Association of SNPs of CD40 Gene with Multiple Sclerosis in Russians

<div><p>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 <i>CD40</i> 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], <i>p</i> = 3×10⁻⁴) and rs1883832 (additive model T allele OR = 1.20, 95% CI = [1.05–1.38], <i>p</i> = 7×10⁻³). In the meta-analysis of our results and the results of four previous studies, we obtain the association <i>p</i>-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 <i>CD40</i> and were in higher LD with rs6074022 than LD with rs1883832.</p></div

Logistic regression association results for SNPs of <i>CD40</i> gene with the development of MS.

<p>Abbreviations: 95% CI, 95% confidence interval; OR, odds ratio; NA, not applicable; RAF, risk allele frequency in control group; SNP, single-nucleotide polymorphism; HWE-p-value of exact test for deviation from Hardy-Weinberg equilibrium in groups; AIC–Akaike Information Criterion. Analysis was performed for four models: co-dominant, dominant, additive and recessive. Significant associations are shown in italic. The best model for each of significant associated SNPs is shown in bold.</p

LD between the SNPs <i>CD40</i> gene.

<p>According to the result of the HapMap Project (v.3). union panel for Utah residents with Northern and Western European (CEU) and Toscans in Italy (TSI). SNPs from our study are shown in red frame.</p

Meta-analysis of our results with previously published data on the association between rs6074022 and MS.

<p>Abbreviation: GenMSA (NL), GenMSA (US), GenMSA (CH), IMSGC (UK), IMSGC (US), BWH/TT, and ANZgene. In the meta-analysis the total OR for all studies was 1.17 (95% CI = 1.10–1.23) with a statistical significance of <i>p</i> = 2.24×10⁻¹². The heterogeneity test (<i>Q</i>-test) did not find significant differences between the studies (<i>χ</i>² (7) = 12.16, <i>p</i> = 0.10).</p