Lourdes Ortiz Fernández1, Patrick Coit1, Vuslat Yilmaz2, Sibel P Yentür2, Fatma Alibaz-Oner3, Kenan Aksu4, Eren Erken5, Nursen Düzgün6, Gokhan Keser4, Ayse Cefle7, Ayten Yazici7, Andac Ergen8, Erkan Alpsoy9, Carlo Salvarani10, Bruno Casali11, Bünyamin Kısacık12, Ina Kötter13, Jörg Henes14, Muhammet Çınar15, Arne Schaefer16, Rahime M Nohutcu17, Alexandra Zhernakova18, Cisca Wijmenga18, Fujio Takeuchi19, Shinji Harihara20, Toshikatsu Kaburaki21, Meriam Messedi22, Yeong-Wook Song23, Timuçin Kaşifoğlu24, F David Carmona25, Joel M Guthridge26, Judith A James26, Javier Martin27, María Francisca González Escribano28, Güher Saruhan-Direskeneli2, Haner Direskeneli3, Amr H Sawalha1. 1. University of Pittsburgh, Pittsburgh, Pennsylvania. 2. Istanbul University, Istanbul, Turkey. 3. Marmara University School of Medicine, Istanbul, Turkey. 4. Ege University School of Medicine, Izmir, Turkey. 5. Cukurova University School of Medicine, Adana, Turkey. 6. Ankara University School of Medicine, Ankara, Turkey. 7. Kocaeli University School of Medicine, Kocaeli, Turkey. 8. Okmeydanı Research and Education Hospital, Istanbul, Turkey. 9. Akdeniz University School of Medicine, Antalya, Turkey. 10. Azienda USL-IRCCS di Reggio Emilia and Università di Modena e Reggio Emilia, Modena, Italy. 11. Azienda Ospedaliera Arcispedale Santa Maria Nuova-IRCCS di Reggio Emilia, Reggio Emilia, Italy. 12. Gaziantep University, Gaziantep, Turkey. 13. University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 14. University Hospital Tuebingen, Tuebingen, Germany. 15. University of Health Sciences Turkey, Ankara, Turkey. 16. Charité University Medicine, Berlin, Germany. 17. Hacettepe University Sihhiye, Ankara, Turkey. 18. University of Groningen and University Medical Center Groningen, Groningen, The Netherlands. 19. Tokyo Seiei University, Tokyo, Japan. 20. University of Tokyo Graduate School of Science, Tokyo, Japan. 21. Jichi Medical University Saitama Medical Center, Saitama, Japan. 22. Research Laboratory of Molecular Bases of Human Diseases 12ES17 and University of Sfax, Sfax, Tunisia. 23. Seoul National University College of Medicine, Seoul, Republic of Korea. 24. Eskisehir Osmangazi University School of Medicine, Eskisehir, Turkey. 25. Universidad de Granada and ibs.GRANADA Instituto de Investigación Biosanitaria, Granada, Spain. 26. Oklahoma Medical Research Foundation, Oklahoma City. 27. Instituto de Parasitología y Biomedicina 'López-Neyra', Granada, Spain. 28. Instituto de Biomedicine de Sevilla, Hospital Universitario Virgen del Rocío, CSIC, Universidad de Sevilla, Seville, Spain.
Abstract
OBJECTIVE: Behçet's disease is a complex systemic inflammatory vasculitis of incompletely understood etiology. This study was undertaken to investigate genetic associations with Behçet's disease in a diverse multiethnic population. METHODS: A total of 9,444 patients and controls from 7 different populations were included in this study. Genotyping was performed using an Infinium ImmunoArray-24 v.1.0 or v.2.0 BeadChip. Analysis of expression data from stimulated monocytes, and epigenetic and chromatin interaction analyses were performed. RESULTS: We identified 2 novel genetic susceptibility loci for Behçet's disease, including a risk locus in IFNGR1 (rs4896243) (odds ratio [OR] 1.25; P = 2.42 × 10-9 ) and within the intergenic region LNCAROD/DKK1 (rs1660760) (OR 0.78; P = 2.75 × 10-8 ). The risk variants in IFNGR1 significantly increased IFNGR1 messenger RNA expression in lipopolysaccharide-stimulated monocytes. In addition, our results replicated the association (P < 5 × 10-8 ) of 6 previously identified susceptibility loci in Behçet's disease: IL10, IL23R, IL12A-AS1, CCR3, ADO, and LACC1, reinforcing the notion that these loci are strong genetic factors in Behçet's disease shared across ancestries. We also identified >30 genetic susceptibility loci with a suggestive level of association (P < 5 × 10-5 ), which will require replication. Finally, functional annotation of genetic susceptibility loci in Behçet's disease revealed their possible regulatory roles and suggested potential causal genes and molecular mechanisms that could be further investigated. CONCLUSION: We performed the largest genetic association study in Behçet's disease to date. Our findings reveal novel putative functional variants associated with the disease and replicate and extend the genetic associations in other loci across multiple ancestries.
OBJECTIVE: Behçet's disease is a complex systemic inflammatory vasculitis of incompletely understood etiology. This study was undertaken to investigate genetic associations with Behçet's disease in a diverse multiethnic population. METHODS: A total of 9,444 patients and controls from 7 different populations were included in this study. Genotyping was performed using an Infinium ImmunoArray-24 v.1.0 or v.2.0 BeadChip. Analysis of expression data from stimulated monocytes, and epigenetic and chromatin interaction analyses were performed. RESULTS: We identified 2 novel genetic susceptibility loci for Behçet's disease, including a risk locus in IFNGR1 (rs4896243) (odds ratio [OR] 1.25; P = 2.42 × 10-9 ) and within the intergenic region LNCAROD/DKK1 (rs1660760) (OR 0.78; P = 2.75 × 10-8 ). The risk variants in IFNGR1 significantly increased IFNGR1 messenger RNA expression in lipopolysaccharide-stimulated monocytes. In addition, our results replicated the association (P < 5 × 10-8 ) of 6 previously identified susceptibility loci in Behçet's disease: IL10, IL23R, IL12A-AS1, CCR3, ADO, and LACC1, reinforcing the notion that these loci are strong genetic factors in Behçet's disease shared across ancestries. We also identified >30 genetic susceptibility loci with a suggestive level of association (P < 5 × 10-5 ), which will require replication. Finally, functional annotation of genetic susceptibility loci in Behçet's disease revealed their possible regulatory roles and suggested potential causal genes and molecular mechanisms that could be further investigated. CONCLUSION: We performed the largest genetic association study in Behçet's disease to date. Our findings reveal novel putative functional variants associated with the disease and replicate and extend the genetic associations in other loci across multiple ancestries.
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