Rubio J P, Stankovich J, Field J, Tubridy N, Marriott M, Chapman C, Bahlo M, Perera D, Johnson L J, Tait B D, Varney M D, Speed T P, Taylor B V, Foote S J, Butzkueven H, Kilpatrick T J
The Howard Florey Institute, Melbourne, Victoria, Australia.
Genes Immun. 2008 Oct;9(7):624-30. doi: 10.1038/gene.2008.59. Epub 2008 Jul 24.
A recent genome-wide association study (GWAS) conducted by the International Multiple Sclerosis Genetics Consortium (IMSGC) identified a number of putative MS susceptibility genes. Here we have performed a replication study in 1134 Australian MS cases and 1265 controls for 17 risk-associated single nucleotide polymorphisms (SNPs) reported by the IMSGC. Of 16 SNPs that passed quality control filters, four, each corresponding to a different non-human leukocyte antigen (HLA) gene, were associated with disease susceptibility: KIAA0350 (rs6498169) P=0.001, IL2RA (rs2104286) P=0.033, RPL5 (rs6604026) P=0.041 and CD58 (rs12044852) P=0.042. There was no association (P=0.58) between rs6897932 in the IL7R gene and the risk of MS. No interactions were detected between the replicated IMSGC SNPs and HLA-DRB1*15, gender, disease course, disease progression or age-at-onset. We used a novel Bayesian approach to estimate the extent to which our data increased or decreased evidence for association with the six most-associated IMSGC loci. These analyses indicated that even modest P-values, such as those reported here, can contribute markedly to the posterior probability of 'true' association in replication studies. In conclusion, these data provide support for the involvement of four non-HLA genes in the pathogenesis of MS, and combined with previous data, increase to genome-wide significance (P=3 x 10(-8)) evidence of an association between KIAA0350 and risk of disease.
国际多发性硬化症遗传学联盟(IMSGC)最近进行的一项全基因组关联研究(GWAS)确定了一些假定的多发性硬化症易感基因。在此,我们针对IMSGC报告的17个与风险相关的单核苷酸多态性(SNP),在1134例澳大利亚多发性硬化症患者和1265名对照中进行了一项重复研究。在通过质量控制筛选的16个SNP中,有4个分别对应不同的非人类白细胞抗原(HLA)基因,与疾病易感性相关:KIAA0350(rs6498169)P = 0.001、IL2RA(rs2104286)P = 0.033、RPL5(rs6604026)P = 0.041和CD58(rs12044852)P = 0.042。IL7R基因中的rs6897932与多发性硬化症风险之间无关联(P = 0.58)。在重复的IMSGC SNP与HLA - DRB1*15、性别、病程、疾病进展或发病年龄之间未检测到相互作用。我们使用一种新颖的贝叶斯方法来估计我们的数据增加或减少与六个最相关的IMSGC基因座关联证据的程度。这些分析表明,即使是本文报道的适度P值,也可在重复研究中显著提高“真实”关联的后验概率。总之,这些数据支持四个非HLA基因参与多发性硬化症的发病机制,并且与先前的数据相结合,将KIAA0350与疾病风险之间关联的证据提高到全基因组显著性水平(P = 3×10⁻⁸)。