ESPE Yearbook of Paediatric Endocrinology

This GWAS meta-analysis combined data from five well known ethnically diverse cohorts (Framingham Heart Study, Atherosclerosis Risk in Communities Study, Multiethnic Study of Atherosclerosis, Taiwan-Metabochip Study for Cardiovascular Disease, and Singapore Prospective Study) to evaluate glycemic and erythrocytic genetic variants impacting HbA1c in individuals of European, African American, and East Asians ancestry. The study found new and known glycemic and erythrocytic genetic variants to influence HbA1c and determined that these variants’ contribution to T2DM risk is strongly determined by ancestry. The paper thus sheds light on important questions on the differential interpretation of HbA1c based on ethnic background. Genetic glycemic variants, while increasing T2DM risk in Europeans and East Asians, are not associated with increased risk in African Americans. Conversely, genetic erythrocytic variants, in particular the G202A variant in G6PD, confer up to 0.8% lower HbA1c values in African Americans, suggesting higher numbers of false negatives on T2DM screening when using the current HbA1c threshold of >6.5%; the optimal threshold to diagnose T2DM in this population is likely lower. This important finding not only underscores the importance to consider genetic determinants in the development, choice and interpretation of screening and diagnostic tests, but also highlights the need to advocate for equitable inclusion of populations of diverse ancestry in biomedical research. A relatively small number of persons of African and Asian ancestry was one of the main limitations of this study, limiting the discovery of new ancestry-specific variants in the very populations in whom questions remain about the interpretation the HbA1c, including about its diagnostic threshold, extrapolation of estimated average glucose, estimation of glycemic control, and complication risk.