Response to Comment on: Maruthur et al. Does Genetic Ancestry Explain Higher Values of Glycated Hemoglobin in African Americans? Diabetes 2011;60:2434–2438

We appreciate the interest of Dagogo-Jack (1) in our study of genetic ancestry and HbA_1c in African Americans (2). We interpret his major concerns as follows: 1) HbA_1c values may have a glucose-independent genetic component and 2) in our study, adjustment for glucose did not fully account for HbA_1c values ≥6.5%.

Our goal was to evaluate if differences in genetic ancestry might explain differences in HbA_1c between individuals of African and European ancestry observed in previous studies. Although the heritability of HbA_1c approaches 60% in twin studies (3) and “glucose-independent” genetic loci for HbA_1c have been found in populations of European descent (4), our results indicate that genetic loci accounting for the heritability of HbA_1c are not likely to be population-specific or have large population differences.

After accounting for fasting glucose, we observed a prevalence of undiagnosed diabetes of 4.4% defined by HbA_1c ≥6.5% (2), but as in prior studies, including that cited by Dagogo-Jack (5), adjustment for glucose was based on a single measurement and should be distinguished from average glucose (6). The within-person variability of a single glucose measurement is substantially higher than that of HbA_1c (7). Thus, we cannot conclude that individuals shifted from the diabetes to the nondiabetes category in our analysis had normal glucose homeostasis. Single HbA_1c and glucose measures communicate different information about glucose homeostasis in an individual. The availability of only a single glucose measure is a limitation of many epidemiological studies of glucose homeostasis, and the discrepancy between measures alone does not establish HbA_1c as an inferior test.

We agree that our analyses cannot provide a definitive explanation for the black-white difference in HbA_1c, but we feel strongly that there is little to suggest a strong genetic ancestral determinant of this difference. Our results support current recommendations for the use of HbA_1c to diagnose diabetes in all ethnic groups (8).