A1c accuracy is important for diabetes management but mismatches in A1c relative to underlying glucose can impede care. Since the basis for mismatches is poorly understood, we assessed the contributions of 22 A1c variants identified in GWAS that were associated with erythrocytic traits but not glycemia. 73,128 MVP patients had continuity of care and monitoring: >1 PCP visit, >1 outpatient random plasma glucose (RPG) and >1 A1c within each of 3 consecutive two-year periods. They had mean age 67 years and BMI 31 kgm-2; 71% were white and 21% were black; 51% had diabetes (ICD 9 codes and diabetes Rx). Mismatches were defined by the hemoglobin glycation index (HGI) calculated from regression residuals of mean A1c on mean RPG within each period, averaged over the 3 periods. We evaluated the associations with HGI of each A1c variant and a genetic risk score (GRS; sum of alleles weighted by their reported A1c effect sizes) by race. Mean HGI was -0.07% A1c units in whites and 0.2% in blacks. Of the 22 variants, 15 at 13 loci were associated with HGI (P<5 x 10-8, ANK1, CNTN5, ERAL1, G6PD, HBS1L/MYB, HK1, HIST1H4A/HFE, MYO9B, SENP1, SPTA1, SYN2, TMPRSS6 and PEIZO1). GRS was associated with HGI (whites P=2 x 10-189, blacks P=1 x 10-233) and explained HGI variance (whites 1.7%, blacks 5.1%), especially in those without diabetes (whites 3.5%, blacks 11.4%). People in the lowest 10% of GRS had a glucose-independent fall in A1c (mean HGI, whites -0.19%, blacks -0.31% A1c units) while those in the highest 10% of GRS had the opposite (mean HGI, whites 0.06%, blacks 0.29%). The variants with the largest effects on HGI were rs1800562/HIST1H4A/HFE [mean HGI, AA: -0.37%, GG: -0.06% A1c units] in whites and rs1050828/G6PD [mean HGI, T: -0.31%; C: 0.29% A1c units] in black men.

Conclusions: HGI is higher in blacks than whites - a glucose-independent higher A1c. Common genetic variation explains 2-11% of the variance in HGI. Accounting for genetic variation in A1c may improve its accuracy in guiding diabetes care.


A. Leong: None. D. Posner: None. B.R. Charest: None. J.B. Meigs: None. P.W. Wilson: None. R.M. Cohen: Stock/Shareholder; Self; Bristol-Myers Squibb Company. D.R. Miller: None. Y.V. Sun: None. K. Cho: None. L.S. Phillips: Other Relationship; Self; DIASYST Inc.. Research Support; Self; Amylin Pharmaceuticals, Eli Lilly and Company, Novo Nordisk Inc., Sanofi-Aventis, PhaseBio Pharmaceuticals, Inc., Roche Diabetes Care Health and Digital Solutions, AbbVie Inc., Vascular Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., GlaxoSmithKline plc., Pfizer Inc.. Other Relationship; Self; Novartis Pharmaceuticals Corporation, Merck & Co., Inc..

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