title: Complex relation of HLA-DRB1*1501, age at menarche, and age at multiple sclerosis onset.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  In both cohorts, participants with at least 1 HLA-DRB1*1501 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-DRB1*1501 risk allele (mean difference = -3.40 years, 95% CI = [-6.42 to -0.37], p = 0.028, N = 156).
  
  
  CONCLUSIONS
  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.
authors: 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.
authors: Riley
authors: R
authors: Bove
authors: 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.
authors: Alicia S
authors: AS
authors: Chua
authors: 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.
authors: Zongqi
authors: Z
authors: Xia
authors: 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.
authors: Lori
authors: L
authors: Chibnik
authors: 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.
authors: Philip L
authors: PL
authors: De Jager
authors: 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.
authors: Tanuja
authors: T
authors: Chitnis