Oligoclonal Band Status in Scandinavian Multiple Sclerosis Patients Is Associated with Specific Genetic Risk Alleles

The presence of oligoclonal bands (OCB) in cerebrospinal fluid (CSF) is a typical finding in multiple sclerosis (MS). We applied data from Norwegian, Swedish and Danish (i.e. Scandinavian) MS patients from a genome-wide association study (GWAS) to search for genetic differences in MS relating to OCB status. GWAS data was compared in 1367 OCB positive and 161 OCB negative Scandinavian MS patients, and nine of the most associated SNPs were genotyped for replication in 3403 Scandinavian MS patients. HLA-DRB1 genotypes were analyzed in a subset of the OCB positive (n = 2781) and OCB negative (n = 292) MS patients and compared to 890 healthy controls. Results from the genome-wide analyses showed that single nucleotide polymorphisms (SNPs) from the HLA complex and six other loci were associated to OCB status. In SNPs selected for replication, combined analyses showed genome-wide significant association for two SNPs in the HLA complex; rs3129871 (p = 5.7×10−15) and rs3817963 (p = 5.7×10−10) correlating with the HLA-DRB1*15 and the HLA-DRB1*04 alleles, respectively. We also found suggestive association to one SNP in the Calsyntenin-2 gene (p = 8.83×10−7). In HLA-DRB1 analyses HLA-DRB1*15∶01 was a stronger risk factor for OCB positive than OCB negative MS, whereas HLA-DRB1*04∶04 was associated with increased risk of OCB negative MS and reduced risk of OCB positive MS. Protective effects of HLA-DRB1*01∶01 and HLA-DRB1*07∶01 were detected in both groups. The groups were different with regard to age at onset (AAO), MS outcome measures and gender. This study confirms both shared and distinct genetic risk for MS subtypes in the Scandinavian population defined by OCB status and indicates different clinical characteristics between the groups. This suggests differences in disease mechanisms between OCB negative and OCB positive MS with implications for patient management, which need to be further studied.脑脊液（CSF）中寡克隆带（OCB）的检出是多发性硬化（MS）的典型表现。我们采用来自挪威、瑞典及丹麦（即斯堪的纳维亚）地区多发性硬化患者的全基因组关联研究（GWAS）数据，旨在探寻与寡克隆带状态相关的多发性硬化遗传差异。本研究对1367例寡克隆带阳性、161例寡克隆带阴性的斯堪的纳维亚多发性硬化患者的全基因组关联研究数据进行比对，并选取9个关联性最强的单核苷酸多态性（SNPs）位点，在3403例斯堪的纳维亚多发性硬化患者中开展基因分型以验证其关联性。我们还在亚组人群（寡克隆带阳性组n=2781、寡克隆带阴性组n=292）中分析了人类白细胞抗原DRB1（HLA-DRB1）基因型，并与890名健康对照者进行对比。 全基因组分析结果显示，人类白细胞抗原（HLA）复合体及其他6个基因座的单核苷酸多态性与寡克隆带状态存在显著关联。在选取用于验证的单核苷酸多态性位点中，联合分析显示人类白细胞抗原复合体中的2个位点具有全基因组显著性关联：rs3129871（p=5.7×10⁻¹⁵）与rs3817963（p=5.7×10⁻¹⁰），分别对应HLA-DRB1*15与HLA-DRB1*04等位基因。本研究还在钙连蛋白-2（Calsyntenin-2）基因中发现了具有提示性关联的单核苷酸多态性位点（p=8.83×10⁻⁷）。 人类白细胞抗原DRB1分析结果显示，HLA-DRB1*15∶01对寡克隆带阳性多发性硬化的风险效应强于寡克隆带阴性患者；而HLA-DRB1*04∶04则与寡克隆带阴性多发性硬化的风险升高、寡克隆带阳性多发性硬化的风险降低相关。HLA-DRB1*01∶01与HLA-DRB1*07∶01在两组患者中均表现出保护效应。 两组患者在发病年龄（AAO）、多发性硬化转归指标及性别分布上均存在显著差异。本研究证实，在斯堪的纳维亚人群中，以寡克隆带状态定义的多发性硬化亚型既存在共同的遗传风险，也存在独特的遗传风险，且两组患者的临床特征存在差异。这提示寡克隆带阴性与阳性多发性硬化的疾病发病机制存在差异，该差异对患者临床管理具有参考价值，有待进一步深入研究。