Genetic Determinants of Variability in Glycated Hemoglobin (HbA1c) in Humans: Review of Recent Progress and Prospects for Use in Diabetes Care

Glycated hemoglobin A(1c) (HbA(1c)) indicates the percentage of total hemoglobin that is bound by glucose, produced from the nonenzymatic chemical modification by glucose of hemoglobin molecules carried in erythrocytes. HbA(1c) represents a surrogate marker of average blood glucose concentration over the previous 8 to 12 weeks, or the average lifespan of the erythrocyte, and thus represents a more stable indicator of glycemic status compared with fasting glucose. HbA(1c) levels are genetically determined, with heritability of 47% to 59%. Over the past few years, inroads into understanding genetic predisposition by glycemic and nonglycemic factors have been achieved through genomewide analyses. Here I review current research aimed at discovering genetic determinants of HbA(1c) levels, discussing insights into biologic factors influencing variability in the general and diabetic population, and across different ethnicities. Furthermore, I discuss briefly the relevance of findings for diabetes monitoring and diagnosis.