A Genome-Wide Association Study of Treated A1C

A Genetic Needle in an Environmental Haystack?

  1. Jose C. Florez
  1. From the Massachusetts General Hospital/Harvard Medical School, Center for Human Genetic Research and Diabetes Research Center (Diabetes Unit), Boston, Massachusetts.
  1. Corresponding author: Jose C. Florez, jcflorez{at}partners.org.

Glycated hemoglobin (A1C), expressed as a percentage of total hemoglobin, results from the nonenzymatic glycation of hemoglobin molecules. Because this irreversible process is directly proportional to intracellular glucose concentrations (which are generally correlated with extracellular glucose levels), A1C can be used as a marker of average ambient glycemia over the mean life span of erythrocytes. Absent alterations in hemoglobin turnover or erythrocyte physiology, A1C adequately captures glucose homeostasis in the organism. Therefore, it has been widely adopted as an indicator of glycemic control in the treatment of diabetic patients (1), and it has recently been proposed as a diagnostic test for diabetes (2).

Variation in A1C is subject to environmental and genetic determinants. Its heritability (the proportion of the variance explained by the familial contribution to the trait, integrating both genetic and early shared environmental components) nears 40% in the general population (3) and 60% in twin studies (4). The distribution of A1C displays a long tail to the right, populated by levels of people whose hyperglycemia signals diabetes. Pharmacological treatment can significantly reduce A1C, providing the rationale for near normalization of A1C as a treatment goal (1). This is particularly true for insulin as a therapeutic modality: barring hypoglycemia and other practical limitations, insulin can be gradually raised until the target A1C has been reached. Thus, presumably higher insulin doses should be able to overcome most endogenous (i.e., genetic) obstacles to lowering A1C. In the setting of treated A1C, therefore, the environmental contribution to the trait acquires a much larger role than that in the native state, and one might suspect that it could overwhelm any genetic component (Fig. 1).

FIG. 1.

Simplified theoretical model illustrating the potential contributors to A1C levels in the native (left) or treated (right) states. The heritability of native A1C is estimated to be …

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