Association analysis of nitric oxide synthases: NOS1, NOS2A and NOS3 genes, with multiple sclerosis.

Background: Multiple sclerosis (MS) is a chronic inflammatory autoimmune disorder of the central nervous system. Aim: To explore the genetic basis of three nitric oxide synthase (NOS) genes: NOS1, NOS2A and NOS3, with susceptibility to MS. Subjects and methods: A total of 122 MS patients and 118 healthy controls screened for NOS1 (rs2682826, rs41279104), NOS2A (CCTTT)n/(TAAA)n and NOS3 (rs1800783, rs1800779, rs2070744, 27bpVNTR) markers, using TaqMan (R) SNP Genotyping Assays and fragment analysis were enrolled in this study. QRT-PCR and ELISA were used to analyse the expression of NOS3 mRNA and Nitric Oxide (NO) levels. Results: Two NOS3 markers were associated with susceptibility to MS and early disease development. The NOS3 rs1800779 G-allele (p=0.04) and GG-genotype (p=0.02) showed association with susceptibility to MS. Short NOS2 (CCTTT)n (p=0.03) and short/long repeat (p=0.04) genotypes also showed associations with MS. These associations were intensified by sub-division of patients into Kuwaiti Arabs and Persians (p<0.05). The NOS3-27 bp-VNTR a-allele was associated with early MS disease onset <= 26 years (p=0.04). The NOS3-27 bp-VNTR a/b-genotype resulted in 23% lower NO production and the NOS3-rs1800779 AA-genotype resulted in lower NOS3 expression. Haplotypes obtained from NOS2A and NOS3 showed increased susceptibility to MS. NOS1 showed no significant association with MS. Conclusion: This study provides evidence for the association between selected NOS2 and NOS3 markers and MS susceptibility.