New Gene Variants Associated With Chronic Obstructive Pulmonary Disease
By Jacquelyn K. Beals, PhD
Medscape Medical News
February 24, 2010 — A genomewide association study combining populations from several earlier studies of pulmonary function has identified a locus on the long arm of chromosome 4 associated with increased susceptibility to chronic obstructive pulmonary disease (COPD). The site is in gene FAM13A, whose variants have been previously linked to pulmonary function. Despite this evidence that greater COPD risk is associated with FAM13A variants, the effects of cigarette smoking far outweigh the genetic influences.
Published online February 21 in Nature Genetics, the study stemmed from observations that COPD prevalence is quite variable among former and current smokers, suggesting that genetic components contribute to COPD susceptibility.
"The effect of this genetic variant and other common variants likely to influence COPD susceptibility are dwarfed by the effect of cigarette smoking on COPD risk," first author Michael H. Cho, MD, MPH, from the Channing Laboratory and Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, told Medscape Pulmonary Medicine in an email.
All patients with COPD (n = 2940) and control patients (n = 1380) in the initial study were current or former smokers. One group was from a case-control genomewide association study investigation in Norway, another from the National Emphysema Treatment Trial (patients with COPD) and the Normative Aging Study (control patients), and a third group from the ECLIPSE Study. All case patients had been diagnosed with moderate to very severe COPD; control patients had normal lung function. Analyses adjusted the case and control groups for age and pack-years of cigarette smoking and found little remaining stratification between the 2 cohorts.
Initial results identified 2 single nucleotide polymorphisms (SNPs) highly associated with COPD (P = 7.18 × 10?8 and P = 8.59 × 10?8), both within FAM13A. The next highest association was for a third SNP within this locus (P = 1.48 × 10?6). Replication in a population from the COPD Gene Study (502 patients with COPD, 504 control patients) demonstrated significant association with COPD for all 3 SNPs, although the third SNP was again the weakest association.
Checking the 2 front-runners in independent family-based cohorts found a lack of association in 1 study, perhaps the result of age at COPD onset and more severe disease, but highly significant association in the other family-based cohort (P = 1.29 × 10?3 and P = 5.15 × 10?4). Combining analysis across all 6 cohorts (3 groups in the initial analysis, the replication group, and both family-based studies) found highly significant association overall (P = 9.47 × 10?11 and P = 1.22 × 10?11).
Not much is known about the function of FAM13A, although cell cultures of nonlung tissues have shown that FAM13A expression increases in hypoxia. Expression of normal FAM13A has also been found to differ in pulmonary cells from patients with severe, as compared with mild, cystic fibrosis.
"Cigarette smoking induces hypoxia, so that fits," commented Scott T. Weiss, MD, professor of medicine, Harvard Medical School; associate physician, Brigham Women's Hospital; and a professor in the Department of Environmental Health, Channing Laboratory, Harvard School of Public Health, Boston, Massachusetts, who was not involved in this study.
"But there are other possibilities as well. Perhaps the gene is involved in lung development, or perhaps there is a differential effect on inflammatory response that is not dependent on hypoxia," Dr. Weiss suggested via email to Medscape Pulmonary Medicine.
Dr. Cho acknowledged that "we don't have any indication yet on how this variant contributes to COPD. A more fundamental question, however, than the effect of the specific variant...on COPD is the primary function of the gene," said Dr. Cho. "The prior studies showing differences in response to hypoxia should give us and others a starting point for investigation."
Although genetic variants play a part in COPD risk, and identifying the variants adds to science'sunderstanding of the disease, cigarette smoking is still the greatest risk factor. For example, every 10 pack-years of smoking increases COPD risk by 50% (odds ratio, 1.5; P = 9.3 × 10?95).
"Patients should not in any way be reassured that they could be protected from the development of COPD based on our results, and all patients should be properly counseled against smoking and receive proper medical assistance to quit smoking. While we believe that this genetic variant is potentially important to understand the pathophysiology of COPD, we do not currently anticipate any clinical interventions to immediately result from this discovery," said Dr. Cho.
Dr. Cho and Dr. Weiss have disclosed no relevant financial relationships.
