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COPD Genetic Risk Factors Vary by Patient Sex, Suggests Research Presented at AMIA

SAN DIEGO — Genetic risk factors for chronic obstructive pulmonary disease can differ widely between men and women, according to the results of genome-wide association studies conducted at the University of Pennsylvania.

A Penn researcher unveiled the results Wednesday in a paper presented at the American Medical Informatics Association annual symposium. AMIA publishes peer-reviewed proceedings of all its scientific conferences.

Although smoking is a main risk factor for COPD, genetic factors also contribute to lung function and disease risk. Previous GWAS — some, like this study, based on UK Biobank data, going back as far as 2015 — have also uncovered variants linked to COPD, but they did not examine risk factors by patient sex.

Women who smoke may have different COPD risk factors than men and require different treatments, according to Jaehyun Joo, a postdoctoral research fellow in the Department of Biostatistics, Epidemiology, and Informatics at Penn.

Joo and colleagues performed sex-stratified GWAS on 12,958 men and 11,311 women with COPD — plus about 200,000 total control subjects — from UK Biobank data. They created an R-based software tool called SnpSetTest, to run an analysis following the versatile gene-based association study, or VEGAS, with some modifications. The VEGAS approach was first published in 2010 by Australian researchers.

"This package uses a different approach from the original VEGAS implementation to compute set-level p values more efficiently," according to the software download page.

In addition to running the VEGAS analysis, the Penn team used SnpSetTest to compare SNP-level GWAS results with gene-based results for this study, which was funded by the US National Institutes of Health.

Previous studies using the NIH COPDGene cohort, a 10,000 subject, highly phenotyped cohort of smokers with and without COPD, found that sex-related genetic factors indicated a high risk of severe, early-onset COPD in women, but little has been revealed about how genetics affect sex divergence in COPD, according to the researchers.

Additionally, past observational studies have found sex-specific differences in decline in lung function among smokers, as well as in recovery of lung function following smoking cessation, with women typically experiencing these phenomena more quickly than men.

Joo and colleagues hypothesized that these differences could have genetic underpinnings. "Research into sex-specific genetic risk factors is lacking," he said.

The GWAS revealed 17 "significant" genome-wide loci for males and 14 for females, Joo said. Nine of those loci overlap in both women and men, while eight were specific for COPD risk in men and five for women. Notably, the locus of C5orf56 on the chromosome 5q31.1 region was "convincingly associated with COPD" in men but not at all in women, the researchers reported.

They found other strong male-specific associations in CFDP1, TMEM170A, and CHST6. The strongest female-specific associations were in ASTN2 and TRIM32. The Penn researchers called these "promising genes to pursue in functional studies to better understand sexual dimorphism in COPD."

"[W]hile most associations were shared between sexes, several regions had sex-specific contributions," they wrote.

The researchers said that they did not functionally validate sex-specific genetic components to support their statistical findings. "Future experimental studies can explore our findings to elucidate the mechanisms underlying the observed differences," they wrote.

In his AMIA presentation, Joo also noted that the UK Biobank data lacked racial diversity, with the research cohort consisting almost entirely of people of European heritage.