• Josiah E Radder, Yingze Zhang, Alyssa D Gregory, Shibing Yu, Neil J Kelly, Joseph K Leader, Naftali Kaminski, Frank C Sciurba, and Steven D Shapiro.
• 1 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, and.
• Am. J. Respir. Crit. Care Med. 2017 Jul 15; 196 (2): 159-171.

RationaleGenetic association studies in chronic obstructive pulmonary disease have primarily tested for association with common variants, the results of which explain only a portion of disease heritability. Because rare variation is also likely to contribute to susceptibility, we used whole-genome sequencing of subjects with clinically extreme phenotypes to identify genomic regions enriched for rare variation contributing to chronic obstructive pulmonary disease susceptibility.ObjectivesTo identify regions of rare genetic variation contributing to emphysema with severe airflow obstruction.MethodsWe identified heavy smokers that were resistant (n = 65) or susceptible (n = 64) to emphysema with severe airflow obstruction in the Pittsburgh Specialized Center of Clinically Oriented Research cohort. We filtered whole-genome sequencing results to include only rare variants and conducted single variant tests, region-based tests across the genome, gene-based tests, and exome-wide tests.Measurements And Main ResultsWe identified several suggestive associations with emphysema with severe airflow obstruction, including a suggestive association of all rare variation in a region within the gene ZNF816 (19q13.41; P = 4.5 × 10-6), and a suggestive association of nonsynonymous coding rare variation in the gene PTPRO (P = 4.0 × 10-5). Association of rs61754411, a rare nonsynonymous variant in PTPRO, with emphysema and obstruction was demonstrated in all non-Hispanic white individuals in the Pittsburgh Specialized Center of Clinically Oriented Research cohort. We found that cells containing this variant have decreased signaling in cellular pathways necessary for survival and proliferation.ConclusionsPTPRO is a novel candidate gene in emphysema with severe airflow obstruction, and rs61754411 is a previously unreported rare variant contributing to emphysema susceptibility. Other suggestive candidate genes, such as ZNF816, are of interest for future studies.

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