Research sheds light on sexual imbalance in schizophrenia, lupus

THere are the obvious sexual prejudices in many diseases. For example, lupus occurs 9 times more often in women than in men. Schizophrenia tends to be much more severe in men.

But what is behind the imbalance? Ah Natural new paper Some conditions can help to find out why some sex appear more common or intense. It also suggests that new therapies may be developed that take into account these gender-based molecular disparities.

Steven McCarroll, director of genomic neurobiology at MIT and Harvard University, said he led the study, saying, “Several illness gender differences and vulnerabilities are very impressive, and scientists I’ve been confused for decades. “” Sex has a lot of impact, but there’s not always a biologically relevant explanation for it. “

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The McCarroll team found that the same genes at risk of schizophrenia are highly protected from another autoimmune disease, such as lupus and Sjogren’s syndrome. The effect of this gene, called C4, was especially pronounced in men. This could help explain why men do not develop lupus and Sjogren’s syndrome much more often than women.

Broadly speaking, this suggests that genes (and the proteins they encode) may act differently depending on the person’s gender.

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Many genes act as double-edged swords. Consider the genes responsible for sickle cell anemia. People with a single disease allele actually have a better ability to fight off the parasitic disease malaria. However, people with two copies of the sickle cell allele develop life-threatening blood disorders.

Similar symptoms appear to occur in schizophrenia, lupus, and Sjogren. C4 seems to offer carriers both advantages and disadvantages.

“There are yin and yang effects here. The same allele that benefits one organ system can cause vulnerabilities in another organ system,” said McCarroll.

The C4 gene encodes complement component 4 protein, which helps immune cells identify cell debris and can be washed out of the body. It has previously been implicated in lupus, Sjogren’s, and schizophrenia. People can carry some copies of the C4 gene on their chromosomes. This allows you to produce more complement C4 protein.

The McCarroll team analyzed the genomes of 1,265 individuals and single nucleotide polymorphism data from 6,700 and 11,500 controls with lupus.

The study found that people with the highest copies of the C4 gene, and thus the highest complement C4 protein, were 7 times less likely to develop the most common form of lupus and 16 times more likely to develop Sjogren’s syndrome. I found it low. However, the person with the highest copy number of the C4 gene was also 1.6 times more likely to develop schizophrenia.

The reverse relationship between schizophrenia and autoimmune disease is the most interesting aspect of the paper, said Herbert Lachman, a schizophrenia genetics researcher at Albert Einstein School of Medicine in New York. ..

“This is consistent with the well-known finding that schizophrenia is less common in patients with rheumatoid arthritis,” Lachman said.

Schizophrenia, along with many other neuropsychiatric disorders, has long been suspected to have autoimmune roots. This paper helps consolidate that theory, said Belinda Lennox, a schizophrenia researcher at Oxford University who was not involved in the study.

When a cell is damaged, its interior leaks into the surrounding tissue. Immune cells, with the help of the complement C4 protein, record this debris and cause damage. Occasionally, immune cells attack the tissue by mistakenly recognizing this pathogen as an invading pathogen. It occurs in autoimmune diseases such as lupus and Sjogren’s syndrome.

In people with low levels of complement C4 protein, less cell debris is tagged, which results in longer survival and more disruption of immune cells.

The McCarroll study also measured complement protein levels in the cerebrospinal fluid and plasma of 1,844 individuals in 589 individuals. They found that women aged 20 to 50 had much less complement protein than men of the same age. This is because C4 gene expression appears to be decreasing at that age.

“It corresponds very well to the age of particular risk of these diseases,” Lennox said. In schizophrenia, men’s peak risk is in their early twenties, when complement proteins are highest.

On the other hand, lupus and Sjogren tend to appear in women between the ages of 20 and 50. Early-onset forms of these disorders are found in women who have no complement proteins at all.

Schizophrenia, along with autoimmune diseases such as lupus and Sjogren, is very complex and not only due to excess or deficiency of the C4 gene, the researchers say.

Hormones along with behavior may be part of the equation. However, there is no complete explanation of why the disease can appear so different between sexes, nor about the genes specific for the X or Y chromosome.

The study could help explain how genes behave differently in humans, and may provide insights into future treatments for these disorders, McCarroll said.

Patricio O’Donnell, Executive Medical Director of Takeda Pharmaceuticals, also provides appetizing clues that may prove fruitful in developing new treatments for schizophrenia and autoimmune diseases. The C4 complement system is an interesting molecular pathway that targets future drug development, he said. For example, identifying a patient’s genotype and determining the copy number of the C4 gene they carry is fairly straightforward. Then use that information to adjust the dosage given.

“This paper really opens the door to thinking about how gender affects the treatment of certain diseases,” O’Donnell said.