| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12p13.31 | {Multiple sclerosis, susceptibility to, 5} | 614810 | 3 | TNFRSF1A | 191190 |
A number sign (#) is used with this entry because of evidence that susceptibility to multiple sclerosis-5 (MS5) is conferred by genetic variation in the TNFRSF1A gene (191190) on chromosome 12p13.
Multiple sclerosis-5 (MS5) is a chronic inflammatory disease of the central nervous system characterized by damage to axonal myelin sheaths and axons, commonly resulting in progressive neurologic disability beginning in early adulthood (summary by Xu et al., 2001).
For a discussion of genetic heterogeneity of multiple sclerosis, see MS1 (126200).
Xu et al. (2001) investigated 27 microsatellite markers from 8 chromosomal regions syntenic to loci of importance for experimental autoimmune diseases in the rat in 74 Swedish MS families. They observed possible linkage with markers in the 12p13-p12 region (highest NPL score of 1.16).
In a metaanalysis of genomewide association studies including 2,624 patients with MS and 7,220 controls, followed by replication in an independent set of 2,215 patients MS and 2,116 controls, De Jager et al. (2009) identified a locus for MS susceptibility on chromosome 12p13 in the TNFRSF1A gene (191190) (rs1800693; combined p = 1.59 x 10(-11)).
Gregory et al. (2012) investigated the rs1800693 SNP in the TNFRSF1A gene (191190.0013) that was discovered through GWAS to be associated with MS but not with other autoimmune conditions such as rheumatoid arthritis (180300), psoriasis (177900), or Crohn disease (266600). By analyzing MS GWAS data in conjunction with the 1000 Genomes Project data, Gregory et al. (2012) provided genetic evidence that strongly implicated rs1800693 as the causal variant in the TNFRSF1A region. Gregory et al. (2012) further substantiated this through functional studies showing that the MS risk allele directs expression of a novel, soluble form of TNFR1 (encoded by TNFRSF1A) that can block tumor necrosis factor (TNF; 191160). Importantly, TNF-blocking drugs can promote onset or exacerbation of MS, but they have proven highly efficacious in the treatment of autoimmune diseases for which there is no association with rs1800693. This indicates that the clinical experience with these drugs parallels the disease association of rs1800693, and that the MS-associated TNRF1 variant mimics the effect of TNF-blocking drugs.
De Jager, P. L., Jia, X., Wang, J., de Bakker, P. I. W., Ottoboni, L., Aggarwal, N. T., Picco, L., Raychaudhuri, S., Tran, D., Aubin, C., Briskin, R., Romano, S., and 22 others. Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nature Genet. 41: 776-782, 2009. [PubMed: 19525953] [Full Text: https://doi.org/10.1038/ng.401]
Gregory, A. P., Dendrou, C. A., Attfield, K. E., Haghikia, A., Xifara, D. K., Butter, F., Poschmann, G., Kaur, G., Lambert, L., Leach, O. A., Promel, S., Punwani, D., and 9 others. TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis. Nature 488: 508-511, 2012. [PubMed: 22801493] [Full Text: https://doi.org/10.1038/nature11307]
Xu, C., Dai, Y., Lorentzen, J. C., Dahlman, I., Olsson, T., Hillert, J. Linkage analysis in multiple sclerosis of chromosomal regions syntenic to experimental autoimmune disease loci. Europ. J. Hum. Genet. 9: 458-463, 2001. [PubMed: 11436128] [Full Text: https://doi.org/10.1038/sj.ejhg.5200653]