Liu Lingyu, Chen Jing, Li Jing, Yang Yunjiao, Zeng Xiaofeng, Tian Xinping
Department of Rheumatology and Clinical Immunology, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital (PUMCH), Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, People's Republic of China.
Department of Rheumatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People's Republic of China.
J Inflamm Res. 2022 Aug 24;15:4817-4831. doi: 10.2147/JIR.S377402. eCollection 2022.
To conduct the first whole exome sequencing (WES) on Takayasu arteritis (TAK) to identify common and rare variants responsible for disease susceptibility.
A total of 200 patients and 1675 healthy controls from China were recruited for this study. Site-based association analysis for common variants and gene-based burden analysis for rare variants were conducted. A weighted genetic risk score (wGRS) was calculated for each patient with TAK based on the independent risk alleles identified in the association analyses. The ability of the patient wGRS to discriminate between different phenotypes was evaluated.
In the site-based analysis, the top association signal was CCHCR1 (rs1265067, p = 8.27 × 10, OR = 2.41), a proxy for HLA-B*52:01. HLA-DQB1 (rs9273902), HLA-DQB2 (rs34109750), and a haplotype block in the human leukocyte antigen (HLA) class III region (represented by rs3130618) also exhibited significant associations independently. In addition, four novel non-HLA susceptibility loci were identified: PRRT4, TLL2, LRP1B, and DLGAP2. Twelve independently associated single nucleotide polymorphisms were used to calculate the wGRS. TAK patients with a higher wGRS were found to have an increased risk of pulmonary artery involvement compared with those with a lower wGRS (p = 5.76 × 10, OR = 13.92). The wGRS algorithm showed good predictive capability for pulmonary artery involvement in TAK (sensitivity, 92.1%; specificity, 59.9%). In the gene-based analysis, risk genes that reached exome-wide significance were not identified.
This WES study on TAK supports a previously reported association within the HLA region. Moreover, novel susceptibility loci were identified outside the HLA region. These risk alleles showed potential associations with pulmonary artery involvement in TAK. However, additional studies are warranted to verify our findings.
对大动脉炎（TAK）进行首次全外显子组测序（WES），以鉴定导致疾病易感性的常见和罕见变异。
本研究招募了来自中国的200例患者和1675名健康对照。对常见变异进行基于位点的关联分析，对罕见变异进行基于基因的负担分析。根据关联分析中确定的独立风险等位基因，为每位TAK患者计算加权遗传风险评分（wGRS）。评估患者wGRS区分不同表型的能力。
在基于位点的分析中，最强的关联信号是CCHCR1（rs1265067，p = 8.27×10，OR = 2.41），它是HLA - B*52:01的替代指标。HLA - DQB1（rs9273902）、HLA - DQB2（rs34109750）以及人类白细胞抗原（HLA）Ⅲ类区域的一个单倍型块（由rs3130618代表）也独立显示出显著关联。此外，还鉴定出四个新的非HLA易感位点：PRRT4、TLL2、LRP1B和DLGAP2。使用12个独立关联的单核苷酸多态性来计算wGRS。发现wGRS较高的TAK患者与wGRS较低的患者相比，肺动脉受累风险增加（p = 5.76×10，OR = 13.92）。wGRS算法对TAK患者的肺动脉受累显示出良好的预测能力（敏感性，92.1%；特异性，59.9%）。在基于基因的分析中，未发现达到全外显子组显著性的风险基因。
这项关于TAK的WES研究支持了先前报道的HLA区域内的关联。此外，在HLA区域外鉴定出了新的易感位点。这些风险等位基因显示出与TAK患者的肺动脉受累存在潜在关联。然而，需要进一步的研究来验证我们的发现。
