GTP-cyclohydrolase (GCH1) is the rate-limiting enzyme for tetrahydrobiopterin (BH4) synthesis and has been shown to regulate pain sensitivity and persistence. Using a candidate gene approach, one haplotype of GCH1 was found to correlate with lower pain in a population of sciatica patients from the Maine Lumbar Spine Study and in two populations of normal subjects tested with experimental pain³. As no obvious functional polymorphisms were found within this haplotype, we have now partially resequenced this gene to search for a polymorphism that directly alters function. DNA of 48 sciatica patients who had zero, one, or two copies of the pain-protective haplotype was resequenced along with DNA from 48 clinically and ethnically diverse individuals. The resequencing was completed with Applied Biosystems VariantSEQR Resequencing System and BigDye Terminator v3.1 Cycle Sequencing Kit; the samples were run on a 3100 Genetic Analyzer. Resequencing focused on the promoter and regions containing exons. Seven known SNPs and one novel SNP were found in the promoter region and one known SNP was found in the 3'UTR region. The distribution of alleles in several of these SNPs appears to correspond to the presence of the pain-protective haplotype in the sciatica patients. These variants will be genotyped in the entire Maine Lumbar Spine Study population and further analyzed for possible functional significance.

³Tegeder et al., Nat Med., 2006