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

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.

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 whole-blood samples and categorized using American Diabetes Association diagnostic cut points (<5.7, 5.7-6.4, and ≥6.5%).

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.

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.