C282Y Homozygosity Increases Erythrocyte Turnover and Decreases HbA1c—A Population-Based Study

Individuals with C282Y/C282Y in the hemochromatosis <i>HFE</i> gene have increased iron levels, which catalyze the formation of reactive oxygen species, and an increased risk of diabetes. These individuals may have disproportionately lower hemoglobin A1c (HbA1c) due to increased erythrocyte turnover, decreased erythrocyte counts, and/or an increased mean corpuscular hemoglobin concentration (MCHC). In the Copenhagen General Population Study (N = 103,734) and the Danish General Suburban Population Study (GESUS, N = 20,003), we investigated the association between C282Y/C282Y (N = 399) and other <i>HFE</i> genotypes with erythrocyte count, MCHC, mean corpuscular volume (MCV), red cell distribution width (RDW), and high-sensitivity C-reactive protein (hsCRP). In GESUS, we additionally investigated the association with oxidative stress (by 8-oxo-7,8-dihydroguanosine and 8-oxo-7,8-dihydro-2'-deoxyguanosine), reticulocyte count, reticulocyte hemoglobin, reticulocyte percentage as a proxy for erythrocyte turnover, and HbA1c in linear regressions adjusted for age, sex, cohort, and blood donation. We investigated the mediation between <i>HFE</i> genotype and HbA1c. Compared to non-carriers, individuals with C282Y/C282Y had increased p-iron, transferrin saturation, ferritin, hsCRP, oxidative stress, reticulocyte counts, reticulocyte percentage (1.24% vs. 1.06%, <i>p</i> = 1.7 × 10^-5) as a proxy for erythrocyte turnover, MCHC (344 vs. 340 g/L, <i>p</i> = 1.7 × 10^-12), MCH, MCV, reticulocyte hemoglobin, p-glucose (5.6 vs. 5.4, <i>p</i> = 0.007), bilirubin, and LDH and decreased RDW, erythrocyte counts (4.49 × 10¹²/L vs. 4.61 × 10¹²/L, <i>p</i> = 6.1 × 10^-11), estimated erythrocyte survival, and HbA1c (36 vs. 38 mmol/mol, <i>p</i> = 0.01). The associations were similar, although attenuated, for other <i>HFE</i> genotypes. The association between the <i>HFE</i> genotype and decreased HbA1c was partially mediated by increased transferrin saturation, MCHC, MCV, and decreased erythrocyte count, but not by hsCRP, reticulocyte count, oxidative stress, or blood donation. In conclusion, while C282Y/C282Y and other <i>HFE</i> genotypes increased erythrocyte turnover, the disproportionately decreased HbA1c level was explained by fewer but larger erythrocytes filled with more hemoglobin and removed earlier from circulation, thus diluting the relative concentration of intracellular glucose per hemoglobin molecule.