Dense Genotyping of Immune Related Loci in a Multi-Ethnic Behçet’s Disease Cohort Identifies Genetic Associations in a Long Noncoding RNA Near QSOX2, RASIP1/FUT2, and IL12A-AS1

Paul Renauer¹, Patrick Coit¹, Travis Hughes², Mikhail Ognenovski¹, Adam Adler³, Lourdes Ortiz-Fernández⁴, Vuslat Yilmaz⁵, Kenan Aksu⁶, Nursen Duzgun⁷, Gokhan Keser⁸, Ayse Cefle⁹, Ayten Yazici¹⁰, Andac Ergen¹¹, Erkan Alpsoy¹², Carlo Salvarani¹³, Bruno Casali¹⁴, Ina Koetter¹⁵, Alexandra Zhernakova¹⁶, Cisca Wijmenga¹⁷, Fujio Takeuchi¹⁸, Shinji Harihara¹⁹, Toshikatsu Kaburaki²⁰, Yeong Wook Song²¹, Francisco David Carmona²², Marta E. Alarcon Riquelme²³, Javier Martín²², Güher Saruhan-Direskeneli²⁴, María Francisca Gonzalez Escribano²⁵, Haner Direskeneli²⁶ and Amr H Sawalha¹, ¹Division of Rheumatology, University of Michigan, Ann Arbor, MI, ²Division of Health Sciences and Technology, Harvard Medical School, Boston, MA, ³Oklahoma Medical Research Foundation, OK, OK, ⁴Immunology department, Hospital Universitario Virgen del Rocío, Sevilla, Spain, ⁵Istanbul University, Istanbul Faculty of Medicine, Department of Physiology, Istanbul, Turkey, ⁶İnternal Medicine Division of Rheumatology, Ege University Medical Faculty, Izmir, Turkey, ⁷Internal Medicines, Rheumatology Department, Ankara University School of Medicine, Ankara, Turkey, ⁸Rheumatology, Ege University Medical Faculty, Izmir, Turkey, ⁹Rheumatology, Kocaeli University Faculty of Medicine, Kocaeli, Turkey, ¹⁰Rheumatology, Kocaeli University School of Medicine, Kocaeli, Turkey, ¹¹Okmeydaný Research and Education Hospital, Istanbul, Turkey, ¹²Department of Dermatology, Akdeniz University School of Medicine, Antalya, Turkey, ¹³Rheumatology, Azienda Ospedaliera ASMN, Istituto di Ricovero e Cura a Carattere Scientifico, Reggio Emilia, Italy, ¹⁴Molecular Biology Laboratory, Azienda Ospedaliera Arcispedale Santa Maria Nuova, Istituto di Ricovero e Cura a Carattere Scientifico, Reggio Emilia, Italy, ¹⁵Internal Medicine IV Rheumatology, Asklepios Klinik Altona, Hamburg, Germany, ¹⁶Rheumatology and Clinical Immunology, University of Groningen, University Medical Center, Groningen, Netherlands, ¹⁷Genetics, University Medical Hospital Groningen, University of Groningen, Groningen, Netherlands, ¹⁸#504 Lab/ Dep of Internal Medicine (Allergy & Rheumatology), Faculty of Medicine, University of Toyko, Tokyo, Japan, ¹⁹Division of Anthropology, Department of Biological Science, The University of Tokyo Graduate School of Science, Tokyo, Japan, ²⁰Ophthalmology, The University of Tokyo School of Medicine, Bunkyo-ku, Japan, ²¹Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea, ²²Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, PTS-Granada, Granada, Spain, ²³Centro de Genomica e Investigación Oncológica, Pfizer-University of Granada-Junta de Andalucía, Granada, Spain, ²⁴Department of Physiology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey, ²⁵Hospital Universitario Virgen del Rocío (IBiS,CSIC,US), Sevilla, Spain, ²⁶Rheumatology, Marmara University, School of Medicine, Istanbul, Turkey

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: Behcet's syndrome, Immunogenetics and genetics

Session Information

Date: Tuesday, November 15, 2016

Title: Vasculitis III: Pathogenic Mechanisms

Session Type: ACR Concurrent Abstract Session

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

Background/Purpose: Behçet’s disease is a chronic relapsing inflammatory disease characterized by recurrent mucocutaneous involvement. We performed dense genotyping in immune related loci in a large multi-ethnic cohort of Behçet’s disease patients and controls to further characterize the genetic basis of this disease.

Methods: We studied 5 independent cohorts of Behçet’s disease patients and controls consisting of 1253 patients and 5799 controls from Turkey, Italy, Spain, Japan, and Korea. Genotyping was performed using the Immunochip platform (Illumina), which includes ~200,000 genetic variants in immune-related genetic loci. Genetic association analysis in each cohort and a meta-analysis were performed to identify genetic susceptibility loci for Behçet’s disease. Additional genetic variants were imputed up to the 1000 Genomes Project density. Conditional genetic analysis and functional mapping using epigenetic marks of enhancer regions and expression quantitative trait loci (eQTL) analyses were performed to further characterize the genetic effects identified.

Results: We identified and fine-mapped genetic associations for Behçet’s disease with a GWAS level of significance in a lncRNA near QSOX2 (OR= 1.82, P= 1.08E-8), RASIP1/FUT2 (OR= 1.41, P= 3.57E-09), and IL12A-AS1 (OR= 1.71, P= 4.19E-08). The genetic association within the RASIP1/FUT2 locus is located within an active enhancer region as indicated by H3K27 acetylation marks. The disease risk variant in this locus is associated with mRNA expression changes of multiple transcripts within this locus, including significantly increased expression of RASIP1 and decreased expression of FUT2 in mucocutaneous tissues, frequently a target in Behçet’s disease. The association in the QSOX2 genetic locus can be localized to genetic variants within WI2-1959D15.1, which is a 1235bp lncRNA, and is associated with increased expression of this transcript. Several previously identified susceptibility loci for Behçet’s disease were also replicated.

Conclusion: We performed dense genotyping in immune-related genes in a multi-ethnic cohort of Behçet’s disease patients and controls, and identified a novel genetic susceptibility locus in a lncRNA near QSOX2, a genetic association with a functional genetic variant within an enhancer region in RASIP1/FUT2, and replicated the recently reported association in IL12A-AS1.

Disclosure: P. Renauer, None; P. Coit, None; T. Hughes, None; M. Ognenovski, None; A. Adler, None; L. Ortiz-Fernández, None; V. Yilmaz, None; K. Aksu, None; N. Duzgun, None; G. Keser, None; A. Cefle, None; A. Yazici, None; A. Ergen, None; E. Alpsoy, None; C. Salvarani, None; B. Casali, None; I. Koetter, None; A. Zhernakova, None; C. Wijmenga, None; F. Takeuchi, None; S. Harihara, None; T. Kaburaki, None; Y. W. Song, None; F. D. Carmona, None; M. E. Alarcon Riquelme, None; J. Martín, None; G. Saruhan-Direskeneli, None; M. F. Gonzalez Escribano, None; H. Direskeneli, None; A. H. Sawalha, None.

To cite this abstract in AMA style:

Renauer P, Coit P, Hughes T, Ognenovski M, Adler A, Ortiz-Fernández L, Yilmaz V, Aksu K, Duzgun N, Keser G, Cefle A, Yazici A, Ergen A, Alpsoy E, Salvarani C, Casali B, Koetter I, Zhernakova A, Wijmenga C, Takeuchi F, Harihara S, Kaburaki T, Song YW, Carmona FD, Alarcon Riquelme ME, Martín J, Saruhan-Direskeneli G, Gonzalez Escribano MF, Direskeneli H, Sawalha AH. Dense Genotyping of Immune Related Loci in a Multi-Ethnic Behçet’s Disease Cohort Identifies Genetic Associations in a Long Noncoding RNA Near QSOX2, RASIP1/FUT2, and IL12A-AS1 [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/dense-genotyping-of-immune-related-loci-in-a-multi-ethnic-behcets-disease-cohort-identifies-genetic-associations-in-a-long-noncoding-rna-near-qsox2-rasip1fut2-and-il12a-as1/. Accessed .

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