Cystic fibrosis severity modifier genes in patients from the north of the Iberian Peninsula and the Balearic Islands

Laburpena

Cystic fibrosis is the most common autosomal recessive rare disease in Caucasian populations. Despite the wide variety of mutations, patients with same mutations may present different clinical symptoms. This variability has led to the study of severity modifying genes.In the present study, a set of 33 SNPs located in 19 genes previously identified as modulatory genes for the severity of CF have been studied in 106 CF patients from the north of the Iberian Peninsula and the Balearic Islands, their parents and health controls.The main objective of this doctoral thesis is to detect the presence of gene variants and to infer a possible interaction between genetics and the common symptomatology of the disease. To carry out this objective, we proceeded to perform the association analysis (ASs) of each individual SNP with the different symptomatologies of the disease. These ASs have also shown that SNPs related to a modulator effect on a given symptomatology, also show associations with other CF symptoms. Several of these associations had not been previously described, thus constituting new findings. Considering genetically linked SNPs, haplotypes ASs were also performed. This approach has scarcely been used in previous studies in this field. The combination of the transversality of the effects of modulator gene SNPs combined with the increased robustness of association results based on haplotypic analyses determined the interest in performing multigene association analyses. This novel approach based on multigene models has allowed us to identify and objectify the impact of risk/protection genotypes, as this strategy better fits the reality of the patients' genome. The study of the modifier genes seems be a useful tool to dig deep on the pathogeny and to identify new therapeutic targets.