Influence of polymorphisms of three TRP genes on pain sensitivity in neuropathic pain patients
SUMMARY Neuropathic pain is a chronic pain syndrome that has been associated with drug-, disease-, or injury-induced damage or destruction of the sensory afferent fibers of the peripheral nervous system (PNS). The type of pain could be manifested not only with positive sensory phenomena, such as pain, dysesthesia, and different types of hyperalgesia, but also with negative sensory phenomena and negative and positive motor symptoms and signs. The pharmacological treatment of the symptoms of painful neuropathy, however, is still considered to be difficult. Nowadays, much attention is focused on the genetic polymorphisms, some of the single nucleotide polymorphisms can be speculated to be associated with the pain sensitivity as a result of amino acid substitution in crucial position. But the detailed knowledge of individual variability on pain perception under neuropathic pain is still poorly understood. Candidate gene studies on the basis of biological hypothesis have been a practical approach to identify relevant genetic variation in complex traits. There is growing evidence showed that single nucleotide polymorphisms in related genes, including TRPV1, TRPA1 and TRPM8, may influence pain sensitivity in animal model of neuropathic pain. In our study, we selected 2 of the SNPs fromTRPV1, 3 of the SNPs from TRPA1 and 6 SNPs from TRPM8 to examine the effect of these variations on clinical neuropathic pain responses, to investigate the contribution of genetic factors on pain sensitivity in humans. There were a total of 296 Germany patients and 253 healthy volunteers recruited in our study for investigation. Owing to the failed collection of clinical data in some cases, finally only 237 patients were enrolled to carry out the association analysis. The results show that patients exhibited markedly gain of sensory function along with the application of cold detection (CDT), thermal sensitivity limen (TSL) on control side. The hypoesthesia, however, was occurred on test side when patients were giving mechanical pain threshold (MPT) and mechanical pain sensitivity (MPS) measure. The comparison of seven subgroups between test and control side showed that there are different pain patterns based on the subgroups. Besides the trigeminal pain and other neuropathy patients, the five other subgroups exhibiting either the loss of sensory function in CDT, WDT, TSL and VDT on central pain, or the gain of sensory function in pressure pain threshold (PPT) in CPRS patient. Referring to the genotype and allele frequencies on patients and controls, there are no significant differences between the two groups, except the TRPV1 polymorphism A1911G. With regard to the association between SNPs and 13 QST parameters, there were some significant correlations related to TRPV1 polymorphisms 1103 C>G and 1911A>G, as well as to TRPA1 polymorphism 710G>A and 3228A>G with several QST parameters in two neuropathic pain subgroups. The CRPS patients carrying homozygote G in TRPA1 3228A>G were more sensitive to pain perception than those patients carrying the heterozygote genotype in the TSL and CDT test, conversely, in some subgroups homozygote TRPV1 1911G carriers were more likely to be insensitive to sensory pain than homozygote 1911A carriers; Similarly, further comparison of the data indicated that patients carrying homozygote TRPA1 710A or 3228G were less sensitive to pain perception than heterozygote and homozygote G710 or 3228A carriers. The results suggest that at least some of these genetic polymorphisms may exert major effects on pain perception possibly by influencing the level of expression of the gene product, depending on its function. Finally, polymorphisms alone or interaction between SNPs may alter transcription, mRNA stability, or the protein half-life, leading to a specific clinical status. For those polymorphisms which do not involve amino acid substitution, the observed association with pain perception could be caused by other functional polymorphisms in the neighbouring genes that posses high LDs with tested SNPs.