Association of SNPs of CD40 Gene with Multiple Sclerosis in Russians

Multiple sclerosis (MS) is a serious, incurable neurological disease. In 2009, the ANZgene studies detected the suggestive association of located upstream of CD40 gene in chromosome 20q13 (p = 1.3×10−7). Identification of the causal variant(s) in the CD40 locus leads to a better understanding of the mechanism underlying the development of autoimmune pathologies. We determined the genotypes of rs6074022, rs1883832, rs1535045, and rs11086996 in patients with MS (n = 1684) and in the control group (n = 879). Two SNPs were significantly associated with MS: rs6074022 (additive model C allele OR = 1.27, 95% CI = [1.12–1.45], p = 3×10−4) and rs1883832 (additive model T allele OR = 1.20, 95% CI = [1.05–1.38], p = 7×10−3). In the meta-analysis of our results and the results of four previous studies, we obtain the association p-value of 2.34×10−12, which confirmed the association between MS and rs6074022 at a genome-wide significant level. Next, we demonstrated that the model including rs6074022 only sufficiently described the association. From our analysis, we can speculate that the association between rs1883832 and MS was induced by LD, whereas rs6074022 was a marker in stronger LD with the functional variant or was the functional variant itself. Our results indicated that the functional variants were located in the upstream region of the gene CD40 and were in higher LD with rs6074022 than LD with rs1883832.

多发性硬化（Multiple sclerosis, MS）是一种严重且无法治愈的神经系统疾病。2009年，ANZgene研究团队在20号染色体q13区域的CD40基因上游区域检测到了具有提示意义的关联（p=1.3×10⁻⁷）。对CD40基因位点致病变异的鉴定，有助于我们更深入地理解自身免疫性疾病的发病机制。本研究对1684名多发性硬化患者与879名对照个体的rs6074022、rs1883832、rs1535045及rs11086996位点进行了基因分型。有两个单核苷酸多态性位点与多发性硬化显著相关：rs6074022（加性模型中C等位基因的比值比（Odds Ratio, OR）=1.27，95%置信区间（Confidence Interval, CI）=[1.12–1.45]，p=3×10⁻⁴）与rs1883832（加性模型中T等位基因的比值比（Odds Ratio, OR）=1.20，95%置信区间（Confidence Interval, CI）=[1.05–1.38]，p=7×10⁻³）。本研究将自身结果与此前四项研究的结果进行荟萃分析（Meta-analysis）后，得到关联分析p值为2.34×10⁻¹²，这一结果在全基因组显著性水平上证实了多发性硬化与rs6074022之间的关联。随后，本研究证实仅包含rs6074022的模型即可充分描述该关联。通过本研究的分析，我们可以推测rs1883832与多发性硬化的关联由连锁不平衡（Linkage Disequilibrium, LD）所介导，而rs6074022是与功能性变异存在更强连锁不平衡的标记位点，或是功能性变异本身。本研究结果显示，功能性变异位于CD40基因的上游区域，且与rs6074022的连锁不平衡程度高于其与rs1883832的连锁不平衡程度。