Complement genes contribute sex-biased vulnerability in diverse disorders

Abstract

Many common illnesses differentially affect men and women for unknown reasons. The autoimmune diseases lupus and Sjögren’s syndrome affect nine times more women than men 1 , whereas schizophrenia affects men more frequently and severely 2 . All three illnesses have their strongest common genetic associations in the Major Histocompatibility Complex (MHC) locus, an association that in lupus and Sjögren’s syndrome has long been thought to arise from alleles of the human leukocyte antigen ( HLA ) genes at that locus 3 – 6 . Here we show that the complement component 4 ( C4 ) genes, which are also in the MHC locus and were recently found to increase risk for schizophrenia 7 , generate 7-fold variation in risk for lupus (95% CI: 5.88–8.61; p < 10 −117 in total) and 16-fold variation in risk for Sjögren’s syndrome (95% CI: 8.59–30.89; p < 10 −23 in total) among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduced risk for lupus and Sjögren’s syndrome. In all three illnesses, C4 alleles acted more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for lupus, 31-fold variation in risk for Sjögren’s syndrome, and 1.7-fold variation in schizophrenia risk among men (vs. 6-fold, 15-fold, and 1.26-fold among women respectively). At a protein level, both C4 and its effector C3 were present at greater levels in men than women in cerebrospinal fluid ( p < 10 −5 for both C4 and C3) and plasma 8 , 9 among adults ages 20–50, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help explain the larger effects of C4 alleles in men, women’s greater risk of SLE and Sjögren’s, and men’s greater vulnerability in schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.

What’s Sex Got to Do With COVID-19? Gender-Based Differences in the Host Immune Response to Coronaviruses

“…A recent study of 50,000 racially diverse subjects found that, compared to men, women have significantly lower levels of C4, an activator of C3. They were also able to prove that this results in a 42% decrease in C3 in women compared to men ( 22 ). In an investigation of Caucasian populations, levels of C3, C5, C7, C8, and C9 were significantly lower in women compared to men.…”

“…Gene analysis study has shown that genes such as Tnf, Hexa , and several mcpt genes that encode these intracellular granule mediators are upregulated in female mice. Mast cells from women store this increase in protein product by increasing the packing density of granules in mast cells ( 22 ). This set of studies was repeated in the presence of various levels of female sex hormones, as previous literature has shown that the menstrual cycle can affect properties of mast cells in rodent models.…”

“…The presence of mannose binding lectin similarly amplified the binding of complement C4 on SARS-CoV in vitro , supporting the activation of the lectin pathway in the SARS-CoV response. C4, which is located at the MHC, is of particular interest because of observed differences between sexes ( 22 ). C4 protein is more abundant in the cerebrospinal fluid and plasma of men compared to women, with a greater difference observed in men and women of childbearing age (20–50 years).…”

“…Human leukocyte antigen (HLA) is located in the MHC gene group along with C4 and has been linked to AD, including type 1 diabetes and rheumatoid arthritis ( 22 ). Human leukocyte antigen enables differentiation between host cells and pathogens through antigen presentation to the T-cell receptor (TCR).…”

CUB and Sushi Multiple Domains 1 (CSMD1) opposes the complement cascade in neural tissues

“…The complement cascade involves a set of secreted, fluid-phase innate immune molecules; these molecules are repurposed in the developing or diseased nervous system to label synapses for elimination (pruning) by microglia, the brain's resident immune cells (Hong et al, 2016;Lehrman et al, 2018;Schafer et al, 2012;Stephan et al, 2012;Stevens et al, 2007;Dejanovic et al, 2018;. Genetic evidence for the relevance of the complement cascade to schizophrenia comes from the finding that structural variation in the complement component 4 (C4) genes within the MHC locus underlies the region's strong genome-wide association signals with schizophrenia risk (Sekar et al, 2016;Kamitaki et al, 2020). The human genome contains two paralogous C4 genes, C4A and C4B.…”