Steroidome Dysregulation and Complement C4 Copy Number Variation in Men With Central Serous Chorioretinopathy

Central serous chorioretinopathy (CSCR) is a retinal disease predominantly affecting middle-aged men, in which systemic glucocorticoid exposure is a well-established risk factor. Genetic studies have implicated copy number variation (CNV) in complement component 4 (C4), located within the RCCX module alongside the steroid 21-hydroxylase gene (CYP21A2), in modifying disease susceptibility. However, the relationship between adrenal steroid metabolism and C4 CNV in CSCR has not been investigated.

We analyzed the serum steroidome of 45 male patients with CSCR and 49 age-matched healthy male controls using liquid chromatography-tandem mass spectrometry (LC-MS/MS). In a subset of 20 patients with complex CSCR, genomic C4A and C4B copy numbers were quantified by qPCR and correlated with circulating steroid metabolites, including indices of CYP21A2 activity.

Patients with CSCR exhibited significant alterations in steroid metabolism compared with controls. In the glucocorticoid pathway, 17-hydroxyprogesterone (17-OHP) was elevated, cortisone was reduced, and the 11-deoxycortisol/17-OHP ratio, reflecting CYP21A2 activity, was significantly lower. In the mineralocorticoid pathway, 11-deoxycorticosterone, dehydrocorticosterone, and aldosterone were decreased, whereas in the androgen pathway dehydroepiandrosterone (DHEA) was increased. In the subgroup with genomic analysis, patients carrying only one C4B copy displayed reduced CYP21A2 activity, as reflected by a lower S/17-OHP ratio, and correlations were observed among C4 copy number, 17-OHP levels, and the S/17-OHP ratio.

Men with CSCR present systemic dysregulation of glucocorticoid, mineralocorticoid, and androgen pathways, linked to impaired CYP21A2 activity. The possible correlation between low C4B copy number and altered steroid metabolism could suggest a role of the RCCX module in CSCR susceptibility, warranting further genetic and functional investigations.