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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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⚃ 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.
⚃ 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.
⚃ 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
⚃ 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.
⚃ 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 [genes]
protect against it occurring (HLA-DRB4*01:01:01 and HLA-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).
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).
⚃ 1.2.9.4 References.
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