Chao Michael J, Ramagopalan Sreeram V, Herrera Blanca M, Lincoln Matthew R, Dyment David A, Sadovnick A Dessa, Ebers George C
Department of Clinical Neurology, Level 3 West Wing, John Radcliffe Hospital, University of Oxford, Oxford OX3 7BN, UK.
Hum Mol Genet. 2009 Jan 15;18(2):261-6. doi: 10.1093/hmg/ddn353.
Multiple sclerosis (MS) susceptibility demonstrates a complex pattern of inheritance. Haplotypes containing HLA-DRB11501 carry most of the genetic risk. Epidemiological evidence implicating epigenetic factors includes complex distortion of disease transmission seen in aunt/uncle-niece/nephew (AUNN) pairs. Unexpectedly, in AUNN families we found that allele frequencies for HLA-DRB11501 were different between the first and second generations affected. Affected aunts had significantly lower HLA-DRB115 frequency compared with their affected nieces (chi(2) = 9.90, P = 0.0016), whereas HLA-DRB115 frequency in affected males remains unaltered across the two generations (chi(2) = 0.23, P = 0.63). We compared transmissions for the HLA-DRB115 allele using a family-based transmission disequilibrium test approach in 1690 individuals from 350 affected sibling pair (ASP) families and 960 individuals from 187 AUNN families. Transmissions differed between the ASP and the AUNN families (chi(2) = 6.92; P = 0.0085). The risk carried by HLA-DRB115 was increased in families with affected second-degree relatives (AUNN: OR = 4.07) when compared with those consisting only first-degree relatives (ASP: OR = 2.17), establishing heterogeneity of risk among HLA-DRB1*15 haplotypes based on whether collateral parental relatives are affected. These observations strongly implicate gene-environment interactions in susceptibility and more specifically, that epigenetic modifications differentiate among human leukocyte antigen class II risk haplotypes and are involved in the determination of the gender bias in MS. These data strongly suggest that the female-specific increasing risk of MS is mediated through these alleles or adjacent variation. The comparison of transmission of the same allele in vertically affected pedigrees (AUNN) to collinear sibling pairs (ASP) may provide a useful screen for putative epigenetic marks.
多发性硬化症（MS）易感性呈现出复杂的遗传模式。包含HLA - DRB11501的单倍型携带了大部分遗传风险。涉及表观遗传因素的流行病学证据包括在姑姑/叔叔 - 侄女/侄子（AUNN）对中观察到的疾病传递的复杂扭曲。出乎意料的是，在AUNN家族中，我们发现受影响的第一代和第二代之间HLA - DRB11501的等位基因频率不同。与受影响的侄女相比，受影响的姑姑的HLA - DRB115频率显著更低（卡方 = 9.90，P = 0.0016），而受影响男性的HLA - DRB115频率在两代之间保持不变（卡方 = 0.23，P = 0.63）。我们使用基于家系的传递不平衡检验方法，对来自350个患病同胞对（ASP）家族的1690人和来自187个AUNN家族的960人进行了HLA - DRB115等位基因传递情况的比较。ASP家族和AUNN家族之间的传递情况存在差异（卡方 = 6.92；P = 0.0085）。与仅由一级亲属组成的家族（ASP：优势比 = 2.17）相比，有二级亲属患病的家族（AUNN：优势比 = 4.07）中HLA - DRB115携带的风险增加，这基于旁系亲属是否患病确定了HLA - DRB1*15单倍型之间风险的异质性。这些观察结果强烈表明基因 - 环境相互作用与易感性有关，更具体地说，表观遗传修饰在人类白细胞抗原II类风险单倍型之间存在差异，并参与了MS中性别偏差的决定。这些数据有力地表明，MS女性特异性增加的风险是通过这些等位基因或相邻变异介导的。将垂直受影响的家系（AUNN）中相同等位基因的传递与共线同胞对（ASP）进行比较，可能为推定的表观遗传标记提供有用的筛选。
