Desmoplakin Variants Are Associated with Idiopathic Pulmonary Fibrosis

Rationale: Sequence variation, methylation differences, and transcriptional changes in desmoplakin (DSP) have been observed in patients with idiopathic pulmonary fibrosis (IPF).Objectives: To identify novel variants in DSP associated with IPF and to characterize the relationship of these IPF sequence variants with DSP gene expression in human lung.Methods: A chromosome 6 locus (7,370,061–7,606,946) was sequenced in 230 subjects with IPF and 228 control subjects. Validation genotyping of disease-associated variants was conducted in 936 subjects with IPF and 936 control subjects. DSP gene expression was measured in lung tissue from 334 subjects with IPF and 201 control subjects.Measurements and Main Results: We identified 23 sequence variants in the chromosome 6 locus associated with IPF. Genotyping of selected variants in our validation cohort revealed that noncoding intron 1 variant rs2744371 (odds ratio = 0.77, 95% confidence interval [CI] = 0.66–0.91, P = 0.002) is protective for IPF, and a previously d...