Loss of Function of Transient Receptor Potential Vanilloid 1 (TRPV1) Genetic Variant Is Associated with Lower Risk of Active Childhood Asthma

Josep M. Antó,Gerard Cantero-Recasens,Juan R. Gonzalez,Miguel A. Valverde,Enric Duran-Tauleria,César Fandos,Francine Kauffmann,Lidwien A.M. Smit

doi:10.1074/jbc.c110.159491

Abstract

Transient receptor potential cation channels of the vanilloid subfamily (TRPV) participate in the generation of Ca(2+) signals at different locations of the respiratory system, thereby controlling its correct functioning. TRPV1 expression and activity appear to be altered under pathophysiological conditions such as chronic cough and airway hypersensitivity, whereas TRPV4 single nucleotide polymorphisms (SNP) are associated with chronic obstructive pulmonary disease. However, to date, there is no information about the genetic impact of either TRPV1 or TRPV4 on asthma pathophysiology. We now report on the association of two functional SNPs, TRPV1-I585V and TRPV4-P19S, with childhood asthma. Both SNPs were genotyped in a population of 470 controls without respiratory symptoms and 301 asthmatics. Although none of the SNPs modified the risk of suffering from asthma, carriers of the TRPV1-I585V genetic variant showed a lower risk of current wheezing (odds ratio = 0.51; p = 0.01), a characteristic of active asthma, or cough (odds ratio = 0.57; p = 0.02). Functional analysis of TRPV1-I585V, using the Ca(2+)-sensitive dye fura-2 to measure intracellular [Ca(2+)] concentrations, revealed a decreased channel activity in response to two typical TRPV1 stimuli, heat and capsaicin. On the other hand, TRPV4-P19S, despite its loss-of-channel function, showed no significant association with asthma or the presence of wheezing. Our data suggest that genetically determined level of TRPV1 activity is relevant for asthma pathophysiology.

Highlights

Transient receptor potential cation channels of the vanilloid subfamily (TRPV) participate in the generation of Ca2؉ signals at different locations of the respiratory system, thereby controlling its correct functioning
We report on the association of two functional single nucleotide polymorphisms (SNP), TRPV1-I585V and TRPV4-P19S, with childhood asthma
TRPV4 activation disrupts alveolar barrier in animal models [18] and has been associated with chronic obstructive pulmonary disease in humans [19]. These evidences make TRPV1 and TRPV4 interesting candidate genes for asthma. To understand their implication in asthma pathophysiology, i.e. whether the etiology or the pathological symptoms are associated with a gain or loss of channel function, we have only considered two nonsynonymous variants that may alter channel activity

Summary

Introduction

Transient receptor potential cation channels of the vanilloid subfamily (TRPV) participate in the generation of Ca2؉ signals at different locations of the respiratory system, thereby controlling its correct functioning. We report on the association of two functional SNPs, TRPV1-I585V and TRPV4-P19S, with childhood asthma. TRPV4-P19S, despite its lossof-channel function, showed no significant association with asthma or the presence of wheezing.

Results

Conclusion