Chromosome 19 single-locus and multilocus haplotype associations with multiple sclerosis - Evidence of a new susceptibility locus in Caucasian and Chinese patients
Chromosome 19 single-locus and multilocus haplotype associations with multiple sclerosis - Evidence of a new susceptibility locus in Caucasian and Chinese patients
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DOI：
10.1001/jama.278.15.1256
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发表时间：
1997-10-15
影响因子：
120.7
通讯作者：
Klitz, W
中科院分区：
文献类型：
--
作者：
Barcellos, LF;Thomson, G;Klitz, W
背景。-多发性硬化症（MS）的易感性涉及遗传复杂的自身免疫成分。然而，除了HLA系统中的基因外，具体的易感性位点是未知的或未确认的。采用单基因座和单倍型分析，研究跨越3个候选区域的几个基因座在2个种族群体多发性硬化（MS）易感性中的作用。这3个区域包括染色体6p21.3上的HLA、染色体19q13.2上的APOE和染色体18 q23上的MBP（髓鞘碱性蛋白）。病例对照关联检验。受试者。-来自加州的120例白人MS患者和107例无关对照个体，以及来自中国北京的32例患者和32例无关对照个体。所有MS患者均根据已发表的标准诊断为临床确诊疾病。（2）基因座和个体等位基因及单倍型的检测。单倍型频率估计与标准的最大似然法。HLA效应是由于II类DR 2单倍型，DRB 1 *1501-DQA 1 *0102-DRB 1 *0602;未观察到其他DRB 1-DQB 1等位基因或其他HLA区域基因座对MS易感性的贡献。染色体18 q23上MBP基因座内的变异对MS没有影响。染色体19q13.2区域内的5个基因座（包括D19 S178、D19 S574、APOE、APOC 2和D19 S219）的单倍型分布在患者和对照样品之间不同。D19 S574在患有MS的高加索患者中显示出显著效果（P=.015），这是由于单个等位基因的频率增加（P=.002）。在其他神经系统疾病中突出的APOE变异对MS易感性没有影响，尽管其位于染色体19q13.2区域内。DR 2与染色体19q13.2或MBP在MS易感性中的交互作用不明显。在高加索人和中国患者样本中，染色体19q13.2单基因座和多基因座单倍型与MS显著相关，表明附近疾病易感基因座的影响。这些初步的观察结果对于描述MS的非HLA遗传易感性是令人鼓舞的一步。
Context.-Susceptibility to multiple sclerosis (MS) involves a genetically complex autoimmune component. However, except for genes in the HLA system, specific susceptibility loci are unknown or unconfirmed.Objective.-To investigate several loci spanning 3 candidate regions for a role in multiple sclerosis (MS) susceptibility in 2 ethnic groups using both single-locus and haplotype analyses. The 3 regions include HLA on chromosome 6p21.3, APOE on chromosome 19q13.2, and MBP (myelin basic protein) on chromosome 18q23.Design.-Case-control association testing.Subjects.-A total of 120 Caucasian patients with MS and 107 unrelated control individuals from California, and 32 patients and 32 unrelated control individuals from Beijing, China. All patients with MS were diagnosed as having clinically definite disease according to published criteria.Main Outcome Measures.-chi(2) Testing of loci and individual alleles and haplotypes. Haplotype frequencies were estimated with standard maximum likelihood methods.Results.-The HLA effect is due to the class II DR2 haplotype, DRB1*1501-DQA1*0102-DRB1*0602; contributions to MS susceptibility from additional DRB1-DQB1 alleles or other HLA region loci were not observed. Variation within the MBP locus on chromosome 18q23 showed no effect in MS. The distribution of haplotypes from 5 loci within the chromosome 19q13.2 region, including D19S178, D19S574, APOE, APOC2, and D19S219, differed between patient and control samples. D19S574 showed a significant effect (P=.015) in Caucasian patients with MS due to the increased frequency of a single allele (P=.002). The APOE variation, prominent in other neurological diseases, showed no influence on MS susceptibility, despite its location within the chromosome 19q13.2 region. interaction effects between DR2 and chromosome 19q13.2 or MBP in MS susceptibility were not apparent.Conclusions.-The significant chromosome 19q13.2 single-locus and multilocus haplotype associations with MS in Caucasian and Chinese patient samples indicate an effect from a nearby disease susceptibility locus. These initial observations are an encouraging step toward the description of non-HLA genetic susceptibility to MS.