Age-dependent Genetic Risk in Pulmonary Fibrosis Patients and Relatives

AbstractO_ST_ABSRationaleC_ST_ABSIdiopathic pulmonary fibrosis (IPF) is an age-related disorder with common and rare genetic risk factors. It is unknown if the effects of PF genetic risk factors differ by chronologic age. ObjectivesTo assess age-specific effects of genetic risk factors in PF patients and their relatives. MethodsWe identified common and rare genetic risk factors using a Columbia whole genome sequencing (WGS) cohort (777 IPF, 2905 controls) and replicated findings using Trans-Omics for Precision Medicine (TOPMed, 1148 IPF, 5202 controls). We assessed age-stratified genetic risk of IPF and assessed for interaction with age across a range of cutoffs. We analyzed 313 FPF pedigrees and compared age-specific prevalence of interstitial lung disease in relatives stratified by proband genetic risk factors. Measurements and Main ResultsAdjusted odds of disease from MUC5B SNP increase with age, while odds of disease from rare variants decrease with age. The magnitude of the interaction term between age and both genetic variables was greatest in younger individuals. There were significant interactions between age <55 and the MUC5B SNP (discovery pinteraction=0.01; replication pinteraction<0.0001) and rare variants (discovery pinteraction<0.0001; replication pinteraction=0.03). Pedigree analysis showed more prevalent disease especially in younger relatives in FPF families with rare variants versus without (p<0.0001). ConclusionsAge modifies the effects of genetic risk factors in IPF. Rare variants confer greater risk in younger individuals whereas the MUC5B SNP confers greater risk in older individuals. Relatives of FPF patients with rare variants exhibit earlier prevalent disease, which has implications for preclinical disease screening.