Study Sheds Light on the Role of X Chromosome Inactivation in Lupus 

31st July 2024 – by Aaruthy Suthahar

Researchers at TwinsUK have conducted a study examining the role of the X chromosome in systemic lupus erythematosus (lupus), an autoimmune disease that predominantly affects females. The study, involving nearly 1,000 female participants, found significant differences in X Chromosome Inactivation (XCI) between lupus patients and healthy controls. 

Lupus is a condition where the immune system attacks the body’s tissues, leading to inflammation and damage. Despite extensive research, the reasons why 90% of lupus patients are female remain unclear. One theory suggests that the sex chromosomes, particularly the X chromosome, may play a role. 

In females, one of the two X chromosomes is randomly inactivated in each cell, a process known as XCI. This study measured changes in XCI in immune cells and discovered that only 7% of lupus patients showed changes in XCI, compared to 30% typically seen in healthy females. Moreover, among those with more severe lupus, only 3% exhibited changes in XCI. 

To further validate these findings, researchers studied twin pairs from TwinsUK where one twin had lupus, and the other did not. The results were consistent: twins with lupus had fewer changes in XCI than their healthy counterparts. 

Interestingly, these findings differ from previous research on other autoimmune diseases such as thyroid disease and rheumatoid arthritis, indicating distinct mechanisms underlying different autoimmune conditions. Instead of a broad pattern of XCI changes, the study found a correlation between XCI and the “interferon signature,” a marker of lupus disease activity. 

These insights suggest that the role of XCI in lupus is unique and may not follow the patterns observed in other autoimmune diseases. More research is needed to understand how these changes in XCI affect immune function and their implications for infection defence, especially as individuals age. 

First author Dr. Amy Roberts explained:   

“Thanks to the TwinsUK volunteers, we were able to demonstrate differences in X chromosome inactivation between healthy controls and people with lupus. Not only does this research help us understand lupus but also how our immune system changes with age – an area we are actively researching further.” 

This study represents a significant step forward in understanding the complex biology of lupus and underscores the importance of examining sex-specific factors in autoimmune diseases. 

Chromosome X marks the spot

25th November 2019 – by Paz Garcia

The X chromosome in women shows up differently in different parts of the body, according to new research published today in Nature Communications.

This means that women may not benefit from technologies that predict health risks based on genes on the X chromosome.

The team, led by researchers from the Department of Twin Research & Genetic Epidemiology, also found that age affects the patterns of X chromosomes, through a process known as “X inactivation”.

Further research is needed to understand the impact of different patterns of X inactivation on healthy ageing in women and how it can be taken into account when developing genetic tools that predict health risks.

What is X inactivation?

Chromosomes are lengths of DNA that contain genes on them.

Males have both an X and a Y chromosome, and females have two X chromosomes (XX). Humans only need one dose of the genes on the X chromosome however, so in females one of the X chromosomes in every cell is “switched off” so they don’t get double the dose. This process is known as X inactivation.

Which of the two X chromosomes is switched off is random, leading to roughly equal levels of each in the body.

Evidence suggests however that in some body parts in women, one X chromosome is much more likely to be inactivated than the other, leading to skewed patterns of X inactivation across different body parts.

What did they do?

The team, led by Dr Kerrin Small and Antonino Zito, studied whether the skew of X chromosome inactivation is linked to genetics, age, smoking and autoimmune diseases.

The researchers studied blood, fat and skin samples from almost 800 twins, including 8 pairs where one twin had rheumatoid arthritis – an autoimmune condition – and the other twin did not.

What did they find?

Blood, fat and skin have different X chromosome inactivation patterns. These patterns become more skewed with age and smoking. In addition, genetics affect the skewed patterns in the blood, but not in fat or skin.

The team also found that twins who have autoimmune conditions have more skewed patterns of X chromosome inactivation in the blood than their co-twins without the condition.

What does this mean?

Researchers will need to take into account the differences in X inactivation throughout the body in females.

First author Antonino Zito explained:

“It’s important to note that X inactivation patterns in the blood are not a reliable indicator of X inactivation in other parts of the body. We need to take this into account when designing genetic tools to predict health risks, which often rely on specialised blood tests. Otherwise, it may be that future genetic health tests are less reliable for older women, as the dose of X chromosome genes in the blood sample is different to that found elsewhere in the body.”

Senior author Dr Kerrin Small added:

“Our results indicate an association between X inactivation patterns and genetics, age, smoking and autoimmune conditions. We will need to carry out further research to understand the relationship between these features, and the implications of skewed X inactivation for healthy ageing in women.”

Zito A, Davies MN, Tsai PC, Roberts S, Andres-Ejarque R, Nardone S, Bell JT, Wong CCY and Small KS. Heritability of skewed X-inactivation in female twins is tissue-specific and dependent on age. Nature Communications (2019)

Recent Blog Post

TwinsUK Launches New Fat Biopsy Study with First Twin Pair 

25th November 2019 - by Paz Garcia The X chromosome in women shows up differently in different parts of the...

Low levels of mercury exposure impact molecular processes  

25th November 2019 - by Paz Garcia The X chromosome in women shows up differently in different parts of the...

TwinsUK Study Shortlisted for Versus Arthritis Research Highlight of the Year 

25th November 2019 - by Paz Garcia The X chromosome in women shows up differently in different parts of the...