Department of Biochemistry, Indian Institute of Science, Bangalore, India.
Department of Biochemistry, Indian Institute of Science, Bangalore, India; Center for BioSystems Science and Engineering (BSSE), Indian Institute of Science, Bangalore, India.
Hum Immunol. 2022 Dec;83(12):797-802. doi: 10.1016/j.humimm.2022.09.008. Epub 2022 Oct 11.
Differences in outcome to COVID-19 infection in different individuals is largely attributed to genetic heterogeneity leading to differential immune responses across individuals and populations. HLA is one such genetic factor that varies across individuals leading to differences in how T-cell responses are triggered against SARS-CoV-2, directly influencing disease susceptibility. HLA alleles that influence COVID-19 outcome, by virtue of epitope binding and presentation, have been identified in cohorts worldwide. However, the heterogeneity in HLA distribution across ethnic groups limits the generality of such association. In this study, we address this limitation by comparing the recognition of CTL epitopes across HLA genotypes and ethnic groups. Using HLA allele frequency data for ethnic groups from Allele Frequency Net Database (AFND), we construct synthetic populations for each ethnic group and show that CTL epitope strength varies across HLA genotypes and populations. We also observe that HLA genotypes, in certain cases, can have high CTL epitope strengths in the absence of top-responsive HLA alleles. Finally, we show that the theoretical estimate of responsiveness and hence protection offered by a HLA allele is bound to vary across ethnic groups, due to the influence of other HLA alleles within the HLA genotype on CTL epitope recognition. This emphasizes the need for studying HLA-disease associations at the genotype level rather than at a single allele level.
个体间对 COVID-19 感染的结果差异主要归因于遗传异质性，导致个体和人群间的免疫反应存在差异。HLA 就是这样一种遗传因素，它在个体间存在差异，导致针对 SARS-CoV-2 的 T 细胞反应的触发方式不同，直接影响疾病易感性。通过表位结合和呈递，已在全球队列中鉴定出影响 COVID-19 结局的 HLA 等位基因。然而，不同种族群体中 HLA 分布的异质性限制了这种关联的普遍性。在这项研究中，我们通过比较跨 HLA 基因型和种族群体的 CTL 表位识别来解决这一限制。使用来自 Allele Frequency Net Database (AFND) 的种族群体的 HLA 等位基因频率数据，我们为每个种族群体构建了合成群体，并表明 CTL 表位强度在 HLA 基因型和人群中存在差异。我们还观察到，在某些情况下，即使没有高反应性的 HLA 等位基因，HLA 基因型也可以具有高 CTL 表位强度。最后，我们表明，由于 HLA 基因型内其他 HLA 等位基因对 CTL 表位识别的影响，HLA 等位基因提供的理论估计的反应性和因此提供的保护必然会因种族群体而异。这强调了需要在基因型水平而不是单个等位基因水平上研究 HLA-疾病关联。
