Department of Neurology (R.B., A.S.C., Z.X., P.L.D.J., T.C.), Partners Multiple Sclerosis Center, Brigham and Women's Hospital, Brookline, MA; and Ann Romney Center for Neurologic Diseases (R.B., A.S.C., Z.X., L.C., P.L.D.J., T.C.), Harvard Medical School (R.B., Z.X., L.C., P.L.D.J., T.C.), Boston, MA.
Neurol Genet. 2016 Jul 26;2(4):e88. doi: 10.1212/NXG.0000000000000088. eCollection 2016 Aug.
To examine the relationship between 2 markers of early multiple sclerosis (MS) onset, 1 genetic (HLA-DRB1*1501) and 1 experiential (early menarche), in 2 cohorts.
We included 540 white women with MS or clinically isolated syndrome (N = 156 with genetic data available) and 1,390 white women without MS but with a first-degree relative with MS (Genes and Environment in Multiple Sclerosis [GEMS]). Age at menarche, HLA-DRB1*1501 status, and age at MS onset were analyzed.
In both cohorts, participants with at least 1 HLA-DRB11501 allele had a later age at menarche than did participants with no risk alleles (MS: mean difference = 0.49, 95% confidence interval [CI] = [0.03-0.95], p = 0.036; GEMS: mean difference = 0.159, 95% CI = [0.012-0.305], p = 0.034). This association remained after we adjusted for body mass index at age 18 (available in GEMS) and for other MS risk alleles, as well as a single nucleotide polymorphism near the HLA-A region previously associated with age of menarche (available in MS cohort). Confirming previously reported associations, in our MS cohort, every year decrease in age at menarche was associated with a 0.65-year earlier MS onset (95% CI = [0.07-1.22], p = 0.027, N = 540). Earlier MS onset was also found in individuals with at least 1 HLA-DRB11501 risk allele (mean difference = -3.40 years, 95% CI = [-6.42 to -0.37], p = 0.028, N = 156).
In 2 cohorts, a genetic marker for earlier MS onset (HLA-DRB1*1501) was inversely related to earlier menarche, an experiential marker for earlier symptom onset. This finding warrants broader investigations into the association between the HLA region and hormonal regulation in determining the onset of autoimmune disease.
在两个队列中研究 2 个早期多发性硬化症（MS）发病标志物（1 个遗传标志物[HLA-DRB1*1501]和 1 个经验性标志物[初潮早]）之间的关系。
我们纳入了 540 名患有 MS 或临床孤立综合征的白人女性（N=156 名有遗传数据）和 1390 名没有 MS 但有一级亲属患有 MS 的白人女性（多发性硬化症中的基因与环境[GEMS]）。分析了初潮年龄、HLA-DRB1*1501 状态和 MS 发病年龄。
在两个队列中，至少携带 1 个 HLA-DRB11501 等位基因的参与者的初潮年龄晚于没有风险等位基因的参与者（MS：平均差异=0.49，95%置信区间[CI]：[0.03-0.95]，p=0.036；GEMS：平均差异=0.159，95%CI：[0.012-0.305]，p=0.034）。在调整了 GEMS 中可获得的 18 岁时的体重指数和其他 MS 风险等位基因以及先前与初潮年龄相关的 HLA-A 区域附近的单核苷酸多态性后，这种关联仍然存在（可在 MS 队列中获得）。在我们的 MS 队列中，确认了先前报道的关联，即初潮年龄每减少 1 年，MS 发病年龄就会提前 0.65 年（95%CI：[0.07-1.22]，p=0.027，N=540）。在至少携带 1 个 HLA-DRB11501 风险等位基因的个体中也发现了更早的 MS 发病（平均差异=-3.40 年，95%CI：[-6.42 至-0.37]，p=0.028，N=156）。
在两个队列中，早期 MS 发病的遗传标志物（HLA-DRB1*1501）与初潮早这一经验性早期症状发病标志物呈负相关。这一发现需要更广泛地研究 HLA 区域与激素调节在确定自身免疫性疾病发病中的关联。
