Fedetz M, Matesanz F, Caro-Maldonado A, Fernandez O, Tamayo J A, Guerrero M, Delgado C, López-Guerrero J A, Alcina A
Instituto de Parasitología y Biomedicina López Neyra, CSIC, Granada, Spain.
Tissue Antigens. 2006 Nov;68(5):446-9. doi: 10.1111/j.1399-0039.2006.00694.x.
Multiple sclerosis (MS) is associated with genetic susceptibility and unknown environmental triggers, possible viral infections, but the specific etiological mechanism that subsequently develops into an inflammatory/autoimmune cascade of events is poorly understood. Recently, genetic variants of 2',5'- oligoadenylate synthetase 1 (OAS1) gene, a critical enzyme involved in innate antivirus response, have been associated with differential enzyme activity and type 1 diabetes in both case-control and family studies. We hypothesized that polymorphisms in the OAS1 gene could influence the susceptibility to MS. To test this hypothesis, we conducted a case-control study of 333 patients with MS and 424 healthy controls and genotyped two OAS1 single nucleotide polymorphisms (SNPs) by restriction fragment length polymorphism method: rs 10774671, A/G SNP altering the splicing site at the seventh exon, and rs 3741981, a nonsynonymous (Ser162Gly) A/G SNP in the third exon. Haplotype but not single-marker analysis revealed an association of the haplotype created by the G allele at rs 10774671 and the A allele at rs 3741981 with the susceptibility to MS (P value = 8.8 x 10(-5)). Subjects carrying this haplotype had an increased risk of MS comparing with those not carrying it (odds ratio = 4.7, 95% confidence interval 2.1-10.9). Our findings indicate that the OAS1 gene polymorphisms may confer susceptibility to MS or serve as markers of functional variants and suggest that OAS1 activity is involved in the etiology of the disease. Future studies in a larger sample and association analysis with functional variants will clarify the role of the OAS1 gene in the susceptibility to MS.
多发性硬化症（MS）与遗传易感性以及未知的环境触发因素有关，可能与病毒感染有关，但随后发展为炎症/自身免疫级联事件的具体病因机制仍知之甚少。最近，在病例对照研究和家系研究中，参与先天性抗病毒反应的关键酶2',5'-寡腺苷酸合成酶1（OAS1）基因的遗传变异与酶活性差异和1型糖尿病相关。我们假设OAS1基因多态性可能影响MS易感性。为验证这一假设，我们对333例MS患者和424名健康对照进行了病例对照研究，并采用限制性片段长度多态性方法对两个OAS1单核苷酸多态性（SNP）进行基因分型：rs 10774671，A/G SNP，改变第七外显子的剪接位点；rs 3741981，第三外显子中的非同义（Ser162Gly）A/G SNP。单倍型分析而非单标记分析显示，rs 10774671的G等位基因和rs 3741981的A等位基因组成的单倍型与MS易感性相关（P值 = 8.8 x 10(-5)）。携带该单倍型的受试者患MS的风险高于未携带该单倍型的受试者（比值比 = 4.7，95%置信区间2.1 - 10.9）。我们的研究结果表明，OAS1基因多态性可能赋予MS易感性或作为功能变异的标志物，并提示OAS1活性参与了该疾病的病因学。未来更大样本量的研究以及与功能变异的关联分析将阐明OAS1基因在MS易感性中的作用。
