04 February 2019 by Adel El Boueiz

A Genome-Wide Association Study to Identify Genetic Determinants of Pulmonary Vascular Remodeling in COPD

Rapid-Fire presentation


COPD is characterized by a loss of vasculature in regions severely affected by emphysema and distal pruning of the remaining vessels. These changes contribute to the development of secondary pulmonary hypertension and are associated with worse clinical outcomes. Although it is clear that hypoxia is not the primary driving force, alternative mechanisms underpinning pulmonary vascular disease in COPD (COPD-PVD) have not yet been well elucidated. Using previously validated non-contrast CT pulmonary vascular morphology data from the COPDGene study, we sought to identify possible genetic determinants of COPD-PVD.


6,231 non-Hispanic white and 2,718 African-American smokers with complete genotyping and phenotypic data were analyzed. The aggregate vessel volume for vessels less than 5 mm2 (BV5) was calculated and normalized to the total blood vessel volume (TBV). Genotyping was performed on the Illumina Omni Express platform with additional markers imputed using the Haplotype Reference Consortium. We tested BV5/TBV for genetic associations adjusting for age, sex, smoking, and genetic ancestry. Race-specific genome-wide association studies were followed by a fixed-effect meta-analysis. SNP-, gene-, and pathway-based approaches were used.


The five top genetic loci associated with BV5/TBV were found near the FAM19A5 (P-value=4.6x10-7), C8orf74 (P-value=5x10-7), ATIC (P-value=1.6x10-6), RTN4RL1 (P-value=2.3x10-6), and TRPC1 (P-value=3x10-6) genes. None of these loci were previously associated with COPD. Prior studies have linked C8orf74 with cardiac hypertrophy in congenital heart diseases and have shown TRPC1 to be up-regulated under hypoxia in isolated murine pulmonary artery smooth muscle cells. Gene set analysis revealed top pathways related to coagulation, development, blood vessel morphogenesis, muscle contraction, WNT signaling, DNA damage, apoptosis, inflammation, and immune response (FDR 5%).


Although no genome-wide significance was reached, this study highlighted new putative genetic factors and biological pathways that may influence pulmonary vascular remodeling in COPD and expand our diagnostic and therapeutic approaches in this patient population.


Grant support: NHLBI K08HL141601, K23HL136905, R01HL135142, R01HL137927, R01HL116473, R01HL116931, R01HL124233, R01HL126596, U01HL089897, and U01HL089856. The COPDGene study (NCT00608764) is also supported by the COPD Foundation through contributions made to an Industry Advisory Committee comprised of AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Novartis, and Sunovion.

Key Contributors

Boueiz A.1,2, San José Estépar R.3, Rahaghi F.2, Castaldi P.J.1,4, Cho M.H.1,2, Washko G.R.2, Silverman E.K.1,2; for the COPDGene investigators. : 1.Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; 2.Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; 3.Applied Chest Imaging Laboratory, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; 4.General Medicine and Primary Care, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.

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