Li Zhuo, Wang Yirui, Fan Wencheng, Zhang Chang, Liu Hao, Zhang Ruixue, Cao Lu, Zhen Qi, Chen Weiwei, Yu Yafen, Li Bao, Mao Yiwen, Bai Yuanming, Wang Daiyue, Luo Sihan, Li Yuanyuan, Qin Qin, Ge Huiyao, Yong Liang, Hu Xia, Yu Yanxia, Sun Liangdan
Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, China.
Institute of Dermatology, Anhui Medical University, Hefei, China.
Front Genet. 2022 Jun 13;13:888361. doi: 10.3389/fgene.2022.888361. eCollection 2022.
Leprosy is very prevalent in many populations around the world, which is well known that both alleles for human leukocyte antigen (HLA) as well as single nucleotide polymorphisms (SNPs) in the HLA region are common in leprosy patients. Previous studies have identified leprosy-associated susceptibility genes that explain only part of disease risk and heritability. In view of the complicated characteristics of the major histocompatibility complex (MHC) region, this study aimed to explore the development and variation of HLA in leprosy and its possible mechanism. Previous genome-wide association data were extracted from Han and minority populations in southern China for HLA fine-mapping studies. Insertion and deletion (INDEL), SNP, and copy number variation (CNV) imputation were determined by using the Thousand People Database (1KGP Phase 3 Dataset) as a reference panel. The HAN-MHC database was used to input the HLA classical alleles and amino acids in the MHC region, and further step-regression analysis was performed to analyze independent variation signals associated with leprosy. The most significant locus rs75324027 (the same locus as rs602875 in the HLA-DR region) [ = 7.49E-09, OR= 0.62, 95%,CI: 0.52-0.73] in the intergene region between HLA-DQA1 and HLA-DRB1 was related with leprosy in M-S(Han leprosy patients in south China)disease. In M-SM (Leprosy patients of ethnic minorities in south China)disease, one of the most significant loci of the HLA-DQB1 gene was 6-32626438-A-T ( = 4.49E-08, OR = 0.36, 95%,CI: 0.25-0.52). Therefore, rs75324027 is a locus in M-S disease, and 6-32626438-a-T may be a new locus in M-SM disease. The interaction between 6 and 32626438-A-T and RS75324027 was analyzed, and A significant interaction relationship was found. In the optimal model, the accuracy of prediction was 0.5974, cross-validation Consistency:10, = 0.0107. In conclusion, this study is the first to assess the association between HLA and leprosy susceptibility in Han and other minority populations in southern China using the Thousand Population database and the Han MHC database. In addition, our analysis validated the previously reported locus rs602875 in the HLA-DR region and for the first time identified an unreported independent locus in leprosy among ethnic minorities in southern China.
麻风病在世界上许多人群中非常普遍，众所周知，人类白细胞抗原（HLA）的两个等位基因以及HLA区域中的单核苷酸多态性（SNP）在麻风病患者中很常见。先前的研究已经确定了与麻风病相关的易感基因，但这些基因仅解释了部分疾病风险和遗传力。鉴于主要组织相容性复合体（MHC）区域的复杂特性，本研究旨在探讨麻风病中HLA的发育和变异及其可能的机制。以前的全基因组关联数据是从中国南方的汉族和少数民族人群中提取的，用于HLA精细定位研究。以千人数据库（1KGP第3阶段数据集）作为参考面板，确定插入和缺失（INDEL）、SNP和拷贝数变异（CNV）。使用HAN-MHC数据库输入MHC区域中的HLA经典等位基因和氨基酸，并进行进一步的逐步回归分析，以分析与麻风病相关的独立变异信号。HLA-DQA1和HLA-DRB1之间基因间区域中最显著的位点rs75324027（与HLA-DR区域中的rs602875为同一位点）[P = 7.49E-09，OR = 0.62，95%CI：0.52 - 0.73]与中国南方汉族麻风病患者的M-S疾病相关。在M-SM（中国南方少数民族麻风病患者）疾病中，HLA-DQB1基因最显著的位点之一是6-32626438-A-T（P = 4.49E-08，OR = 0.36，95%CI：0.25 - 0.52）。因此，rs75324027是M-S疾病中的一个位点，而6-32626438-A-T可能是M-SM疾病中的一个新位点。分析了6-32626438-A-T与RS75324027之间的相互作用，发现了显著的相互作用关系。在最佳模型中，预测准确性为0.5974，交叉验证一致性：10，P = 0.0107。总之，本研究首次使用千人数据库和HAN-MHC数据库评估了中国南方汉族和其他少数民族人群中HLA与麻风病易感性之间的关联。此外，我们的分析验证了先前报道的HLA-DR区域中的位点rs602875，并首次在中国南方少数民族的麻风病中鉴定出一个未报道的独立位点。
