HLA-B51/B5 and the risk of Behçet's disease: a systematic review and meta-analysis of case-control genetic association studies

Abstract

Objective: To quantify by meta-analysis the genetic effect of the HLA-B5 or HLA-B51 (HLA-B51/B5) allele on the risk of developing Behçet's disease (BD) and to look for potential effect modifiers.

Methods: Relevant studies were identified using the PubMed Medline database and manual searches of the literature. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by using the random-effects model. Subgroup meta-analyses and meta-regression analyses were undertaken to investigate the effects of selected study-level parameters on the pooled OR. Heterogeneity was assessed using the I2 statistic. Pooled results were used to calculate population-attributable risks (PAR) for BD in relationship to HLA-B51/B5.

Results: A total of 4,800 patients with BD and 16,289 controls from 78 independent studies (published 1975-2007) were selected. The pooled OR of HLA-B51/B5 allele carriers to develop BD compared with noncarriers was 5.78 (95% CI 5.00-6.67), with moderate between-study heterogeneity (I2 = 61%). The subgroup analyses stratifying studies by geographic locations (Eastern Asia, Middle East/North Africa, Southern Europe, Northern/Eastern Europe) yielded consistent OR ranges (5.31-7.20), with I2 ranges of 52-70%. Univariate random-effects meta-regression indicated the percentage of male BD cases (P = 0.008) as a source of heterogeneity. The PAR within the various geographic areas were estimated at 32-52%.

Conclusion: The strength of the association between BD and HLA-B51/B5, and its consistency across populations of various ethnicities, lends further support to this allele being a primary and causal risk determinant for BD. Variations according to sex support an interaction of this allele with BD characteristics.

Figure 1

Flow chart of studies identified through the systematic review of the literature. BD = Behçet’s disease.

Figure 2

Forest plot of results of published studies on the association between HLA–B51/B5 and Behçet’s disease (BD) (listed chronologically). Odds ratios (ORs) for the risk of HLA–B51/B5 allele carriers to develop BD compared with noncarriers. The dashed vertical line indicates the pooled value for the entire population considered. *See Materials and Methods for a list of other criteria applied. 95% CI = 95% confidence interval; E = Eastern; Serol. = serologic; JBDRC = Japanese Behçet’s Disease Research Committee; N = North; M = Middle; NR = not reported; S = Southern; ISG = International Study Group; Molec. = molecular.

Figure 3

Funnel plot for publication bias. The dashed vertical line indicates the pooled estimate. Precision was assessed by the inverse variance method.