Patients with cystic fibrosis (CF) who carry certain mutations in the HFE gene, which are also behind an iron overload disorder, have poorer lung function that declines faster and a higher risk of CF-related diabetes (CFRD) and intestinal blockage, a study reports.
These findings support the idea that HFE variations can be genetic modifiers of CF, that is, genetic factors that change the clinical manifestations and outcomes of the disease.
The study, “Mutations in the HFE gene can be associated with increased lung disease severity in cystic fibrosis,” was published in the journal Gene.
Several gene variations other than those affecting the CFTR gene, the defective gene in CF, have been identified that potentially influence CF symptom presentation, in particular the severity of lung disease.
The rate of lung function decline varies between patients, regardless of whether or not they have the same type of CFTR mutation. Such variability may result from “non-CFTR genetic modifiers, differences in environmental factors, or access to multidisciplinary clinical care,” according to the researchers.
In an earlier and smaller study, scientists found that CF patients who inherited a gene mutation in HFE also had more severe lung disease than those without the mutation.
Mutations in this gene underlie a condition called hereditary hemochromatosis, which causes the body to absorb too much iron from the diet and results in iron buildup inside cells and tissues.
A single copy of an HFE mutation usually does not result in hemochromatosis, but it may increase the risk of liver disease, neurodegenerative disease, type 2 diabetes, and cancer, “suggesting either impaired iron handling … or some iron-independent function of HFE may contribute to other risk factors for these diseases,” the researchers wrote.
In this study, the same team of researchers further investigated the association between HFE gene mutations and CF outcomes, including lung disease severity, risk of CFRD, and bowel obstruction disorders — namely meconium illeus or distal intestinal obstruction syndrome — in adults with CF.
A group of 163 adult CF patients was recruited from the Prince Charles Hospital in Queensland, Australia. In each patient, HFE was genotyped and screened for mutations, the results of which were correlated with lung disease severity, prevalence of diabetes, and history of bowel problems.
From the overall studied population, 61 (37.4%) patients carried an HFE mutation — 37 had the H63D mutation, 21 carried the C282Y mutation, and three patients had both mutations. Nearly all individuals had a single copy of each mutation.
Patients who carried the C282Y mutation — the most common cause of hereditary hemochromatosis — had poorer lung function and a significantly faster decline in lung capacity. Compared with patients with a normal HFE, those with the C282Y mutation had a lower predicted percentage of forced expiratory volume in one second (FEV1), 66% versus 54%, respectively; the decline in FEV1 was also more accelerated, less than 80 mL per year versus 110 mL per year, respectively.
Moreover, the presence of a C282Y mutation was significantly correlated with a higher prevalence of CFRD (58% versus 33% in those not having the mutation), and a trend toward increased bowel obstruction (38% versus 19%).
In addition, H63D mutations also seemed to affect CF manifestations, but to a lesser extent. Patients carrying these mutations experienced accelerated decline in lung capacity and an increased risk for having bowel obstruction.
The serum iron levels did not differ between CF patients with distinct HFE mutations, suggesting that a single copy of one of these mutations was not sufficient to cause widespread iron overload in CF patients. However, the team reasoned that it may be enough to worsen any iron mishandling caused by CFTR mutations in cells, aggravating CF manifestations.
Overall, the team concluded that the results support a role for HFE gene mutations, in particular C282Y, as genetic modifiers that accelerate lung function decline and increase the odds of gastrointestinal complications in CF patients.
“Screening the CF population for the presence of HFE mutations may be useful to identify patients at risk of iron-related disease modulation,” the researchers wrote.
They also call for more research to understand if ” interventions that target iron availability should be introduced to potentially ameliorate HFE mutation-mediated modulation of CF disease outcomes.”