A genome-wide association study of chronic spontaneous urticaria risk and heterogeneity.

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 × 10⁻⁹), 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 colocalization =.997). The arginine residue at position 56 of HLA-DQA1 was also associated with increased risk of CU index–high (P = 6.15 × 10⁻⁵, 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 × 10⁻³, odds ratio > 1.72). A GWAS of CSU identified 2 genome-wide significant loci, highlighting the shared genetics between CU index and autoimmune disorders. [ABSTRACT FROM AUTHOR]