Multiple sclerosis (MS) is a chronic disease of the central nervous

Multiple sclerosis (MS) is a chronic disease of the central nervous system responsible for a large portion of neurological disabilities in young adults. for multiple testing). Further, a dense set Aciclovir (Acyclovir) supplier of 211 SNPs evenly covering the gene and the flanking regions was selected from the dbSNP database and analyzed in two large, independent MS cohorts: in 211 Finnish and 554 Canadian MS families. A multipoint SNP analysis indicated linkage to and its telomeric flanking region in both populations, and SNP haplotype and genotype combination analyses revealed an allelic variant of which covers the region between introns 3 and 8, to be over-represented in Finnish MS cases (odds ratio = 1.34, 95% confidence interval 1.07C1.68). A second allelic variant, covering the same region of the gene, showed somewhat stronger evidence for association in the Canadian families (odds ratio = 1.64, 95% confidence interval 1.39C1.94). Initial functional relevance for disease predisposition was suggested by the expression analysis: The transcript levels of showed correlation with the copy number of the Finnish and Canadian risk haplotypes in CD4-negative mononuclear cells of five Finnish multiplex families and in lymphoblast cell lines of 11 Centre d’Etude du Polymorphisme Humain (CEPH) individuals of European origin. Synopsis Complex diseases such as multiple sclerosis (MS) likely result from problems in Aciclovir (Acyclovir) supplier networks of interactions between several genes and largely unidentified environmental and lifestyle factors. Identification of MS-specific genes has been challenging. HLA-DRB1*15 is the only consistent locus observed in most populations; however, the recent genome scan on more than 700 European families implicated 17q as a second-best MS ACE locus [12]. Since MS families from the high-risk region of Finland initially revealed linkage to 17q, the authors used the regionally ascertained set of 63 families to identify a MS predisposing gene within a major nonCHLA locus on 17q. The initial association was observed with single nucleotide polymorphisms (SNPs) located in intron 3 of the (protein kinase C alpha) gene in Finnish MS families and replicated in an independent set of 148 MS families from Finland and 554 from Canada, two populations with a different genetic background. Combining the data of two SNP variants revealed two allele combinations of which were over-represented in Finnish or Canadian MS cases (odds ratio = 1.34, 95% confidence interval, 1.07C1.68, and odds ratio = 1.64, 95% confidence interval 1.39C1.94, respectively). Linkage and association of the gene, encoding a regulator of immune responses, in two populations imply its involvement in the etiology of MS. Introduction Multiple sclerosis (MS) is a chronic disease of the central nervous system responsible for a large portion of neurological disabilities in young adults. Similar to what occurs in numerous complex diseases, twin, adoption, and epidemiological studies indicate a complex etiology in which both unknown environmental factors and genetic predisposition are required to generate the disease [1C3]. Genome scans have revealed several putative susceptibility loci [4C7]. In addition to the human leukocyte antigen (HLA) Aciclovir (Acyclovir) supplier locus on 6p, loci on 5p, 17q, and 19q have been replicated in multiple study samples [8C11]. Further, a recent high-density linkage screen utilizing 4,500 SNPs in 730 multiplex MS families of Northern European descent implicated the chromosome 17q as a locus with the second most significant maximum logarithm of odds (MLS) score (2.45) after the HLA [12]. The prevalence of MS in Finland is 50C100/105, similar to other populations of Northern European descent living in a temperate climate [13]. However, in the Southern Ostrobothnian health-care district of Sein?joki, located on the western coast of Finland, distinctly higher incidence (12/105) and prevalence (200/105) rates have been established [14,15]. This regional subisolate also shows exceptional familial clustering of MS [16]. Our genome-wide analyses have identified four main loci in Finnish MS families: the HLA class II region, the MBP locus on 18q, and two linked regions on 5p12-p14 and 17q22-q24 [7,17C19]. The relatively wide 17q locus, syntenic to rat experimental allergic encephalomyelitis locus on rat chromosome 10 [20] was further restricted by haplotype analysis in Finnish families from the high-risk region to a 3.4-Mb region containing fewer than 20 transcripts [21]. The chromosomal architecture surrounding this critical MS locus was found to be complex, the area being flanked by large duplicated segments and areas enriched with palindromic sequence stretches, which are present also.