity in these efforts.


J.S.House: None. D.M.Rotroff: Research Support; Novo Nordisk, Stock/Shareholder; Clarified Precision Medicine. V.Fonseca: Consultant; Abbott, Asahi Kasei Corporation, Bayer AG, Novo Nordisk, Sanofi, Research Support; Fractyl Health, Inc., Jaguar Gene Therapy, Stock/Shareholder; Abbott, Amgen Inc., BRAVO4Health, Mellitus Health. J.M.Hempe: None. J.Mychaleckyj: None. A.Doria: Research Support; Novo Nordisk Foundation. J.B.Buse: Consultant; Alkahest, Anji, AstraZeneca, Boehringer Ingelheim International GmbH, Cirius Therapeutics, Inc., Eli Lilly and Company, Fortress biotech, GentiBio, Glycadia, Glyscend, Janssen Pharmaceuticals, Inc., Mellitus Health, Moderna, Inc., Pendulum Therapeutics, Praetego, LLC, Stability Health, Valo, Zealand Pharma A/S, Other Relationship; Adocia, AstraZeneca, Eli Lilly and Company, Intarcia Therapeutics, Inc., MannKind Corporation, Novo Nordisk, Sanofi, Senseonics, vTv Therapeutics, Research Support; AstraZeneca, Dexcom, Inc., Eli Lilly and Company, Novo Nordisk, vTv Therapeutics, Stock/Shareholder; Glyscend, Mellitus Health, Pendulum Therapeutics, PhaseBio Pharmaceuticals, Inc., Praetego, LLC, Stability Health. A.Motsinger-reif: None.



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