TY - JOUR T1 - Genetic susceptibility to COPD JF - Thorax JO - Thorax SP - 722 LP - 722 DO - 10.1136/thorax.55.8.722b VL - 55 IS - 8 AU - C RUSE AU - S G PARKER AU - P BURTON AU - A WARDLAW Y1 - 2000/08/01 UR - http://thorax.bmj.com/content/55/8/722.3.abstract N2 - We read with interest the report by Yimet al of a failure to observe an association between polymorphisms of the microsomal epoxide hydrolase (mEPHX) gene and chronic obstructive pulmonary disease (COPD).1 This contrasts with the findings of earlier studies.2 There is debate in the literature on the place of association studies in the investigation of late onset complex disorders.3Failure to replicate an initial report of a positive association is common4-6 and it is important that the reasons for this are established.The authors correctly state that their failure to replicate the results of earlier studies may be a reflection of the marked racial differences in the frequency of the mEPHX gene within their population. However, their study also lacks power. Given, for example, their reported frequency of 75% for the wild type homozygous exon 4, a sample size of 80 subjects would only be able to detect a difference of 22% (e.g. 75% versus 53%) between the case and control groups (two tailed p value = 0.05, power = 0.8).Phenotypic heterogeneity is a problem in the genetic dissection of complex traits and hampers comparisons between studies. The authors are rigorous in their spirometric criteria used to define cases. However, their COPD group also includes never smokers and those with minimal pack-year histories. It is not restricted to adult onset disease, potentially containing chronic asthmatics. This phenotypically heterogeneous group could reduce the likelihood of demonstrating an association. The calculation of phenotypic “scores” is one solution to the clinical diversity which the label “COPD” describes.7 Finally, the importance of age and sex matching cannot be understated, not only because controls may develop disease, … Dr C-G YooDr S IshiokaDr C-G Yoo ER -