A two-stage study on multiple sclerosis susceptibility and chromosome 2q33

Abstract

We have performed a two-stage study to analyse the association of polymorphism on chromosome 2q33 with multiple sclerosis (MS). In all, 17 markers were analysed in stage-1 in 134 Finnish MS families and the observed associations were tested in stage-2 in 186 MS families. We did not find previously reported allelic or haplotype associations with CTLA4. We obtained a weak signal of two distinct predisposing genes, one proximal the other distal of CTLA4. The putative proximal gene was associated with the marker rs3977 in families lacking HLA-DR2 (P ¼ 0.02 and 0.02) and the other distal gene was associated with D2S1271 in families from a high-risk region in western Finland (P ¼ 0.02 and 0.01). Based on the 43 cM distance and the lack of linkage disequilibrium between these loci, we conclude that the two association signals are independent. Our results provide preliminary evidence for two distinct MS susceptibility genes on 2q33 outside of CTLA4.

Genetics of primary progressive multiple sclerosis

“…The G 49 allele of CTLA-4 was associated with MS susceptibility in two Scandinavian casecontrol studies (Harbo et al, 1999;Ligers et al, 1999) as well as in Olmsted County (Kantarci et al, 2003), and may influence disease severity in Japanese MS (Fukazawa et al, 1999b). However, multiple other case-control studies found no association with MS susceptibility (Masterman et al, 2000;Rasmussen et al, 2001;Bocko et al, 2003;van Veen et al, 2003a;Bonetti et al, 2004;Teutsch et al, 2004;Fukazawa et al, 2005;Lorentzen et al, 2005;Roxburgh et al, 2006). A family-based study in Canadian MS also found no association (Dyment et al, 2004); however, familybased studies with replication in French and southern European MS found an association, especially in families carrying the HLA-DRB1*15 haplotype (Alizadeh et al, 2003).…”

Polymorphism of the promoter region and exon 1 of the CTLA4 gene in endemic pemphigus foliaceus (fogo selvagem)

“…Two recent publications analyzing numerous polymorphic markers of chromosome 2q33, encompassing the CD28, CTLA4 and ICOS genes indicated that there may be other susceptibility markers in this genomic region and that those probably differ among diseases. Polymorphisms in a noncoding region downstream of the CTLA4 gene (13) were associated with autoimmune endocrinopathies (Graves' disease, autoimmune hypothyroidism, type 1 diabetes), while markers closer to CD28 and to ICOS but not CTLA4 markers were associated with multiple sclerosis in a two-stage study of the Finnish population (18).…”

“…The role of CTLA-4 in immunosuppression and the coincidence of different autoimmune diseases in some families and individuals have led some researchers to suggest that particular variants of some genes, including CTLA4, may predispose to autoimmunity in general (16,17). Notwithstanding the considerable evidence of a role for CTLA4 polymorphism in autoimmune disease pathogenesis, the effect of the susceptible alleles or genotypes is generally low and several studies have not revealed any significant associations (18,19).…”

Multiple sclerosis and the CTLA4 autoimmunity polymorphism CT60: no association in patients from Germany, Hungary and Poland

“…In another study, two markers in the CTLA-4 gene region among 17 tested within 2q33 showed some weak association in Finnish MS families [15]. Recently, association of ICOS haplotypes with IL10-secretion and relapsing-remitting MS has been reported [16].…”