Identification of a shared genetic risk locus for Kawasaki disease and immunoglobulin A vasculitis by a cross-phenotype meta-analysis

• Published in: Rheumatology (Oxford, England) England), 2022-03, Vol.61 (3), p.1204-1210
• Main Authors: Carmona, Elio G, García-Giménez, Jose A, López-Mejías, Raquel, Khor, Chiea Chuen, Lee, Jong-Keuk, Taskiran, Ekim, Ozen, Seza, Hocevar, Alojzija, Liu, Lili, Gorenjak, Mario, Potočnik, Uroš, Kiryluk, Krzysztof, Ortego-Centeno, Norberto, Cid, María C, Hernández-Rodríguez, José, Castañeda, Santos, González-Gay, Miguel A, Burgner, David, Martín, Javier, Márquez, Ana
• Format: Article
• Language: English
• Subjects: Clinical Science; Genetic Loci; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; Humans; IgA Vasculitis - genetics; Mucocutaneous Lymph Node Syndrome - genetics; Phenotype; Phosphoric Diester Hydrolases - genetics; Polymorphism, Single Nucleotide
• ISSN: 1462-0324; 1462-0332
• DOI: 10.1093/rheumatology/keab443

Abstract Objectives Combining of genomic data of different pathologies as a single phenotype has emerged as a useful strategy to identify genetic risk loci shared among immune-mediated diseases. Our study aimed to increase our knowledge of the genetic contribution to Kawasaki disease (KD) and IgA vasculitis (IgAV) by performing the first comprehensive large-scale analysis on the genetic overlap between them. Methods A total of 1190 vasculitis patients and 11 302 healthy controls were analysed. First, in the discovery phase, genome-wide data of 405 KD patients and 6252 controls and 215 IgAV patients and 1324 controls, all of European origin, were combined using an inverse variance meta-analysis. Second, the top associated polymorphisms were selected for replication in additional independent cohorts (570 cases and 3726 controls). Polymorphisms with P-values ≤5 × 10−8 in the global IgAV–KD meta-analysis were considered as shared genetic risk loci. Results A genetic variant, rs3743841, located in an intron of the NAGPA gene, reached genome-wide significance in the cross-disease meta-analysis (P = 8.06 × 10−10). Additionally, when IgAV was individually analysed, a strong association between rs3743841 and this vasculitis was also evident [P = 1.25 × 10−7; odds ratio = 1.47 (95% CI 1.27, 1.69)]. In silico functional annotation showed that this polymorphism acts as a regulatory variant modulating the expression levels of the NAGPA and SEC14L5 genes. Conclusion We identified a new risk locus with pleiotropic effects on the two childhood vasculitides analysed. This locus represents the strongest non-HLA signal described for IgAV to date.