Tackling Inherited Blindness

Objectives: To assess the effect of variations in GTP cyclohydrolase gene (GCH1) on pain sensitivity in humans. Methods: Thermal and cold pain sensitivity were evaluated in a cohort of 735 healthy volunteers. Among this cohort, the clinical pain responses of 221 subjects after the surgical removal of impacted third molars were evaluated. Genotyping was done for 38 single nucleotide polymorphisms (SNPs) whose heterozygosity > 0.2 in GCH1. Influence of the genetic variations including SNPs and haplotypes on pain sensitivity were analyzed. Results: Minor allele frequencies and linkage disequilibrium show significant differences in European Americans, African Americans, Hispanic Americans and Asian Americans. Association analyses in European Americans do not replicate the previously reported important influence of GCH1 variations on pain sensitivity. Conclusion: Considering population stratification, previously reported associations between GCH1 genetic variations and pain sensitivity appear weak or negligible in this well characterized model of pain. Background The role of 6(R)-t-erythro-5,6,7,8-tetrahydrobiopterin (BH4) in pain is suggested by the up-regulation of two of the three enzymes in the synthesis cascade of BH4 in the dorsal root ganglion following sciatic nerve injury [1]. GTP cyclohydrolase (GCH) catalyzes the rate limiting step, and sepiapterin reductase catalyzes the final conversion of 6-pyruvoyltetrahydropterin to the BH4. It was recently reported that single nucleotide polymorphisms (SNPs) in the gene encoding GCH (GCH1) alter both responses in healthy humans to noxious stimuli and the susceptibility of patients to development of neuropathic and inflammatory pain [2]. The authors also suggest a pain protective haplotype associated with the risk of developing persistent pain syndromes, which could be a useful tool to assess an individual's risk potential for chronic pain [2]. Based on this reported role of GCH in pain both in animals and humans, we investigated its contribution to genetic inter-individual variation in clinical pain sensitivity and analgesic responses. We have investigated the association between pain responses to experimental and clinical painful stimuli and genetic variations including SNPs and haplotypes of GCH1. Published: 7 March 2007 Molecular Pain 2007, 3:6 doi:10.1186/1744-8069-3-6 Received: 23 February 2007 Accepted: 7 March 2007 This article is available from: http://www.molecularpain.com/content/3/1/6 © 2007 Kim and Dionne; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.