Investigation of genetic factors in multiple sclerosis

Multiple sclerosis (MS) is a chronic disease where the transmission of signals in the central nervous system is affected leading to a broad range of symptoms. The aetiology of the disease is unknown but multiple genetic and environmental factors are believed to play a part. While no environmental factor has been unequivocally established a lot has happened with regard to our knowledge of the genetic component of MS. Besides the consistent replication of associations with the HLA Class II region, association analyses have disclosed several genes of interest in MS including IL7R, IL2RA, CLEC16A, CD58 and RPL5. The HLA association shows the strongest effect on risk for MS, odds ratio for the other genes are in the range 1.1 1.4. It is not known how many genes that are implicated in MS pathogenesis, an estimation is that there will be 20-100 genes, thus there remain genetic variants yet uncovered.

The main aim of this thesis was to identify genetic variants that affect susceptibility to MS. Such knowledge could aid in the development of better therapies whilst current therapy highlights potential candidate genes to be studied for association with disease.

We investigated eight genes for association with susceptibility to MS - in total 113 genetic markers were evaluated using a case-control candidate gene association approach. Over 4,700 patients and approximately 5,000 controls contributed to this research where single nucleotide polymorphisms (SNPs) in the following genes were studied: ITGA4, the gene coding for the target of the MS-drug Tysabri®; IL23R, a gene associated with the autoimmune disease inflammatory bowel disease (IBD); TRAF1/C5, a region reported to be associated with the autoimmune disease rheumatoid arthritis (RA); NGFR, RTN4R, LINGO1, TNFRSF19, four genes which codes for the Nogo receptor complex, a potential therapeutical target, and IRF5, a gene associated with other autoimmune diseases including systemic lupus erythematosus (SLE) and RA.

We found two SNPs (rs4728142 and rs3807306) and one insertion/deletion polymorphism (CGGGG) located in the promoter and first intron of IRF5 to be associated with MS susceptibility (OR=1.1 for all three markers, P=10-5 for the two SNPs and P=10-4 for CGGGG) based on a combined analysis of association results from a Spanish, a Finnish and a Scandinavian cohort. 9,125 individuals contributed to the finding including 3,847 patients, 3,745 controls and 511 trio families (one patient and both parents). Furthermore, one SNP (rs741072) located in exon 6 of NGFR was found to be associated with risk of MS (OR=1.16, P=0.001) based on a dataset consisting of 2,108 patients and 1,871 controls of Scandinavian ancestry. Further studies are needed to verify the role of IRF5 and NGFR in the pathogenesis of MS.

List of scientific papers

I. ODoherty C, Roos IM, Antiguedad A, Aransay AM, Hillert J, Vandenbroeck K (2007). ITGA4 polymorphisms and susceptibility to multiple sclerosis. J Neuroimmunol. 189(1-2): 151-7. Epub 2007 Aug 8
https://pubmed.ncbi.nlm.nih.gov/17689671

II. Roos IM, Kockum I, Hillert J (2008). The interleukin 23 receptor gene in multiple sclerosis: a case-control study. J Neuroimmunol. 194(1-2): 173-80
https://pubmed.ncbi.nlm.nih.gov/18164077

III. Lima bomfim I, Modin H, Duvefelt K, Lindgren CM, Zucchelli M, Kere J, Kockum I, Hillert J (2009). TRAF1/C5 genetic variants in sporadic and familial multiple sclerosis. [Manuscript]

IV. Lima Bomfim I, Duvefelt K, Alfredsson L, Olsson T, Kockum I, Hillert J (2009). The nerve growth factor receptor gene affects susceptibility to multiple sclerosis. [Manuscript]

V. Kristjansdottir G, Sandling JK, Bonetti A, Roos IM, Milani L, Wang C, Gustafsdottir SM, Sigurdsson S, Lundmark A, Tienari PJ, Koivisto K, Elovaara I, Pirttilä T et. al (2008). Interferon regulatory factor 5 (IRF5) gene variants are associated with multiple sclerosis in three distinct populations. J Med Genet. 45(6): 362-9. Epub 2008 Feb 19
https://pubmed.ncbi.nlm.nih.gov/18285424

VI. Lima Bomfim I, Wang C, Khademi M, Sandling J, Brynedal B, Lorentzen ÅR, Bach Sondergaard H, Oturai AB, Gulowsen Celsius E, Alfredsson L, Syvänen AC, Kockum I, Olsson T, Hillert J (2009). IRF5 implicated in the pathogenesis of multiple sclerosis. [Manuscript]