The same gene variant is beneficial in men but detrimental in women

A gene variant has been shown to have different effects on patients based on their genetic sex.

Scientists at the Cincinnati Children's Hospital Medical Centre, Ohio, report that the glucocorticoid receptor gene variant – known as rs6190 – seems to help build muscle mass and reduce diabetes risk in men, as detailed in the study they published in Science Advances. Contrastingly in women, the same variant appears to increase cholesterol levels and elevate the risk of heart disease, as shown by the study – led by the same researchers – currently 'in press' and due to be formally published in the Journal of Clinical Investigation.

'These results indicate that biological sex is likely an important factor to consider when treating muscle mass loss and maintaining cholesterol levels in check,' said Dr Mattia Quattrocelli, an associate professor at Cincinnati Children's and senior author of both publications. 'The combination of the sex effect with the rs6190 variant effect suggests more aggressive monitoring or treatment for women with that variant when addressing other hormonal and clinical changes.'

Glucocorticoids are hormones that play a pivotal role in the regulation of blood sugar, fat and proteins during muscle development. For glucocorticoids to fulfil their function, muscle cells – the main cells to dispose of excess blood sugar – must carry glucocorticoid receptors. To study how rs6190 changes these receptors' function, the researchers developed a mouse model using CRISPR genome editing to mimic the effects of rs6190.

The researchers found that male rs6190 mice were leaner and had less body fat that than normal mice, when fed high-fat and high-calorie diets. They also observed that rs6190 mice were able to absorb and use more glucose during exercise, allowing them to run longer and exert more force. In muscle, these changes were associated with increased activation of the genes Foxc1 and Arid5A, which appear to help canonical insulin action in muscle cells, and reduce lipids, respectively.

Additionally, the team found that in the liver, rs6190 causes the genes Pcsk9 and Bhlhe40 to become less active. This lead in female mice to cholesterol elevation, including both low-density lipoprotein and high-density lipoprotein.

'In both studies, studying the variant helped point us to the key genes involved. Importantly, this means the findings are more likely to apply to larger populations than only those who have the rs6190 variant,' said Dr Quattrocelli.

These findings were further validated with human medical data from the UK Biobank and All Of Us. In both datasets, it was observed that women carrying the rs6190 variant were more likely to have high cholesterol and plaque build-up in their arteries, whereas this effect was absent in men. Moreover, carriers of rs6290 were more likely to have lower BMI, leaner mass and higher hand grip strength, although with smaller magnitude in women.

The research team hypothesise that hormonal differences between men and women could explain why a shared gene variant can have such different effects on cholesterol and plaque build-up.

'This suggests that if we can develop safe ways to regulate these genes in human muscle, we could be able to more effectively re-balance disrupted, unhealthy metabolisms, whether or not the people share the rs6190 variant,' said Dr Quattrocelli.