Recent study findings from TMA research fellow Dr. Simon Rothwell will soon be published in the medical journal Annals of Rheumatic Diseases. This work is related to myositis autoantibodies and unique genetic differences that we previously did not know about. This is a summary of the soon-to-be published results of this study.

What was already known?

The idiopathic inflammatory myopathies, known collectively as myositis, are a rare group of autoimmune diseases. In these autoimmune diseases, the immune system, which normally protects the body against infections, attacks its own muscle tissue leading to muscle wastage and weakness. Other complications may also occur, such as characteristic skin rashes, interstitial lung disease, and cancer.

Currently, we do not know the exact causes of myositis, however they are thought to be ‘complex diseases.’ This means that both genetic and environmental risk factors play a role in the disease. Previous studies have shown that a part of DNA known as the major histocompatibility complex (MHC) is involved. This is also the case in other autoimmune diseases such as rheumatoid arthritis or lupus. The MHC contains many genes that are important in the immune system, especially those that allow the body to recognize the difference between self (our own body), and non-self (such as bacteria and viruses).

What was discovered?

Many myositis patients have specific proteins called antibodies in their blood. As these antibodies target our own body, they are known as ‘autoantibodies’. Patients with the same autoantibody may have similar features of disease, follow a similar disease course, or respond to treatment in a similar way. In this study, we investigated whether genes that contribute to disease risk are different in patients with different autoantibodies.

We have previously collected genetic data from myositis patients in 14 countries across the world as part of the Myositis Genetics Consortium (MYOGEN). For this study we also collected information about which autoantibodies these patients had. We then grouped myositis patients together based on these autoantibodies, and compared their DNA to people without the disease to identify possible genetic differences.

We found that for some autoantibody groups, there were unique genetic differences that we previously did not know about. We knew that a region of DNA was involved with this disease, but our study identified specific genes within this region that we think are directly involved with disease. We are also beginning to understand what these changes in DNA actually do in our body, and why they are involved in disease.

One specific autoantibody is present in both adults and children with myositis. This is of particular importance, as there is a strong risk of cancer in adults with this autoantibody. However, there is no increased risk of cancer in children with this autoantibody. This study has shown for the first time that there are differences in the DNA between adults and juvenile patients. This may explain why the disease in adults and children with this autoantibody looks different.

Why is this important/what is the benefit to patients?

Myositis is a rare disease. Because it is rare, not much is known about genetic risk factors.  This is the largest genetic study to investigate differences between myositis patients with different autoantibodies. These study findings show that grouping patients by autoantibody is important for conducting meaningful genetics research.

The clinical features of this disease can vary greatly between patients. Understanding the genetics of myositis may help us to discover why certain patients have a specific form of disease. It may be that there are different environmental risks of which we are not yet aware, and this is an ongoing area of research.

Due to the continued efforts of the Myositis Genetics Consortium (Myogen) collaborators across the world collecting patients’ DNA samples for research, this is the largest study of its kind in myositis. This study paves the way for future studies that may lead to drug treatments or strategies for this debilitating and under-researched disease.

Rothwell, S, Chinoy, H, Lamb, JA, Miller, FW, Rider, LG, Wedderburn, LR, McHugh, NJ, Targoff, IN, Mammen, AL, Betteridge, Z E, Tansley, SL, Bowes, J, Vencovsky, J, Deakin, C T, Danko, K, Limaye, V, Selva-O’Callaghan, A, Pachman, LM, Reed, A M, Molberg, O, Benveniste, O, Mathiesen, P, Radstake, T, Doria, A, De Bleecker, J L, Lee, A, Hanna, MG, Machado, P M, Oliier, WE, Gregersen, PK, Padyukov, L, O’Hanlon, TP, Cooper, RG, Lundberg, IE, Myositis Genetics Consortium (MYOGEN). Focused HLA Analysis in Caucasians with Myositis Identifies Significant Associations with Autoantibody Subgroups. Annals of Rheumatic Diseases. In Press 2019.

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