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

Abstract

Objectives: Behcet's disease tends to be more severe in men than women. This study was undertaken to investigate sex-specific genetic effects in Behcet's disease. Methods: A total of 1762 male and 1216 female patients with Behcet'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 Behcet's disease was calculated and compared between male and female patients. Results: Genetic association analysis comparing male to female patients with Behcet'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 x 10-8). Meta-analysis of the effect in rs2848712 across six populations confirmed these results. Genetic risk score for Behcet's disease was significantly higher in male compared to female patients from Turkey. Higher genetic risk for Behcet's disease was observed in male patients in HLA-B/ MICA (rs116799036, OR = 1.45, P = 1.95 x 10-8), HLA-C (rs12525170, OR = 1.46, P = 5.66 x 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 Behcet'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 Behcet's disease.