人类白细胞抗原（HLA）基因座多样性的降低可能会对宿主识别肿瘤新抗原的能力产生不利影响，从而增加疾病负担。我们假设 HLA 基因座杂合性的增加与患结直肠癌 (CRC) 的风险降低相关。我们使用来自一项基于人群的研究的基因型数据估算了 HLA I 类和 II 类四位数等位基因，该研究涉及来自美国的 5,406 例病例和 4,635 名对照。结直肠癌分子流行病学研究（MECC）。对每个 HLA 基因座的杂合性以及 HLA-I 类（A、B 和 C）和 HLA-II 类基因座（DQB1、DRB1 和 DPB1）的杂合基因型数量进行了定量。 Logistic 回归分析用于估计与 HLA 杂合性相关的 CRC 风险。所有位点具有纯合基因型的个体作为参考类别，并根据性别、年龄、基因分型平台和血统对分析进行调整。此外，我们研究了 HLA 多样性与肿瘤相关 T 细胞库特征之间的关联，通过肿瘤浸润淋巴细胞 (TIL；N=2,839) 和免疫测序 (N=2,357) 进行测量。所有三个 I 类基因均具有杂合基因型的个体CRC 发生率降低（OR：0.74；95% CI：0.56-0.97，p= 0.031）。 II 类基因座也观察到类似的关联，OR 为 0.75（95% CI：0.60-0.95，p= 0.016）。对于 I 类和 II 类组合，具有所有杂合基因型的个体发生 CRC 的几率显着低于具有 0 或一个杂合基因型的个体（OR：0.66，95% CI：0.49-0.87，p = 0.004）。 HLA I 类和/或 II 类多样性与较高的 T 细胞受体 (TCR) 丰度和较低的 TCR 克隆性相关，但结果没有统计学意义。我们的研究结果支持 HLA I 类和 -II 类基因座的杂合子优势，表明HLA 遗传变异在 CRC 病因学中的重要作用。版权所有 © 2023 Tsai, Qu, Bonner, Sanz-Pamplona,​​ Lindsey, Melas, McDonnell, Idos, Walker, Tsang, Da Silva, Moratalla-Navarro, Maoz, Rennert, Kast,格林森、莫雷诺、雷纳特、格鲁伯和施密特。

Reduced diversity at Human Leukocyte Antigen (HLA) loci may adversely affect the host's ability to recognize tumor neoantigens and subsequently increase disease burden. We hypothesized that increased heterozygosity at HLA loci is associated with a reduced risk of developing colorectal cancer (CRC).We imputed HLA class I and II four-digit alleles using genotype data from a population-based study of 5,406 cases and 4,635 controls from the Molecular Epidemiology of Colorectal Cancer Study (MECC). Heterozygosity at each HLA locus and the number of heterozygous genotypes at HLA class -I (A, B, and C) and HLA class -II loci (DQB1, DRB1, and DPB1) were quantified. Logistic regression analysis was used to estimate the risk of CRC associated with HLA heterozygosity. Individuals with homozygous genotypes for all loci served as the reference category, and the analyses were adjusted for sex, age, genotyping platform, and ancestry. Further, we investigated associations between HLA diversity and tumor-associated T cell repertoire features, as measured by tumor infiltrating lymphocytes (TILs; N=2,839) and immunosequencing (N=2,357).Individuals with all heterozygous genotypes at all three class I genes had a reduced odds of CRC (OR: 0.74; 95% CI: 0.56-0.97, p= 0.031). A similar association was observed for class II loci, with an OR of 0.75 (95% CI: 0.60-0.95, p= 0.016). For class-I and class-II combined, individuals with all heterozygous genotypes had significantly lower odds of developing CRC (OR: 0.66, 95% CI: 0.49-0.87, p= 0.004) than those with 0 or one heterozygous genotype. HLA class I and/or II diversity was associated with higher T cell receptor (TCR) abundance and lower TCR clonality, but results were not statistically significant.Our findings support a heterozygote advantage for the HLA class-I and -II loci, indicating an important role for HLA genetic variability in the etiology of CRC.Copyright © 2023 Tsai, Qu, Bonner, Sanz-Pamplona, Lindsey, Melas, McDonnell, Idos, Walker, Tsang, Da Silva, Moratalla-Navarro, Maoz, Rennert, Kast, Greenson, Moreno, Rennert, Gruber and Schmit.