Does genetic ancestry explain higher values of glycated hemoglobin in African Americans?

OBJECTIVE - Glycated hemoglobin (HbA_1c) values are higher in African Americans than whites, raising the question of whether classification of diabetes status by HbA_1c should differ for African Americans. We investigated the relative contribution of genetic ancestry and nongenetic factors to HbA_1c values and the effect of genetic ancestry on diabetes classification by HbA_1c in African Americans. RESEARCH DESIGN AND METHODS - We performed a cross-sectional analysis of data from the community-based Atherosclerosis Risk in Communities (ARIC) Study. We estimated percentage of European genetic ancestry (PEA) for each of the 2,294 African Americans without known diabetes using 1,350 ancestry-informative markers. HbA_1c was measured from wholeblood samples and categorized using American Diabetes Association diagnostic cut points (<5.7, 5.7-6.4, and ≥6.5%). RESULTS - PEA was inversely correlated with HbA_1c (adjusted r = -0.07; P < 0.001) but explained <1% of its variance. Age and socioeconomic and metabolic factors, including fasting glucose, explained 13.8% of HbA_1c variability. Eleven percent of participants were classified as having diabetes; adjustment for fasting glucose decreased this to 4.4%. Additional adjustment for PEA did not significantly reclassify diabetes status (net reclassification index = 0.034; P = 0.94) nor did further adjustment for demographic, socioeconomic, and metabolic risk factors. CONCLUSIONS - The relative contribution of demographic and metabolic factors far outweighs the contribution of genetic ancestry to HbA_1c values in African Americans. Moreover, the impact of adjusting for genetic ancestry when classifying diabetes by HbA_1c is minimal after taking into account fasting glucose levels, thus supporting the use of currently recommended HbA_1c categories for diagnosis of diabetes in African Americans.