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The TNFalpha receptor TNFRSF1A and genes encoding the amiloride-sensitive sodium channel ENaC as modulators in cystic fibrosis.
- Source :
-
Human genetics [Hum Genet] 2006 Apr; Vol. 119 (3), pp. 331-43. Date of Electronic Publication: 2006 Feb 04. - Publication Year :
- 2006
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Abstract
- The CFTR mutations in cystic fibrosis (CF) lead to ion transport anomalities which predispose to chronic infection and inflammation of CF airways as the major determinants for morbidity and mortality in CF. Discordant clinical phenotypes of siblings with identical CFTR mutations and the large variability of clinical manifestations of patients who are homozygous for the most common mutation F508del suggest that both environment and genes other than CFTR contribute substantially to CF disease. The prime candidates for genetic modifiers in CF are elements of host defence such as the TNFalpha receptor and of ion transport such as the amiloride-sensitive epithelial sodium channel ENaC, both of which are encoded side by side on 12p13 (TNFRSF1A, SCNN1A) and 16p12 (SCNN1B, SCNN1G). Thirty-seven families with F508del-CFTR homozygous siblings exhibiting extreme clinical phenotypes that had been selected from the 467 pairs of the European CF Twin and Sibling Study were genotyped at 12p13 and 16p12 markers. The ENaC was identified as a modulator of CF by transmission disequilibrium at SCNN1G and association with CF phenotype intrapair discordance at SCNN1B. Family-based and case-control analyses and sequencing of SCNN1A and TNFRSF1A uncovered an association of the TNFRSF1A intron 1 haplotype with disease severity. Carriers of risk haplotypes were underrepresented suggesting a strong impact of both loci on survival. The finding that TNFRSF1A, SCNN1B and SCNN1G are clinically relevant modulators of CF disease supports current concepts that the depletion of airway surface liquid and inadequate host inflammatory responses trigger pulmonary disease in CF.
- Subjects :
- Adolescent
Adult
Chromosomes, Human, Pair 12
Chromosomes, Human, Pair 16
Family
Female
Gene Frequency
Haplotypes
Humans
Linkage Disequilibrium
Male
Middle Aged
Sequence Analysis, DNA
Siblings
Cystic Fibrosis genetics
Epithelial Sodium Channels genetics
Epithelial Sodium Channels physiology
Receptors, Tumor Necrosis Factor, Type I genetics
Receptors, Tumor Necrosis Factor, Type I physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0340-6717
- Volume :
- 119
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Human genetics
- Publication Type :
- Academic Journal
- Accession number :
- 16463024
- Full Text :
- https://doi.org/10.1007/s00439-006-0140-2