Department of Human Genetics, Genentech Inc, South San Francisco, Calif.
Department of Human Genetics, Genentech Inc, South San Francisco, Calif; Department of Cancer Immunology, Genentech Inc, South San Francisco, Calif.
J Allergy Clin Immunol. 2023 May;151(5):1351-1356. doi: 10.1016/j.jaci.2022.10.019. Epub 2022 Nov 4.
Chronic spontaneous urticaria (CSU) is a dermatologic condition characterized by spontaneous, pruritic hives and/or angioedema that persists for 6 weeks or longer with no identifiable trigger. Antihistamines and second-line therapies such as omalizumab are effective for some CSU patients, but others remain symptomatic, with significant impact on quality of life. This variable response to treatment and autoantibody levels across patients highlight clinically heterogeneous subgroups.
We aimed to highlight pathways involved in CSU by investigating the genetics of CSU risk and subgroups.
We performed a genome-wide association study (GWAS) of 679 CSU patients and 4446 controls and a GWAS of chronic urticaria (CU)-index, which measures IgG autoantibodies levels, by comparing 447 CU index-low to 183 CU index-high patients. We also tested whether polygenic scores for autoimmune-related disorders were associated with CSU risk and CU index.
We identified 2 loci significantly associated with disease risk. The strongest association mapped to position 56 of HLA-DQA1 (P = 1.69 × 10), where the arginine residue was associated with increased risk (odds ratio = 1.64). The second association signal colocalized with expression-quantitative trait loci for ITPKB in whole blood (P = .997). The arginine residue at position 56 of HLA-DQA1 was also associated with increased risk of CU index-high (P = 6.15 × 10, odds ratio = 1.86), while the ITKPB association was not (P = .64). Polygenic scores for 3 autoimmune-related disorders (hypothyroidism, type 1 diabetes, and vitiligo) were associated with CSU risk and CU index (P < 2.34 × 10, odds ratio > 1.72).
A GWAS of CSU identified 2 genome-wide significant loci, highlighting the shared genetics between CU index and autoimmune disorders.
慢性自发性荨麻疹（CSU）是一种皮肤科疾病，其特征为自发性、瘙痒性风团和/或血管性水肿，持续 6 周或更长时间，且无明确诱因。抗组胺药和奥马珠单抗等二线疗法对一些 CSU 患者有效，但其他患者仍有症状，对生活质量有重大影响。这种治疗反应和患者间自身抗体水平的差异突出了临床异质性亚组的存在。
通过研究 CSU 风险和亚组的遗传学，来突出 CSU 涉及的途径。
我们对 679 名 CSU 患者和 4446 名对照进行了全基因组关联研究（GWAS），并对慢性荨麻疹（CU）指数进行了 GWAS，该指数通过比较 447 名 CU 指数低和 183 名 CU 指数高的患者来衡量 IgG 自身抗体水平。我们还测试了自身免疫性疾病的多基因评分是否与 CSU 风险和 CU 指数相关。
我们确定了与疾病风险显著相关的 2 个位点。最强的关联位于 HLA-DQA1 的 56 号位置（P=1.69×10），其中精氨酸残基与风险增加相关（优势比=1.64）。第二个关联信号与全血中 ITPKB 的表达数量性状基因座重合（P=0.997）。HLA-DQA1 的 56 号位置的精氨酸残基也与 CU 指数高的风险增加相关（P=6.15×10，优势比=1.86），而 ITKPB 的关联则没有（P=0.64）。3 种自身免疫性疾病（甲状腺功能减退症、1 型糖尿病和白癜风）的多基因评分与 CSU 风险和 CU 指数相关（P<2.34×10，优势比>1.72）。
CSU 的 GWAS 确定了 2 个全基因组显著位点，突出了 CU 指数与自身免疫性疾病之间的共同遗传学。
