Reductions in FEV1/FVC tied to levels of genetic risk

Decreases in FEV1/FVC and airflow obstruction—hallmarks of chronic obstructive pulmonary disease (COPD)—may be partially attributable to genetic predisposition to higher or lower risks to interactions caused by smoking. Results from a U.K. Biobank cohort study showed that while smoking was harmful across all genetic risk groups, it was worse for those in the highest decile of estimated genetic risk.

The findings are published in JAMA Network Open.

“Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction, traditionally defined by a low percent of forced vital capacity exhaled in the first second (FEV1 /FVC), and cigarette smoking is the greatest environmental risk factor. Only a minority of smokers develop COPD, and genetic factors are thought to account for some of this variation in susceptibility, with approximately 40% of the variability in spirometric measures of pulmonary function attributed to genetic variation. Therefore, it has long been thought that airflow obstruction may develop partially as the result of gene-by-smoking interactions,” wrote co-senior author Terri H. Beaty, PhD, Johns Hopkins Bloomberg School of Public Health, Baltimore, and colleagues.

In this study, they used data from the U.K. Biobank to identify U.K. citizens of European ancestry who were ages 40 to 69 years old to assess the possible interactions between cigarette smoking and polygenic risks scores as associated with reduced lung function. The primary outcome was FEV1/FVC.

“It has long been questionable why only a minority of smokers develop COPD, characterized by airflow obstruction due to reduced lung function. It’s well known that reduced lung functions are strongly influenced by cigarette smoking. Spirometric measures of lung function are partially explained by genetic components. It raises the potential for gene-smoking interactions. We hypothesized that the harmful effects of smoking on reduced lung function might differ by an individual’s genetic susceptibility,” Beaty told BreakingMED in an email correspondence.

In all, they included 318,730 individuals (mean age: 56.5 years; 44.4% men), among whom 24,915 (8%) had moderate-to-severe COPD. Beaty and colleagues assessed three measures of cigarette smoking exposure, including pack-years of smoking, ever- versus never-smoking status, and current versus former- and never-smoking status. They also calculated a polygenic risk score (PRS) for lung function based on genome-wide association study (GWAS) results for FEV1 and FEV1/FVC.

Beaty and fellow researchers found that FEV1/FVC was associated with PRS (β: −0.03; 95% CI: −0.031 to −0.03) and pack-years (β: −0.0064; 95% CI: −0.0064 to −0.0063), as well as the interaction term (β: −0.0028; 95% CI: −0.0029 to −0.0026). Researchers observed a stepwise increment in estimated effect sizes for these interaction terms ((β) per 10 pack-years of smoking.

These were as follows:

  • 11-20 pack-years: β: −0.0038; 95% CI: −0.0046 to −0.0031.
  • 31 to 40 pack-years: β: −0.013; 95% CI: −0.014 to −0.012.
  • Over 50 pack-years: β:−0.017; 95% CI: −0.019 to −0.016.

Beaty and colleagues also found a significant interaction between PRS with ever- or never-smoking status (β: −0.0064; 95% CI: −0.0068 to −0.0060) and current or not-current smoking (β: −0.0091; 95% CI: −0.0097 to −0.0084).

In all levels of pack-years of smoking, FEV1/FVC was significantly lower in those with the highest genetic risk (tenth decile) than those with the lowest risk. For every 20 pack-years of smoking, individuals with the highest genetic risk had an almost 2-fold reduction in FEV1/FVC compared with those with the lowest genetic risk.

“Based on our findings, the take-home message is that smoking cessation is crucial to prevent reduced lung function and obstructive lung disease regardless of an individual’s genetic risk and that those in the highest risk groups (smokers at high genetic risk) might benefit from intensive smoking cessation programs,” noted Beaty.

When asked whether these results were surprising, she responded that they were.

“We expected that smoking would be harmful across all genetic risk groups given that smoking is a strong risk factor for obstructive lung disease. However, we were not sure if the harmful effects of smoking on reduced lung function would significantly differ by individual’s genetic risk,” Beaty said. “Despite the efforts to answer this question exploring gene-smoking interaction, most of the studies were limited to test a single variant and have not reported evidence of an interaction. In our study, we attempted to utilize a genome-wide polygenic risk score, an aggregate measure of ~2 million genetic variants, to estimate an individual’s genetic risk.”

In an accompanying editorial, Dana B. Hancock, PhD, of RTI International, Triangle Park, North Carolina, summarized the findings, limitations, and need for more work.

“In summary, PRS-by-smoking interaction expands upon prior work and provides more conclusive evidence than before, showing that individuals at high genetic risk face the greatest detrimental outcomes of smoking on lung function and COPD. While promising, these interaction findings still merit replication in independent cohorts. This step is limited by other data sets of comparable size as UK Biobank not being readily available. Sample sizes are even further constrained for non-European ancestries and hamper the accuracy of PRSs in diverse populations. PRS-by-smoking studies to date have largely, if not exclusively, focused on individuals of European ancestry. Extension of these studies into other ancestries is critically important to address health disparities in prevention and treatment of smoking behaviors and lung disease. This extension underscores the urgent need for more data from diverse population,” Hancock wrote.

Although more study is needed to further clarify the interactions between genetics and smoking and the risks of COPD, Beaty outlined the possible practical applications of estimating genetic risk in patients who smoke.

“First of all, we envision that an individual’s genetic profile summarized as a PRS in this study can contribute to the assessment of COPD risk at all levels of smoking exposure. Particularly, for patients who smoke, we emphasize that regardless of their genetic risk, abstaining from smoking should be recommended. One can further allocate more resources to target the patients who are most susceptible to the harmful effects of smoking for the intensive smoking cessation programs,” Beaty said.

Study limitations include that the U.K. Biobank is a single cohort studied cross-sectionally, the use of self-reported measures of smoking, inability to study early life interactions of genetics and smoking and lung function, overfitting of the PRS with spirometric measures, and inclusion of only individuals with European ancestry.

  1. For every reported 20 pack-years of smoking, smokers with the highest genetic risk compared with those with the lowest genetic risk had nearly twice the reduction in FEV1/FVC.

  2. More study is needed, but researchers are hopeful that by studying the associations between smoking and genetic risk, they can better understand the processes involved in the pathogenesis of COPD.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

Beaty has received grants from the National Heart, Lung, and Blood Institute (NHLBI) during the conduct of this study.

Hancock reported no disclosures.

Cat ID: 154

Topic ID: 89,154,730,143,192,154,195,925