Multiple genes potentially underlie the third locus associated with FEV1 at 5q33. The most strongly associated SNPs in this region, rs3995090 and rs6889822 (P = 4.29 × 10−9 and P = 8.17 × 10−9; Table 2 and Fig. 2d), are located in an intron in HTR4 and are part of a cluster of associated SNPs also spanning a SPINK5-like gene, SPINK7, SPINK9 and FBXO38. HTR4, which encodes 5-hydroxytryptamine receptor-4, is expressed in neurons in the respiratory pre-Bötzinger complex. Activation of this G protein–coupled receptor protects spontaneous respiratory activity18. Notably, selective antagonism of HTR4 in human bronchial strips in vitro attenuates the facilitation of electric field–stimulated cholinergic contraction by 5-hydroxytryptamine, suggesting a role for HTR4 in mediating airway caliber19. HTR4 expression has recently been confirmed in airway epithelial type II cells, where receptor stimulation seems to regulate cytokine responses20. The SPINK family of serine protease inhibitors may have a role in antimicrobial protection of mucous epithelia21. F-box protein-38 (encoded by FBXO38) is a member of a family of proteins that are believed to mediate protein-protein interactions and protein degradation22.
