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Ancestral haplotype 8.1 in cystic fibrosis

Abstract : Cystic fibrosis is an autosomic recessive disease due to mutations in the gene CFTR. There is a great phenotypic variability among patients with identical mutations and with identical environment. These data suggest that others genes, called modifier genes, may affect the lung phenotype. Lung disease, characterized by airway inflammation, is a key component of morbi-mortality. The ancestral haplotype AH8.1, involved in the inflammatory response, is composed of 4 variants: LTa +252A/G, TNF -308G/A, HSPA1B +1267A/G and AGER - 429T/C. The aim of the study was to test whether this haplotype AH8.1 was associated with lung disease severity in cystic fibrosis. We showed in a cohort of 404 European patients, carriers of different mutations of CFTR, that AH8.1 is associated with a greater lung disease severity. We did not succeed to replicate our results in a homogeneous cohort of 1039 French patients F508del homozygotes. We proceed with this study in patients, carriers of other CFTR mutations. Variants of this haplotype were also studied separately. We have shown that AGER-429T/C, not only modulates the severity of lung disease, but was also associated in vitro with a greater production of the protein RAGE. All these results suggest to date that AH8.1 haplotype could modulate the lung disease severity in patients not homozygous for the F508del CFTR mutation. Moreover, the variant AGER-429T/C modulated the lung disease severity and the protein RAGE may be considered as a biomarker in cystic fibrosis.
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Submitted on : Wednesday, May 29, 2013 - 3:19:54 PM
Last modification on : Thursday, December 10, 2020 - 3:42:37 AM
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  • HAL Id : tel-00827653, version 1


Julie Beucher. Ancestral haplotype 8.1 in cystic fibrosis. Physiologie [q-bio.TO]. Université Pierre et Marie Curie - Paris VI, 2012. Français. ⟨NNT : 2012PAO66142⟩. ⟨tel-00827653⟩



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