FAQ on the Role of Genetics in Myocarditis
Written by DeLisa Fairweather, PhD
Does myocarditis have a genetic cause?
A: No, genetic diseases or disorders are caused by a mutation within a gene that is important for normal function. There have been no reports of genetic mutations as a cause of myocarditis. Most research into a genetic cause for myocarditis has found that genes that regulate inflammation are important in determining susceptibility to disease 1-6. Viral infections are the most common cause of myocarditis; however, some recent studies have identified some genes that are associated with the development of dilated cardiomyopathy can also increase the risk of developing myocarditis in a small number of patients including BAG3 (molecular chaperone protein), LMNA (lamins), MYH7 (beta-myosin heavy chain), TNNI3 (cardiac troponin I), TNNT2 (cardiac troponin T), DSP (desmoplakin), and TTN (titin) (Kontorovich AR, Patel N, Moscati A, Richter F, Peter I, Purevjav E, Selejan SR, Kindermann I, Towbin JA, Bohm M, Klingel K, Gelb BD. Myopathic Cardiac Genotypes Increase Risk for Myocarditis. JACC Basic Transl Sci. 2021; 6:584-592; Seidel F, Holtgrewe M, Al-Wakeel-Marquard N, Opgen-Rhein B, Dartsch J, Herbst C, Beule D, Pickardt T, Klingel K, Messroghli D, Berger F, Schubert S, Kühnisch J, Klaassen S. Pathogenic Variants Associated With Dilated Cardiomyopathy Predict Outcome in Pediatric Myocarditis. Circ Genom Precis Med. 2021; 14:e003250). Dilated cardiomyopathy is inherited in 20–50% of cases where more than 30 genes have been implicated in the development of DCM with pathogenic variants in TTN (titin) most frequently associated with disease (Jain A, Norton N, Bruno KA, Cooper LT Jr, Atwal PS, Fairweather D. Sex Differences, Genetic and Environmental Influences on Dilated Cardiomyopathy. J Clin Med. 2021; 10:2289; Schultheiss HP, Fairweather D, Caforio ALP, Escher F, Hershberger RE, Lipshultz SE, Liu PP, Matsumori A, Mazzanti A, McMurray J, Priori SG. Dilated cardiomyopathy. Nat Rev Dis Primers. 2019; 5:32).
Is myocarditis associated with genetic polymorphisms?
A: Yes, genetic polymorphisms describe the presence of more than one form of a gene that results in altered function. These changes can influence susceptibility to disease. Numerous polymorphisms have been identified that either influence an individual’s ability to clear infection or alter the function of the immune response (i.e. inflammation) 1,3.
What role does “epigenetics” play in susceptibility to myocarditis?
A: Epigenetics describes the ability of environmental factors like infections or chemicals to influence the function and/or regulation of genes. Virtually no information exists on how the environment affects gene function during myocarditis. However, recent evidence suggests that epigenetic modifications of genes that regulate inflammation, fibrosis, and cardiac function exist in patients with dilated cardiomyopathy and heart failure 7-9.
Do chromosomes affect myocarditis?
A: Yes, a study in an animal model of myocarditis reports that sex chromosome complement (i.e. whether an individual is XY or XX, for example) influences the severity of inflammation during myocarditis 10. This influence of sex chromosome on inflammation is in addition to the effect of sex hormones such as testosterone or estrogen 10. Gene polymorphisms found on Chromosome Y were found to promote susceptibility to myocarditis in males 11. Thus, both testosterone and genes present on the Y Chromosome lead to increased cases and severity of myocarditis in men.
- Ligons DL, Guler ML, Li HS, Rose NR (2009) A locus on chromosome 1 promotes susceptibility of experimental autoimmune myocarditis and lymphocyte cell death. Clin Immunol130:74-82.
- Cooper LT Jr, Onuma OK, Sagar S, Oberg AL, Mahoney DW, Asmann YW, Liu P (2010) Genomic and proteomic analysis of myocarditis and dilated cardiomyopathy. Heart Fail Clin6:75-85.
- Wiltshire SA, Leiva-Torres GA, Vidal SM (2011) Quantitative trait locus analysis, pathway analysis, and consomic mapping show genetic variants of Tnni3k, Fpgt, or H28control susceptibility to viral myocarditis. J Immunol 186:6398-6405.
- Heidecker B, Kittleson MM, Kasper EK, Wittstein IS, Champion HC, Russell SD, Hruban RH, Rodriguez ER, Baughman KL, Hare JM (2011) Transcriptomic biomarkers for the accurate diagnosis of myocarditis. Circulation123:1174-1184.
- Onyimba JA, Coronado MJ, Garton AE, Kim JB, Bucek A, Bedja D, Gabrielson KL, Guilarte TR, Fairweather D (2011) The innate immune response to coxsackievirus B3 predicts progression to cardiovascular disease and heart failure in male mice. Biol Sex Differ2:2.
- Coronado MJ, Brandt JE, Kim E, Bucek A, Bedja D, Abston ED, Shin J, Gabrielson KL, Mitzner W, Fairweather D (2012) Testosterone and interleukin-1b increase cardiac remodeling during acute coxsackievirus B3 myocarditis via serpin A 3n. Am J Physiol Heart Circ Physiol 302:H1726-H1736.
- Movassagh M, Vujic A, Foo R (2011) Genome-wide DNA methylation in human heart failure. Epigenomics3:103-109.
- Movassagh M, Choy MK, Knowles DA, Cordeddu L, Haider S, Down T, Siggens L, Vujic A, Simeoni I, Penkett C, Goddard M, Lio P, Bennett MR, Foo RS (2011) Distinct epigenomic features in end-stage failing human hearts. Circulation124:2411-2422.
- Baccarelli A, Ghosh S (2012) Environmental exposures, epigenetics and cardiovascular disease. Curr Opin Clin Mutr Metab Care15:323-329.
- Robinson DP, Huber SA, Moussawi M, Roberts B, Teuscher C, Watkkins R, Arnold AP, Klein SL (2011) Sex chromosome complement contributes to sex differences in coxsackievirus B3 but not influenza A virus pathogenesis. Biol Sex Differ2:8.
- Case LK, Toussaint L, Moussawi M, Roberts B, Saligrama N, Brossay L, Huber SA, Teuscher C (2012) Chromosome Y regulates survival following murine coxsackievirus B3 infection. G3 (Bethesda)2:115-121.