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Complement genes contribute sex-biased vulnerability in diverse disorders
Nolan Kamitaki1,2, Aswin Sekar3,4, Robert E Handsaker3,4
1Department of Genetics, Harvard Medical School, Boston, MA, USA. nolan_kamitaki@hms.harvard.edu.
Insights
Genetic variations in complement component 4 (C4) genes influence risk for autoimmune diseases like lupus and Sjögren's syndrome, and schizophrenia, with differential effects observed between sexes.
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.
Abstract:
Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren's syndrome affect nine times more women than men1, whereas schizophrenia affects men with greater frequency and severity relative to women2. All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjögren's syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus3-6. Here we show that variation of the complement component 4 (C4) genes C4A and C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia7, generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjögren's syndrome 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 reduce risk for SLE and Sjögren's syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjögren's syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma8,9 in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women's greater risk of SLE and Sjögren's syndrome and men's greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.
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