Genes in the vicinity of CFTR modulate the cystic fibrosis phenotype in highly concordant or discordant F508del homozygous sib pairs

Abstract

Cystic fibrosis (CF) is the most common severe autosomal recessive disease among Caucasians and is caused by lesions within the cystic fibrosis transmembrane conductance regulator ( CFTR) gene. The variability of CF disease severity suggests the effect of modifying factors. Thirty-four highly concordant and highly discordant F508del homozygous sib pairs, who have been selected out of a group of 114 pairs for extreme disease phenotypes by nutritional and pulmonary status, were typed at single nucleotide polymorphisms (SNPs) and short tandem repeat polymorphisms (STRPs) in the 24-cM CFTR-spanning region between D7S525 and D7S495. Allele frequencies differed significantly at D7S495, located within a 21-cM distance 3' of CFTR, comparing concordant mildly affected, concordant severely affected and discordant sib pairs, as judged by hypothesis-free permutation analysis by Monte Carlo simulation. A rare haplotype of two SNPs within the leptin gene promotor was found exclusively among the concordant mildly affected pairs. All concordant sib pairs shared the paternal F508del chromosome between CFTR and D7S495, whilst the cohort of discordant sib pairs inherited equal proportions of recombined and non-recombined parental chromosomes. We conclude that disease manifestation in CF is modulated by loci in the partially imprinted region 3' of CFTR that determine stature, food intake and energy homeostasis, such as the Silver-Russel-Syndrome candidate gene region and LEP.

Expression levels of FAS are regulated through an evolutionary conserved element in intron 2, which modulates cystic fibrosis disease severity

“…From a group of 114 F508del homozygous patient pairs, 12 concordant mild pairs (CON þ ) wherein both siblings exhibit mild disease and 11 concordant severe pairs (CONÀ) wherein both siblings exhibit severe disease and 14 discordant pairs wherein one sibling is mildly affected whereas the other is severely affected and their parents were recruited. 4,14,33,34 The CON þ , CONÀ and FAS expression modulates CF disease severity V Kumar et al discordant pairs were comparable with respect to age at day of recruitment and gender distribution.…”

Genome Diversity ofPseudomonas aeruginosaPAO1 Laboratory Strains

“…These segments were queried for the number of deleted bases by direct blotting electrophoresis and subsequent chemiluminescence visualization of combinatorial biotinylated PCR products (26).…”

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

“…Functionally, non-equivalent variants of these trans-acting factors can thus introduce discordance within sib pairs, while concordant pairs, lacking the cis-responsive element which is detected by the association study comparing concordant and discordant pairs, are not sensitive to the allelic variants of the regulator. 26,31,39 Genotyping Genotyping of markers in IL1B and the microsatellite in IFNGR1 was carried out as detailed elsewhere. 26 Primers for genotyping of the STAT3 microsatellite in intron 6 are: 5¢-TTCTGCCTGGTCACTGACTG and biotin 5¢-GGAGGTACG GGTCCTCAAAG, the biotin label being optional if another system for detection is used.…”

“…These two single nucleotide exchanges, that is, rs9376268 and a novel SNP located 455 bp upstream of rs9376268 (Figure 2c), are the only sequence differences comparing the 7 kb -spanning core haplotypes of chromosomes from concordant to discordant patient pairs ( Figure 2b and Table 3). As the contrast between concordant and discordant patient pairs has revealed this association, the molecular mechanism by which one or both of these SNPs modify CF intrapair discordance among CF patients must involve a factor encoded in trans 26,31,39 to IFNGR1. A plausible scenario would be a transcription factor-binding site unique to chromosomes carrying the haplotype 1-2-2 at rs9376269-rs1327475-rs9376268 present on nearly 80% of discordant chromosomes.…”