A new study published in the journal Nature has homed in on the sex-specific activity of a certain gene that both increases the risk of developing schizophrenia and decreases the risk of developing lupus. The research suggests a person’s sex can directly amplify the effects of a genetic variation, offering novel insights into how some diseases appear in different rates in men and women.
“We all know about illnesses that either women or men get a lot more, but we’ve had no idea why,” says Steven McCarroll, co-senior author on the new study. “This work is exciting because it gives us one of our first handles on the biology.”
The new research focuses on a gene called C4. This gene expresses a protein known as complement component 4, which the body uses to tag unnecessary cellular debris for removal by immune cells.
Variants in the C4 gene have previously been found to be major risk factors for schizophrenia, however, C4 also can be protective against other diseases such as lupus or Sjögren’s syndrome.
“C4 gene variants come with this yin and yang of heightened and reduced vulnerability in different organ systems,” says McCarroll.
The new research affirmed this yin-yang C4 observation, finding those people with more copies of the C4 gene were 16 times less likely to develop Sjögren’s syndrome and seven times less likely to develop lupus, compared to those with the fewest C4 genes. On the other hand, those with the most C4 genes were also found to be 1.6 times more likely to develop schizophrenia.
This observation is a compelling enough finding, shedding intriguing light on the autoimmune origins of both lupus and schizophrenia. But the next stage of the research homed in on sex-specific differences in C4 activity.
The research discovered men and women can express different volumes of C4 proteins, despite showing essentially similar genetic profiles. What this means is that men seemed to generally present with higher volumes of C4 protein expression, compared to women.
Tracking this data onto the sex-specific differences in disease rates suggested this difference in C4 activity may help explain why men are much more likely to develop schizophrenia, while women are much more likely to develop lupus or Sjögren’s syndrome.
“Large genetic effects tend to come from rare variants, while common gene variants generally have small effects,” says McCarroll. “The C4 gene variants are common, yet they are very impactful in lupus and Sjögren’s.”
There are plenty of unanswered questions raised by the study. For example, it is unclear at this stage exactly how men and women with similar genetic profiles express different volumes of this protein – is there a biological difference between men and women that causes similar genes to express proteins in varying volumes? It is also unclear how this sex-specific difference manifests in subjects with intersex traits.
In the short term McCarroll suggests there are several immediate takeaways from this study, from generally adding weight to the hypothesis arguing sex must be taken more seriously when conducting new clinical drug trials, to illustrating the need for a clearer understanding of the complexity in therapeutically manipulating specific genes.
“For example, researchers will need to make sure that drugs that tone down the complement [C4] system do not unintentionally increase risk for autoimmune disease,” says McCarroll. “Scientists will also need to consider the possibility that such drugs may be differentially helpful in male and female patients.”
The new study was published in the journal Nature.
Source: Harvard University
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