Dr Mitchell's second grant was awarded for a continuation of her investigations into DNA 'identifiers associated with autoimmune Addison's disease, this time looking at "gene translation"'within the structure of the adrenal gland.
The outermost layer of the adrenal gland is known as the adrenal cortex. The main function of the adrenal cortex is to make steroid hormones, most importantly glucocorticoids (cortisol), mineralocorticoids (aldosterone) and adrenal androgens (DHEA). Rarely, the immune system attacks the adrenal cortex, which results in autoimmune Addison’s disease (AAD).
AAD has a strong genetic basis. It is seen in pairs of twins more often than would be expected by chance and can also run in families – although earlier research by my department at the University of Newcastle suggests that Addison’s appears among the children of those with the condition in less than 2% of cases.
Genetic studies over the past few decades have uncovered a number of genes which are associated with an increased risk of developing AAD, however very few of these are specific to AAD: most are common to many autoimmune conditions including autoimmune thyroid diseases, type 1 diabetes and rheumatoid arthritis, for example the MHC, CTLA4, PTPN22 and BACH2 genes. Due to the shared genetic background of these autoimmune diseases, it is quite common to see these conditions in some of the family members of an individual with AAD. A family history of coeliac, B12 deficiency, vitiligo, insulin-dependent diabetes, thyroid disease or rheumatoid arthritis can often be a clue towards autoimmune Addison’s.
We know very little about the genetic factors unique to the adrenal cortex that might be contributing to it being targeted by the immune system in people with AAD. In thinking about factors which might be unique to the adrenal cortex, you can look at genes which are translated into proteins which are only found (or 'expressed') in the adrenal cortex. Changes in these genes might be resulting in tiny changes to the structure of proteins expressed in the adrenal cortex, and it might be those tiny changes which are resulting in the immune system turning on the adrenal cortex and causing AAD.
This research project will use DNA samples donated by people with AAD in the UK to look at changes (known as single nucleotide polymorphisms or SNPs) in some genes which are expressed specifically in the adrenal cortex. We will compare these changes to those in a group of healthy controls to see the differences. Using Sequenom technology, we will be able to look at a number of SNPs in one experiment. We hope that the results will give us a better understanding of why people develop AAD rather than other autoimmune conditions.
I am very grateful to the ADSHG for the £5,000 research grant which will allow me to carry out this work and I look forward to sharing the results with you when they are available. Many of the DNA samples I will be analysing have been donated by members of the ADSHG in previous blood sample donations to our department. We are always interested to receive new blood from recently diagnosed group members, and you can find details of how to donate below.
Dr Anna Mitchell
Genetic research: give blood
Prof Simon Pearce remains interested to obtain blood samples from new group members with autoimmune Addison’s. These are analysed for DNA components to try and identify the genetic origins of autoimmune Addison’s, in a programme that Prof Pearce has been running since 2006.
You need to ask your GP if they are willing to take the blood sample and send it to Prof Pearce. If your GP agrees to do so, Prof Pearce will post you a short questionnaire and blood specimen bottle, with instructions.
Please contact Dr Anna Mitchell on: firstname.lastname@example.org.
You can read about Dr Mitchell’s previous research project, 'Uncovering the purpose of the pseudogene', in the In-kind assistance for medical research article within the research section of the website.
This article was first published in the June 2017 edition of the ADSHG newsletter.