Pfizer Research and Development, Pfizer Inc., Cambridge, MA, USA.
Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Nat Commun. 2024 Jul 31;15(1):6469. doi: 10.1038/s41467-024-50583-8.
Genetic variation in the human leukocyte antigen (HLA) loci is associated with risk of immune-mediated diseases, but the molecular effects of HLA polymorphism are unclear. Here we examined the effects of HLA genetic variation on the expression of 2940 plasma proteins across 45,330 Europeans in the UK Biobank, with replication analyses across multiple ancestry groups. We detected 504 proteins affected by HLA variants (HLA-pQTL), including widespread trans effects by autoimmune disease risk alleles. More than 80% of the HLA-pQTL fine-mapped to amino acid positions in the peptide binding groove. HLA-I and II affected proteins expressed in similar cell types but in different pathways of both adaptive and innate immunity. Finally, we investigated potential HLA-pQTL effects on disease by integrating HLA-pQTL with fine-mapped HLA-disease signals in the UK Biobank. Our data reveal the diverse effects of HLA genetic variation and aid the interpretation of associations between HLA alleles and immune-mediated diseases.
人类白细胞抗原（HLA）基因座的遗传变异与免疫介导性疾病的风险相关，但 HLA 多态性的分子效应尚不清楚。在这里，我们在 UK Biobank 中对 45330 名欧洲人进行了研究，检测了 HLA 遗传变异对 2940 种血浆蛋白表达的影响，并在多个血统群体中进行了复制分析。我们检测到 504 种受 HLA 变异影响的蛋白质（HLA-pQTL），包括自身免疫疾病风险等位基因的广泛跨效应。超过 80%的 HLA-pQTL 精细映射到肽结合槽中的氨基酸位置。HLA-I 和 II 影响在适应性和固有免疫的相似细胞类型中表达但在不同途径中的蛋白质。最后，我们通过将 HLA-pQTL 与 UK Biobank 中精细映射的 HLA 疾病信号相结合，研究了 HLA-pQTL 对疾病的潜在影响。我们的数据揭示了 HLA 遗传变异的多种影响，并有助于解释 HLA 等位基因与免疫介导性疾病之间的关联。
