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

Ann Hum Biol. 2013 Jul;40(4):368-75. doi: 10.3109/03014460.2013.786756. Epub 2013 Jul 5.


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®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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Case-Control Studies
  • Electrophoresis, Capillary
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Genetic Markers
  • Genetic Predisposition to Disease
  • Haplotypes
  • Humans
  • Kuwait / epidemiology
  • Male
  • Multiple Sclerosis / epidemiology
  • Multiple Sclerosis / genetics*
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase Type I / genetics*
  • Nitric Oxide Synthase Type I / metabolism
  • Nitric Oxide Synthase Type II / genetics*
  • Nitric Oxide Synthase Type II / metabolism
  • Nitric Oxide Synthase Type III / genetics*
  • Nitric Oxide Synthase Type III / metabolism
  • Real-Time Polymerase Chain Reaction
  • Young Adult


  • Genetic Markers
  • Nitric Oxide
  • NOS1 protein, human
  • NOS2 protein, human
  • NOS3 protein, human
  • Nitric Oxide Synthase Type I
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III