HFE C282Y Mutation as a Genetic Modifier Influencing Disease Susceptibility for JAK2 V617F Positive Chronic Myeloproliferative Disease.
Authors: Andrikovics Hajnalka , Meggyesi Nora , Szilvasi Aniko , Tamaska Julia , Halm Gabriella , Lueff Sandor , Nahajevszky Sarolta , Egyed Miklos , Varkonyi Judit , Mikala Gabor , Sipos Andrea , Tordai Attila , Masszi Tamas 
Published: April 2020

Common HFE gene point mutations (C282Y, H63D and S65C) are responsible for hemochromatosis type 1 in homozygous or compound heterozygous states. Although HFE-related hemochromatosis is inherited in a recessive manner, heterozygous carriers were shown to have higher iron parameters (serum iron and ferritin levels, transferrin saturation) without progressive iron overload. Heterozygous HFE carriership has been implicated as a genetic modifier of several diseases, where iron homeostasis play an important role in disease susceptibility or disease progression (porphyria cutanea tarda, myelodyslasia). We investigated 336 unrelated patients with chronic myeloproliferative disease (CMPD) [176 patients with polycythemia vera (PV), 131 patients with essential thrombocythemia (ET) and 29 patients with chronic idiopathic myelofibrosis (CIMF)] and 171 first time blood donors as controls for allele frequencies (AFs) of HFE mutations by Light Cycler allele discrimination method. The presence of the acquired JAK2 V617F mutation in CMPD was investigated by allele specific PCR. Laboratory (hemoglobin, white blood cell and platelet count) and clinical features (sex, age at diagnosis, splenomegaly, presence of thrombotic, myelofibrotic or leukemic transformation) were recorded in the patient group. Compared to controls (4.7 +/− 2.3%), decreased HFE C282Y AF was found in patient group (1.8 +/− 1.0%; p=0.02; OR=0.38 [0.17–0.85]). Decreased HFE C282Y AFs were detected in all patient subgroups according to diagnosis (PV, ET, CIMF) and according to JAK2 V617F mutational status, but the difference remained significant only in the patient group with PV or with JAK2 V617F positive CMPD (PV:1.7 +/− 1.4%; p=0.04; JAK2 V617F positive patients: 1.6+/− 1.1%). H63D and S65C mutational status did not differ significantly between control (12.0+/−3.5% and 1.3+/−1.8%) and patient groups (13.1+/−2.6% and 0.5+/−0.5%). JAK2 V617F frequency was 86.9% (153/176) in PV, 60.3% (79/131) in ET, and 72.4% (21/29) in CIMF. We found significantly elevated hemoglobin levels and WBC values (measured at the time of diagnosis) in the V617F-positive PV (and ET patient groups compared to V617F-negative patients. The incidence of vascular complications (arterial and venous thrombosis or bleeding) was higher in JAK2 V617F CMPD. The age of CMPD onset and the rate of different complications were not altered by HFE mutational status. Our data confirm earlier observations that JAK2 V617F-positive ET shares clinical features (elevated hemoglobin) with PV. We found that HFE C282Y mutation may be associated with a protective role against CMPD (also CMPD associated with JAK2 positivity). Chronic iron deficiency or latent anemia may trigger disease susceptibility for CMPD, and HFE C282Y positivity can play a protective role against chronic iron deficiency.