Sex-specific analysis in Behçet's disease reveals higher genetic risk in male patients

Yun Gun Jo; Lourdes Ortiz-Fernández; Patrick Coit; Vuslat Yilmaz; Sibel P Yentür; Fatma Alibaz-Oner; Kenan Aksu; Eren Erken; Nursen Düzgün; Gokhan Keser; Ayse Cefle; Ayten Yazici; Andac Ergen; Erkan Alpsoy; Carlo Salvarani; Bünyamin Kısacık; Ina Kötter; Jörg Henes; Muhammet Çınar; Arne Schaefer; Rahime M Nohutcu; Fujio Takeuchi; Shinji Harihara; Toshikatsu Kaburaki; Meriam Messedi; Yeong-Wook Song; Timuçin Kaşifoğlu; Javier Martin; María Francisca González Escribano; Güher Saruhan-Direskeneli; Haner Direskeneli; Amr H Sawalha

doi:10.1016/j.jaut.2022.102882

Sex-specific analysis in Behçet's disease reveals higher genetic risk in male patients

J Autoimmun. 2022 Oct:132:102882. doi: 10.1016/j.jaut.2022.102882. Epub 2022 Aug 18.

Authors

Yun Gun Jo¹, 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, Bünyamin Kısacık¹¹, Ina Kötter¹², Jörg Henes¹³, Muhammet Çınar¹⁴, Arne Schaefer¹⁵, Rahime M Nohutcu¹⁶, Fujio Takeuchi¹⁷, Shinji Harihara¹⁸, Toshikatsu Kaburaki¹⁹, Meriam Messedi²⁰, Yeong-Wook Song²¹, Timuçin Kaşifoğlu²², Javier Martin²³, María Francisca González Escribano²⁴, Güher Saruhan-Direskeneli², Haner Direskeneli³, Amr H Sawalha²⁵

Affiliations

¹ Division of Rheumatology, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA.
² Department of Physiology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
³ Division of Rheumatology, Department of Internal Medicine, Marmara University, School of Medicine, Istanbul, Turkey.
⁴ Division of Rheumatology, Department of Internal Medicine, Ege University, School of Medicine, Izmir, Turkey.
⁵ Division of Rheumatology, Department of Internal Medicine, Çukurova University, School of Medicine, Adana, Turkey.
⁶ Division of Rheumatology, Department of Internal Medicine, Ankara University, School of Medicine, Ankara, Turkey.
⁷ Division of Rheumatology, Department of Internal Medicine, Kocaeli University, School of Medicine, Kocaeli, Turkey.
⁸ Ophthalmology Clinic, Okmeydanı Research and Education Hospital, Istanbul, Turkey.
⁹ Department of Dermatology and Venereology, Akdeniz University, School of Medicine, Antalya, Turkey.
¹⁰ Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia and Università di Modena e Reggio Emilia, Modena, Italy.
¹¹ Division of Rheumatology, Department of Internal Medicine, Gaziantep University, Faculty of Medicine, Gaziantep, Turkey.
¹² Division of Rheumatology and Systemic Inflammatory Diseases, University Hospital Eppendorf, Hamburg, and Clinic for Rheumatology and Immunology, Bad Bramstedt, Germany.
¹³ Center for Interdisciplinary Rheumatology, Immunology and Autoinflammatory Diseases (INDIRA) and Internal Medicine II (hematology, Oncology, Rheumatology and Immunology), University Hospital Tuebingen, Tuebingen, Germany.
¹⁴ Division of Rheumatology, Department of Internal Medicine, University of Health Sciences Turkey, Gulhane Faculty of Medicine, Ankara, Turkey.
¹⁵ Department of Periodontology, Oral Medicine and Oral Surgery, Institute for Dental and Craniofacial Sciences, Charité-University Medicine Berlin, Berlin, Germany.
¹⁶ Department of Periodontology, Faculty of Dentistry, Hacettepe University Sihhiye, Ankara, Turkey.
¹⁷ School of Pharmaceutical Science, University of Shizuoka, Shizuoka, Japan.
¹⁸ Department of Biological Sciences, Graduate School of Science, University of Tokyo, Tokyo, Japan.
¹⁹ Department of Ophthalmology, Jichi Medical University Saitama Medical Center, Japan.
²⁰ Research Laboratory of Molecular Bases of Human Diseases, 12ES17, Faculty of Medicine of Sfax, University of Sfax, 3029 Sfax, Sfax, Tunisia.
²¹ Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, And College of Medicine, Medical Research Center, Seoul National University, Seoul, South Korea.
²² Division of Rheumatology, Department of Internal Medicine, Osmangazi University, School of Medicine, Eskisehir, Turkey.
²³ Instituto de Parasitología y Biomedicina 'López-Neyra', IPBLN-CSIC, PTS Granada, Granada, Spain.
²⁴ Servicio de Inmunología, IBiS, Hospital Universitario Virgen Del Rocío/CSIC/Universidad de Sevilla, Spain.
²⁵ Division of Rheumatology, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA; Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Lupus Center of Excellence, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: asawalha@pitt.edu.

Abstract

Objectives: Behçet's disease tends to be more severe in men than women. This study was undertaken to investigate sex-specific genetic effects in Behçet's disease.

Methods: A total of 1762 male and 1216 female patients with Behçet's disease from six diverse populations were studied, with the majority of patients of Turkish origin. Genotyping was performed using an Infinium ImmunoArray-24 BeadChip, or extracted from available genotyping data. Following imputation and extensive quality control measures, genome-wide association analysis was performed comparing male to female patients in the Turkish cohort, followed by a meta-analysis of significant results in all six populations. In addition, a weighted genetic risk score for Behçet's disease was calculated and compared between male and female patients.

Results: Genetic association analysis comparing male to female patients with Behçet's disease from Turkey revealed an association with male sex in HLA-B/MICA within the HLA region with a GWAS level of significance (rs2848712, OR = 1.46, P = 1.22 × 10^-8). Meta-analysis of the effect in rs2848712 across six populations confirmed these results. Genetic risk score for Behçet's disease was significantly higher in male compared to female patients from Turkey. Higher genetic risk for Behçet's disease was observed in male patients in HLA-B/MICA (rs116799036, OR = 1.45, P = 1.95 × 10^-8), HLA-C (rs12525170, OR = 1.46, P = 5.66 × 10^-7), and KLRC4 (rs2617170, OR = 1.20, P = 0.019). In contrast, IFNGR1 (rs4896243, OR = 0.86, P = 0.011) was shown to confer higher genetic risk in female patients.

Conclusions: Male patients with Behçet's disease are characterized by higher genetic risk compared to female patients. This genetic difference, primarily derived from our Turkish cohort, is largely explained by risk within the HLA region. These data suggest that genetic factors might contribute to differences in disease presentation between men and women with Behçet's disease.

Keywords: Behçet's disease; GWAS; Genetics; HLA class I; MHC; Sex-bias.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural

MeSH terms

Behcet Syndrome* / diagnosis
Behcet Syndrome* / epidemiology
Behcet Syndrome* / genetics
Female
Genetic Testing
Genome-Wide Association Study
HLA-C Antigens
Humans
Male
Risk Factors

Substances

HLA-C Antigens

Grants and funding

R01 AR070148/AR/NIAMS NIH HHS/United States