Glucocorticoid Metabolism in Down Syndrome
Research type
Research Study
Full title
Glucocorticoid Metabolism in Down Syndrome
IRAS ID
227805
Contact name
AG Mckechanie
Contact email
Duration of Study in the UK
2 years, 0 months, 0 days
Research summary
Down Syndrome (DS) is the most common cause of intellectual disability in the UK. Individuals with DS have a third copy of chromosome 21. Amongst other health problems, individuals with DS have higher rates of obesity and dementia compared to those without DS. Obesity itself is known to be directly associated with hypertension and type 2 diabetes and can significantly impact quality of life. Whilst some factors explaining the relationship between DS and obesity are known, it is not clear if underlying abnormalities in metabolism can help explain this relationship further.
Glucocorticoids, such as cortisol, are hormones which regulate stress, inflammation, infection and blood pressure. High glucocorticoid levels or alteration in glucocorticoid metabolism are associated with conditions such as obesity and high blood pressure. We have discovered a new pathway for the breakdown of glucocorticoids driven by the enzyme Carbonyl Reductase 1 (CBR1). CBR1 produces a glucocorticoid metabolite called 20β-dihydrocortisol (20β-DHF) which we have shown activates glucocorticoid receptors. We have found that CBR1 activity and production of 20β-DHF is increased in obesity in the general population. The CBR1 gene is located on chromosome 21 and its activity may be significantly increased in individuals with DS. The impact of this amplification on glucocorticoid metabolism in individuals with DS is unclear. There is currently no published data on glucocorticoid metabolism in DS.
Down Syndrome (DS) is the most common cause of intellectual disability in the UK. Individuals with DS have a third copy of chromosome 21. Amongst other health problems, individuals with DS have higher rates of obesity and dementia compared to those without DS.
Obesity is known to be directly associated with high blood pressure and type 2 diabetes and can significantly impact quality of life. The impact of obesity on this population is supported by work carried out by Down’s Syndrome Scotland whose members identified obesity as a major area of concern for them (Down’s Syndrome Scotland, 2017).
Despite its frequency there is a paucity of literature investigating the inciting causes of obesity and its co-morbidities in individuals with DS.
Glucocorticoids, such as cortisol, are hormones which regulate stress, inflammation and blood pressure. Changes in glucocorticoid metabolism are associated with, obesity, hypertension and impaired cognitive function in the general population. We have discovered a new pathway for the glucocorticoid metabolism driven by the enzyme Carbonyl Reductase 1 (CBR1) producing 20β-dihydrocortisol (20β-DHF). We have found that CBR1 activity and 20β-DHF levels are increased in obesity in the general population. The CBR1 gene is located on chromosome 21 and its activity is significantly increased in individuals with DS. The impact of the amplification of CBR1 on glucocorticoid metabolism in individuals with DS is unclear. In this study we aim to address the gap in our knowledge of glucocorticoid metabolism in individuals with DS. We hypothesise that individuals with DS have elevated levels of 20β-DHF which may contribute to obesity and its associated morbidities in these individuals. We will recruit individuals with and without DS to compare the glucocorticoid profile in urine and (where possible) blood by liquid chromatography-mass spectrometry and associations with obesity and cognition.REC name
Scotland A: Adults with Incapacity only
REC reference
18/SS/0034
Date of REC Opinion
1 Aug 2018
REC opinion
Further Information Favourable Opinion