title: Expression levels of FAS are regulated through an evolutionary conserved element in intron 2, which modulates cystic fibrosis disease severity.
abstract: We have analyzed frequent naturally occurring variants in the autogene FAS in two independent cystic fibrosis (CF) patient populations. Analysis of FAS expression levels from intestinal epithelial biopsies from 16 unrelated F508del-CFTR homozygotes showed a correlation between FAS intron 2 SNP rs7901656 and signals for Affymetrix GeneChip U133 Plus 2.0 probeset 204781_s_at consistent with a dominant model (P=0.0009). Genotype and haplotype analysis at six informative SNPs spanning the FAS gene locus was carried out on 37 nuclear families representing extreme clinical phenotypes that were selected from the European CF Twin and Sibling Study population of more than 300 affected sibling pairs. Case-control comparison of the haplotype composed of rs2296603-rs7901656-rs1571019 encompassing intron 2 of FAS reached significance (P=0.0246). Comparative phylogenetic analysis and functional annotation of the FAS intron 2 sequence revealed a conserved non-coding sequence surrounding rs7901656 and predicted binding sites for four transcription factors whereby the binding site of c-Rel is altered by rs7901656. Taken together, these findings from two independent CF patient cohorts indicate that allelic variants within FAS intron 2 alter FAS gene expression and that these functional variants modulate the manifestation of CF disease.
authors.affiliation: Department of Pediatric Pneumology and Neonatology, Hannover Medical School, Hannover, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Kumar
authors.forename: T
authors.initials: T
authors.lastname: Becker
authors.forename: S
authors.initials: S
authors.lastname: Jansen
authors.forename: A
authors.initials: A
authors.lastname: van Barneveld
authors.forename: K
authors.initials: K
authors.lastname: Boztug
authors.forename: S
authors.initials: S
authors.lastname: Wölfl
authors.forename: B
authors.initials: B
authors.lastname: Tümmler
authors.forename: F
authors.initials: F
authors.lastname: Stanke
mesh_terms: D000483:Alleles; D001483:Base Sequence; D015331:Cohort Studies; D003550:Cystic Fibrosis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000276:immunology; D019143:Evolution, Molecular; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007438:Introns; D008297:Male; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D016415:Sequence Alignment; D035781:Siblings; D019014:fas Receptor / Q000235:genetics* / Q000276:immunology / Q000378:metabolism
chemical_list: D019014:fas Receptor; D019005:Cystic Fibrosis Transmembrane Conductance Regulator