C4 Genes as a Double-Edged Sword: Sex-Based Differences in Lupus, Schizophrenia, and Sjögren’s Syndrome


Women can do anything that men can do, and vice versa. Well, while that sentiment may be true in our everyday life, it isn’t quite true on a genetic level. Stat News explains how new research explored why certain conditions, like Sjögren’s syndrome, impact one biological sex more than the other. We’ll explain below. But if you want the full research findings, you can read them in the scientific journal Nature.

Lupus, Schizophrenia, and Sjögren’s syndrome


Schizophrenia is a mental illness which impacts behavior, emotions, and thoughts. Symptom onset usually begins in someone’s late teens through their early 30s. It tends to be much more severe in males, and also often emerges earlier.  Risk factors of developing schizophrenia include genetics, environment, and brain structure.

Symptoms include:

  • Changes in hearing, smell, touch, taste, and vision
  • A disconnect from reality
  • Auditory and visual hallucinations
  • Paranoia or delusions
  • A flat affect
  • Depression, loss of pleasure, or reduced motivation
  • Difficulty concentrating, focusing, or paying attention
  • Memory loss
  • Difficulty processing

Learn more about schizophrenia from the NIH.


Lupus is an autoimmune disorder in which the body mistakenly attacks bodily tissues and organs, including the lungs, heart, brain, kidneys, joints, skin, and even blood cells. Females are 9x more likely to develop lupus than males. Other risk factors include being African-American, Asian-American, or Hispanic; being between the ages of 15 and 45; and medications. Symptoms of lupus include a butterfly-shaped rash on the face, joint pain, fever, fatigue, Raynaud’s phenomenon, chest pain, memory loss, and worsening skin lesions. Learn more about lupus here.

Sjögren’s syndrome

Sjögren’s syndrome is named after a Swedish ophthalmologist who saw a connection between dry eyes and chronic arthritis. This autoimmune disorder affects 10x more women than men, and symptoms usually occur between the ages of 45 and 55. The body’s immune system mistakenly attacks any glands that produce moisture, like your salivary glands or lacrimal glands (these produce tears).

Sjögren’s syndrome can be primary (in people with no other rheumatic diseases) or secondary (in those with another rheumatic disease like lupus or rheumatoid arthritis). Symptoms include acid reflux, fatigue, stiff and painful joints, changes in taste and smell, gingivitis, irritated or painful eyes, eye infections, swollen glands, and dry nasal passages, mouth, lips, throat, vagina, and skin. Learn more about Sjögren’s syndrome here.

The Research

For years, researchers questioned why certain diseases or disorders affected one biological sex more than the other. It turns out that the answer might be genes. But interestingly, some genes are “double-edged swords.” Basically, they may protect against certain conditions while raising the risk of developing others.

For example, someone with one mutated allele for sickle cell anemia is better able to fight off malaria. But having two copies of the allele causes someone to have a serious blood disorder that results in misshapen red blood cells.

Steven McCarroll, Director of Genomic Neurobiology at the Broad Institute, wanted to examine the genetic connection between lupus, schizophrenia, and Sjögren’s syndrome. The C4 gene seems to change the way in which males and females develop these conditions. Normally, the C4 gene creates the complement component 4 protein which helps to flush cellular debris (the inside of broken or damaged cells) from the body. However, people with less C4 see their immune system attack that debris, thinking it’s a foreign invader.

Understanding C4

McCarroll and his research team started their research by analyzing:

  • Single nucleotide polymorphism data from 6,700 patients with lupus
  • Genomes of 1,265 people
  • Blood plasma from 1,844 people
  • C4 levels in 589 patients’ cerebrospinal fluid
  • 11,500 controls.

People who had more of the C4 gene were 7x less likely to develop lupus and 16x less likely to develop Sjögren’s syndrome. But remember that double-edged sword? Well, increased C4 copies also increased the risk of schizophrenia by 1.6x.

But this gives insight into some biological differences! Women between the ages of 20 and 50 had less C4 protein than men; they are also more likely to develop lupus or Sjögren’s syndrome, especially as the protein levels fall. However, men have the highest C4 levels in their 20s. That’s normally when schizophrenia begins presenting.

However, the researchers clarify that the C4 gene is not the only reason for biological differences or differences in disease presentation. Hormones, behavior, and environment may also play a role. But recognizing that C4 plays some part could help researchers and doctors develop better, more targeted treatments.

Jessica Lynn

Jessica Lynn

Jessica Lynn has an educational background in writing and marketing. She firmly believes in the power of writing in amplifying voices, and looks forward to doing so for the rare disease community.

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