School of Medicine, University of Pittsburgh Pittsburgh, PA, United States
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Desire Casares1, Manuel Martínez-Bueno2, Maria Orietta Borghi3, Guillermo Pons-Estel4, PRECISESADS Clinical Consortium2, Yu Zuo5, Gerard Espinosa6, Alexandra Zhernakova7, Cisca Wijmenga7, Timothy Radstake8, Lucas van den Hoogen9, Guillermo Reales10, Chris Wallace10, Joel Guthridge11, Judith James11, Ricard Cervera12, Pierluigi Meroni13, Javier Martin14, Jason Knight5, Marta Alarcon-Riquelme15 and Amr Sawalha1, 1University of Pittsburgh, Pittsburgh, PA, 2Centre for Genomics and Oncological Research, Granada, Spain, 3University of Milan, Milan, Italy, 4CREAR, Rosario, Argentina, 5University of Michigan, Ann Arbor, MI, 6Hospital Clinic, Barcelona, Spain, 7University of Groningen, Groningen, Netherlands, 8University Medical Center Utrecht, Carlisle, IL, 9Radboudumc and Sint Maartenskliniek, Nijmegen, Netherlands, 10University of Cambridge, Cambridge, United Kingdom, 11Oklahoma Medical Research Foundation, Oklahoma City, OK, 12Hospital Clínic de Barcelona, Barcelona, Spain, 13IRCCS Istituto Auxologico Italiano, Cusano Milanino, Milan, Italy, 14Instituto de Parasitologia y Biomedicina Lopez-Neyra - CSIC, Granada, Spain, 15Center for Genomics and Oncological Research (GENYO), Granada, Spain
Background/Purpose: Primary antiphospholipid syndrome (PAPS) is a rare autoimmune disease characterized by the presence of antiphospholipid antibodies and the occurrence of thrombotic events and pregnancy complications. Although the etiology of PAPS is incompletely understood, previous studies have suggested a role for genetic susceptibility in this disease. The goal of our study was to identify novel susceptibility loci associated with PAPS by performing a large genome-wide association study across five different populations of European ancestry.
Methods: A total of 482 patients with PAPS and 5,006 controls from five independent populations were included. Genotyping was performed using the Illumina Infinium ImmunoArray, Global Screening Array, and the Infinium Human Core platforms. PLINK software was used for quality control and association analyses adjusting for population structure. Genotype imputation was performed in each independent cohort using the TOPMed Imputation Server and the TOPMed version R2 as reference panel. Summary statistics from each population were meta-analyzed and further in silico functional analyses were performed. A weighted polygenic risk score was calculated and compared between populations. Hierarchical clustering and Mahalanobis distance analyses were used to assess genetic similarities between PAPS and other immune-mediated diseases.
Results: The meta-analysis of 7 million variants revealed two significant loci (p-value< 5x10-8) and 43 suggestive loci (p-value< 1x10-5) associated with PAPS. Significant signals are located near STAT4 (rs11889341, OR [95% CI]=0.61 [0.52-0.71], p-value=1.39x10-9) and HLA-DRA (rs9269041, OR [95% CI]=0.63 [0.54-0.74], p-value=2.07x10-8). Biological process enrichment analysis revealed association of PAPS susceptibility loci with pathways related to the nervous system (p-value=1.91x10-5) and the immune response (p-value=3.39x10-3). Our data suggest a higher genetic risk for PAPS in East Asian compared to European populations. Genetic similarity analysis showed that PAPS is genetically most closely related to neuromyelitis optica, systemic sclerosis, and Sjögren's syndrome.
Conclusion: Our results provide new insights into the genetic basis of PAPS across multiple populations. Genetic similarities of PAPS with other immune-mediated diseases characterized by neurological and vascular involvement might provide additional insights into the etiology and pathogenesis of antiphospholipid syndrome.
D. Casares: None; M. Martínez-Bueno: None; M. Borghi: None; G. Pons-Estel: GlaxoSmithKlein(GSK), 1, 5, 6, Janssen, 1, 5, 6, Novartis, 1, 6, Pfizer, 5, 6, Werfen/Inova, 5, 6; P. Clinical Consortium: None; Y. Zuo: None; G. Espinosa: None; A. Zhernakova: None; C. Wijmenga: None; T. Radstake: AbbVie/Abbott, 3; L. van den Hoogen: None; G. Reales: None; C. Wallace: None; J. Guthridge: None; J. James: Bristol-Myers Squibb(BMS), 5, GlaxoSmithKlein(GSK), 2, Novartis, 2, Progentec Biosciences, 5; R. Cervera: None; P. Meroni: None; J. Martin: None; J. Knight: Jazz Pharmaceuticals, 2; M. Alarcon-Riquelme: None; A. Sawalha: None.
