Chronic obstructive pulmonary disease (COPD) results from complex interactions between both environmental and genetic factors. This is evidenced by the considerable variation found in the risk of developing COPD despite the established dose-response relationship from the biggest known risk factor, tobacco smoking. Thus, genetic susceptibility remains poorly understood given the best-characterised genetic determinant of COPD, severe alpha-1-antitrypsin (AAT) deficiency, only affects1–2% of all COPD patients.
A genome-wide association study implicated an intronic single nucleotide polymorphism (SNP) rs3748312 within AAT gene as the strongest locus associated with lung function (a heritable surrogate predictor of COPD). Thus, this was investigated as part of a larger research project aimed at identifying rare sequence variants of the AAT gene that may be associated with COPD.
A sample of 230 COPD patients of European descent either predicted to carry one of six haplotypes conferring COPD risk, or who presented with severe early-onset COPD were genotyped for SNP rs3748312 within the AAT gene utilising TaqMan® assay with >5% of samples sequenced for concordance. The data was compared against control data of 60 patients of European ancestry from dbSNP.
In examining the allelic distribution (p=0.049, OR 0.57 95% CI: 0.323–1.003) borderline significance was noted, however no significant difference between cases and controls was found in the genotype distribution (p=0.096OR 0.583, 95% CI 0.308–1.106).
This preliminary study suggests the SNP merits further work in a more adequately powered investigation with adjustment for covariates such as age, smoking history and lung function given the borderline nature of the findings indicative of a protective effect for developing COPD with the minorallele (A). It is feasible that associated functional SNPs in linkage disequilibrium reflect the true association.