Myositis is a rare inflammatory muscle disease that causes muscle weakness and pain. This article explores the intricate relationship between genetics and myositis, clarifying how inherited factors can contribute to its development.
What is Myositis?
Myositis is a group of rare autoimmune diseases characterized by chronic inflammation of the muscles. In individuals with myositis, the body’s immune system mistakenly attacks its own healthy muscle tissue, leading to inflammation, swelling, and eventual muscle weakness. This immune system malfunction can cause a range of symptoms, including difficulty with everyday activities like climbing stairs, rising from a chair, or lifting objects overhead.
The inflammation primarily affects skeletal muscles, which are responsible for movement. While muscle weakness is a hallmark symptom, myositis can also manifest with other symptoms such as muscle pain, fatigue, and in some cases, skin rashes or lung involvement. Myositis is often associated with other autoimmune conditions like lupus or rheumatoid arthritis, indicating a broader immune system dysregulation.
Genetic Predisposition to Myositis
Myositis is not typically inherited in a straightforward manner, like conditions passed directly from parent to child through a single gene. Instead, individuals may have a genetic predisposition, inheriting gene variations that increase their susceptibility to developing the condition without directly causing it.
A significant portion of this genetic influence comes from the Human Leukocyte Antigen (HLA) complex, a group of genes on chromosome 6 that plays a major role in immune system function. HLA genes produce proteins that help the immune system distinguish between the body’s own cells and foreign invaders like viruses or bacteria. Certain variations within these HLA genes can alter how the immune system functions, potentially making an individual more prone to autoimmune responses where the body attacks its own tissues, including muscles.
Specific Genetic Links Across Myositis Types
Genetic factors associated with myositis vary among its different forms. The HLA region is consistently identified as the most strongly associated genetic area across various myositis phenotypes. Different HLA alleles can influence susceptibility to specific types of myositis and even particular autoantibody subgroups.
Polymyositis (PM) and Dermatomyositis (DM) are frequently linked to specific HLA alleles. For instance, the HLA 8.1 ancestral haplotype (AH8.1), which includes alleles like HLA-DRB103:01, DQA105:01, and DQB102:01, is a major genetic risk factor for these conditions. While HLA-DRB103:01 shows strong associations with both adult and juvenile dermatomyositis, and HLA-B08:01 with polymyositis, multiple alleles within the AH8.1 are often needed for the full risk effect.
Inclusion Body Myositis (IBM) has a more complex genetic picture, often appearing sporadically, though genetic markers have been identified. A strong association exists with HLA-DRB103:01, and independent associations have been noted with HLA-DRB101:01 and HLA-DRB113:01, which are unique to IBM among the inflammatory myopathies. These genetic variations suggest an autoimmune component in IBM, even in cases that are not directly inherited.
Juvenile Dermatomyositis (JDM) also shows distinct genetic associations, often involving HLA genes. HLA-DRB103:01 is strongly associated with JDM, and a specific amino acid position (position 37) within HLA-DRB1 may help distinguish JDM from adult-onset DM. Additionally, HLA-DQA10501 on non-DR3 haplotypes has been linked to increased risk in Caucasian JDM patients.
Necrotizing Autoimmune Myopathy (NAM), particularly the statin-induced form, has genetic links as well. Individuals with the HLA-DRB111:01 allele have an increased likelihood of developing anti-HMGCR myopathy, a subtype of NAM associated with statin use. The SLCO1B1 gene, which influences statin blood levels, can also increase the risk of myopathy, with a higher risk for those with certain genetic variants.
The Interplay of Genes and Environment
While genetic predisposition can increase the likelihood of developing myositis, it is rarely the sole factor. Environmental triggers are often necessary for the disease to manifest in genetically susceptible individuals. This suggests that myositis is a multifactorial disease, resulting from a complex interaction between an individual’s genetic makeup and external factors.
Potential environmental factors include viral infections, which can sometimes precede myositis onset. Viruses like enteroviruses, parvovirus B19, Coxsackie B virus, and HIV have been investigated for their role in triggering the immune response that leads to muscle inflammation. Certain medications, such as statins, are also recognized environmental triggers, particularly for necrotizing autoimmune myopathy.
Exposure to toxins and ultraviolet (UV) radiation can also contribute to myositis development, especially in dermatomyositis. UV light is known to exacerbate the rash associated with dermatomyositis, and studies suggest a correlation between global surface UV radiation intensity and the prevalence of dermatomyositis. These environmental exposures, in combination with an individual’s genetic background, can influence the immune system’s delicate balance, ultimately leading to the onset of myositis.