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

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.

Fig. 1.

(A) A Manhattan plot showing the results of the case-case genetic association analysis of male and female patients with Behcet’s disease of Turkish origin. The −Log₁₀(P) value for each variant is plotted against its chromosomal position. The red line represents the genome-wide level of significance (P < 5 × 10⁻⁸) and the blue line represents the suggestive level of significance (P < 1 × 10⁻⁵). (B) Regional plot displaying SNPs in LD with rs2848712 in the HLA region in the Turkish population (LD = 1 is blue, LD = 0.99–0.80 is red, LD = 0.79–0.60 is orange, LD = 0.59–0.40 is green, and LD = 0.39–0.00 is black). The −Log₁₀(P) value for each variant is plotted against its physical position on chromosome 6. The red line represents GWAS level of significance (P < 5 × 10⁻⁸) and the blue line represents suggestive level of significance (P < 1 × 10⁻⁵). (Assembly_GRCh37/hg19 by Ensembl was used).

Fig. 2.

Meta-analysis forest plot of rs2848712 (HLA-B/MICA) depicting the sex-specific differences in genetic association from different populations at this locus. Individual cohorts are shown in blue and the total study population in red.

Fig. 3.

(A) Density plot of genetic risk scores (GRS) for Behçet’s disease in Turkish patients. The frequencies of individuals are plotted against their respective GRS (men in blue and women in red), showing higher genetic risk in men than women (P = 3.18 × 10⁻⁸). (B) Density plot of GRS in Turkish patients with Behçet’s disease without the SNPs in the HLA region (men in blue and women in red). The difference between men and women disappears (P = 0.34). (C) Density plot of GRS in healthy Turkish controls (men in blue and women in red) displaying no significant difference between men and women (P = 0.61).