HbA1c Levels Are Genetically Determined Even in Type 1 Diabetes
Evidence From Healthy and Diabetic Twins
HbA1c, a measure of blood glucose regulation, reflects glucose levels in the preceding months. In diabetes, HbA1c levels predict the risk of microvascular complications. The aim of this study was to determine whether genetic factors could influence HbA1c levels in normal subjects and type 1 diabetic patients.
We performed a classical twin study of HbA1c in healthy nondiabetic female twins and 42 monozygotic (MZ) and 47 dizygotic (DZ) pairs. Interclass correlations (r) were higher in MZ (r = 0.77) compared with DZ (r = 0.53) twin pairs, suggesting a substantial genetic effect; this was confirmed by quantitative genetic model fitting. Additive genetic effects (heritability) explained 62% (95% CI 47–75) of population variance in HbA1c; the remainder was attributable to the influence of unique environment (23% [15–36]) and age (14% [5–28]). Multivariate modeling showed that genetic factors also have a substantial influence on fasting glucose levels (51%). However, HbA1c heritability could not be explained by genes in common with fasting glucose.
These significant correlations for HbA1c in both concordant and discordant pairs indicate a diabetes-independent familial effect. Thus, HbA1c levels are largely genetically determined and independent of the genes influencing fasting glucose. Even in type 1 diabetes, familial (i.e., diabetes-independent) factors influence protein glycation, implying that familial factors may explain, in part, the risk for microvascular complications, as indicated by high HbA1c levels.
Genetic factors could influence glycation of proteins by glucose-dependent or glucose-independent mechanisms. Glucose metabolism is, in part, genetically determined, and our study is in line with other twin and family studies that have shown substantial heritability of fasting glucose and postload glucose levels (22). Our heritability estimate of 51% for fasting glucose is comparable with another recent twin study that reported a heritability of 50% (19). However, fasting glucose plays only a small role in determining HbA1c levels in normal subjects, just as it does not precisely predict HbA1c levels in diabetic patients (6,23). Therefore, postprandial glucose may play a more important role in determining HbA1c levels. Although glycation of proteins is nonenzymatically determined, it is possible that genetic factors influence events upstream or downstream of the glycation process. What is surprising is that diabetes-independent familial factors appear to influence HbA1c levels in type 1 diabetic patients. These diabetes-independent factors are likely to affect the levels of both blood glucose and HbA1c and, hence, the risk of developing diabetic microvascular complications.
Alternatively, genetic factors could influence glycation of proteins by glucose-independent mechanisms. Thus, levels of HbA1c can be influenced by rates of hemoglobin glycation, red cell survival, oxygen tension, 2,3-diphosphoglycerate levels, intra-erythrocyte pH, and erythrocyte glucose permeability (24,25,26). Certainly, HbA1c reproducibility is improved by testing blood samples taken within 4 months (i.e., within the normal erythrocyte life span).
Glycation of proteins is probably important in leading to diabetic microvascular complications, and inhibition of protein glycation can prevent their development (27). These diabetic microvascular complications tend to cluster in families, partly because of genes that remain unidentified (28). Studies seeking these genes have focused on determinants of blood pressure and tissue oxidation; our present study suggests that genes influencing levels of protein glycation and/or glucose metabolism could also be important.
Clinically, it will be important to establish the extent to which HbA1c levels reflect genetically determined protein glycation as distinct from genetically determined glucose metabolism, which could account for the occasional anomalies between HbA1c levels and blood glucose levels, microvascular complications, or both (1,2,26). Our present observations explain the tendency for HbA1c to “track” at certain levels in particular individuals. Because much of the variation in HbA1c levels between individuals is inherited, elevated HbA1c levels may indicate an increased familial risk of diabetic microvascular disease.