Researchers Shed Light on Genetics Behind Sex-based Vulnerability to Sjögren’s, Other Diseases

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Genetic variations in the complement system — a part of the immune response — contribute to differences between men and women in their susceptibility to Sjögren’s syndrome, lupus, and schizophrenia, according to a study.

In particular, the study showed that higher levels of complement component 4 (C4) in men protect them against Sjögren’s and lupus, but increase their risk of developing schizophrenia.

“It’s helpful to be able to think about sex-biased disease biology in terms of specific molecules, beyond vague references to ‘hormones,’” Steven McCarroll, PhD, the study’s co-senior author at Harvard Medical School and the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, said in a Harvard news story.

“We now realize that the complement system shapes vulnerability for a wide variety of illnesses,” McCarroll added.

The study, “Complement genes contribute sex-biased vulnerability in diverse disorders,” was published in the journal Nature.

Many common illnesses affect men and women differently, but the underlying reasons for these discrepancies remain largely unknown.

For example, Sjögren’s syndrome and lupus, both autoimmune diseases, affect nine times more women than men, while schizophrenia affects more men and with greater severity.

Variations in a particular DNA part known as the major histocompatibility complex (MHC) locus were shown to contribute to the risk of developing any of the three diseases.

However, until now, the identity of the MHC’s genes driving this effect was known only for schizophrenia — the C4 genes — while for the two autoimmune diseases, suspicions fell on the human leukocyte antigen (HLA) genes. HLA variations were previously associated with a risk of other autoimmune diseases.

The C4 genes, C4A and C4B, contain the instructions to produce two forms of the C4 protein, which work to facilitate the clearance of debris from dead and injured cells. A person can have up to eight copies of C4 genes.

This most recent work led by researchers at the Blavatnik Institute at Harvard Medical School and the Broad Institute showed that variations in the C4 genes also contribute to the risk of Sjögren’s and lupus, but in an opposite way.

The study involved the genetic analysis of more than 600 Sjögren’s patients, 8,000 lupus patients, 28,000 people with schizophrenia, and healthy individuals of European and African American ancestry.

Results showed that people with the highest number of copies of C4A and C4B were 16 times less likely to develop Sjögren’s and had a sevenfold lower risk for lupus than those with fewer C4 copies. Notably, the protective effect of the C4A copy number was superior to that of C4B.

In contrast, the highest number of copies of C4A, but not C4B, was associated with a 1.6 times higher risk of developing schizophrenia, which is consistent with previous reports.

These findings highlighted that “C4 gene variants come with this yin and yang of heightened and reduced vulnerability in different organ systems,” said McCarroll, noting that including people with different ancestries was key to the study’s success.

“It will really help for genetics to expand more strongly beyond European ancestries and learn from genetic variation and ancestries all over the world,” McCarroll said.

Analysis of complement protein levels in the cerebrospinal fluid (CSF) of 589 people and blood of 1,844 people showed that the effects of C4 copy numbers were stronger in men than in women. The CSF is the liquid that bathes the brain and spinal cord.

In people with similar C4 copy numbers, men had a mean of 27% more C4 protein in the CSF than women, indicating that C4 genes produce more protein in men, further skewing disease susceptibility and protection. CSF levels of C3, a complement protein activated by C4, were also an average of 42% higher among men than women.

Moreover, women had significantly lower blood levels of C4 and C3 proteins than men during their reproductive years of adulthood (ages 20–50) — the range at which Sjögren’s, lupus, and schizophrenia vulnerabilities vary by sex.

Interestingly, Sjögren’s patients showed significantly lower C4 blood levels than unaffected individuals with the same C4 gene copy number, suggesting that mechanisms other than C4 genetics contribute to this complement deficit.

The team hypothesized that higher C4 levels have a protective effect against autoimmunity likely due to a faster clearance of cellular debris, lowering the chances that specific immune cells wrongly recognize them as foreign molecules and promote an immune response against them.

Nolan Kamitaki, the study’s first author, emphasized, however, that “the complement system contributes to the sex bias, but it’s only one of probably many genetic and environmental contributors.”

McCarroll also noted that the data highlighted the need to make sure that complement-suppressing therapies “do not unintentionally increase risk for autoimmune disease” and to consider that these therapies “may be differentially helpful in male and female patients.”

Interestingly, early data suggest the existence of sex-based vulnerabilities to COVID-19 infection, as men appear to die more often from the disease than women, similar to that reported for previous coronavirus outbreaks. However, whether the C4 protein is involved in this potential susceptibility difference remains unknown.

“Complement molecules are potentially important in any immune or inflammatory condition, and in COVID-19, it seems the immune response can be part of a downward spiral in some patients. But we don’t know the key details yet,” McCarroll said.