How genetic risk factors affect the function of immune cells in MS

Jordon, Margaret cropped.jpg
Investigator

Supervisor

Funding

  • MS Research Australia-NHMRC Betty Cuthbert Fellowship - $304,596 for 2013 - 2016

Summary

After a worldwide effort, a large number of genetic risk factors have been identified for MS. This project will attempt to identify how some of these genes may contribute to the risk of developing disease. This project will examine three candidate genes in greater detail, known as RGS1, HHEX and THEMIS. The first phase will take specific types of immune cell, known as natural killer cells and monocytes, from people with MS and people without disease.

The natural killer cells and monocytes will be grown in the laboratory and used to make comparisons between diseased and healthy cells. Dr Jordan will also compare different versions of each gene and different levels of gene activity in the cells to determine what kind of effect this has on function. The second phase will use animal models with specific versions of each gene to test how this affects susceptibility to an MS-like illness in the mice.

Progress to Date

Three genes forming the focus of this project were initially identified from a sample of 39 healthy controls and 30 untreated patients with relapsing remitting MS. Since this initial analysis, the data sample size has been increased to 110 healthy controls and 80 untreated people with MS, forming one of the largest genetic datasets derived from the immune system of people with MS. Analysis of this data set, revealed an additional gene of interest - AHI1.

Using a powerful technique called microarray analysis, Dr Jordan looked for changes in the activity of these four genes in different parts of the immune system in affected and unaffected individuals. These analyses have shown that the activity of these genes is different in people with MS and that different types of immune cells show different levels of activities. Illustrating the multifarious and complex nature of MS genetics.

Utilizing animals which have genetic changes that mean they lack the activity of each of these four genes has revealed that these four genes have a range of effects in immune cells. Animals without a functional Themis gene displayed a milder form of the MS-like disease, and animals with an Rgs1 deficiency displayed a modified immune system but no observable difference in disease outcome. The two remaining genes made no observable difference to the immune system or the disease. Further analyses are currently underway to more thoroughly analyse these genes, and understand how the expression of these genes may affect the function of different types of immune cells and how they modify the severity of the disease.

In summary, this project has used modern genomic techniques to identify how MS genes affect the white blood cells so that we can develop better predictive and diagnostic tools that may lead to new therapies for MS.

Publications

  • Jordan MA, Field J, Foo G, Johnson L, Laverick L, Gresle M, Spelman T, Stankovich J, Butzkueven H and Baxter AG. Causes of Multiple Sclerosis: a functional genomics approach. Front. Immunol. (2013) Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00482
  • Jordan MA, Field J, Butzkueven H, Baxter AG. Genetic Predisposition-Humans, in Mackay IR, Rose N (ed), The Autoimmune Diseases, 5th Edition, Elsevier. Boston, (2014) pp 341-364 (Chapter 26) ISBN: 978-0-12-384929-8.
  • Gresle M, Jordan MA, Spelman T, Stankovich J, Johnson L, Laverick L, Hamlett A, Baxter A, Butzkueven H, Field J. Multiple Sclerosis risk SNPs modify gene expression in immune cells. MS Journal 2015. OP 2.2 (Progress in MS research conference, 2015 oral presentation).
  • Field J, Merlo D, Johnson LJ, Giuffrida L, Perera AD, Calvert S, Akkermann R, Ma G, ANZgene Consortium, Gresle M, Laverick L, Foo G, Spelman T, Jordan MA, Baxter A, Butzkueven H, Kilpatrick TJ, Binder MD. Low and moderate frequency variants in MERTK are independently associated with Multiple Sclerosis susceptibility with discordant association dependent upon HLA-DRB1*1501 status. MS Journal 2015. PP1.37 (Progress in MS research conference, 2015 poster presentation).
  • Binder MD, Fox AD, Merlo D, Johnson LJ, Giuffrida L, Calvert S, Akkermann R, Ma GZM, ANZgene, Perera AW, Gresle M, Laverick L, Foo G, Spelman T, Jordan MA, Baxter AG, Foote S, Butzkueven H, Kilpatrick TJ, Field J. Common and low frequency variants in MERTK are independently associated with Multiple Sclerosis susceptibility with discordant association dependent upon HLA-DRB1*1501 status. PLOS Genetics (Accepted 19.1.2016).

Updated 08/06/2016