Genome-wide studies define new genetic mechanisms of IgA vasculitis

作者：Lili Liu, Li Zhu, Sara Monteiro-Martins, Aaron T. Griffin, Lukas Vlahos, Masashi Fujita, Cecilia Berrouet, Francesca Zanoni, Maddalena Marasà, Jun Y. Zhang, Shu‐Feng Zhou, Yaşar Çalışkan, Oleh M. Akchurin, Samhar Al‐Akash, Augustina Jankauskiene, Monica Bodria, Aftab S. Chishti, Ciro Esposito, Vittoria Esposito, Donna Claes, Vladimı́r Tesař, Thomas K. Davis, Dmitry Samsonov, Dorota Kamińska, Tomasz Hryszko, Gianluigi Zaza, Joseph T. Flynn, Franca M. Iorember, Francesca Lugani, Dana V. Rizk, Bruce A. Julian, Guillermo Hidalgo, Mahmoud Kallash, Luigi Biancone, Antonio Amoroso, Luisa Bono, Laila‐Yasmin Mani, Bruno Vogt, Fangming Lin, Raji Sreedharan, Patricia L. Weng, Daniel Ranch, Nianzhou Xiao, Alejandro Quiroga, Raed Bou Matar, Michelle N. Rheault, Scott E. Wenderfer, Dave Selewski, Sigrid Lundberg, Cynthia Silva, Sherene Mason, John D. Mahan, Tetyana L. Vasylyeva, Krzysztof Mucha, Bartosz Foroncewicz, Leszek Pączek, Michał Florczak, Małgorzata Olszewska, Agnieszka Gradzińska, Maria Szczepańska, Edyta Machura, Andrzej Badeński, Helena Krakowczyk, Przemysław Sikora, Norbert Kwella, Monika Miklaszewska, Dorota Drożdż, Marcin Zaniew, Krzysztof Pawlaczyk, Katarzyna Siniewicz‐Luzeńczyk, Andrew S. Bomback, Gerald B. Appel, Claudia Izzi, Francesco Scolari, Anna Materna‐Kiryluk, Małgorzata Mizerska-Wasiak, Laureline Berthelot, Évangéline Pillebout, Renato C. Monteiro, Jan Novák, Todd J. Green, William E. Smoyer, Margaret Hastings, Robert Wyatt, Raoul D. Nelson, Javier Martı́n, Miguel Á. González‐Gay, Philip L. De Jager, Anna Köttgen, Andrea Califano, Ali G. Gharavi, Hong Zhang, Krzysztof Kiryluk · 发表于：medRxiv · 年份：2024 · DOI：10.1101/2024.10.10.24315041 · 被引用次数：5 · 研究领域：Vasculitis and related conditions、Cell Adhesion Molecules Research、Atherosclerosis and Cardiovascular Diseases

Abstract IgA vasculitis (IgAV) is a pediatric disease with skin and systemic manifestations. Here, we conducted genome, transcriptome, and proteome-wide association studies in 2,170 IgAV cases and 5,928 controls, generated IgAV-specific maps of gene expression and splicing from blood of 255 pediatric cases, and reconstructed myeloid-specific regulatory networks to define disease master regulators modulated by the newly identified disease driver genes. We observed significant association at the HLA - DRB1 (OR=1.55, P=1.1×10 −25 ) and fine-mapped specific amino-acid risk substitutions in DRβ1. We discovered two novel non-HLA loci: FCAR (OR=1.51, P=1.0×10 −20 ) encoding a myeloid IgA receptor FcαR, and INPP5D (OR=1.34, P=2.2×10 −09 ) encoding a known inhibitor of FcαR signaling. The FCAR risk locus co-localized with a cis-eQTL increasing FCAR expression; the risk alleles disrupted a PRDM1 binding motif within a myeloid enhancer of FCAR . Another risk locus was associated with a higher genetically predicted levels of plasma IL6R. The IL6R risk haplotype carried a missense variant contributing to accelerated cleavage of IL6R into a soluble form. Using systems biology approaches, we prioritized IgAV master regulators co-modulated by FCAR , INPP5D and IL6R in myeloid cells. We additionally identified 21 shared loci in a cross-phenotype analysis of IgAV with IgA nephropathy, including novel loci PAID4, WLS , and ANKRD55 .