Rubio J P, Speed T P, Bahlo M, Kilpatrick T J, Foote S J
Department of Statistics, University of California, Berkeley, USA.
Ann Acad Med Singap. 2000 May;29(3):322-30.
Multiple sclerosis (MS) is the most common genetic disease of the nervous system with onset usually in young adulthood. Four genome-wide searches in different Caucasian populations for MS susceptibility loci have been performed, but none reported any linkage at a level that would be regarded as significant according to current criteria. Significant linkage of MS to allelic variants of the major histocompatibility (MHC) locus on chromosome 6p21 has been established although its overall contribution to MS susceptibility has proven difficult to quantify. The objective of this review is not only to provide the reader with an update of MS genetics research, but also to provide a basic knowledge of the techniques being employed to map MS susceptibility genes. The different methodologies are discussed, and specific studies are reviewed in context.
This review is based on findings from original articles, however, the results of recent candidate gene studies are intended to update previous review articles.
There remains no concrete non-MHC locus for MS, although there are enough findings of sufficient interest to warrant further investigation and optimism. Stratification of genome scan data based on MHC class II suggests that it interacts differentially with non-MHC loci and that it contributes moderately to disease susceptibility. Candidate gene studies have continued to return negative and ambiguous results, and follow-up fine mapping of suggestive linkages from the UK genome scan has proven unsuccessful in identifying significant linkages. Genetic analysis of crosses between mouse strains that are differentially susceptible to experimental allergic encephalomyelitis (EAE) has yielded linkages corresponding to putative MS susceptibility loci. However, recent successes in transgenic mice may provide an alternative to EAE, regarded by some as a poor model of MS.
The first whole genome search for a common human disease was performed over five years ago, and it is now clear, from the lack success in this field, that the genetic complexity of these traits has been underestimated. The genome-wide searches for MS susceptibility genes have suffered from insufficient statistical power, which has probably been compounded by disease and genetic heterogeneity. Studies in isolated populations and better laboratory and clinical definitions of disease are both steps in the right direction to solving these problems. Not withstanding the negative effects of genetic heterogeneity, pooling of resources for meta-analyses may provide the increase in statistical power required for detection of loci that exert a moderate or small effect on disease predisposition.
多发性硬化症（MS）是最常见的神经系统遗传性疾病，通常在成年早期发病。已经在不同的高加索人群中进行了四项全基因组搜索以寻找MS易感基因座，但根据目前的标准，没有一项报告了任何具有显著意义的连锁关系。尽管已证明其对MS易感性的总体贡献难以量化，但已确定MS与6号染色体p21上主要组织相容性（MHC）基因座的等位基因变体存在显著连锁关系。本综述的目的不仅是为读者提供MS遗传学研究的最新情况，还提供用于定位MS易感基因的技术的基础知识。讨论了不同的方法，并结合具体研究进行了综述。
本综述基于原始文章的研究结果，然而，近期候选基因研究的结果旨在更新之前的综述文章。
尽管有足够多令人感兴趣的发现值得进一步研究并带来乐观情绪，但仍未找到MS的具体非MHC基因座。基于MHC II类对基因组扫描数据进行分层分析表明，它与非MHC基因座存在不同的相互作用，并且对疾病易感性有中等程度的贡献。候选基因研究继续得出阴性和不明确的结果，对英国基因组扫描中提示性连锁关系的后续精细定位未能成功识别出显著的连锁关系。对实验性自身免疫性脑脊髓炎（EAE）易感性不同的小鼠品系杂交进行的遗传分析产生了与推定的MS易感基因座相对应的连锁关系。然而，转基因小鼠最近取得的成功可能为EAE提供了一种替代方法，有些人认为EAE是MS的一个较差模型。
对一种常见人类疾病的首次全基因组搜索是在五年多以前进行的，从该领域缺乏成功的情况现在可以清楚地看出，这些性状的遗传复杂性被低估了。对MS易感基因的全基因组搜索受到统计能力不足的困扰，疾病和遗传异质性可能使情况更加复杂。对隔离人群的研究以及对疾病更好的实验室和临床定义都是朝着解决这些问题迈出的正确方向的步骤。尽管存在遗传异质性的负面影响，但汇集资源进行荟萃分析可能会提高检测对疾病易感性有中等或微小影响的基因座所需的统计能力。
