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

Daniel J Smith; Kerenaftali Klein; Gunter Hartel; Claire E Wainwright; Scott C Bell; Gregory J Anderson; David W Reid

doi:10.1016/j.gene.2018.10.002

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

Gene. 2019 Jan 30:683:12-17. doi: 10.1016/j.gene.2018.10.002. Epub 2018 Oct 3.

Authors

Daniel J Smith¹, Kerenaftali Klein², Gunter Hartel³, Claire E Wainwright⁴, Scott C Bell⁵, Gregory J Anderson⁶, David W Reid⁷

Affiliations

¹ The Adult Cystic Fibrosis Centre, The Prince Charles Hospital, 4032, Queensland, Australia; School of Medicine, University of Queensland, 4029, Queensland, Australia; Lung Infection and Inflammation Laboratory, QIMR Berghofer Medical Research Institute, 4029, Queensland, Australia. Electronic address: daniel.smith@health.qld.gov.au.
² Cancer and Population Studies, QIMR Berghofer Medical Research Institute, 4029, Queensland, Australia.
³ Department of Statistics, QIMR Berghofer Medical Research Institute, 4029, Queensland, Australia.
⁴ School of Medicine, University of Queensland, 4029, Queensland, Australia; Queensland Children's Medical Research Institute, Queensland, 4029, Australia; Department of Respiratory and Sleep Medicine, The Lady Cilento Children's Hospital, 4101, Queensland, Australia.
⁵ The Adult Cystic Fibrosis Centre, The Prince Charles Hospital, 4032, Queensland, Australia; School of Medicine, University of Queensland, 4029, Queensland, Australia; Lung Bacteria Laboratory, QIMR Berghofer Medical Research Institute, 4029, Queensland, Australia.
⁶ Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, 4029, Queensland, Australia.
⁷ The Adult Cystic Fibrosis Centre, The Prince Charles Hospital, 4032, Queensland, Australia; School of Medicine, University of Queensland, 4029, Queensland, Australia; Lung Infection and Inflammation Laboratory, QIMR Berghofer Medical Research Institute, 4029, Queensland, Australia.

PMID: 30291871
DOI: 10.1016/j.gene.2018.10.002

Abstract

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.

Keywords: Cystic fibrosis; Diabetes mellitus; Hemochromatosis; Infection; Inflammation; Intestinal obstruction.

MeSH terms

Adult
Amino Acid Substitution*
Cystic Fibrosis / genetics*
Cystic Fibrosis / physiopathology*
Female
Genetic Association Studies
Hemochromatosis Protein / genetics*
Humans
Male
Severity of Illness Index
Vital Capacity

Substances

HFE protein, human
Hemochromatosis Protein