Petersdorf Effie W, O'hUigin Colm
University of Washington, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, D4-115, Seattle, WA 98109, United States.
Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Microbiome and Genetics Core, Building 37, Room 4140B, Bethesda, MD 20852, United States.
Hum Immunol. 2019 Jan;80(1):67-78. doi: 10.1016/j.humimm.2018.10.002. Epub 2018 Oct 12.
The MHC continues to have the most disease-associations compared to other regions of the human genome, even in the genome-wide association study (GWAS) and single nucleotide polymorphism (SNP) era. Analysis of non-coding variation and their impact on the level of expression of HLA allotypes has shed new light on the potential mechanisms underlying HLA disease associations and alloreactivity in transplantation. Next-generation sequencing (NGS) technology has the capability of delineating the phase of variants in the HLA antigen-recognition site (ARS) with non-coding regulatory polymorphisms. These relationships are critical for understanding the qualitative and quantitative implications of HLA gene diversity. This article summarizes current understanding of non-coding region variation of HLA loci, the consequences of regulatory variation on HLA expression, the role for evolution in shaping lineage-specific expression, and the impact of HLA expression on disease susceptibility and transplantation outcomes. A role for phased sequencing methods for the MHC, and perspectives for future directions in basic and applied immunogenetic studies of the MHC are presented.
与人类基因组的其他区域相比，即使在全基因组关联研究（GWAS）和单核苷酸多态性（SNP）时代，主要组织相容性复合体（MHC）仍然与最多的疾病相关。对非编码变异及其对HLA同种异型表达水平的影响进行分析，为HLA疾病关联和移植中的同种异体反应性的潜在机制提供了新的线索。新一代测序（NGS）技术能够确定HLA抗原识别位点（ARS）中变异与非编码调控多态性的相位。这些关系对于理解HLA基因多样性的定性和定量影响至关重要。本文总结了目前对HLA基因座非编码区变异的认识、调控变异对HLA表达的影响、进化在塑造谱系特异性表达中的作用，以及HLA表达对疾病易感性和移植结果的影响。还介绍了MHC相位测序方法的作用，以及MHC基础和应用免疫遗传学研究未来方向的展望。
