Rare and Common Variants in <i>KIF15</i> Contribute to Genetic Risk of Idiopathic Pulmonary Fibrosis.

Pubmed ID: 35417304

Pubmed Central ID: PMC9954334

Journal: American journal of respiratory and critical care medicine

Publication Date: July 1, 2022

MeSH Terms: Humans, Telomere, Exome, Idiopathic Pulmonary Fibrosis, Kinesins, Telomerase

Grants: UL1 TR001105, R01 HL093096, R01 HL130796, UH3 HL145266, R01 HL130142, I01 BX000446, K23 HL148498

Authors: Wang B, Noth I, Newton CA, Zhang D, Martinez FJ, Raghu G, Garcia CK, Li Q, Povysil G, Kobeissy PH, Amelotte M, Jaouadi H, Maher TM, Molyneaux PL, Todd JL, Palmer SM, Haefliger C, Platt A, Petrovski S, Garcia JA, Goldstein DB

Cite As: Zhang D, Povysil G, Kobeissy PH, Li Q, Wang B, Amelotte M, Jaouadi H, Newton CA, Maher TM, Molyneaux PL, Noth I, Martinez FJ, Raghu G, Todd JL, Palmer SM, Haefliger C, Platt A, Petrovski S, Garcia JA, Goldstein DB, Garcia CK. Rare and Common Variants in KIF15 Contribute to Genetic Risk of Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 2022 Jul 1;206(1):56-69.

Studies:

Abstract

<b>Rationale:</b> Genetic studies of idiopathic pulmonary fibrosis (IPF) have improved our understanding of this disease, but not all causal loci have been identified. <b>Objectives:</b> To identify genes enriched with rare deleterious variants in IPF and familial pulmonary fibrosis. <b>Methods:</b> We performed gene burden analysis of whole-exome data, tested single variants for disease association, conducted KIF15 (kinesin family member 15) functional studies, and examined human lung single-cell RNA sequencing data. <b>Measurements and Main Results:</b> Gene burden analysis of 1,725 cases and 23,509 control subjects identified heterozygous rare deleterious variants in <i>KIF15</i>, a kinesin involved in spindle separation during mitosis, and three telomere-related genes (<i>TERT</i> [telomerase reverse transcriptase], <i>RTEL1</i> [regulator of telomere elongation helicase 1], and <i>PARN</i> [poly(A)-specific ribonuclease]). KIF15 was implicated in autosomal-dominant models of rare deleterious variants (odds ratio [OR], 4.9; 95% confidence interval [CI], 2.7-8.8; <i>P</i> = 2.55 × 10<sup>-7</sup>) and rare protein-truncating variants (OR, 7.6; 95% CI, 3.3-17.1; <i>P</i> = 8.12 × 10<sup>-7</sup>). Meta-analyses of the discovery and replication cohorts, including 2,966 cases and 29,817 control subjects, confirm the involvement of <i>KIF15</i> plus the three telomere-related genes. A common variant within a <i>KIF15</i> intron (rs74341405; OR, 1.6; 95% CI, 1.4-1.9; <i>P</i> = 5.63 × 10<sup>-10</sup>) is associated with IPF risk, confirming a prior report. Lymphoblastoid cells from individuals heterozygous for the common variant have decreased KIF15 and reduced rates of cell growth. Cell proliferation is dependent on KIF15 in the presence of an inhibitor of Eg5/KIF11, which has partially redundant function. <i>KIF15</i> is expressed specifically in replicating human lung cells and shows diminished expression in replicating epithelial cells of patients with IPF. <b>Conclusions:</b> Both rare deleterious variants and common variants in <i>KIF15</i> link a nontelomerase pathway of cell proliferation with IPF susceptibility.