Graves Jennifer S, Barcellos Lisa F, Shao Xiaorong, Noble Janelle, Mowry Ellen M, Quach Hong, Belman Anita, Casper T Charles, Krupp Lauren B, Waubant Emmanuelle
UCSF Pediatric Multiple Sclerosis Center, San Francisco, CA, USA
Genetic Epidemiology and Genomics Lab, School of Public Health, and California Institute for Quantitative Biosciences, University of California-Berkeley, Berkeley, CA, USA.
Mult Scler. 2016 Oct;22(12):1528-1535. doi: 10.1177/1352458515624269. Epub 2016 Jan 14.
Genetic ancestry, sex, and individual alleles have been associated with multiple sclerosis (MS) susceptibility.
To determine whether established risk factors for disease onset are associated with relapse rate in pediatric MS.
Whole-genome genotyping was performed for 181 MS or high-risk clinically isolated syndrome patients from two pediatric MS centers. Relapses and disease-modifying therapies were recorded as part of continued follow-up. Participants were characterized for 25-hydroxyvitamin D serum status. Ancestral estimates (STRUCTURE v2.3.1), human leukocyte antigen (HLA)-DRB1*15 carrier status (direct sequencing), sex, and a genetic risk score (GRS) of 110 non-HLA susceptibility single-nucleotide polymorphisms (SNPs) were evaluated for association with relapse rate with Cox and negative binomial regression models.
Over 622 patient-years, 408 relapses were captured. Girls had greater relapse rate than boys (incident rate ratio (IRR) = 1.40, 95% confidence interval (CI) = 1.04-1.87, p = 0.026). Participants were genetically diverse; ~40% (N = 75) had <50% European ancestry. HLA-DRB115 status modified the association of vitamin D status (p = 0.022) with relapse rate (per 10 ng/mL, in DRB115+ hazard ratio (HR) = 0.72, 95% CI = 0.58-0.88, p = 0.002; in DRB1*15- HR = 0.96, 95% CI = 0.83-1.12, p = 0.64). Neither European ancestry nor GRS was associated with relapse rate.
We demonstrate that HLA-DRB1*15 modifies the association of vitamin D status with relapse rate. Our findings emphasize the need to pursue disease-modifying effects of MS genes in the context of environmental factors.
遗传血统、性别和个体等位基因与多发性硬化症（MS）易感性相关。
确定已确定的疾病发病风险因素是否与儿童MS的复发率相关。
对来自两个儿童MS中心的181例MS或高危临床孤立综合征患者进行全基因组基因分型。作为持续随访的一部分，记录复发情况和疾病改善治疗。对参与者的25-羟基维生素D血清状态进行特征分析。使用Cox和负二项回归模型评估祖先估计（STRUCTURE v2.3.1）、人类白细胞抗原（HLA）-DRB1*15携带者状态（直接测序）、性别以及110个非HLA易感性单核苷酸多态性（SNP）的遗传风险评分（GRS）与复发率的相关性。
在超过622患者年的时间里，共记录到408次复发。女孩的复发率高于男孩（发病率比（IRR）=1.40，95%置信区间（CI）=1.04-1.87，p=0.026）。参与者在遗传上具有多样性；约40%（N=75）的欧洲血统不到50%。HLA-DRB115状态改变了维生素D状态（p=0.022）与复发率的关联（每10 ng/mL，在DRB115+中风险比（HR）=0.72，95%CI=0.58-0.88，p=0.002；在DRB1*15-中HR=0.96，95%CI=0.83-1.12，p=0.64）。欧洲血统和GRS均与复发率无关。
我们证明HLA-DRB1*15改变了维生素D状态与复发率的关联。我们的研究结果强调在环境因素背景下探索MS基因疾病改善作用的必要性。
