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This page provides information and references to the possible link between a genetic predisposition to autoimmune disorders and sIBM.
⬛ What is a genetic predisposition?
⬛ Overview: The Human Leukocyte Antigen (HLA).
⬛ The major histocompatibility complex (MHC).
⬛ Genes in the HLA have been linked to a predisposition to developing IBM.
What is a genetic predisposition?
A genetic predisposition (sometimes also called genetic susceptibility) is an increased likelihood of developing a particular disease based on a person's genetic makeup. A genetic predisposition results from specific genetic variations that are often inherited from a parent. These genetic changes contribute to the development of a disease but do not directly cause it. Some people with a predisposing genetic variation will never get the disease while others will, even within the same family.
In people with a genetic predisposition, the risk of disease can depend on multiple factors in addition to an identified genetic change. These include other genetic factors (sometimes called modifiers) as well as lifestyle and environmental factors. Diseases that are caused by a combination of factors are described as multifactorial. Although a person's genetic makeup cannot be changed, some lifestyle and environmental modifications (such as having more frequent disease screenings and maintaining a healthy weight) may be able to reduce disease risk in people with a genetic predisposition. For example, it known that there are genetic predispositions to developing lung cancer. Some people with these predispositions will develop cancer lung cancer whether they smoke or not. But, knowing that you have these predispositions, you could likely reduce your chances of developing lung cancer by not smoking. The environmental factors that may contribute to developing IBM are unknown at the present time.
Above from: https://ghr.nlm.nih.gov/primer/mutationsanddisorders/predisposition
Overview: The Human Leukocyte Antigen (HLA).
The Human Leukocyte Antigen (HLA) is the human version of the major histocompatibility complex (MHC), a group of genes found in many vertebrates. The genes in these regions produce proteins (antigens) critical in the function of the immune system. One job of these antigens is to detect cells entering the body and to differentiate cells as either foreign or from within the body (self). Healthy body cells are left alone, body cells infected by foreign cells (like a virus) are attacked and killed, as are foreign cells found in the body (e.g., like virus cells in the blood). HLA proteins regulate the immune system and its responses, defending the body from outside infections. Unfortunately, sometimes these cells get mixed up between foreign and body (self) and can cause the immune system to attack normal, healthy body cells. When this happens, it is called an autoimmune disease.
The major histocompatibility complex (MHC).
The major histocompatibility complex (MHC) is a large group of many related genes on chromosome number 6. It includes two main groups that interest us; class I and II genes that play crucial roles in immune responses. Each of these genes is very polymorphic—this means that each gene can be expressed in two or more possible ways. For example, the gene that controls a jaguar's skin color has two versions (called morphs); a jaguar can have light-morph or dark-morph skin coloring. As a result of the many possible variations in the MHC genes, there is a wide variety of different immune responses seen in the population. In other words, not everyone has the same built-in type, or degree, of immune response. For some reason, some combinations and interactions of these different genes being expressed sometimes leads to autoimmune disorders. The main characteristic of these disorders is that the immune system turns against normal cells and attacks structures within the body.
It is helpful to understand that not everyone in the population has the same makeup of genes in the MHC/HLA. As human populations diversified and explored different areas they were exposed to different kinds of pathogens (bugs). Through evolution, the genes in the MHC/HLA of different human populations changed and adapted to particular environments. These early changes in ancient groups of people created major differences in the genetic makeup of the MHC/HLA region seen in different populations today. These variations in the MHC/HLA of people affects autoimmune disorders and their frequency seen today.
Some 30% of the genes in the overall MHC/HLA are related to immune function, and the MHC/HLA has been associated with over 100 diseases, most of which are immune-related. Examples include type 1 diabetes, ankylosing spondylitis, Graves' disease, Addison's disease, and myasthenia gravis.
Genes in the HLA have been linked to a predisposition to developing IBM.
For some reason, the particular mix of genes that evolved in Caucasian populations, particularly those of Northern European origin, has created predispositions to developing IBM today. Other populations that seem predisposed to developing IBM include certain Australian populations and certain Japanese populations. These genes are in a part of the HLA called the 8.1 ancestral haplotype (a haplotype is a group of related genes).
Here is the breakdown:
■ Human Leukocyte Antigen (HLA) on chromosome number 6
■ 8.1 ancestral haplotype (AH)
■ Genes in the subsection HLA-DR3 have been linked to a predisposition to developing IBM
■ Other gene areas have also been linked to IBM: e.g., HLA-DR52
The main function of the MHC/HLA genes is clearing infection and thereby ensuring survival of species. HLA genes evolved during thousands of years as humans moved through different parts of the world. The major HLA class II genes are critical in generating efficient immune response to pathogens. Unfortunately, these cells sometime target self and cause autoimmunity. Thus, autoimmunity is the price paid for clearance of infections and survival of the species. (based on Mangalam, Taneja, & David, 2013).
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