A74-07 Clonal Hematopoiesis of Indeterminate Potential and Interstitial Lung Abnormalities in Patients at Risk for Idiopathic Pulmonary Fibrosis

Introduction Idiopathic pulmonary fibrosis (IPF) and clonal hematopoiesis of indeterminate potential (CHIP) both increase in prevalence with age. In CHIP, a single hematopoietic stem cell acquires mutations that give it a clonal advantage and skew its differentiation towards specific lineages based on the mutated gene. These clonally expanded leukocytes produce proinflammatory cytokines that may contribute to the development of multiple age-related diseases. Interstitial lung abnormalities (ILAs) on high-resolution chest CT (HRCT) are the best imaging biomarker of subclinical pulmonary fibrosis. We hypothesized that CHIP is associated with ILAs in asymptomatic relatives of patients with familial IPF. Methods Asymptomatic first-degree relatives of familial IPF patients enrolled in a prospective cohort study and underwent serial screening HRCTs to detect and monitor for the progression of ILAs. Peripheral blood DNA was sequenced using a custom capture assay. CHIP driver mutations were identified using GATK mutect2, and variants with allele fraction (VAF) > 2% were considered diagnostic of CHIP . Unadjusted and adjusted (for age, sex, smoking status) Chi-Squared tests and logistic regression models evaluated the association of CHIP with (1) the presence of ILA on the enrollment HRCT, (2) the presence of ILA on at least 1 HRCT, or (3) ILA progression (new or worse ILA identified during follow-up). Results Among the 548 participants with at least 1 screening HRCT, the median age was 53 years (IQR 46-60) and 49 (9.0%) had CHIP. CHIP prevalence increased with age. When compared to age, sex, and smoking status-matched controls, asymptomatic relatives of patients with familial IPF with CHIP were older but otherwise had similar PBMC telomere lengths, PFT parameters, and monocyte counts compared to those without CHIP. Out of the 139 subjects with ILA on their enrollment HRCT, there was no association with CHIP (chi-squared p = 0.26). For 172 patients who ever developed an ILA in the study, there was no association with CHIP (chi-squared p = 0.38). For 278 patients with at least one follow-up HRCT, 23 (8.2%) had CHIP, and CHIP was not associated with ILA progression (Adjusted OR 0.5, 95% CI 0.162-1.49 p = 0.25). Conclusions CHIP is common in patients at risk for IPF and the CHIP driver mutations are consistent with previous findings. ILA progression is not associated with CHIP when adjusting for age, sex, and smoking status. CHIP may be a mediator of age-associated risk for IPF.