He Bing, Giedraitis Vilmantas, Ligers Arturs, Binzer Michael, Andersen Peter M, Forsgren Lars, Sandkuijl Lodewijk A, Hillert Jan
Division of Neurology, Huddinge University Hospital, Karolinska Institute, Sweden.
Eur J Hum Genet. 2002 Apr;10(4):271-5. doi: 10.1038/sj.ejhg.5200802.
Multiple sclerosis (MS) is a chronic inflammatory disease resulting in demyelination in the central nervous system (CNS). Increasing evidence supports that genetic factors confer susceptibility to MS. One locus, the HLA complex (6p21), has been identified as important in MS, but no other loci have been clearly implicated, neither by a candidate gene approach, nor by a genomic screen strategy. Here, we studied a genetically isolated population in the northern-most part of Sweden, which demonstrates a high incidence of MS, using haplotype sharing analysis. Genealogical analysis demonstrated that 22 MS patients originate from a single common ancestral couple in the eighteenth century. Five affected individuals from four nuclear families were selected for an initial genomic screen with 390 microsatellite markers. Seven shared haplotypes in six different chromosomal regions were observed. After genotyping for these haplotypes with the same and additional markers in 15 MS patients and healthy relatives, some portion of a conserved haplotype spanning 10 cM at 17p11 was found to be shared by 12 of 15 affected individuals. The statistical analysis revealed a significant excess of transmission of alleles of three markers to affected individuals (P<0.05) by the transmission/disequilibrium test (TDT). An identical four-marker haplotype was shared by six of 15 patients (40%; P<0.01). Surprisingly, DR-typing revealed no significant sharing of the HLA region. In conclusion, our data suggests a novel susceptibility gene for MS in chromosome 17p11.
多发性硬化症（MS）是一种慢性炎症性疾病，可导致中枢神经系统（CNS）脱髓鞘。越来越多的证据支持遗传因素使个体易患MS。一个基因座，即HLA复合体（6p21），已被确定在MS中起重要作用，但通过候选基因方法或基因组筛选策略均未明确涉及其他基因座。在此，我们使用单倍型共享分析研究了瑞典最北部一个遗传隔离的人群，该人群显示出较高的MS发病率。系谱分析表明，22例MS患者源自18世纪的一对共同祖先夫妇。从四个核心家庭中选取了五名患病个体，用390个微卫星标记进行初步基因组筛选。在六个不同的染色体区域观察到七个共享单倍型。在用相同和额外的标记对15例MS患者及其健康亲属进行这些单倍型基因分型后，发现15名患病个体中有12名共享了跨越17p11上10 cM的保守单倍型的一部分。统计分析通过传递/不平衡检验（TDT）显示，三个标记的等位基因向患病个体的传递显著过量（P<0.05）。15名患者中有6名（40%；P<0.01）共享了相同的四标记单倍型。令人惊讶的是，DR分型显示HLA区域没有显著的共享。总之，我们的数据表明17p11染色体上存在一个新的MS易感基因。
