EVI5 is a risk gene for multiple sclerosis

Abstract

HLA-DRB1 is the major locus associated with risk for multiple sclerosis (MS). A recent genome-wide study showed three additional single-nucleotide polymorphisms (SNPs), within the IL2RA and IL7RA genes respectively, also to be associated with MS. Consistent association but lower significance was found for 13 other SNPs. In this study, we aimed to verify association of these SNPs with MS in 46 MS patients and 194 controls from a Dutch genetically isolated population. Apart from the human leukocyte antigen locus, the EVI5 gene on chromosome 1 was confirmed as a novel risk gene, with odds ratios (ORs) even higher than those from the MS Consortium (ORs 2.01 and 1.9; P ¼ 0.01). The risk effect of EVI5 was further validated for the general MS population in an independent set of 1318 MS patients from the Canadian Collaborative Project on the Genetic Susceptibility to MS. On the basis of the transmission disequilibrium testing, a weak but significant risk effect was observed (OR 1.15; P ¼ 0.03 and OR 1.15; P ¼ 0.04). This study confirms EVI5 as another risk locus for MS; however, much of the genetic basis of MS remains unidentified.

Replication of KIAA0350, IL2RA, RPL5 and CD58 as multiple sclerosis susceptibility genes in Australians

“…The EV15 SNP, rs6680578, is shaded because it was significantly deviated (Po0.001) from the Hardy-Weinberg equilibrium in controls, and is included in this table because the association between EV15 and MS was recently replicated elsewhere. 11 Replication of MS susceptibility genes JP Rubio et al probabilities. Posterior probabilities were also marginally higher than prior probabilities for rs12722489 (IL2RA), which did not reach our Pp0.05 significance threshold.…”

“…Recently the International MS Genetics Consortium (IMSGC) published the first SNP-based GWAS for MS with the aim of identifying novel MS susceptibility genes, and a list of 17 SNPs in 13 different gene loci were reported as showing statistical evidence (P ¼ 6 Â 10 À3 to P ¼ 9 Â 10 À81 ) of association with disease susceptibility. 5 Replication studies have since been performed, and provide support for a causal link between variation in the interleukin 7 receptor (IL7R), [6][7][8] interleukin 2 receptor alpha (IL2RA, also known as CD25), [8][9][10] EV15 11 and disease pathogenesis.…”

Tag-SNP analysis of the GFI1-EVI5-RPL5-FAM69 risk locus for multiple sclerosis

“…SNPs rs6680578 and rs11164838 have been analyzed in previous studies with discordant results. To address this issue, we performed a meta-analysis with the data obtained from IMSGC, 8 Canadian, 11 Australian 18 and Spanish (this study) cohorts, as shown in Figure 2. The summary effect estimate for rs6680578 is significant with a combined OR¼1.12, 95% CI (1.07-1.17) and an estimated heterogeneity variance of no significance (P¼0.395).…”

“…11 Both SNPs had a weak but significant contribution in this population. However, a replication study of four SNPs in the GFI-EVI5-RPL5-FAM69A locus, conducted on 1134 Australian MS patients, 18 showed no association.…”

“…The association of two of these SNPs has been replicated in a posterior study with 1318 MS Canadian patients. 11 In this study, our aim was to validate the association of the GFI1-EVI5-RPL5-FAM69A locus in a Caucasian Spanish population and to try to identify the gene responsible for the association with MS by a Tag-SNP strategy that captures 279 common variants at a pairwise r 2 Z0.6.…”