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Environmental Factor, September 2015

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Genes strongly associated with myositis risk identified

By Tara Ann Cartwright and Kelly Lenox

Headshot of Fred Miller

Miller is deputy chief of the NIEHS Clinical Research Branch and head of the Environmental Autoimmunity Group. He is based at the National Institutes of Health Clinical Center in Bethesda. (Photo courtesy of Steve McCaw)

Headshot of Lisa Rider

Rider is deputy chief of Miller’s group. (Photo courtesy of Steve McCaw)

NIEHS scientists are among the authors of a paper that identified the primary genetic risk factors associated with myositis and its main forms in the Caucasian population in Europe and the U.S. The paper, published Aug. 20 in the journal Genes and Immunity, is the largest study conducted to date on this rare disease spectrum (see sidebar).

Fostering collaboration

NIEHS clinical researchers Frederick Miller, M.D., Ph.D., and Lisa Rider, M.D., and biologist Terrence O’Hanlon, Ph.D., are part of an international collaboration called the Myositis Genetics Consortium (MYOGEN), a group Miller established six years ago. The goal of the research group is to identify genetic factors associated with myositis.

Two years ago, MYOGEN published its first genome-wide association study. The authors identified a genetic region known as the major histocompatibility complex (MHC) as the primary region associated with adult and juvenile dermatomyositis. More importantly, the researchers demonstrated that dermatomyositis shares non-MHC genetic features with other autoimmune diseases.

In the new study, the consortium focused on the most common myositis forms — dermatomyositis and polymyositis. The researchers wanted to understand more about the specific risk factors in the MHC, particularly in a region on chromosome 6 called the human leukocyte antigen (HLA) region. This region has shown a strong genetic association with human autoimmune diseases. A particular group of these genes, called the 8.1 ancestral haplotype (AH8.1), is found in a significant number of Caucasians and is linked with myositis syndromes.

Potential cause of myositis

The researchers analyzed and compared 1,710 cases of either adult- or juvenile-onset myositis, with 4,724 control subjects. They found that multiple genes that make up AH8.1 define the genetic risk for all types of myositis.

"The highly conserved HLA 8.1 ancestral haplotype is unique in that it defies the normal process of genetic mutations and chromosomal switching, therefore suggesting that it has provided a survival benefit in Caucasian populations," said Miller.

Link to other autoimmune diseases

Rider said that AH8.1 also has a role in many immune functions that could contribute to the development of other autoimmune diseases. For instance, people with AH8.1 tend to have higher levels of autoantibodies and more death of white blood cells. In addition, intestinal bacteria that make up the microbiome have been shown to be influenced by certain HLA variants that are also risk factors for several autoimmune diseases. 

Miller said MYOGEN will use the findings as the basis for future work. "We should be able to use these data to develop the molecular profiles that could allow for novel diagnostics and therapeutics for myositis and other autoimmune diseases," he said.


Miller FW, Chen W, O’Hanlon TP, Cooper RG, Vencovsky J, Rider LG, Danko K, Wedderburn LR, Lundberg IE, Pachman LM, Reed AM, Ytterberg SR, Padyukov L, Selva-O’Callaghan A, Radstake TR, Isenberg DA, Chinoy H, Ollier WE, Scheet P, Peng B, Lee A, Byun J, Lamb JA, Gregersen PK, Amos CI. 2015. Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes. Genes Immun; doi:10.1038/gene.2015.28 [Online 20 August 2015].

Miller FW, Cooper RG, Vencovsky J, Rider LG, Danko K, Wedderburn LR, Lundberg IE, Pachman LM, Reed AM, Ytterberg SR, Padyukov L, Selva-O'Callaghan A, Radstake TR, Isenberg DA, Chinoy H, Ollier WE, O'Hanlon TP, Peng B, Lee A, Lamb JA, Chen W, Amos CI, Gregersen PK; Myositis Genetics Consortium. 2013. Genome-wide association study of dermatomyositis reveals genetic overlap with other autoimmune disorders. Arthritis Rheum 65(12):3239–3247.

(Tara Ann Cartwright, Ph.D., is a former postdoctoral fellow in the NIEHS Intracellular Regulation Group.)

Myositis clinical research at NIEHS

In addition to genetic factors, Miller’s group is studying environmental risk factors for myositis. They are especially interested in individuals with myositis who have served in the military, because of the high incidence rate of this disease. Healthy individuals are also needed. Men and women may enroll at the National Institutes of Health Clinical Center in Bethesda, Maryland, the NIEHS Clinical Research Unit in Research Triangle Park, North Carolina, or through their physician’s office.

The study has the following eligibility requirements:

  • Healthy individuals or those diagnosed with myositis during military service
  • Active, reserve, and inactive duty personnel
  • Able to give consent, complete questionnaires, and donate blood

Individuals that meet the criteria should contact . Please refer to the study using the identifying number: NCT01734369.

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