Complement C4 gene copy numbers modulate serum immune protein profiles in patients with first-episode psychosis and healthy controls in a sex-specific manner

Abstract

<h3>Background</h3><p>The copy number of complement component C4 genes (<em>C4A</em> and <em>C4B</em>) has been associated with schizophrenia risk, particularly in men. Psychotic disorders are associated with alterations in serum immune protein levels, but whether the <em>C4A/B</em> copy numbers are related to circulating immune protein levels is not known.</p><h3>Methods</h3><p>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 <em>C4A/B</em> 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 <em>C4A/B</em> copy numbers using Spearman's rank correlations.</p><h3>Results</h3><p>The median <em>C4A</em> and <em>C4B</em> copy numbers did not differ between patients and controls. <em>C4A</em> copy number correlated broadly and positively with serum cytokine and chemokine levels across all measurement points in FEP patients, while correlations with <em>C4B</em> 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 <em>C4A</em> copy number and negative correlations with <em>C4B</em> copy number were observed in male FEP patients.</p><h3>Conclusions</h3><p><em>C4A</em> and <em>C4B</em> 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 <em>C4</em> gene variations in psychotic disorders.</p>