Yeo Tai Wai, De Jager Philip L, Gregory Simon G, Barcellos Lisa F, Walton Amie, Goris An, Fenoglio Chiara, Ban Maria, Taylor Craig J, Goodman Reyna S, Walsh Emily, Wolfish Cara S, Horton Roger, Traherne James, Beck Stephan, Trowsdale John, Caillier Stacy J, Ivinson Adrian J, Green Todd, Pobywajlo Susan, Lander Eric S, Pericak-Vance Margaret A, Haines Jonathan L, Daly Mark J, Oksenberg Jorge R, Hauser Stephen L, Compston Alastair, Hafler David A, Rioux John D, Sawcer Stephen
Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
Ann Neurol. 2007 Mar;61(3):228-36. doi: 10.1002/ana.21063.
Variation in the major histocompatibility complex (MHC) on chromosome 6p21 is known to influence susceptibility to multiple sclerosis with the strongest effect originating from the HLA-DRB1 gene in the class II region. The possibility that other genes in the MHC independently influence susceptibility to multiple sclerosis has been suggested but remains unconfirmed.
Using a combination of microsatellite, single nucleotide polymorphism, and human leukocyte antigen (HLA) typing, we screened the MHC in trio families looking for evidence of residual association above and beyond that attributable to the established DRB1*1501 risk haplotype. We then refined this analysis by extending the genotyping of classical HLA loci into independent cases and control subjects.
Screening confirmed the presence of residual association and suggested that this was maximal in the region of the HLA-C gene. Extending analysis of the classical loci confirmed that this residual association is partly due to allelic heterogeneity at the HLA-DRB1 locus, but also reflects an independent effect from the HLA-C gene. Specifically, the HLA-C*05 allele, or a variant in tight linkage disequilibrium with it, appears to exert a protective effect (p = 3.3 x 10(-5)).
Variation in the HLA-C gene influences susceptibility to multiple sclerosis independently of any effect attributable to the nearby HLA-DRB1 gene.
已知位于6号染色体p21区域的主要组织相容性复合体（MHC）的变异会影响多发性硬化症的易感性，其中最强的效应源自II类区域的HLA - DRB1基因。有研究提出MHC中的其他基因可能独立影响多发性硬化症的易感性，但尚未得到证实。
我们结合使用微卫星、单核苷酸多态性和人类白细胞抗原（HLA）分型，在三联体家庭中筛查MHC，以寻找除已确定的DRB1 * 1501风险单倍型之外的残余关联证据。然后，我们通过将经典HLA位点的基因分型扩展到独立的病例和对照受试者来完善此分析。
筛查证实存在残余关联，且表明在HLA - C基因区域这种关联最为显著。对经典位点的扩展分析证实，这种残余关联部分归因于HLA - DRB1位点的等位基因异质性，但也反映了HLA - C基因的独立作用。具体而言，HLA - C * 05等位基因或与之紧密连锁不平衡的一个变异似乎发挥了保护作用（p = 3.3 x 10(-5)）。
HLA - C基因的变异独立于附近HLA - DRB1基因的任何效应，影响多发性硬化症的易感性。
