Candidate genes and chromosomal loci in multiple sclerosis

Abstract: Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system with a putatively autoimmune etiology. The pathophysiological basis of MS is incompletely known, although both genetic and environmental factors are presumed to be of importance. Epidemiological analyses of familial clustering, twin concordance and adoptees support the notion that several genetic factors are likely to confer susceptibility - i.e., that MS is a complex trait. So far only the HLA gene complex has been clearly identified as important; but many patients fail to carry the associated haplotype, and estimations suggest that this locus contributes only a minor part of the overall genetic susceptibility. Several studies support the importance of nitric oxide synthase (NOS) as a component in the pathogenesis of MS. The neuronal NOS isoenzyme (NOS 1) participates in diverse biologic processes such as neurotransmission, regulation of body fluid homeostasis and neuroendocrine physiology. Our linkage study, using two intragenic markers, failed to provide evidence for a susceptibility locus in this gene. Thus, a contribution of the NOS 1 gene to the genetic background of MS is unlikely in this population. We also investigated a number of candidate genes encoding cytokines (IFN-[gamma], IL-2, -4, -10, IL4R, TGF-[beta]1 and [beta]2 and myelin proteins (CNPase, MAG, OMGP, PLP) in MS by linkage and association studies. No evidence for linkage was observed, apart from a slightly positive LOD score of 0.88 for the gene encoding IFN-[gamma] and possible linkage with the gene encoding TGF-[beta]2 by APM analysis. None of the markers was associated with MS. We investigated three intragenic markers and one flanking marker in the gene encoding cytotoxic T lymphocyte antigen 4 (CTLA-4) for possible importance in MS susceptibility. We observed that patients with MS were significantly more often homozygous for the G49 allele in exon 1 compared with controls and that they carried the T-318 promoter allele significantly less often. However, there was no evidence of linkage for either the exon 4 marker or the flanking marker (D2S116) by any of the various linkage analyses employed. These observations are similar to findings in other supposedly autoimmune disorders, and this raises the possibility that dysregulation of CTLA-4-driven down-regulation of T cell activation could influence the pathogenesis of MS. Recently, four preliminary genome-encompassing surveys were completed for MS, revealing several loci of possible genetic linkage, worthy of further study. We have therefore chosen to investigate a number of these non-HLA loci to determine whether they might play a role for the risk of MS in the Swedish ethnic group. We observed association and linkage for 2 loci (on 12q23 and 7ptr-15) of a total of 11 evaluated (also on chromosomes 2p23, 5q11-13, 6q25, 7q2l-22, 1lq2-23, 13q33-34, l6p13.2, l8p11 and Xp2l.3), which suggests novel susceptibility genes for MS on l2q23 and 7ptr-15. Recently, loci of importance for animal models of autoimmune diseases have been identified. Loci for collagen-induced arthritis (CIA) and oil-induced arthritis (OIA) on rat chromosomes 4, 10, 1 and 7, in regions syntenic to the human regions 2p12, 3p25, 7q35, l0q11, 12pl2-13, 17q2l-25, 19q13 and 22ql2-13, are of particular interest, since they appear to coincide with loci of importance for a number of autoimmune models. We analyzed 28 markers in human regions syntenic to the CIV/OIA loci. We found that 3 out of 5 human chromosomal regions (7q34-36, which includes the T-cell receptor [beta]-chain gene region and is syntenic to Cia3; 12p13, syntenic to Oia2; and 17q25, syntenic to Cia5) may be involved in susceptibility to familial and sporadic MS in the Swedish population. Interestingly, the same three regions have also shown suggestive evidence for linkage in previous human genomic screens in MS. This clustering of factors in -distinct autoimmune diseases suggests the existence of a common set of susceptibility genes.