Multiple single nucleotide polymorphisms of the transient receptor potential vanilloid 1 (TRPV1) genes associate with cough sensitivity to capsaicin in healthy subjects

Background: Cough is a common symptom in several respiratory diseases and may occur in healthy subjects as a defense mechanism against noxious inhalants. Cough response is mediated by transient receptor potential vanilloid- 1 (TRPV1) expressed by C-fibers in the airways. Capsaicin (CPS) activates TRPV1 and is regularly used as a tool to study cough response. Although single nucleotide polymorphisms (SNPs) of TRPV1 are implicated in CPS binding, their role in cough response is not fully elucidated. Aims: In this study we investigated the relationship between capsaicin cough challenge sensitivity and multiple TRPV1 polymorphisms. Methods: The dose-response of cough induced by CPS inhalation was determined in 20 unselected healthy volunteers and the concentration of CPS causing two coughs (C2) was calculated. The SNPs I585V(rs8065080), T505A(rs17633288), T469I(rs224534), I315 M(rs222747), P91S(rs222749), and K2N(rs9894618) were characterized in blood DNA from each subject. The association between combinations of TRPV1 SNPs and CPS sensitivity of each subject was assessed by linear regression. Results: All subjects were wild type for T505A and K2N, while they exhibited two to six SNPs with high capsaicin responsiveness. The major contribution to CPS sensitivity in vivo (C2) was due to four combined SNPs: 315 M, 585I, 469I and 91S (p = 0.015). We found, however, that the presence of a minimum of two polymorphisms, such as 91S combined with 315 M (p=0.032) or 91S with 585I (p=0.025), was sufficient to detect an effect on C2. Conclusion: Capsaicin cough challenge sensitivity in healthy subjects is dependent on multiple TRPV1 polymorphisms.