UCSF Pediatric MS Center, San Francisco, CA, USA; School of Medicine, University of Tasmania, Hobart, Australia.
Genetic Epidemiology and Genomics Lab, School of Public Health, and California Institute of Quantitative Biosciences, UC Berkeley, Berkeley, CA, USA; School of Medicine, University of Tasmania, Hobart, Australia.
Mult Scler Relat Disord. 2018 Jan;19:161-165. doi: 10.1016/j.msard.2017.10.008. Epub 2017 Oct 14.
While common variant non-HLA (human leukocyte antigen) alleles have been associated with MS risk, their role in disease course is less clear. We sought to determine whether established multiple sclerosis (MS) genetic susceptibility factors are associated with relapse rate in children and an independent cohort of adults with MS.
Genotyping was performed for 182 children with MS or clinically isolated syndrome with high risk for MS from two Pediatric MS Centers. They were prospectively followed for relapses. Fifty-two non-HLA MS susceptibility single nucleotide polymorphisms (SNPs) were evaluated for association with relapse rate. Cox regression models were adjusted for sex, genetic ancestry, disease-modifying therapy (DMT), 25-OH vitamin D level and HLA-DRB1*15:01/03 status. Investigation of pediatric subject SNP results was performed using a second cohort of 141 adult MS subjects of Northern European ancestry from the Southern Tasmanian Multiple Sclerosis Longitudinal Study.
For pediatric subjects, 408 relapses were captured over 622 patient-years of follow-up. Four non-HLA risk SNPs (rs11154801, rs650258, rs12212193, rs2303759) were associated with relapses (p < 0.01) in the pediatric subjects. After adjustment for genetic ancestry, sex, age, vitamin D level, DMT use and HLA-DRB1*15 status, having two copies of the MS risk allele within AHI1 (rs11154801) was associated with increased relapses among children (HR = 1.75,95%CI = 1.18-2.48, p = 0.006) and this result was also observed among adults (HR = 1.81,95%CI = 1.05-3.03, p = 0.026).
Our results suggest that the MS genetic risk variant within the gene AHI1 may contribute to disease course in addition to disease susceptibility.
虽然常见的变异型非 HLA（人类白细胞抗原）等位基因与 MS 风险相关，但它们在疾病过程中的作用尚不清楚。我们旨在确定已确定的多发性硬化症 (MS) 遗传易感性因素是否与儿童和 MS 的另一个独立成人队列的复发率相关。
对来自两个儿科 MS 中心的 182 名 MS 或具有 MS 高风险的临床孤立综合征患儿进行基因分型。前瞻性随访以确定复发情况。评估了 52 个非 HLA MS 易感性单核苷酸多态性 (SNP) 与复发率的关联。Cox 回归模型调整了性别、遗传背景、疾病修饰治疗 (DMT)、25-羟维生素 D 水平和 HLA-DRB1*15:01/03 状态。使用来自南塔斯马尼亚多发性硬化纵向研究的 141 名北欧血统的成年 MS 受试者的第二个队列对儿科受试者 SNP 结果进行了研究。
对于儿科受试者，在 622 患者年的随访中，共捕获了 408 次复发。在儿科受试者中，有 4 个非 HLA 风险 SNP（rs11154801、rs650258、rs12212193、rs2303759）与复发相关（p < 0.01）。在调整遗传背景、性别、年龄、维生素 D 水平、DMT 使用和 HLA-DRB1*15 状态后，AHI1（rs11154801）中携带两个 MS 风险等位基因与儿童复发增加相关（HR = 1.75，95%CI = 1.18-2.48，p = 0.006），这一结果在成人中也得到了观察（HR = 1.81，95%CI = 1.05-3.03，p = 0.026）。
我们的研究结果表明，AHI1 基因内的 MS 遗传风险变异可能除了与疾病易感性相关外，还可能与疾病过程有关。
