Cadherin 5 is regulated by corticosteroids and associated with central serous chorioretinopathy

Abstract

Central serous chorioretinopathy (CSC) is characterized by leakage of fluid from the choroid into the subretinal space and, consequently, loss of central vision. The disease is triggered by endogenous and exogenous corticosteroid imbalance and psychosocial stress and is much more prevalent in men. We studied the association of genetic variation in 44 genes from stress response and corticosteroid metabolism pathways with the CSC phenotype in two independent cohorts of 400 CSC cases and 1,400 matched controls. The expression of cadherin 5 (CDH5), the major cell-cell adhesion molecule in vascular endothelium, was downregulated by corticosteroids which may increase permeability of choroidal vasculature, leading to fluid leakage under the retina. We found a significant association of four common CDH5 SNPs with CSC in male patients in both cohorts. Two common intronic variants, rs7499886:A>G and rs1073584:C>T, exhibit strongly significant associations with CSC; P = 0.00012; odds ratio (OR) = 1.5; 95%CI [1.2;1.8], and P = 0.0014; OR = 0.70; 95%CI [0.57;0.87], respectively. A common haplotype was present in 25.4% male CSC cases and in 35.8% controls (P = 0.0002; OR = 0.61, 95% CI [0.47-0.79]). We propose that genetically predetermined variation in CDH5, when combined with triggering events such as corticosteroid treatment or severe hormonal imbalance, underlie a substantial proportion of CSC in the male population.

Keywords: CDH5; Cadherin 5; central serous chorioretinopathy; genetic association; retinal disease.

Fig 1

Haplotype structure of the CDH5 locus. A: Linkage disequilibrium and haplotype structure of the entire CDH5 locus. B: structure of the locus as defined by the five out of 10 htSNPs typed in this study.

Fig 2

Immunohistochemical labeling of CDH5 (green fluorescence) in the choroid of an 86-year-old female donor. Note labeling in the choriocapillaris (CC) and at the margins of endothelial cells in larger choroidal vessels. Arrowheads indicate intercellular junctions and asterisks indicate vessel lumens. The yellow autofluorescence in the RPE is due to lipofuscin and the blue fluorescence is due to nuclear counterstaining with DAPI. Scale bar = 50 μm.

Fig 3

Suppression of the CDH5 gene by steroids in vitro. A: Normalized level of Cdh5 in mouse endothelial cells shows striking down regulation of mRNA following treatment with prednisolone (Prd) at two concentrations. Expression of Cdh5 was significantly reduced in all steroid treated cultures (P < 0.05). B: Organ cultures of human RPE/choroid downregulate expression of the CDH5 gene when exposed to prednisolone. When compared with the expression levels of RLPB1, CDH5 expression in prednisolone treated cultures was suppressed by greater than fourfold compared with the control cultures (CTL; P < 0.05). In all cases, no fold change is set to 0 and error bars indicate standard deviation.

Fig 4

Anatomy of intercellular endothelial junctions in organ cultures of human RPE-choroid. A–C: Choriocapillaris endothelial cell junctions. In each case the vascular lumen (asterisk) is oriented toward the bottom of the micrograph. Compared with the control cultures (A), cultures treated with prednisolone displayed more EC junctions with misaligned or overhanging adjacent leaflets (B, arrow). In rare cases, there was a gap between the EC leaflets in steroid treated cultures (C, arrow). Scale bar = 500 nm. D: Distribution of junctions in control and prednisolone treated cultures in the outer choroid. Prednisolone treated cultures exhibited decreased junction size (P < 0.05).

Fig 5

Reduced Cdh5 expression in mouse RPE-choroid-sclera in eyes injected with triamcinolone. When delivered by subretinal injection, triamcinolone significantly decreased expression of Cdh5 compared with the saline injected eyes, P = 0.02. In contrast, expression of the tight junction component Cldn1 increased in steroid treated eyes. No fold change is set to 0.