⚂ 1.2.9 Genetic predisposition of

Inclusion Body Myositis (IBM).

Site presented by Bill Tillier

Print or print to save as PDF.

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

Webpage Menu:

⚃  Introduction.

⚃ What is a genetic predisposition?

⚃ Overview: The Human Leukocyte Antigen (HLA).

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

⚃ 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.


⚃  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


⚃ 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.


⚃ 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).


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


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).


⚃ References.

Argov, Z., Eisenberg, I., & Mitrani-Rosenbaum, S. (1998). Genetics of inclusion body myopathies. Current Opinion in Rheumatology, 10(6), 543-547. https://journals.lww.com/co-rheumatology/abstract/1998/11000/genetics_of_inclusion_body_myopathies.6.aspx

Badrising, U. A., Schreuder, G. M. T., Giphart, M. J., Geleijns, K., Verschuuren, J. J. G. M., & Wintzen, A. R. (2004). Associations with autoimmune disorders and HLA class I and II antigens in inclusion body myositis. Neurology, 63(12), 2396-2398. https://doi.org/10.1212/01.WNL.0000148588.15052.4C

Chinoy, H., Ollier, W. E. ., & Cooper, R. G. (2004). Have recent immunogenetic investigations increased our understanding of disease mechanisms in the idiopathic inflammatory myopathies? Current Opinion in Rheumatology, 16(6), 707-713. https://doi.org/10.1097/01.bor.0000142339.24380.b7

Creary LE, Mallempati KC, Gangavarapu S, et al. Deconstruction of HLA-DRB1*04:01:01 and HLA-DRB1*15:01:01 class II haplotypes using next-generation sequencing in European-Americans with multiple sclerosis. Multiple Sclerosis (Houndmills, Basingstoke, England). 2019 May;25(6):772-782. DOI: 10.1177/1352458518770019. PMID: 29683085; PMCID: PMC6365219.

Dalakas, M. C. (2005). Autoimmune muscular pathologies. Neurological Sciences, 26(S1), s7-s8. https://link.springer.com/article/10.1007/s10072-005-0390-0

Davis, M. M., & Brodin, P. (2018). Rebooting Human Immunology. Annual Review of Immunology, 36(1), 843-864. https://doi.org/10.1146/annurev-immunol-042617-053206

Diaz-Gallo, L. M., Ramsköld, D., Shchetynsky, K., Folkersen, L., Chemin, K., Brynedal, B., … Padyukov, L. (2018). Systematic approach demonstrates enrichment of multiple interactions between non-HLA risk variants and HLA-DRB1 risk alleles in rheumatoid arthritis. Annals of the Rheumatic Diseases, 77(10), 1454-1462. https://doi.org/10.1136/annrheumdis-2018-213412

Garlepp, M. J. (1993). Immunogenetics of inflammatory myopathies. Bailliere's Clinical Neurology, 2(3), 579-597. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8156144

Garlepp, M. J., Laing, B., Zilko, P. J., Ollier, W. & Mastaglia, F. L. (1994). HLA associations with inclusion body myositis. Clin. Exp. Immunol. 98, 40-45 https://doi.org/10.1111/j.1365-2249994.tb06604.x

Gossrau, G., Gestrich, B., Koch, R., Wunderlich, C., Schröder, J. M., Schroeder, S., … Lampe, J. B. (2004). Apolipoprotein E and alpha-1-antichymotrypsin polymorphisms in sporadic inclusion body myositis. European Neurology, 51(4), 215-220. https://doi.org/10.1159/000078488

Johari, M., Arumilli, M., Palmio, J., Savarese, M., Tasca, G., Mirabella, M., … Udd, B. (2017). Association study reveals novel risk loci for sporadic inclusion body myositis. European Journal of Neurology, 24(4), 572-577. https://doi.org/10.1111/ene.13244

Ka, S., Lee, S., Hong, J., Cho, Y., Sung, J., Kim, H.-N., … Jung, J. (2017). HLAscan: genotyping of the HLA region using next-generation sequencing data. BMC Bioinformatics, 18(1), 258. https://doi.org/10.1186/s12859-017-1671-3

Kang, E. H., Go, D. J., Mimori, T., Lee, S. J., Kwon, H. M., Park, J. W., … Song, Y. W. (2019). Novel susceptibility alleles in HLA region for myositis and myositis specific autoantibodies in Korean patients. Seminars in Arthritis and Rheumatism, 000. https://doi.org/10.1016/j.semarthrit.2019.03.005

Kaufman, J. (2018). Unfinished Business: Evolution of the MHC and the Adaptive Immune System of Jawed Vertebrates. Annual Review of Immunology, 36(1), 383-409. https://doi.org/10.1146/annurev-immunol-051116-052450

Koffman, B. M., Sivakumar, K., Simonis, T., Stroncek, D., & Dalakas, M. C. (1998). HLA allele distribution distinguishes sporadic inclusion body myositis from hereditary inclusion body myopathies. Journal of Neuroimmunology, 84(2), 139-142. https://doi.org/10.1016/S0165-5728(97)00245-2

Kurdi, M., Alshareef, A., Bamaga, A. K., Fadel, Z. T., Alrawaili, M. S., Hakamy, S., Mohamed, F., Abuzinadah, A. R., Addas, B. M., & Butt, N. S. (2021). The assessment of major histocompatibility complex (MHC) Class-I expression in different neuromuscular diseases. Degenerative Neurological and Neuromuscular Disease, Volume 11 , 61-68. https://doi.org/10.2147/DNND.S340117

Lampe, J. B., Gossrau, G., Kempe, A., Fussel, M., Schwurack, K., Schroder, R., … Lochmuller, H. (2003). Analysis of HLA class I and II alleles in sporadic inclusion-body myositis. Journal of Neurology, 250(11), 1313-1317. https://link.springer.com/article/10.1007/s00415-003-0204-3

Mangalam, A. K., Taneja, V., & David, C. S. (2013). HLA Class II Molecules Influence Susceptibility versus Protection in Inflammatory Diseases by Determining the Cytokine Profile. The Journal of Immunology, 190(2), 513-519. https://doi.org/10.4049/jimmunol.1201891

Mastaglia, F. L. (2005). Neuromuscular disorders: molecular and therapeutic insights. The Lancet Neurology, 4(1), 6-7. https://doi.org/10.1016/S1474-4422(04)00946-9

Mastaglia, F. L., Needham, M., Scott, A., James, I., Zilko, P., Day, T., … Christiansen, F. T. (2009). Sporadic inclusion body myositis: HLA-DRB1 allele interactions influence disease risk and clinical phenotype. Neuromuscular Disorders, 19(11), 763-765. https://doi.org/10.1016/j.nmd.2009.07.015

Mastaglia, F., Price, P., Walters, S., Fabian, V., Miller, J., & Zilko, P. (2006). Familial inclusion body myositis in a mother and son with different ancestral MHC haplotypes. Neuromuscular Disorders, 16(11), 754-758. https://doi.org/10.1016/j.nmd.2006.06.009

Miller, F. W., Chen, W., O'Hanlon, T. P., Cooper, R. G., Vencovsky, J., Rider, L. G., … Amos, C. I. (2015). Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes. Genes and Immunity, 16(7), 470-480. https://www.nature.com/articles/gene201528

Needham, M., & Mastaglia, F. (2017). Advances in inclusion body myositis: genetics, pathogenesis and clinical aspects. Expert Opinion on Orphan Drugs, 5(5), 431-443. https://doi.org/10.1080/21678707.2017.1318056

Needham, M., James, I., Corbett, A., Day, T., Christiansen, F., Phillips, B., & Mastaglia, F. L. (2008). Sporadic inclusion body myositis: Phenotypic variability and influence of HLA-DR3 in a cohort of 57 Australian cases. Journal of Neurology, Neurosurgery & Psychiatry, 79(9), 1056-1060. https://doi.org/10.1136/jnnp.2007.138891

Needham, M., Mastaglia, F. L., & Garlepp, M. J. (2007). Genetics of inclusion-body myositis. Muscle & Nerve, 35(5), 549-561. https://doi.org/10.1002/mus.20766

O'Hanlon, T. P., Carrick, D. M., Targoff, I. N., Arnett, F. C., Reveille, J. D., Carrington, M., … Miller, F. W. (2006). Immunogenetic Risk and Protective Factors for the Idiopathic Inflammatory Myopathies. Medicine, 85(2), 111-127. https://doi.org/10.1097/01.md.0000217525.82287.eb

Ohnuki, Y., Suzuki, S., & Shiina, T. (2017). Inflammatory myopathies and human leukocyte antigen. Clinical and Experimental Neuroimmunology, 8(4), 313-317. https://doi.org/10.1111/cen3.12422

Oldfors, A., & Fyhr, I.M. (2001). Inclusion body myositis: genetic factors, aberrant protein expression, and autoimmunity. Current Opinion in Rheumatology, 13(6), 469-475. https://journals.lww.com/co-rheumatology/abstract/2001/11000/inclusion_body_myositis__genetic_factors,_aberrant.3.aspx

Oldfors, A., & Lindberg, C. (2005). Diagnosis, pathogenesis and treatment of inclusion body myositis. Current Opinion in Neurology, 18(5), 497-503. https://journals.lww.com/co-neurology/abstract/2005/10000/diagnosis,_pathogenesis_and_treatment_of_inclusion.4.aspx

Parham, P., & Guethlein, L. A. (2018). Genetics of Natural Killer Cells in Human Health, Disease, and Survival. Annual Review of Immunology, 36(1), 519-548. https://doi.org/10.1146/annurev-immunol-042617-053149

Price, P., Santoso, L., Mastaglia, F., Garlepp, M., Kok, C. C., Allcock, R., & Laing, N. (2004). Two major histocompatibility complex haplotypes influence susceptibility to sporadic inclusion body myositis: critical evaluation of an association with HLA-DR3. Tissue Antigens, 64(5), 575-580. https://doi.org/10.1111/j.1399-0039.2004.00310.x

Rojana-udomsart, A., Bundell, C., James, I., Castley, A., Martinez, P., Christiansen, F., … Mastaglia, F. (2012). Frequency of autoantibodies and correlation with HLA-DRB1 genotype in sporadic inclusion body myositis (s-IBM): A population control study. Journal of Neuroimmunology, 249(1-2), 66-70. https://doi.org/10.1016/j.jneuroim.2012.04.007

Rojana-udomsart, A., James, I., Castley, A., Needham, M., Scott, A., Day, T., … Mastaglia, F. (2012). High-resolution HLA-DRB1 genotyping in an Australian inclusion body myositis (s-IBM) cohort: An analysis of disease-associated alleles and diplotypes. Journal of Neuroimmunology, 250(1-2), 77-82. https://doi.org/10.1016/j.jneuroim.2012.05.003

Rojana-udomsart, A., Mitrpant, C., James, I., Witt, C., Needham, M., Day, T., … Mastaglia, F. L. (2013). Analysis of HLA-DRB3 alleles and supertypical genotypes in the MHC Class II region in sporadic inclusion body myositis. Journal of Neuroimmunology, 254(1-2), 174-177. https://doi.org/10.1016/j.jneuroim.2012.09.003

Rojana-udomsart, A., Needham, M., Luo, Y. B., Fabian, V., Walters, S., Zilko, P. J., & Mastaglia, F. L. (2011). The association of sporadic inclusion body myositis and Sjogren's syndrome in carriers of HLA-DR3 and the 8.1 MHC ancestral haplotype. Clinical Neurology and Neurosurgery, 113(7), 559-563. https://doi.org/10.1016/j.clineuro.2011.03.016

Rosen, A., & Casciola-Rosen, L. (2016). Autoantigens as Partners in Initiation and Propagation of Autoimmune Rheumatic Diseases. Annual Review of Immunology, 34(1), 395-420. https://doi.org/10.1146/annurev-immunol-032414-112205

Rothwell, S., Chinoy, H., Lamb, J. A., Miller, F. W., Rider, L. G., Wedderburn, L. R., … Lundberg, I. E. (2019). Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups. Annals of the Rheumatic Diseases, 78(7), 996-1002. https://doi.org/10.1136/annrheumdis-2019-215046

Rothwell, S., Cooper, R. G., Lundberg, I. E., Gregersen, P. K., Hanna, M. G., Machado, P. M., … Mann, H. (2017). Immune-Array Analysis in Sporadic Inclusion Body Myositis Reveals HLA-DRB1 Amino Acid Heterogeneity Across the Myositis Spectrum. Arthritis & Rheumatology, 69(5), 1090-1099. https://doi.org/10.1002/art.40045

Rothwell, S., Lamb, J., & Chinoy, H. (2016). New developments in genetics of myositis. Current Opinion in Rheumatology, 28(6), 651-656. https://journals.lww.com/co-rheumatology/abstract/2016/11000/new_developments_in_genetics_of_myositis.14.aspx

Rothwell, S., Lilleker, J. B., & Lamb, J. A. (2017). Genetics in inclusion body myositis. Current Opinion in Rheumatology. https://doi.org/10.1097/BOR.0000000000000431

Scott, A. P., Laing, N. G., Mastaglia, F., Needham, M., Walter, M. C., Dalakas, M. C., & Allcock, R. J. N. (2011). Recombination mapping of the susceptibility region for sporadic inclusion body myositis within the major histocompatibility complex. Journal of Neuroimmunology, 235(1-2), 77-83. https://doi.org/10.1016/j.jneuroim.2011.02.011

Slater, N., Sooda, A., McLeish, E., Beer, K., Brusch, A., Shakya, R., Bundell, C., James, I., Chopra, A., Mastaglia, F. L., Needham, M., & Coudert, J. D. (2024). High-resolution HLA genotyping in inclusion body myositis refines 8.1 ancestral haplotype association to DRB1*03:01:01 and highlights pathogenic role of arginine-74 of DRβ1 chain. Journal of Autoimmunity, 142, 103150. https://doi.org/10.1016/j.jaut.2023.103150 DOWNLOAD PDF.

Unanue, E. R., Turk, V., & Neefjes, J. (2016). Variations in MHC Class II Antigen Processing and Presentation in Health and Disease. Annual Review of Immunology, 34(1), 265-297. https://doi.org/10.1146/annurev-immunol-041015-055420

Villani, A. C., Sarkizova, S., & Hacohen, N. (2018). Systems Immunology: Learning the Rules of the Immune System. Annual Review of Immunology, 36(1), 813-842. https://doi.org/10.1146/annurev-immunol-042617-053035