The possibility that there are multiple functional genes in this locus controlling for different aspects of COPD is a valid one; CHRNA3 and CHRNA5 have been shown to be significantly associated with pack/years smoking and emphysema in COPD patients, whereas the most significant association for FEV1 was in an intron of IREB2 [32]. This evidence concerns the gene IREB2 and chronic obstructive pulmonary disease.