The COPD genetic association compendium: a comprehensive online database of COPD genetic associations

Abstract

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. COPD is thought to arise from the interaction of environmental exposures and genetic susceptibility, and major research efforts are underway to identify genetic determinants of COPD susceptibility. With the exception of SERPINA1, genetic associations with COPD identified by candidate gene studies have been inconsistently replicated, and this literature is difficult to interpret. We conducted a systematic review and meta-analysis of all population-based, case-control candidate gene COPD studies indexed in PubMed before 16 July 2008. We stored our findings in an online database, which serves as an up-to-date compendium of COPD genetic associations and cumulative meta-analysis estimates. On the basis of our systematic review, the vast majority of COPD candidate gene era studies are underpowered to detect genetic effect odds ratios of 1.2-1.5. We identified 27 genetic variants with adequate data for quantitative meta-analysis. Of these variants, four were significantly associated with COPD susceptibility in random effects meta-analysis, the GSTM1 null variant (OR 1.45, CI 1.09-1.92), rs1800470 in TGFB1 (0.73, CI 0.64-0.83), rs1800629 in TNF (OR 1.19, CI 1.01-1.40) and rs1799896 in SOD3 (OR 1.97, CI 1.24-3.13). In summary, most COPD candidate gene era studies are underpowered to detect moderate-sized genetic effects. Quantitative meta-analysis identified four variants in GSTM1, TGFB1, TNF and SOD3 that show statistically significant evidence of association with COPD susceptibility.

Figure 1.

Results of Medline and HuGENet search for case–control COPD genetic association studies. The Medline search yielded 1604 articles. Abstract level review resulted in 130 articles, which were narrowed to 104 articles after full text review. Studies included in the database met the following criteria: peer-reviewed, English language publications of case–control studies of genetic associations with COPD in humans with a total sample size of 10 or more.

Figure 2.

Distribution of the difference in mean/median age (A) and pack-year tobacco exposure (B) between case and control groups. Data taken from subset of studies reporting age and pack-year data for both cases and controls (61 and 41% of all studies, respectively). Difference is calculated as mean/median in cases minus controls.

Figure 3.

Power analysis of COPD candidate gene studies. For each tested genetic association in our database, we calculated the sample size necessary for 90% power to detect genetic effect sizes of 1.2, 1.5 and 2.0 based on the observed minor allele frequency and case:control ratio (left column). The right column shows how many times larger the necessary sample size is compared with the observed sample size for a given genetic effect.

Figure 4.

Forest plots of the four meta-analyses meeting nominal statistical significance. Random effects meta-analysis was performed using an allele-based genetic model. Of 27 studied variants, meta-analyses for GSTM1 null (A), rs1800470 in TGFB1 (B), rs1800629 in TNF (C) and rs1799895 in SOD3 (D) yielded summary effect size estimates with P-values <0.05. In Figure 4A, nu = null, pre = wild-type allele. Fractional allele counts result from situations in which a single case group has been contrasted with multiple control groups. In this instance the case allele counts have been divided by the overall number of contrasts to avoid double counting.