Identification of Novel Genetic Susceptibility Loci in Primary Antiphospholipid Syndrome

Elizabeth Gensterblum¹, Travis Hughes², Manuel Martínez-Bueno³, Maria Orietta Borghi⁴, Guillermo J. Pons-Estel⁵, Gerard Espinosa⁶, Alexandra Zhernakova⁷, Cisca Wijmenga⁸, Ricard Cervera⁵, Pier Luigi Meroni⁹, Marta Alarcón-Riquelme^3,10 and Amr Sawalha¹, ¹Division of Rheumatology, University of Michigan, Ann Arbor, MI, ²Division of Health Sciences and Technology, Harvard Medical School, Boston, MA, ³Center for Genomics and Oncological Research (GENYO), Pfizer-University of Granada-Andalusian Regional Government, Health Sciences Technology Park, Granada, Spain, ⁴University of Milan, IRCCS Istituto Auxologico Italiano, Milan, Italy, ⁵Department of Autoimmune Diseases, Institut Clínic de Medicina i Dermatologia, Hospital Clínic de Barcelona, Barcelona, Spain, ⁶Autoimmune Diseases Department. Hospital Clínic de Barcelona, Barcelona, Spain, ⁷Rheumatology and Clinical Immunology, University of Groningen, University Medical Center, Groningen, Netherlands, ⁸Genetics, University Medical Hospital Groningen, University of Groningen, Groningen, Netherlands, ⁹Hospital G.Pini, University of Milano, IRCSS Instute Auxologico Italiano, Milan, Italy, ¹⁰Unit for Chronic Inflammatory Diseases, Institute for Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: Antiphospholipid syndrome and genetics

Session Information

Date: Monday, November 14, 2016

Title: Antiphospholipid Syndrome

Session Type: ACR Concurrent Abstract Session

Session Time: 2:30PM-4:00PM

Background/Purpose: Antiphospholipid syndrome (APS) is an autoimmune disease with incompletely understood etiology, characterized by recurrent thrombosis and pregnancy complications. We conducted this study to understand the genetic basis of primary APS.

Methods: We studied two independent cohorts of primary APS patients of European descent, consisting of 89 patients and 3072 healthy controls from Spain, and 133 patients and 1560 healthy controls from Italy. Genotyping of ~200,000 variants was performed using the HumanImmuno v1 BeadChip. Genetic association analysis was performed following rigorous quality control measures. A meta-analysis between the two cohorts was performed to identify susceptibility loci for primary APS. Additional genetic variants within loci of suggestive genetic association were imputed up to the 1000 Genomes Project density and then included in the analysis.

Results: We identified a novel genetic susceptibility locus for primary APS in PLEK, encoding pleckstrin, which plays an important role in hemostasis and platelet function (odds ratio= 1.71, P=7.89 x 10-6). Importantly, expression quantitative trait loci (eQTL) analysis revealed that the disease risk allele in PLEK is associated with significant reduction in PLEK mRNA expression (P=2.6 x 10-6), and is located within an active enhancer region identified by histone H3K27 acetylation and DNase hypersensitivity. Our data also confirmed the genetic association between APS and STAT4 (odds ratio= 1.66, P=4.67 x 10-6). The association within the HLA was the most significant genetic association detected for APS in our study, with the most robust effect within HLA class II upstream of HLA-DQA1 (OR 1.87, P=2.45 x 10-8).

Conclusion: This is the first genome-wide association study in primary APS. Our findings suggest a novel putative functional genetic susceptibility locus for primary APS in PLEK, and identify genetic susceptibility loci within the HLA class II locus and the common autoimmunity locus in STAT4. *MAR and AS equally contributed to this work

Disclosure: E. Gensterblum, None; T. Hughes, None; M. Martínez-Bueno, None; M. O. Borghi, None; G. J. Pons-Estel, None; G. Espinosa, None; A. Zhernakova, None; C. Wijmenga, None; R. Cervera, None; P. L. Meroni, None; M. Alarcón-Riquelme, None; A. Sawalha, None.

To cite this abstract in AMA style:

Gensterblum E, Hughes T, Martínez-Bueno M, Borghi MO, Pons-Estel GJ, Espinosa G, Zhernakova A, Wijmenga C, Cervera R, Meroni PL, Alarcón-Riquelme M, Sawalha A. Identification of Novel Genetic Susceptibility Loci in Primary Antiphospholipid Syndrome [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/identification-of-novel-genetic-susceptibility-loci-in-primary-antiphospholipid-syndrome/. Accessed .

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