Walsh Emily C, Mather Kristie A, Schaffner Stephen F, Farwell Lisa, Daly Mark J, Patterson Nick, Cullen Michael, Carrington Mary, Bugawan Teodorica L, Erlich Henry, Campbell Jay, Barrett Jeffrey, Miller Katie, Thomson Glenys, Lander Eric S, Rioux John D
Center for Genome Research, Whitehead Institute for Biomedical Research, Cambridge, MA 02139, USA.
Am J Hum Genet. 2003 Sep;73(3):580-90. doi: 10.1086/378101. Epub 2003 Aug 14.
Numerous studies have clearly indicated a role for the major histocompatibility complex (MHC) in susceptibility to autoimmune diseases. Such studies have focused on the genetic variation of a small number of classical human-leukocyte-antigen (HLA) genes in the region. Although these genes represent good candidates, given their immunological roles, linkage disequilibrium (LD) surrounding these genes has made it difficult to rule out neighboring genes, many with immune function, as influencing disease susceptibility. It is likely that a comprehensive analysis of the patterns of LD and variation, by using a high-density map of single-nucleotide polymorphisms (SNPs), would enable a greater understanding of the nature of the observed associations, as well as lead to the identification of causal variation. We present herein an initial analysis of this region, using 201 SNPs, nine classical HLA loci, two TAP genes, and 18 microsatellites. This analysis suggests that LD and variation in the MHC, aside from the classical HLA loci, are essentially no different from those in the rest of the genome. Furthermore, these data show that multi-SNP haplotypes will likely be a valuable means for refining association signals in this region.
众多研究已明确表明主要组织相容性复合体（MHC）在自身免疫性疾病易感性中起作用。此类研究聚焦于该区域少数经典人类白细胞抗原（HLA）基因的遗传变异。尽管鉴于其免疫作用，这些基因是很好的候选基因，但这些基因周围的连锁不平衡（LD）使得难以排除具有免疫功能的邻近基因对疾病易感性的影响。利用单核苷酸多态性（SNP）的高密度图谱对LD和变异模式进行全面分析，可能会使我们对所观察到的关联性质有更深入的了解，同时也有助于识别因果变异。我们在此展示了对该区域的初步分析，使用了201个SNP、9个经典HLA位点、2个TAP基因和18个微卫星。该分析表明，除了经典HLA位点外，MHC中的LD和变异与基因组其他区域基本无异。此外，这些数据表明多SNP单倍型可能是细化该区域关联信号的一种有价值的手段。
