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Sex differences in autoimmune disorders and schizophrenia

Researchers may have uncovered one explanation for sex differences in certain diseases. BlackJack3D / E+ via Getty Images

Although both men and women can be affected by the same diseases, researchers have found that your sex can raise your risk of certain diseases and affect the severity of symptoms. For example, women are nine times more likely to have the autoimmune conditions systemic lupus erythematosus (SLE) and Sjögren’s syndrome.

Mental health issues like anxiety and depression also affect more women than men. However, men are affected by schizophrenia more often than women and tend to have more severe symptoms.

SLE, Sjögren’s syndrome, and schizophrenia have all been linked to a region of the genome called the major histocompatibility complex (MHC) locus. This region contains a set of genes needed for the immune system. Both SLE and Sjögren’s syndrome have been linked to specific variants (alleles) in the human leukocyte antigen (HLA) gene within the MHC locus. An increased risk for schizophrenia has also been linked to certain genes within the MHC locus, called the complement component 4 (C4) genes C4A and C4B. The complement system helps immune cells kill pathogens, clear out damaged or dead cell debris, and is involved in brain cell development.

A team led by Dr. Steven McCarroll at Harvard University and the Broad Institute of MIT and Dr. Timothy Vyse of King's College London investigated whether variants in the C4 genes might also affect risk for SLE and Sjögren’s syndrome, and whether they contribute to the sex differences of these three diseases. Because C4 genes exists both in different numbers and alleles, the team first devised a way to identify C4 alleles using whole-genome sequence data. They then applied their approach to analyze large genetic studies of people with SLE and Sjögren’s syndrome.

Their work was funded in part by NIH’s National Human Genome Research Institute (NHGRI) and National Institute of Mental Health (NIMH). Results were published on May 11, 2020, in Nature.

The researchers found that people with the most C4 genes were seven times less likely to have SLE and 16 times less likely to have Sjögren’s syndrome than those with the least number of C4 genes. C4A more strongly protected people from developing either illness than C4B. In contrast, those with the most C4 genes were 1.6 times more likely to develop schizophrenia. For all three illnesses, men were more impacted by the C4 alleles than women.

The team also measured the amount of complement protein in the cerebrospinal fluid of nearly 600 people and the blood plasma of about 1,800. Men aged 20 through 50 had more C4 proteins as well as C3 (the complement protein that C4 activates) than women of the same age. This suggests that differences in levels of complement proteins may explain why men’s risk is more strongly impacted by the C4 alleles.

“It's helpful to be able to think about sex-biased disease biology in terms of specific molecules, beyond vague references to ‘hormones,’” McCarroll says. “We now realize that the complement system shapes vulnerability for a wide variety of illnesses.”

However, the complement system is likely only one of many genetic and environmental factors that contribute to sex bias in disease.

—by Tianna Hicklin, Ph.D.