Lim Che Kang, Bronson Paola G, Varade Jezabel, Behrens Timothy W, Hammarström Lennart
Department of Laboratory Medicine, Karolinska Institutet, Karolinska University, Hospital Huddinge, Stockholm, Sweden.
Department Clinical Translation Research, Singapore General Hospital, Singapore, Singapore.
Front Genet. 2021 Dec 17;12:736235. doi: 10.3389/fgene.2021.736235. eCollection 2021.
Immunoglobulin A Deficiency (IgAD) is a polygenic primary immune deficiency, with a strong genetic association to the human leukocyte antigen (HLA) region. Previous genome-wide association studies (GWAS) have identified five non-HLA risk loci (, , and ). In this study, we investigated the genetic interactions between different HLA susceptibility haplotypes and non-MHC genes in IgAD. To do this, we stratified IgAD subjects and healthy controls based on HLA haplotypes ( = 10,993), and then performed GWAS to identify novel genetic regions contributing to IgAD susceptibility. After replicating previously published HLA risk haplotypes, we compared individuals carrying at least one HLA risk allele ( or or ) with individuals lacking an HLA risk allele. Subsequently, we stratified subjects based on the susceptibility alleles/haplotypes and performed gene-based association analysis using 572,856 SNPs and 24,125 genes. A significant genome-wide association in (rs4097492; = 7.63 × 10) was observed in the cohort carrying at least one MHC risk allele. We also identified a significant gene-based association for ( = 2.1 × 10) in patients not carrying known HLA susceptibility alleles. Our findings indicate that the etiology of IgAD differs depending on the genetic background of HLA susceptibility haplotypes.
免疫球蛋白A缺乏症（IgAD）是一种多基因原发性免疫缺陷病，与人类白细胞抗原（HLA）区域有很强的遗传关联。以往的全基因组关联研究（GWAS）已经确定了五个非HLA风险位点（……）。在本研究中，我们调查了IgAD中不同HLA易感单倍型与非MHC基因之间的遗传相互作用。为此，我们根据HLA单倍型对IgAD患者和健康对照进行分层（n = 10,993），然后进行GWAS以确定导致IgAD易感性的新遗传区域。在复制先前发表的HLA风险单倍型后，我们将携带至少一个HLA风险等位基因（……）的个体与缺乏HLA风险等位基因的个体进行比较。随后，我们根据易感等位基因/单倍型对受试者进行分层，并使用572,856个单核苷酸多态性（SNP）和24,125个基因进行基于基因的关联分析。在携带至少一个MHC风险等位基因的队列中观察到一个全基因组显著关联（rs4097492；P = 7.63×10……）。我们还在未携带已知HLA易感等位基因的患者中发现了一个基于基因的显著关联（……；P = 2.1×10……）。我们的研究结果表明，IgAD的病因因HLA易感单倍型的遗传背景而异。
