The copy number of complement component C4 genes (C4A and C4B) has been associated with schizophrenia risk, particularly in men. Psychotic disorders are associated with alterations in serum immune protein levels, but whether the C4A/B copy numbers are related to circulating immune protein levels is not known.

Two Finnish first-episode psychosis (FEP) cohorts were studied, comprising 105 FEP patients and 71 controls who were assessed at baseline and at two-month and one-year follow-ups. The C4A/B copy numbers were analyzed by genomic RT-PCR. We measured immune protein concentrations using a 38-plex Luminex assay at all available time points and correlated the results with the C4A/B copy numbers using Spearman's rank correlations.

The median C4A and C4B copy numbers did not differ between patients and controls. C4A copy number correlated broadly and positively with serum cytokine and chemokine levels across all measurement points in FEP patients, while correlations with C4B copy numbers were negative. Correlations in controls were weaker and less consistent. When analyzed separately in males and females, the broadest and most significant positive correlations of immune protein levels with C4A copy number and negative correlations with C4B copy number were observed in male FEP patients.

C4A and C4B gene copy variations influence immunoinflammatory responses and serum levels of many immune proteins. This phenomenon was pronounced in male FEP patients, suggesting that they may be more vulnerable to tissue injury or infections. The results underscore the importance of investigating sex-specific effects of C4 gene variations in psychotic disorders.