Polygenic Risk Score Could Better Predict Severe COPD Risk

Martin D. Tobin, PhD

A group of particularly greater at-risk chronic obstructive pulmonary disease (COPD) patients could be identified with the help of a polygenic risk score, according to population-based cohort assessments.

In a new study conducted by an international team of investigators—led by Martin D. Tobin, PhD, of the University of Leicester, and Michael H. Cho, MD, of Brigham and Women’s Hospital—a polygenic risk score comprised of genome-wide association study of lung function helped predict individuals at increased risk of moderate-to-severe COPD, cigarette smoking-associated emphysema, and reduced lung growth.

The risk score could help inform future COPD mechanism research, eventually benefitting preventive and prognostic developments into a chronic pulmonary condition which is still little-understood and limitedly treated.

Tobin, Cho and colleagues created a polygenic risk score using metrics of lung function—including FEV₁ and FEV₁/FVC—from the UK Biobank and SpiroMeta. As investigators noted, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) definition for COPD entails the presence of persistent respiratory symptoms with airflow obstruction based on a low FEV₁/FVC ration, and a graded spirometry based on predicted FEV₁ percentage.

“COPD primarily develops in the context of toxic environmental exposures, including cigarette smoking and biofuel combustion,” they wrote.” However, not all exposed individuals develop airflow obstruction, which suggests that some individuals could have a genetic susceptibility to the disease.”

The team tested the polygenic risk score in 9 cohorts of multiple ethnicities for an association with moderate-to-severe COPD as per FEV₁/FVC <.07 and FEV₁ <80% predicted.

Logistic regression models—adjusted for age, sex, height, smoking pack-years, and principal genetic ancestry—were used to test the associations. Investigators noted most clinically accessed COPD patients have been of European ancestry.

Parenchymal and airway pathology, as well as patterns of reduced lung growth, were studied through quantitative and qualitative CT imaging phenotypes.

The polygenic risk score was associated with COPD in European (OR per SD, 1.81; 95% CI, 1.74-1.88) and non-European (1.42; 95% CI, 1.34-1.51) populations. When compared with the first decile, the tenth decile of the polygenic risk score was associated with COPD (European OR, 7.99; 95% CI, 6.56-9.72; non-European OR, 4.83; 95% CI, 3.45-6.77).

Polygenic risk scores were superior to previously described genetic risk scores, and when combined with clinical risk factors of patient age, sex, and smoking pack-years, showed improved COPD prediction versus a model using just clinical factors.

Though the highest decile of combined polygenic risk score was associated a four-fold greater odds of COPD than the lowest decile in non-Europeans, investigators stressed the study was not designed to assess disparities in the quality and availability of genetic data in Europeans versus non-Europeans.

“The development of polygenic risk scores in multi-ethnic populations using appropriate methods will be crucial for the widespread implementation of precision medicine, and to prevent widening of health-care disparities,” they wrote.

Overall, the polygenic risk score was associated with CT imaging phenotypes including wall area percent, quantitative and qualitative emphysema measures, local histogram emphysema patterns, and destructive subtypes of emphysema.

“The past decade has seen important progress in genomic medicine,” investigators wrote. “Leveraging recent large GWASs, we developed a polygenic risk score that has substantial predictive power and complements clinical risk factors for COPD across nine different cohorts.”

As genomics become more involved in healthcare, investigators anticipate their findings could more greatly benefit COPD research, prevention, and care.

The study, “Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts,” was published online in The Lancet Respiratory Medicine.