Polymorphisms in the CIITA −168A/G (rs3087456) and CIITA +1614G/C (rs4774) may influence severity in multiple sclerosis patients

ABSTRACT It is currently unknown how genetic factors may influence the clinical course of multiple sclerosis (MS). Objective: We examined the impact of CIITA polymorphisms −168A/G (rs3087456) and +1614G/C (rs4774) on the risk of disability progression, severity and on responses to first-line immunomodulator treatments. Methods: Genomic DNA was extracted from blood samples. We used ABI3730xl and GeneMapper v.4.0 software to identify genotype variations. All patients were followed up and clinically reassessed at three-month intervals. Disability progression was measured by the Expanded Disability Status Scale and disease severity by the Multiple Sclerosis Spasticity Scale (MSSS). Results: We included 37 men and 80 women. We found no evidence regarding the influence of the single nucleotide polymorphisms studied in the Expanded Disability Status Scale or therapeutic response of the evaluated drugs. We performed a logistic regression analysis with the MSSS and found that a less severe MS course was associated with wild type CIITA −168AA and CIITA +1614GG, as the chance of the patient progressing to MSSS2 and MSSS3 decreased in 61% and 75% with CIITA −168AA and 66% and 75% with CIITA +1614GG, respectively (p < 0.0001). Although less significant, the CIITA +1614 GC also pointed to a less severe MS course and the chance of the patient progressing to MSSS3 decreased 79% (p = 0.015). We also observed that the CIITA −168GG genotype was more frequent in MSSS2 and MSSS3 and had 40% lower odds ratio to becoming more severe MS. Conclusion: These data suggest that CIITA −168AA, CIITA +1614GG and CIITA +1614 GC polymorphisms may be associated with a better MS clinical course. This knowledge may be useful for a better understanding of MS and its therapeutic management.

摘要：目前尚不清楚遗传因素如何影响多发性硬化症（Multiple Sclerosis, MS）的临床进程。
目的：本研究探讨CIITA基因多态性−168A/G（rs3087456）与+1614G/C（rs4774）对残疾进展风险、疾病严重程度以及一线免疫调节剂治疗应答的影响。
方法：从血液样本中提取基因组DNA。采用ABI3730xl基因测序仪与GeneMapper v.4.0软件进行基因型变异鉴定。对所有入组患者进行随访，并每3个月开展一次临床复评。采用扩展残疾状态量表（Expanded Disability Status Scale, EDSS）评估残疾进展情况，采用多发性硬化痉挛量表（Multiple Sclerosis Spasticity Scale, MSSS）评估疾病严重程度。
结果：本研究共纳入37例男性患者与80例女性患者。未发现所研究的单核苷酸多态性（Single Nucleotide Polymorphisms, SNP）对扩展残疾状态量表评分或受试药物治疗应答存在影响的相关证据。针对多发性硬化痉挛量表评分开展logistic回归分析后发现，MS病情较轻与CIITA基因−168AA野生型及+1614GG野生型存在关联：携带CIITA −168AA基因型的患者进展至MSSS2级与MSSS3级的风险分别降低61%与75%，携带CIITA +1614GG基因型的患者进展至上述两级的风险分别降低66%与75%（p < 0.0001）。尽管显著性稍弱，但CIITA +1614GC基因型同样提示MS病情较轻，该基因型携带者进展至MSSS3级的风险降低79%（p = 0.015）。此外还观察到，CIITA −168GG基因型在MSSS2级与MSSS3级患者中分布更为频繁，其使MS病情加重的比值比降低40%。
结论：上述数据表明，CIITA −168AA、CIITA +1614GG以及CIITA +1614GC多态性可能与MS更良好的临床进程相关。该研究结果有助于进一步理解多发性硬化症的发病机制并优化其治疗管理方案。