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

Abstract

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. 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 lossof-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. TRPV12 and TRPV4 are nonselective cation channels, members of the vanilloid subfamily of transient receptor potential cation channels (1). TRPV1 is expressed primarily on nociceptive neurons and can be activated by capsaicin, noxious heat, and protons (2). The widely distributed TRPV4 cationic channel participates in the transduction of mechanical and/or osmotic stimuli in different tissues (3, 4). TRPV4 channels also respond to heat, acidic pH, and endogenous arachidonic acid metabolites (5, 6).Both channels are expressed in airway sensory nerves (TRPV1) (7) and epithelial (8, 9) and smooth muscle cells (TRPV4) (10). As integrators of different physical and chemical stimuli, they participate in the generation of Ca 2ϩ signals (11, 12) that contribute to airway defense mechanisms such as cough (13,14) and mucociliary clearance (9), but TRPV1 and TRPV4 also show a pathophysiological downside. TRPV1 activity has been related to different aspects of chronic respiratory disease such as neurogenic inflammation (15, 16), irritant-induced chronic cough (13,14), and airway hypersensitivity (17). TRPV4 activation disrupts alveolar barrier in animal models (18) and has been associated with chronic obstructive pulmonary disease in humans (19). Together, 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 onl...

Identification of a Binding Motif in the S5 Helix That Confers Cholesterol Sensitivity to the TRPV1 Ion Channel

“…7A). In a genetic and functional screening of hTRPV1 variants obtained from a human population, Cantero-Recasens et al (48) found that at amino acid 585, 51% are heterozygous (Ile/Val), 15% are homozygous for Val/Val, and 34% homozygous for Ile/Ile. They found these variants could be activated by capsaicin, which we have confirmed.…”

TRPV1 polymorphisms influence capsaicin cough sensitivity in men

“…HeLa cells were transiently transfected with the wild type TRPV1, the triple mutant TRPV1-I315-I469-V585 and the single mutant TRPV1-V585 as described previously (6). Calcium signalling experiments were used to assess channel activity using capsaicin as an agonist.…”

“…As Capsaicin is known to activate TRPV1 (2) we extracted genomic DNA from blood using a Qiagen DNA Blood mini kit and sequenced the TRPV1 gene to identify polymorphisms, as described previously (6).…”

“…In a case-controlled study investigating 149 polymorphisms from 14 TRP channels, SNPs in TRPV1 and TRPV3 showed association with migraines in the Spanish population (5). In cough and airway diseases, the presence of the polymorphism TRPV1-I585V was recently found to be associated with a significantly reduced risk of cough in asthmatic children (6). Another casecontrolled study investigated the association between TRP SNPs, irritant exposure and cough.…”

Expert opinion on the cough hypersensitivity syndrome in respiratory medicine

“…An insertion/deletion polymorphism in the angiotensinconverting enzyme (ACE) gene, however, may predispose to the development of ACE inhibitor-related cough [82]. A single study has suggested that a polymorphism in the TRPV1 gene might reduce the risk of cough and wheeze in subjects with asthma, although the risk of asthma was not changed [83]. Finally, another study suggested that two polymorphisms in the neurokinin 2 receptor gene are associated with heightened sensitivity to capsaicin in chronic cough patients [84].…”