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PURPOSE: HbA1c levels are higher in blacks than non-Hispanic whites (NHWs). We investigated whether genetics could explain this difference in Diabetes Prevention Program (DPP) participants.

METHODS: We tested (i) genetic variants causing hemoglobinopathies, (ii) a genetic risk score (GRS) based on 60 variants associated with HbA1c from genome-wide association meta-analysis, and (iii) principal component (PC) factors that capture continental ancestry derived from genetic markers distributed across the genome.

RESULTS: Of 2658 eligible DPP participants, 537 (20%) self-identified as black and 1476 (56%) as NHW. Despite comparable fasting and 2-hour glucose levels, blacks had higher HbA1c (mean ± SD = 6.2 ± 0.6%) compared with NHWs (5.8 ± 0.4%; P 0.001). In blacks, the genetic variant causing sickle cell trait was associated with higher HbA1c [β (SE) = +0.44 (0.08)%; P = 2.1 × 10-4]. The GRS was associated with HbA1c in both blacks and NHWs. Self-identified blacks were distributed along the first PC axis, as expected in mixed ancestry populations. The first PC explained 60% of the 0.4% difference in HbA1c between blacks and NHWs, whereas the sickle cell variant explained 16% and GRS explained 14%.

CONCLUSIONS: A large proportion of HbA1c difference between blacks and NHWs was associated with the first PC factor, suggesting that unidentified genetic markers influence HbA1c in blacks in addition to nongenetic factors.