Ritari Jarmo, Koskela Satu, Hyvärinen Kati, Partanen Jukka
Finnish Red Cross Blood Service, Helsinki, Finland.
Finnish Red Cross Blood Service, Helsinki, Finland.
Hum Immunol. 2022 May;83(5):391-398. doi: 10.1016/j.humimm.2022.02.003. Epub 2022 Feb 24.
The human leukocyte antigen (HLA) system is the single most important genetic susceptibility factor for many autoimmune diseases and immunological traits. For systematic population-level analysis of HLA-phenotype association landscape we imputed the alleles of classical HLA genes in a discovery cohort of 146,630 and replication cohort of 89,340 Finns of whom SNP genotype data and 3,355 disease phenotypes were available as part of the FinnGen project. In total, 3,649 statistically significant single HLA allele associations in 368 phenotypes were found. Known susceptibility associations clearly dominated the landscape but we discovered also a few previously poorly established HLA associations such as DQA101:03 and DQB106:03 with mental and behavioural disorders due to cannabinoids (p-value = 10; beta = 0.6). As certain HLAs were found to be involved in both autoimmune and infectious diseases, we studied further the independence of their associations and statistical pleiotropy. We found that altogether 11 shared HLA alleles were associated independently with both autoimmune and infectious diseases. The most prominent of these were DQA103:01 and DQB103:02 both of which associated with three infectious and three autoimmune phenotypes. All the shared HLAs showed risk effects in both disease groups, suggesting that infections can increase the risk for autoimmune diseases. The population-level landscape analysis is an excellent resource for estimating the contribution and genetic models of HLA genes in many different phenotypes and for fine-mapping primary associations.
人类白细胞抗原（HLA）系统是许多自身免疫性疾病和免疫性状中最重要的单一遗传易感性因素。为了对HLA表型关联格局进行系统性的群体水平分析，我们在一个由146,630人组成的发现队列和一个由89,340名芬兰人组成的复制队列中对经典HLA基因的等位基因进行了推断，这些芬兰人的SNP基因型数据和3355种疾病表型可作为芬兰基因项目的一部分获取。总共在368种表型中发现了3649个具有统计学意义的单个HLA等位基因关联。已知的易感性关联明显主导了这一格局，但我们也发现了一些先前尚未明确确立的HLA关联，例如DQA101:03和DQB106:03与大麻素所致精神和行为障碍的关联（p值 = 10；β = 0.6）。由于某些HLA被发现同时涉及自身免疫性疾病和感染性疾病，我们进一步研究了它们关联的独立性和统计多效性。我们发现共有11个共享的HLA等位基因分别与自身免疫性疾病和感染性疾病独立相关。其中最显著的是DQA103:01和DQB103:02，它们均与三种感染性和三种自身免疫性表型相关。所有共享的HLA在两个疾病组中均显示出风险效应，这表明感染可能会增加自身免疫性疾病的风险。群体水平格局分析是评估HLA基因在许多不同表型中的贡献和遗传模式以及对主要关联进行精细定位的极佳资源。
