⚂ 1.2.9 Genetic predisposition of

Inclusion Body Myositis (IBM).

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This page provides information and references to the possible link between a genetic predisposition to autoimmune disorders and IBM.

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⚃  Introduction.

⚃  1.2.9.1 What is a genetic predisposition?

⚃  1.2.9.2 Overview: The Human Leukocyte Antigen (HLA).

⚃  1.2.9.3 Genes in the HLA have been linked to a predisposition to developing IBM.

⚃  1.2.9.4 References.

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⚃  Introduction.

Due to their genetic make-up, some individuals within the population appear to be more at risk of developing inclusion body myositis than others.
≻ IBM is not directly genetic and is not passed on to subsequent generations.
≻ It appears that IBM is related to a region of genes that increase the likelihood or chance of developing various autoimmune disorders.
≻ This is called a genetic predisposition.

It is clear that many factors contribute to the development of inclusion body myositis and genetic predisposition appears to be one risk factor.

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⚃ 1.2.9.1  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 is 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

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⚃ 1.2.9.2 Overview: The Human Leukocyte Antigen (HLA).

The major histocompatibility complex (MHC) – also called the HLA – is a group of some 200 genes on chromosome number 6.
≻ The genes in this region produce proteins that are antigens; critical in the function of the immune system.

HLA proteins regulate the immune system and its responses, defending the body from outside infections.
≻ 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).

Each of these genes is very polymorphic; each gene can be expressed in two or more possible ways – the gene is seen in different versions; each version is called an allele.
≻ As a result of the many possible variations in the MHC/HLA genes, there is a wide variety of different immune responses seen in people – this allows the genes to fine-tune the adaptive immune system.
≻ 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.

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⚃ 1.2.9.3 Genes in the HLA have been linked to a predisposition to developing IBM.

MHC/HLA genes evolved over thousands of years as humans moved through different parts of the world and encountered different types of immune threats.
≻ 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 – 8.1 AH (a haplotype is a group of related genes).
≻ The 8.1 AH is comprised of six HLA types (corresponding to six HLA genes).
≻ The 8.1 AH is associated with some 30 different autoimmune disorders.

Here is the breakdown:

  – The Human Leukocyte Antigen (HLA) region on chromosome number 6

     – 8.1 ancestral haplotype (AH)

        – HLA-DRB1*03:01:01 predisposes or increases the likelihood of having IBM, and two alleles protect against it occurring (DRB4*01:01:01 and DQA1*01:02:01).
≻ People who have the predisposing allele without the protective alleles show a fourteenfold increased risk of developing IBM over the general Caucasian population and also develop IBM five years earlier (Slater et al., 2024).

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Modified from Fig. 1, Creary et al., 2019.

Summary:

The main function of the MHC/HLA genes is clearing infection and thereby ensuring survival of species.
≻ The major HLA 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 protection against infections and survival of the species. (based on Mangalam, Taneja, & David, 2013).

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⚃ 1.2.9.4 References.

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