An Insertion Variant in CRH Confers an Increased Risk of Central Serous Chorioretinopathy

Abstract

Purpose: To identify a novel corticotropin-releasing hormone (CRH) gene variant relevant in patients with central serous chorioretinopathy (CSC).

Methods: We performed a genetic study of CSC in families and sporadic cases with controls. Using whole-exome sequencing and linkage analysis, we identified a heterozygous insertion variant, Gln52insPro, in the CRH gene that cosegregated in two Chinese families with CSC. This variant was evaluated among an additional 1307 patients with CSC and 1438 ethnicity-matched control individuals from three independent Chinese cohorts.

Results: The CRH variant was strongly associated with CSC in these cohorts of Chinese patients (Pmeta = 1.24 × 10-11; odds ratio, 3.01; 95% confidence interval, 2.15-4.21). The risk variant Gln52insPro decreased CRH gene expression.

Conclusions: Our results implicate the hypothalamic-pituitary-adrenal stress response system in the pathogenesis of CSC and provide a novel rationale for therapeutic intervention.

Figure.

CRH variant in two families and 1307 sporadic patients with CSC. (A) Pedigree of two CSC families. All the family members from family A and family B were evaluated by whole-exome sequencing, and the 154_155insCGC variant in the CRH gene was segregated in all the affected family A and family B members. The arrow pointing to the filled symbol indicates the index proband patient; the crossed lines indicate deceased subjects. W, wild-type allele; M, mutant allele. (B) Color fundus photography, indocyanine green angiography (ICGA) and optical coherence tomography (OCT) of the patient (family A, II:4) and normal family member (family A, II:3). The black arrows indicate normal choroid vessels, and the white arrows point to dilated choroid vessels. *Subretinal fluids. (C) The heterozygous mutation 154_155insCGC, rs562792458, p. Pro51_Gln52insPro (M) was found in all patients with CSC in family A and family B. (D) The OR plot shows the allelic effects of the 154_155insCGC allele of rs562792458 in 1307 sporadic patients and 1438 controls in 3 independent cohorts. The error bars represent the 95% CIs of the ORs. (E) A homolog study showed that the CRH gene is relatively conserved in most animals.