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< 5×10^-8) and 43 suggestive loci (p-value< 1×10^-5) associated with PAPS. Significant signals are located near STAT4 (rs11889341, OR [95% CI]=0.61 [0.52-0.71], p-value=1.39×10^-9) and HLA-DRA (rs9269041, OR [95% CI]=0.63 [0.54-0.74], p-value=2.07×10^-8). Biological process enrichment analysis revealed association of PAPS susceptibility loci with pathways related to the nervous system (p-value=1.91×10^-5) and the immune response (p-value=3.39×10^-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.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-genome-wide-association-study-suggests-new-susceptibility-loci-for-primary-antiphospholipid-syndrome/