An investigation of NOS2A promoter polymorphisms in Australian multiple sclerosis patients

Abstract

As with other major autoimmune diseases, susceptibility to multiple sclerosis (MS) is believed to result from the complex interaction of a number of genes, each with modest effect. Extensive research of experimental autoimmune encephalomyelitis in mice and several direct MS studies have implicated NOS2A, which encodes the inducible form of nitric oxide synthase, and the genetic region encoding NOS2A, 17q11.2, has been identified in a number of genome wide screens as being potentially associated with MS. We investigated four single nucleotide polymorphisms in the proximal promoter region of NOS2A, in a case -control group of 100 Australian MS patients and 100 controls and in 203 MS patients and their unaffected parents. We found a trend toward excess transmission of the À277A allele (tag for the AGCC haplotype) to HLA-DRB1*1501-positive MS patients (P (uncorrected) ¼ 0.05). We initially discovered a trend toward over-representation of the AGCC haplotype in HLA-DRB1*1501-positive compared to HLA-DRB1*1501-negative MS patients in the case-control cohort. However, when combined with the probands from the transmission disequilibrium analysis, this trend was nullified. Nonetheless, despite the lack of significant evidence of association for the NOS2A promoter polymorphisms with MS, the gene remains an interesting candidate for MS susceptibility, particularly with regard to the HLA-DRB1*1501 haplotype.

Genetic variation in nitric oxide synthase 2A (NOS2A) and risk for multiple sclerosis

“…Finally, given the importance of DRB1*15 in MS, we stratified families based on carrier status of this risk allele for analyses of all NOS2A SNPs and haplotypes to look for differences. Previous results suggested NOS2A associations were more prominent in DRB1*15-positive MS cases 20,21 and/or families, however the current study does not confirm this finding.…”

“…20 Evidence for excess transmission of the T allele remained significant even after correction for multiple testing in HLA-DRB1*15-positive families. Because the associated SNP confers a synonymous coding change, and other smaller NOS2A studies in MS have either suggested trends 21,22 or failed to detect an association, [23][24][25] much larger studies are needed to confidently confirm or exclude a role for this important locus in disease susceptibility.…”

Linkage disequilibrium analysis in the genetically isolated Norfolk Island population

“…This is consistent with previous work (Bugeja et al, 2005) and is to be expected given the close proximity of the SNPs, the relatedness of the Norfolk population and the prevalence of the minor SNP allele (410%). With the exception of the À1026/ À1659 marker pair, all the SNPs studied in the Norfolk population were found to be in complete and significant LD with each other.…”

Preliminary evidences of a NOS2A protective effect from Relapsing–Remitting Multiple Sclerosis

“…Further negative results derived from an Australian study of 4 SNPs in the same gene promoter region, although a trend to significance suggested an interaction between the studied NOS2A promoter polymorphisms and the HLA-DRB1 ⁎ 1501 genotype in predisposing to MS [21].…”

“…A multilocus genotyping assay provided evidence for a strong linkage and association between the NOS2A locus and MS [6], although 4 independent casecontrol studies failed to demonstrate further association with several polymorphisms located in the promoter region of the NOS2A gene [18][19][20][21].…”