D23-25 Age-dependent Genetic Risk in Pulmonary Fibrosis Patients and Relatives

Rationale

Idiopathic 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.

Objectives

To assess age-specific effects of genetic risk factors in PF patients and their relatives.

Methods

We 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 Results

Adjusted 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 in 1st and 2nd degree relatives in FPF families with rare variants versus without (pGLMM<0.0001). In age-stratified analysis, we find that the greatest difference in ILD prevalence occurred in younger age relatives aged 40-50 (FPF families with rare variants versus without rare variants, 18% vs. 5%, pGLMM=0.006) and aged 50-60 (FPF families with rare variants versus without rare variants, 28% vs. 14%, pGLMM=0.002). In families where a rare variant was identified in the proband, 69/179 (39%) of affected relatives were below age 60.

Conclusions

Age 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. Since it can take up to a decade for early interstitial lung abnormalities to transform into definite fibrosis on CT, screening at age 50 may miss early ILA in up to two out of five relatives of FPF patients with rare damaging variants.

This abstract is funded by: NIH