Inherited predisposition to idiopathic pulmonary fibrosis in the Newfoundland population

Pirzada, Ashar (2014) Inherited predisposition to idiopathic pulmonary fibrosis in the Newfoundland population. Masters thesis, Memorial University of Newfoundland.

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Abstract

Idiopathic pulmonary fibrosis (IPF) is a late-onset disease characterized by inflammation and scarring of the lung parenchyma. 10-15% of IPF is attributed to genetic causes. The prevalence of familial pulmonary fibrosis (FPF) is up to 10x higher in Newfoundland & Labrador (NL) in comparison to other populations of European origin such as the United Kingdom (UK) and Finland. The five genes (TERT, TERC, ABCA3, SFTPC and SFTPA2) known to carry variants causing FPF have been screened in our NL cohort with no pathogenic variants found. This suggested there is/are novel variant(s) to be identified. Previous work done in this cohort utilized microsatellite genome-wide scans, fine-mapping/haplotyping and SNP genotyping to find loci associated with FPF. From these loci on chromosome 16 and 6, ten positional and functional candidate genes were previously sequenced with no pathogenic variants identified. In this thesis, selection and sequencing of candidate genes from previously mapped loci is performed. Nine candidate genes were sequenced by Sanger sequencing in FPF Family R0942; however, no pathogenic variant was discovered out of28 variants found. Also, genotyping was carried out on a common MUC5B rs35795950 promoter polymorphism that has been recently implicated with both sporadic and familial forms of pulmonary fibrosis (PF). A case-control analysis was carried out using 110 affected individuals and 277 healthy controls from the Newfoundland population. Results showed a significant association between rs35705950 genotypes and IPF. The odds ratio for individuals affected with IPF who were heterozygous and homozygous for the variant allele of this SNP were 5.4 (95% confidence interval, 3.3 to 9.6, P < .001) and 12.2 (95% confidence interval, 3.3 to 44.7, P < .00 1), respectively. Furthermore, two of our FPF fami lies (R0942 and R11 36) showed familial segregation of the variant allele with the phenotype. In these families, all affected individuals were carriers of the variant T allele. Furthermore, a Simplified rapid Segregation Analysis (S ISA) analysis demonstrated that the probability by chance that co-segregation of the variant T allele with PF in family R0942 was 1.56%. This thesis supports the suggestion that the minor T allele of rs35705950 is likely a contributor to the pathogenesis of IPF in the NL cohort. The MUC5B gene encodes for a major gel-forming mucin macromolecule in respiratory secretions and is upregulated in other lung diseases. Further evidence of association is provided by tissue expression studies done through previous research.

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