Complement C4 Genes and Sex-Biased Disease Susceptibility

There are many examples of diseases in which there is a sex bias, however, the underlying biology of this bias has remained poorly understood. Such examples include autoimmune diseases, which occur nine times more commonly in women than in men, whilst schizophrenia is more prevalent in men than in women and the disease course is more severe. Initial reports from the COVID-19 pandemic ( are also suggesting a more severe disease course in men and a higher mortality rate.

An article published in Nature on 11 May 2020 ( showed that polymorphisms in the Complement C4 genes (C4A and C4B) are associated with increased risk for Schizophrenia, a 7-fold variation in risk for SLE, and a 16-fold variation for Sjögren’s Disease. The C4 alleles acted more strongly in men than in women with the variation in risk being significantly increased for SLE (2.3 times greater), Sjögren’s Disease (2 times greater) and schizophrenia (1.3 times greater).

Cerebrospinal fluid and plasma levels of C4 and C3 (effector of C4) were higher in men than in women between the ages of 20 and 50-years which corresponded to the ages of differential disease susceptibility. The authors suggest that the differences in complement protein levels between sexes may help clarify the stronger effect of the C4 alleles in men.

Synexa Life Sciences has a broad portfolio of complement assays to measure the levels of complement, CH50 and cell bound complement activation products. We are also able to support clients with the assessment of complement dependent cytotoxicity (CDC) and complement gene polymorphisms.


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