Genetics
Polymyositis as a complex disease
Polymyositis is not a single-gene disease. On the contrary, it is considered a complex or multifactorial disorder, due to the effect of multiple genes in combination with lifestyle and environmental factors. In other words, it would be initiated by immune activation following specific environmental trigger events in genetically predisposed individuals.
How to investigate the genetic component
Much progress has been made in recent years in understanding the genetic determinants of the disease. Many different approaches have been used in order to identify specific immunogenetic risk factors for polymyositis: genome wide and targeted association studies are the most common, togehter with gene-environment interaction perspectives [1]. One of the main problems with association studies is recruiting cohorts of sufficient size to enable studies on more homogeneous sub-populations within the polymyositis disease spectrum, so as to try to reveal further specific genetic determinants. Furthermore, many association with genetic variants identified in Caucasian cohorts are not generally found in other non- Caucasoid populations, illustrating the importance of stratification by ethnicity in such studies.
Genetic associations
The strongest genetic associations in polymyositis have been shown within the major histocompatibility complex (MHC). This may be partly attributed to the influence of MHC molecules on T-cell receptor development, peripheral tolerance, and immune response to environmental agents. In particular, alleles forming part of the 8.1 Caucasian MHC common ancestral haplotype (also known as “8.1 haplotype”) have been identified as a major risk factor for polymyositis in Caucasian populations [2]. Many other genetic associations have been established outside of the traditional 8.1 haplotype region and even outside of major histocompatibility complex. A recent extensive study conducted on Caucasian patients by MYOGEN, a fully international Myositis Genetics Consortium, summarizes these results [3]. According to this study, PTPN22 locus results to be one of the most strongly associated regions in polymyositis. Furthermore, smoking status and statin use with MHC alleles have been suggested as possible gene-environment interactors [4].
Future perspectives
Many of these predisposing factors have been previously associated with other autoimmune disorders, suggesting a partially overlapping etiopathogenesis. Nevertheless, we still have limited understanding of the complete genetic component of the disease. Many efforts will be necessary in the future in order to increase the size of the studied samples, to detect novel genetic variants through large scale sequencing techniques and to predict their functional consequences. Furthermore, the majority of research to date has been published on Caucasian populations, and it is not yet clear how much variability in disease susceptibility there is between different ethnic groups. Additional multiethnic comparisons may help to identify the functional genetic variants and to interpret differences in clinical presentation and disease severity between different populations.
Article contributed by Dr. SARA NUOVO, MD.
Footnotes:
[1] Rothwell S, Cooper RG, Lamb JA, Chinoy H. Strategies for evaluating idiopathic inflammatory myopathy disease susceptibility genes. Curr Rheumatol Rep. 2014 Oct;16(10):446.
[2] Miller FW, Chen W, O'Hanlon TP, Cooper RG, Vencovsky J, Rider LG, Danko K, Wedderburn LR, Lundberg IE, Pachman LM, Reed AM, Ytterberg SR, Padyukov L, Selva-O'Callaghan A, Radstake TR, Isenberg DA, Chinoy H, Ollier WE, Scheet P, Peng B, Lee A, Byun J, Lamb JA, Gregersen PK, Amos CI. Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes. Genes Immun. 2015 Oct;16(7):470-80.
[3] Rothwell S, Cooper RG, Lundberg IE, Miller FW, Gregersen PK, Bowes J, Vencovsky J, Danko K, Limaye V, Selva-O'Callaghan A, Hanna MG, Machado PM, Pachman LM, Reed AM, Rider LG, Cobb J, Platt H, Molberg Ø, Benveniste O, Mathiesen P, Radstake T, Doria A, De Bleecker J, De Paepe B, Maurer B, Ollier WE, Padyukov L, O'Hanlon TP, Lee A, Amos CI, Gieger C, Meitinger T, Winkelmann J, Wedderburn LR, Chinoy H, Lamb JA; Myositis Genetics Consortium. Dense genotyping of immune-related loci in idiopathic inflammatory myopathies confirms HLA alleles as the strongest genetic risk factor and suggests diffferent genetic background for major clinical subgroups.
Ann Rheum Dis. 2015 Sep 11. pii: annrheumdis-2015-208119.
[4]Mammen AL, Gaudet D, Brisson D, Christopher-Stine L, Lloyd TE, Leffell MS, Zachary AA. Increased frequency of DRB1*11:01 in anti-hydroxymethylglutaryl-coenzyme A reductase-associated autoimmune myopathy. Arthritis Care Res (Hoboken). 2012 Aug;64(8):1233-7.
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