Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, United States.
Hum Immunol. 2022 Mar;83(3):241-247. doi: 10.1016/j.humimm.2021.11.008. Epub 2022 Feb 22.
HLA genotyping has undergone a rapid progression in resolution since the development of DNA-based typing methods. Despite the advent of high-resolution next-generation sequencing, the bulk of solid organ genotyping is performed at intermediate resolution, which provides multiple possible two-field results for each classical HLA loci. As a result, several methodologies have been developed to impute the most likely allele-level (two-field) HLA genotype for the purposes of donor-recipient compatibility analysis. The advent of molecular mismatch analysis, however, has placed a new emphasis on the accuracy of imputation. While seminal molecular mismatch studies have relied on the imputation of intermediate resolution genotyping, several recent studies have performed analysis showing that imputation generates inaccuracies in epitope identification. While the clinical impact of these errors is not clear, it is important that these concerns do not preclude future progress in understanding the utility of molecular mismatch analysis in transplantation. In the future, advances in genotyping methods will result in routine two-field resolution that will abrogate these concerns. In the meantime, however, studies are needed in order to address the role of molecular mismatch in diverse patient populations and to carefully address the potential of molecular mismatch analysis in the context of imputation.
自从基于 DNA 的分型方法发展以来，HLA 基因分型在分辨率上经历了快速的发展。尽管高通量下一代测序的出现，大多数实体器官基因分型仍在中等分辨率下进行，这为每个经典 HLA 基因座提供了多个可能的双等位基因结果。因此，已经开发了几种方法来推断最可能的等位基因水平（双等位基因）HLA 基因型，以进行供体-受者相容性分析。然而，分子错配分析的出现对推断的准确性提出了新的要求。虽然开创性的分子错配研究依赖于中等分辨率基因分型的推断，但最近的几项研究表明，推断会导致表位识别不准确。虽然这些错误的临床影响尚不清楚，但重要的是，这些担忧不应阻碍未来对理解分子错配分析在移植中的应用的研究进展。在未来，基因分型方法的进步将导致常规的双等位基因分辨率，从而消除这些担忧。然而，在此期间，需要进行研究以确定分子错配在不同患者群体中的作用，并在推断的背景下仔细考虑分子错配分析的潜力。
