Complement genes contribute sex-biased vulnerability in diverse disorders

Area of Science:

• Genetics
• Immunology
• Neuroscience

Background:

• Sex-based differences in disease prevalence, such as higher rates of SLE and Sjögren's in women and schizophrenia in men, are well-documented but poorly understood.
• The Major Histocompatibility Complex (MHC) locus is genetically associated with these conditions, with a historical focus on Human Leukocyte Antigen (HLA) genes.

Purpose of the Study:

• To investigate the role of complement component 4 (C4) gene variations within the MHC locus in explaining sex-specific disease risks.
• To determine if C4 gene alleles contribute to the differential vulnerability observed in systemic lupus erythematosus (SLE), Sjögren's syndrome, and schizophrenia.

Main Methods:

• Analysis of C4 gene (C4A and C4B) variations and their association with disease risk in large cohorts.
• Quantification of C4 and C3 protein levels in cerebrospinal fluid and plasma to assess sex-based differences.
• Examination of the interaction between C4 genotypes, sex, and disease risk for SLE, Sjögren's syndrome, and schizophrenia.

Main Results:

• C4 gene variations significantly alter the risk for SLE (7-fold) and Sjögren's syndrome (16-fold), with C4A offering stronger protection than C4B.
• Alleles increasing schizophrenia risk were found to decrease SLE and Sjögren's syndrome risk.
• C4 gene alleles exhibited stronger effects in men than women across all three diseases, with sex-specific variations in risk ranging from 1.7-fold for schizophrenia to 31-fold for Sjögren's syndrome.
• Higher levels of C4 and C3 proteins were observed in men compared to women in plasma and cerebrospinal fluid.

Conclusions:

• Complement component 4 (C4) gene variations are a significant factor in the sex-based dimorphism of vulnerability to SLE, Sjögren's syndrome, and schizophrenia.
• Sex differences in complement system protein levels may underlie the potent effects of C4 alleles in men and contribute to observed disease prevalence disparities.
• The complement system is implicated as a key contributor to sexual dimorphism in susceptibility to various common illnesses.