ACTH-induced cortisol release is related to the copy number of the C4B gene encoding the fourth component of complement in patients with non-functional adrenal incidentaloma

Summary Objective According to our previous findings, carriers of the C4B*Q0 genotype, which means zero or one copy of the C4B gene, which is located in the RCCX copy number variation region on chromosome 6, have a significantly shorter life‐expectancy and higher risk of cardiovascular disease than non‐carriers. We have postulated that the C4B*Q0 genotype is linked to variant(s) of the neighboring CYP21A2 gene encoding a steroid 21‐hydroxylase with altered function. Design Single‐center, observational, retrospective study. Patients Seventy‐six patients with non‐functional, benign adrenal incidentaloma. Measurements Serum cortisol, aldosterone, 17‐hydroxyprogesterone, corticosterone and ACTH levels basally and after ACTH‐stimulation, metyrapone or dexamethasone tests were determined. C4B gene copy number was quantified. Results The ratio of ACTH‐stimulated and baseline cortisol concentrations was significantly higher (P = 0·001) in the group of patients carrying the C4B*Q0 genotype compared to the rest of the patients. This difference remained significant (P = 0·004) after adjustment for sex and age, as well as for tumor size. A significant (P = 0·018), adjusted difference between carriers and non‐carriers was found also for ACTH‐induced/basal aldosterone ratio. In C4B*Q0 carriers, metyrapone hardly reduced the serum cortisol level, while in non‐carriers it induced a highly significant (P = 0·002) decrease. Conclusions The C4B*Q0 genotype may be associated with hyperreactivity of the HPA axis (manifested as an increased responsiveness to ACTH‐stimulation), probably through enhanced function of steroid 21‐hydroxylase. Since hyperreactivity of the HPA axis is known to be associated with an increased risk of cardiovascular disease, our present findings may explain the increased cardiovascular morbidity and mortality of C4B*Q0 carriers.