Melatonin Pathway Genes and Multiple Sclerosis: A Genetic Insight from Finnish Patients

Multiple sclerosis (MS) is a complex immune-mediated neurdenerative disease characterized by demyelination in the central nervous system. It is influenced by both genetic and environmental factors, with higher prevalence rates in regions with less sunlight exposure. This blog post explores a study conducted by Renuka Natarajan and colleagues, investigating the relationship between melatonin pathway genes and MS among Finnish patients. The study highlights the genetic associations that may contribute to disease progression and disability status in MS, emphasizing the importance of melatonin biosynthesis and its receptors.

The Role of Melatonin in MS
Melatonin, a hormone produced by the pineal gland, is crucial for regulating sleep-wake cycles and has potent antioxidant properties. The synthesis of melatonin involves several key enzymes: tryptophan hydroxylase (TPH) 1 and 2, which convert tryptophan to serotonin; arylalkylamine N-acetyltransferase (AANAT), which acetylates serotonin to N-acetylserotonin; and hydroxyindole-O-methyltransferase, which converts N-acetylserotonin to melatonin. The physiological effects of melatonin are mediated through its receptors, MT1 and MT2, encoded by the MTNR1B gene.

Study Design and Population
The study involved 590 subjects, including 193 MS patients and 397 healthy controls. The MS patients were categorized into three subtypes: relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), and primary progressive MS (PPMS). The researchers genotyped seven single nucleotide polymorphisms (SNPs) across four genes (TPH1, TPH2, AANAT, and MTNR1B) to investigate their association with MS subtypes and disability status.

Key Findings 1. TPH2 Gene Associations: The T allele of SNP rs4570625 in the TPH2 gene promoter was significantly overrepresented in patients with progressive MS (SPMS and PPMS), suggesting a higher risk for these subtypes.

The TPH2 haplotype rs4570625-rs10506645TT was associated with severe disability in PPMS patients, while the TPH2 haplotype rs4570625-rs10506645TC appeared protective against disability in SPMS patients.

2. MTNR1B Gene Associations: The MTNR1B haplotype rs10830963-rs4753426GT was associated with the risk of PPMS, and the haplotype rs10830963-rs4753426GC was associated with the risk of SPMS.

These findings suggest that variations in the MTNR1B gene influence disease progression in different MS subtypes.

Implications for MS Pathogenesis
The study provides compelling evidence that melatonin pathway genes, particularly TPH2 and MTNR1B, are involved in the pathogenesis and progression of MS. The genetic variations identified may lead to dysregulation of melatonin synthesis and function, contributing to neuroinflammation and neurodegeneration observed in MS patients. This dysregulation could be a potential therapeutic target for modulating disease progression and severity.

Conclusion
The association of melatonin pathway genes with MS subtypes and disability status underscores the significance of melatonin in disease progression. Understanding the genetic factors influencing melatonin biosynthesis and function could pave the way for novel therapeutic strategies aimed at mitigating the impact of MS. This study highlights the intricate interplay between genetics and environmental factors in MS, emphasizing the need for a holistic approach to managing this complex disease.

References:
Natarajan, R., Einarsdottir, E., Riutta, A., Hagman, S., Raunio, M., Mononen, N., ... & Elovaara, I. (2012). Melatonin pathway genes are associated with progressive subtypes and disability status in multiple sclerosis among Finnish patients. Journal of neuroimmunology, 250(1-2), 106-110.