Impact of Genetic Determinants of HbA1c on Type 2 Diabetes Risk and Diagnosis.

PURPOSE OF REVIEW: Glycated hemoglobin (A1c) is used to diagnose type 2 diabetes and monitor glycemic control. Specific genetic variants interfere with A1c and effects/frequencies of some variants vary by ancestry. In this review, we summarize findings from large trans-ethnic meta-analyses of genome-wide association studies (GWAS) of A1c and describe some variants influencing erythrocyte biology and interfering with A1c. RECENT FINDINGS: Recent GWAS meta-analyses have revealed 60 loci associated with A1c in multi-ethnic populations. The main A1c genetic driver in African Americans is rs1050828 (G6PD). Some identified loci are located in/near genes known as monogenic causes of erythrocytic disorders (ANK1, SPTA1) or iron disorders (TMPRSS6, HFE). Uncommon genetic variants (not revealed by GWAS) that are known to cause hemoglobinopathies may also influence A1C levels, partly by interfering with laboratory assays. Specific genetic variants that have a large impact on A1c levels may influence clinical practice, especially in individuals of African descent. Efforts to reveal novel A1c loci should focus on increasing representation of GWAS in non-European ancestries, and on using better genome-wide coverage of uncommon variants that are specific to each population.