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Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis.

ABSTRACT: The identification of small molecules that target specific CFTR variants has ushered in a new era of treatment for cystic fibrosis (CF), yet optimal, individualized treatment of CF will require identification and targeting of disease modifiers. Here we use genome-wide association analysis to identify genetic modifiers of CF lung disease, the primary cause of mortality. Meta-analysis of 6,365 CF patients identifies five loci that display significant association with variation in lung disease. Regions on chr3q29 (MUC4/MUC20; P=3.3 × 10(-11)), chr5p15.3 (SLC9A3; P=6.8 × 10(-12)), chr6p21.3 (HLA Class II; P=1.2 × 10(-8)) and chrXq22-q23 (AGTR2/SLC6A14; P=1.8 × 10(-9)) contain genes of high biological relevance to CF pathophysiology. The fifth locus, on chr11p12-p13 (EHF/APIP; P=1.9 × 10(-10)), was previously shown to be associated with lung disease. These results provide new insights into potential targets for modulating lung disease severity in CF.

SUBMITTER: Corvol H

PROVIDER: S-EPMC4589222 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis.

Corvol Harriet H Blackman Scott M SM Boëlle Pierre-Yves PY Gallins Paul J PJ Pace Rhonda G RG Stonebraker Jaclyn R JR Accurso Frank J FJ Clement Annick A Collaco Joseph M JM Dang Hong H Dang Anthony T AT Franca Arianna A Gong Jiafen J Guillot Loic L Keenan Katherine K Li Weili W Lin Fan F Patrone Michael V MV Raraigh Karen S KS Sun Lei L Zhou Yi-Hui YH O'Neal Wanda K WK Sontag Marci K MK Levy Hara H Durie Peter R PR Rommens Johanna M JM Drumm Mitchell L ML Wright Fred A FA Strug Lisa J LJ Cutting Garry R GR Knowles Michael R MR

Nature communications 20150929

The identification of small molecules that target specific CFTR variants has ushered in a new era of treatment for cystic fibrosis (CF), yet optimal, individualized treatment of CF will require identification and targeting of disease modifiers. Here we use genome-wide association analysis to identify genetic modifiers of CF lung disease, the primary cause of mortality. Meta-analysis of 6,365 CF patients identifies five loci that display significant association with variation in lung disease. Reg ...[more]

PMID: 26417704

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Project description:BackgroundLung disease progression is variable among cystic fibrosis (CF) patients and depends on DNA mutations in the CFTR gene, polymorphic variations in disease modifier genes, and environmental exposure. The contribution of genetic factors has been extensively investigated, whereas the mechanism whereby environmental factors modulate the lung disease is unknown. In this project, we hypothesized that (i) reiterative stress alters the epigenome in CF-affected tissues and (ii) DNA methylation variations at disease modifier genes modulate the lung function in CF patients.ResultsWe profiled DNA methylation at CFTR, the disease-causing gene, and at 13 lung modifier genes in nasal epithelial cells and whole blood samples from 48 CF patients and 24 healthy controls. CF patients homozygous for the p.Phe508del mutation and ≥18-year-old were stratified according to the lung disease severity. DNA methylation was measured by bisulfite and next-generation sequencing. The DNA methylation profile allowed us to correctly classify 75% of the subjects, thus providing a CF-specific molecular signature. Moreover, in CF patients, DNA methylation at specific genes was highly correlated in the same tissue sample. We suggest that gene methylation in CF cells may be co-regulated by disease-specific trans-factors. Three genes were differentially methylated in CF patients compared with controls and/or in groups of pulmonary severity: HMOX1 and GSTM3 in nasal epithelial samples; HMOX1 and EDNRA in blood samples. The association between pulmonary severity and DNA methylation at EDNRA was confirmed in blood samples from an independent set of CF patients. Also, lower DNA methylation levels at GSTM3 were associated with the GSTM3*B allele, a polymorphic 3-bp deletion that has a protective effect in cystic fibrosis.ConclusionsDNA methylation levels are altered in nasal epithelial and blood cell samples from CF patients. Analysis of CFTR and 13 lung disease modifier genes shows DNA methylation changes of small magnitude: some of them are a consequence of the disease; other changes may result in small expression variations that collectively modulate the lung disease severity.

Dataset Information

Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis.

Publications

Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis.

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