Natarajan et al. Melatonin pathway genes are associated with progressive subtypes and disability status in multiple sclerosis among Finnish patients. J Neuroimmunol. 2012 Jun.(epub)
In this study we investigated the relationship between melatonin pathway and MS in a high-risk Finnish population by studying the single nucleotide polymorphisms (SNPs) in the genes coding for critical enzymes and receptors involved in the melatonin pathway.
A total of 590 subjects (193 MSers and 397 healthy controls) were genotyped for seven SNPs in four genes including tryptophan hydroxylases (TPH)1 and 2, arylalkylamine N-acetyltransferase (AANAT) and http://ars.els-cdn.com/content/image/1-s2.0-S152166161100163X-gr1.jpg1B (MTNR1B). An overrepresentation of T allele carriers of a functional polymorphism (G-703T, rs4570625) in the promoter region of TPH2 gene was observed in the progressive MS subtypes. The haplotype rs4570625-rs10506645TT of TPH2 gene was associated with the risk of severe disability in primary progressive MS (PPMS), while haplotype rs4570625-rs10506645TC appeared to be protective against disability in secondary progressive MS (SPMS).
In the MTNR1B gene, the haplotype rs10830963-rs4753426GC was associated with the risk of SPMS, whereas another haplotype rs10830963-rs4753426GT showed an association with the risk of PPMS. These data showing the association of polymorphisms in the TPH2 and MTNR1B genes with the progressive subtypes of MS and disability suggest dysregulation in melatonin pathway. Melatonin pathway seems to be involved in disease progression, and therefore its potential effects in overcoming MS-related neurodegeneration may be worth evaluating in future clinical trials.
Melatonin levels varies during the daily. It works by stimulating the melatonin receptor.This project has look at single nucleotide polymorphisms and found some that seem to be associated with the development of progressive MS. These are variations in the gene with changes in one of the four nucleotides e.g. T = thymidine, G = guanine C = cytosine, A=adenosine. G-703Trs4570625 indicates a switch of thymidine at position 703 of the gene SNP rs4570625 to guanine in the promoter (the bit before the coding sequence of the gene) which drives expression of the gene product.
How melatonin influences MS is unknown, there may be influences on sleep patterns and there is experimental evidence for it to be an immune modulator...this will be further impetus for Prof H to get Project M off the ground.