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Page count: 51

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology that has a poor prognosis for affected individuals. Multiple risk factors and genes are associated with IPF suggesting a complex multifactorial pathogenesis. It has also been proposed that there are familial and sporadic forms of IPF. The aims of this study were to examine whether the impact of 10 known pulmonary fibrosis risk loci of IPF differs between familial and sporadic pulmonary fibrosis and to evaluate the relationship between smoking exposure and a family history of pulmonary fibrosis. IPF case baseline characteristics were compared by family history of disease with continuous measures using two-sample t-tests and with categorical measures using chi-square tests. Mixed models were used to further evaluate the relationship between smoking and family history of pulmonary fibrosis. Multivariable logistic regression models were used to evaluate the relationship between risk loci and family history of disease. Interaction terms were added to the logistic regression models to evaluate if gene-gene or gene-smoking associations differed by family history of disease. A total of 1838 pulmonary fibrosis cases were genotyped with 381 (21%) having a family history of pulmonary fibrosis and 1457 (79%) having no family history of disease. Age did not vary between familial and sporadic cases (p=0.53). The frequency of current or former smokers was marginally higher in sporadic cases (p=0.046). Mean pack years of smoking was higher in sporadic cases than it was in familial cases (p 0.004). The frequency of the risk alleles did not differ in familial and sporadic pulmonary fibrosis cases when evaluated individually and collectively (p0.17). No risk alleles showed significant pairwise interaction differences in familial and sporadic cases (p>0.15). Marginal interaction differences between familial and sporadic cases were found in one risk loci (rs4727443) and a history of smoking (p=0.03). In conclusion, no difference in risk allele frequency for these 10 loci was observed in a large population of familial and sporadic pulmonary fibrosis non-Hispanic white (NHW) cases while exposure to tobacco smoke was significantly higher in sporadic cases.