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

Area of Science:

• Genetics and Molecular Biology
• Hematology
• Endocrinology

Background:

• Hemochromatosis HFE C282Y/C282Y genotype is linked to increased iron levels and diabetes risk.
• Altered red blood cell dynamics, including erythrocyte turnover and hemoglobin concentration, may influence HbA1c measurements in these individuals.

Purpose of the Study:

• To investigate the association between HFE genotypes and erythrocyte parameters.
• To explore the relationship between HFE genotype, erythrocyte turnover, and HbA1c levels.
• To identify mediating factors in the association between HFE genotype and HbA1c.

Main Methods:

• Analysis of large population cohorts (Copenhagen General Population Study and GESUS).
• Investigated HFE genotypes (C282Y/C282Y and others) against erythrocyte count, MCHC, MCV, RDW, hsCRP, oxidative stress markers, and HbA1c.
• Utilized linear regressions and mediation analysis.

Main Results:

• C282Y/C282Y carriers exhibited increased iron, hsCRP, oxidative stress, reticulocyte counts, MCHC, and MCV, alongside decreased erythrocyte counts and HbA1c compared to non-carriers.
• Other HFE genotypes showed similar, though attenuated, associations.
• Decreased HbA1c was partially mediated by increased transferrin saturation, MCHC, MCV, and decreased erythrocyte count.

Conclusions:

• HFE genotypes, particularly C282Y/C282Y, are associated with increased erythrocyte turnover and altered red blood cell indices.
• The observed lower HbA1c in HFE carriers is attributed to a combination of fewer, larger erythrocytes with higher hemoglobin concentration, and earlier removal from circulation, diluting intracellular glucose concentration.