Mutations in the HFE gene can be associated with increased lung disease severity in cystic fibrosis.

BACKGROUND AND OBJECTIVE: Genetic modifiers contribute to variable disease phenotype in cystic fibrosis (CF). We explored the association between mutations in the hemochromatosis (HFE) gene and disease severity in adults with CF.

METHODS: HFE genotyping was performed in 163 adults with CF attending a single centre. Results were correlated with lung disease severity, prevalence of CF-related diabetes (CFRD) and history of meconium ileus (MI) or distal intestinal obstruction syndrome (DIOS).

RESULTS: Subjects with the C282Y substitution in the HFE protein (C282Y mutation) had a lower FEV1 percentage predicted (54% versus 66%, p = 0.029) and accelerated rate of FEV1 decline (-110 mL versus -80 mL per year respectively, p < 0.001) compared to subjects with a normal HFE genotype. C282Y substitutions were associated with increased rates of CFRD (58% versus 33%, p = 0.026) and a trend towards increased MI or DIOS (38% versus 19%, p = 0.05). H63D HFE substitutions were associated with a more rapid rate of decline in forced vital capacity (p = 0.01) and increased risk of MI or DIOS (p = 0.02).

CONCLUSIONS: In subjects with CF, the C282Y HFE substitution was associated with worse lung function, and increased rates of CFRD and gastrointestinal complications. The H63D HFE substitution also impacted on disease phenotype, but to a lesser extent. The results support a role for HFE gene mutations as modifiers of CF phenotype.