Association of a Haplotype in the NR3C2 Gene, Encoding the Mineralocorticoid Receptor, With Chronic Central Serous Chorioretinopathy

Abstract

IMPORTANCE Chronic central serous chorioretinopathy (cCSC) is a chorioretinal disease with unknown disease etiology. The glucocorticoid receptor and the mineralocorticoid receptor, 2 glucocorticoid-binding receptors, might be involved in the pathogenesis of cCSC.OBJECTIVE To assess the association of functional variants and haplotypes in the glucocorticoid receptor (NR3C1) and mineralocorticoid receptor (NR3C2) genes with cCSC. DESIGN, SETTING, AND PARTICIPANTSIn this case-control genetic association study, 336 patients with cCSC and 1314 unaffected controls, collected at 3 university medical centers from September 1, 2009, to May 1, 2016, underwent KASP genotyping for selected variants in NR3C1 (rs56149945, rs41423247, and rs6198) and NR3C2 (rs2070951 and rs5522).MAIN OUTCOMES AND MEASURES Genetic associations of 3 NR3C1 variants and 2 NR3C2 variants with cCSC. RESULTS Among the 336 patients (274 men and 62 women; mean [SD] age, 52 [10] years), after correction for multiple testing, rs2070951 in the NR3C2 gene was significantly associated with cCSC (odds ratio, 1.29; 95% CI, 1.08-1.53; P = .004). Moreover, the GA haplotype of single-nucleotide polymorphisms rs2070951 and rs5522 in NR3C2 conferred risk for cCSC (odds ratio, 1.39; 95% CI, 1.15-1.68; P = .004), whereas the CA haplotype decreased risk for cCSC (odds ratio, 0.72; 95% CI, 0.60-0.87; P < .001). Three known variants in NR3C1 that alter the activity of the glucocorticoid receptor (rs56149945, rs41423247, and rs6198) were not associated with cCSC.CONCLUSIONS AND RELEVANCE In this study, the variant rs2070951 and the GA haplotype in NR3C2 were associated with an increased risk for cCSC. Results of this genetic study support a possible role for the mineralocorticoid receptor in the pathogenesis of cCSC. Since these haplotypes have previously been associated with perceived stress, this study provides a clue to bridging clinical risk factors for cCSC to underlying genetic associations.

The Effect of Corticosteroids on Human Choroidal Endothelial Cells: A Model to Study Central Serous Chorioretinopathy

“…8,9 Because corticosteroids bind to both the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), it has been hypothesized that both are involved in the pathogenesis of CSC. 5,[9][10][11][12] Because of the plausible role of the choroidal endothelium in the pathophysiology of CSC, culturing of human choroidal endothelial cells (CECs) is of particular interest. [13][14][15][16] Endothelial cells (ECs) are heterogenic cells that show substantial sitespecific structural and biochemical variation due to their interaction with their surroundings.…”

Response of central serous chorioretinopathy evaluated by multimodal retinal imaging

“…[7][8][9][10] Several studies well documented the role of corticosteroids in CSC, referring to both glucocorticoid (cortisol) and mineralocorticoid (aldosterone) hormones. [11][12][13][14][15] Zhao and associates 16 reported that intravitreous injection of aldosterone, a specific mineralocorticoid receptor (MR) activator, induced choroidal vessel dilation and leakage in rodents' eyes. As MR antagonists reversed this effect, two specific MR antagonists (spironolactone and eplerenone) were used in the treatment of CSC with promising results in bestcorrected visual acuity (BCVA) and central macular thickness (CMT) outcomes.…”

miR‐454 performs tumor‐promoting effects in oral squamous cell carcinoma via reducing NR3C2

“…In this research, we found that miR-454 expression was upregulated in OSCC samples and acted as a positive regulator in the cell viability, colony formation, invasion, and migration of OSCC cells.NR3C2, as an important downstream target gene of miR-454, was confirmed in our experiment. NR3C2 encodes a mineralocorticoid receptor (MR) that acts as a ligand-dependent transcription factor mediating the function of aldosterone in salt and water balance 28.…”