Epigenetics and hypertrophic cardiomyopathy: investigating the relationship between DNA methylation and phenotype expression in individuals with disease causing mutations associated with HCM.

Introduction Hypertrophic cardiomyopathy (HCM) is the most common, monogenically inherited cardiac condition seen in our population. It is known that there can be marked phenotypic variation, even within families that is not fully explained by genotype alone. This study explores the potential role of DNA methylation, one epigenetic mechanism, in modifying disease expression and severity in HCM. Background and Methods This study examined the clinical, methylation and biomarker profiles of two independent cohorts. A prospectively recruited cohort made up of 160 Northern Irish individuals, was recruited from the population of Northern Irish patients known to carry disease causing mutations associated with HCM. The Northern Irish cohort was categorised by phenotype as unaffected, non-obstructive HCM or obstructive HCM and underwent comprehensive clinical assessment, cardiac imaging and laboratory analysis. Global DNA methylation was assessed in the Northern Irish cohort using LINE-1 methylation as well as quantification of circulating proteins of interest which were HEY2, MSR1 and MYBPC3. A separate Spanish cohort, comprised of 34 patients with HCM and other ischaemic and non-ischaemic cardiomyopathies, underwent targeted gene methylation analysis of HEY2, MFSD2B and MYBPC3. Circulating protein quantification and correlation with clinical and imaging parameters was also completed in the Spanish cohort. Results In the Northern Irish cohort clinical features associated with HCM such as atrial fibrillation, left atrial enlargement, diastolic dysfunction, heart failure, ventricular tachycardia, and the presence of late gadolinium enhancement on cardiac MRI were most common in affected participants, with the severity of these features generally greatest in the obstructive group. NT-pro BNP correlated strongly with markers of disease severity and was associated with the presence of an HCM phenotype. No significant differences were observed in LINE-1 methylation or circulating HEY2, MSR1 or MYBPC3 levels between phenotype groups, although undetectable MYBPC3 levels were associated with left atrial and ventricular dilatation. In the Spanish cohort, there were significantly greater mean MYBPC3 methylation levels in the HCM group compared with the non-ischaemic group. This corresponded with the finding of significantly lower circulating MYBPC3 protein levels in the HCM group compared to the non-ischaemic group. Neither circulating HEY2 and MSR1 protein levels nor MFSD2B and HEY2 methylation levels consistently distinguished between HCM and non-HCM groups. Conclusion This study suggests limited utility of circulating methylation and protein biomarkers for predicting phenotype in HCM. It also reinforces the clinical value of NT-pro BNP as a readily available biomarker which may support the clinical assessment of individuals known to carry disease causing mutations associated with HCM. Thesis is embargoed until 31 July 2031.