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 ¼ 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 ¼ 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.

Ceramide in <i>Pseudomonas aeruginosa</i> Infections and Cystic Fibrosis

“…At present, it is unknown how apoptosis regulates the local defense to the pathogen, but it has been speculated that apoptotic cells downmodulate the inflammation and prevent an overshooting response. It is very interesting to note that recent studies by Kumar and colleagues with two independent cohorts of cystic fibrosis patients have demonstrated that allelic variants within intron 2 of the CD95 gene modulate the manifestation of cystic fibrosis [67]. This finding suggested that CD95-mediated signalling or apoptosis plays a role in P. aeruginosa infections in cystic fibrosis patients.…”

The Role of Sphingolipids and Ceramide in Pulmonary Inflammation in Cystic Fibrosis

“…Studies from Kumar et al . on two independent CF patient cohorts demonstrate that allelic variants within intron 2 of the CD95 gene modulate the manifestation of CF disease further suggesting a role of CD95-mediated signalling/ apoptosis in cystic fibrosis [21]. …”

Initial interrogation, confirmation and fine mapping of modifying genes: STAT3, IL1B and IFNGR1 determine cystic fibrosis disease manifestation

“…The candidate genes STAT3, IL1B and IFNGR1 were extracted from the transcriptome data generated from the intestinal epithelium of F508del-CFTR homozygotes and non-CF controls. 26,32 STAT3 was observed to be upregulated in F508del-CFTR homozygous patients who do not exhibit residual chloride conductance based on transcriptome data from rectal suction biopsies from four F508del-CFTR homozygous patients without residual function, and three F508del-CFTR homozygous patients with median residual function and five F508del-CFTR homozygous patients with high CFTR-mediated residual function. IL1B and IFNGR1 were upregulated in CF as compared with non-CF control individuals based on the comparison of transcriptome data from 14 F508del-CFTR homozygous CF vs 8 non-CF rectal epithelial tissue samples.…”

“…Consequently, several studied candidate genes were derived from the field of immunity, immunology and host defense such as the cytokines IL8, [24][25][26] IL1B 25,26 and TGFB1. [28][29][30] We report our data on three candidate genes as modifiers of CF investigated in the framework of the European CF Twin and Sibling Study, 26 based on which we have described previously the immunorelevant receptors for TNFa 31 and FAS 32 as CF modifiers. For this work, the signal transducer and activator of translation 3 (STAT3), the cytokine interleukin 1b (IL1B) and the receptor for interferon g (IFNGR1) have been selected based on transcriptome data comparing F508del-CFTR homozygous CF patients stratified for low, medium or high residual chloride secretion and non-CF controls.…”