Nature: Complement Genes Treat Male and Female Differently

Although the cause of many common diseases is unclear, big data have shown that there are different effects in men and women. For example, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren's syndrome affect women more than 9 times than men, while men suffer from schizophrenia more often and more severely than women.

• Three Complement Genes-related Diseases

SLE, Sjögren's syndrome, and schizophrenia are all associated with major histocompatibility complex (MHC) gene loci.

In order to explore the possible mechanism of gender differences in the incidence of these three diseases at the same gene locus, on May 11, 2020, the Steven A. McCarroll research group of the Harvard Medical School in the United States and the Timothy J. Vyse research group of King’s College London in the United Kingdom co-authored an article in Nature titled Complement Genes Contribute Sex-biased Vulnerability in Diverse Disorders, revealing that the C4 alleles C4A and C4B of the complement gene component are gender-sensitive to autoimmune diseases and schizophrenia.

• Relationship Between Complment Components and SLE

SLE is a systemic autoimmune disease of unknown cause. Although there are certain environmental triggers (such as infections and severe sunburn), the disease is largely inherited. SLE often shows insufficient complement protein, and severe, early-onset patients even show complete loss of complement components (C4, C2, C1Q).

These evidences led the researchers to focus on the mechanisms of gender differences in SLE, Sjögren's syndrome, and schizophrenia to the possibility of complement system gene copy number and allelic imbalance.

The researchers conducted the largest SLE genetic correlation study to date (6,748 patients with SLE vs 11,516 European ancestry control subjects) to evaluate the relationship between the copy number combinations of the C4A and C4B genes and risk levels of SLE.

The researchers found that there is a consistent correlation between the two factors. For each C4B copy number, a higher C4A gene copy number is associated with a reduced risk of SLE; conversely, for each C4A copy number, a higher C4B copy number is associated with a slight reduction in the risk of SLE. C4A has a strong protective effect on SLE, while C4B is weaker. The C4 gene is the main driving factor for this risk level variation.

• Different C4 RNA Expression Between Men and Women

Further, the researchers want to explore the reasons why the C4 allele and the three diseases affect men and women differently. The different effects of the C4 allele on men's risks relative to women may come from different C4 RNA expression, different C4 protein levels, or gender differences in downstream responses to C4, etc.

The researchers analyzed C4 RNA expression levels in different genders and different human tissues and found that there was no significant gender difference in C4 RNA expression in brain, blood, liver, and lymphoblastoid cells. However, the number of C4 protein corresponding to each C4 gene copy in adult male cerebrospinal fluid is 27% higher than that in female cerebrospinal fluid, and the level of C3 protein is about 42% higher in males than females.

The work of the McCarroll and the Vyse group uncovered the corresponding relationship between the complement protein allele copy number combination and the risk of different autoimmune diseases. For the gender difference in SLE, Sjögren's syndrome and schizophrenia, this researche gives a possible explanation, which provides an important reference for more reasonable and safer treatment in the future.