HEMATOLOGICAL SEQUELAE OF HFE P.C282C HOMOZYGISITY IN FOUR LARGE GENETIC COHORTS

Genetic cohorts provide powerful tools to assess in an unbiased manner the longterm consequences of specific genotypes. HFE p.C282Y homozygosity is characterized by disordered systemic iron homeostasis leading to hereditary hemochromatosis in a subset of people. Recent studies have suggested that HFE p.C282Y homozygosity is overrepresented in polycythemia vera (PV) and disordered hepcidin suggested to govern the erythroid phenotype. We have performed a phenome wide association meta-analysis on four genetic cohorts (970,000 individuals, 5982 being HFE homozygous). The analysis included extensive case-control and continuous quantitative phenotypes. We present here the results for hematological phenotypes. 

The cohorts were from Iceland (deCODE genetics), the UK (UK Biobank), Denmark (Copenhagen Hospital Biobank/Danish Blood Donor Study) and USA (Intermountain Healthcare).  Sub-cohorts within UK and Iceland included data on clonal hematopoiesis, including JAK2-V617F mutations. 

C282Y homozygotes had a higher prevalence of PV (OR=7.24 p=4.37x10^-24), while no association was seen with clonal hematopoiesis (OR=1.09, 95% CI 0.88 to 1.34, p=0.43). Strong association was found between C282Y homozygosity and increased hemoglobin (0.41 SDs,  p=6.84x10^-142), MCH (0.98 p=<1x10^-300) and MCV (0.82 p=<1x10^-300). RBC was decreased (-0.27 p=1.06x10^-50), while reticulocyte count (0.30, p=1.42x10^-54) and percentage (0.36 p=7.91x10^-79) were increased. C282Y homozygotes diagnosed with PV, unlike other PV cases lacked association with JAK2-V617F mutations and their hematological phenotyped matched the phenotype seen in non-PV C282Y homozygotes and were distinct from the hematological phenotype seen in PV. 

Homozygous individuals have increased risk of non-clonal primary polycythemia, while association with polycythemia vera is likely due to misdiagnosis exacerbated by increased hemoglobin levels.