Could fat tissue hold the key to why some people experience more severe COVID-19?

17th August 2020

Lower levels of a key molecule in fat tissue are linked with health conditions that are risk factors for severe COVID-19, according to new research from TwinsUK.

ACE2 is a molecule our body’s cells use to regulate processes in our blood vessels, such as blood pressure, wound healing and inflammation. It also plays a key role in managing our heart and kidney functions to keep us healthy.

We know from recent research however that the coronavirus that causes COVID-19 also uses ACE2 molecules in the body as a gateway to infect our cells.

Faced with these two counteracting roles for ACE2, the TwinsUK team wanted to understand the link between ACE2 and the severity of COVID-19 experienced by individuals,  particularly as conditions such as obesity and type 2 diabetes, as well as heart and kidney conditions, put people at greater risk of severe COVID-19.

The body makes ACE2 molecules using instructions provided by the ACE2 gene. The researchers analysed ACE2 gene expression levels in fat tissue from over 760 TwinsUK participants and a further approximately 700 participants from the METSIM and FUSION studies. The team studied how ACE2 gene expression levels in fat tissue were linked with participants’ known pre-existing conditions, and measures of health such as cholesterol levels.

Lead authors Dr Julia El-Sayed Moustafa and Dr Kerrin Small explained:

“Doctors and researchers quickly realised that reactions to SARS-CoV-2 (coronavirus) infection vary widely between people, and that obesity and type 2 diabetes, as well as other factors, increase the risk of suffering from severe COVID-19. Through this research, we show that people living with these conditions often have lower gene expression levels of ACE2 in their fat tissue compared to the general population.”

Drs El-Sayed Moustafa and Small continued:

“Fat tissue is important not only for energy storage, but also for signalling in the body. Further studies will be needed to establish whether lower starting levels of ACE2 gene expression in this important tissue then contribute to COVID-19 severity.”

El-Sayed Moustafa et al. ACE2 expression in adipose tissue is associated with COVID-19 cardio-metabolic risk factors and cell type composition. medRxiv, 2020.

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)

Do different types of cells in fat matter in health research?

28th May 2019 – by Paz Garcia

Cartoon of doctor measuring person's waist

The variability of cell types found in fat are partly under genetic control and need to be taken into account in health research, according to new TwinsUK research.

Fat is made up of a variety of different types of cells, including ones that store fat and others that form the immune system.

Researchers from the Department of Twin Research and Genetic Epidemiology investigated the mixture of cells that make up fat in samples from over 1,000 donors.

The work was published in the American Journal of Human Genetics.

Why did they do this research?

While we may not usually think of it in such terms, fat is actually the largest organ in the body that releases hormones.

We know that fat plays a role in the development of various health conditions such as heart disease and type 2 diabetes. Many researchers have therefore focused on studying fat.

Researchers however have largely not considered the proportions of the different types of cells in fat in their analyses.

The TwinsUK team therefore decided to investigate the different types of cells present in fat.

What did they do?

The researchers analysed fat samples collected from 766 twins from TwinsUK and 326 donors from another study.

The team used computational methods to estimate the relative proportions of four different types of cells in each fat sample.

They also looked at whether the proportions of cells were genetically inherited and linked with traits of obesity.

What did they find?

There is a lot of variation between people in the proportions of different cells they have in their fat.

The team found that proportions of cell types in fat is genetically inherited and is linked to body fat distribution.

What does this mean?

Researchers studying the links between fat and health conditions will need to take into account the variety of different cells present in fat. Dr Craig Glastonbury, first author on the study, explained:

“Our results indicate that it is critical to account for cell-type composition on a range of standard analyses.”

In addition, the findings could help us understand why some people are at greater risk of certain conditions. Dr Kerrin Small, who worked on the study, explained:

“The results suggest that some people are genetically predisposed to have more cells that store fat, which could lead to greater fat accumulation and greater risk of conditions like heart disease and type 2 diabetes.”

What’s next?

In their paper, the researchers say that more research will be needed to understand the relationship between genetics, cells in fat and the impact on health and disease.

Why do more women develop lupus than men?

15th May 2019 – by Paz Garcia

Photograph of Selena Gomez
Singer and actor Selena Gomez has spoken publicly about living with lupus

King’s College London researchers have identified a new gene which may explain why so many more women develop lupus than men.

Systemic lupus erythematosus – known as SLE or lupus – is an autoimmune condition where the immune system mistakenly attacks the joints, skin and other organs, leading to inflammation.

It’s thought to affect about 65,000 people in the UK. 9 out of every 10 people with the condition are female.

The team included Dr Amy Roberts and Dr Kerrin Small from the Department of Twin Research and Genetic Epidemiology.

The paper was published today in Nature Communications.

Why did they do this research?

Previous research suggests that the X chromosome plays a role in lupus.

Chromosomes are lengths of DNA that contain certain 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.

Evidence suggests however that some genes on the switched off X chromosome escape this inactivation.

The team therefore decided to investigate suspect genes on X chromosomes, to see if there were any links with lupus.

What did they find?

The team analysed genetic information and cells collected as part of a number of existing research programmes, including from TwinsUK.

The researchers identified a gene on the X chromosome called CXorf21 as the likely culprit.

They found that the gene was closely linked to another gene known to play a role in lupus which also escapes inactivation in switched off X chromosomes.

The team also found that activity in this gene could be increased in a number of different ways. These included when the gene was not inactivated in switched off X chromosomes and when exposed to immune system molecule interferon – both classic hallmarks of lupus.

What does this mean?

We now have a better understanding of the genetics behind lupus, and why it affects so many more women than men. This could help us develop new screening strategies to pick up new diagnoses sooner, and ultimately help us develop treatments for the condition.

Dr Amy Roberts, who co-led the research, explained:

“It is not understood why females are more at risk than males for developing lupus, or indeed most other autoimmune diseases. Historically this has been attributed to hormonal differences.

However, genes encoded on the X chromosome are good candidates because these are the only chromosomes that are different between the sexes. We examined once such gene, CXorf21, which creates a protein of unknown function. We found that females have more of the CXorf21 protein than males.

Our study supports the idea that males and females have different risks for autoimmune conditions due to genetics. More work is now needed to fully understand the function of this protein, which ultimately could lead to both a better understanding of the disease and potential for improved treatments.”

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