A study in familial hypercholesterolemia suggests reduced methylomic plasticity in men with coronary artery disease

Abstract

Aim: To assess whether DNA methylation is associated with coronary artery disease (CAD). Materials & methods: An epigenome-wide analysis has been performed on leucocytes from familial hypercholesterolemic (FH) men with (n = 6) or without CAD (n = 6). The results were replicated in an extended sample of FH men (n = 61) and in non-FH men (n = 100) for two of the top differentially methylated loci. Results: FH men with CAD had significantly more hypomethylated and hypermethylated loci and showed less DNA methylation level variability compared with men without CAD (p < 0.001). Moreover, COL14A1 and MMP9 DNA methylation levels were associated with CAD, age of onset of CAD or CAD risk factors. Conclusion: These results suggest that epigenome-wide changes are associated with CAD occurrence in men.

Keywords::

• arterial remodeling
• candidate genes
• cardiovascular diseases
• DNA methylation
• epigenome-wide association study
• gene expression
• missing heritability

Acknowledgments

Authors are thankful to all participants and the staff of the ECOGENE-21 Laboratory and Clinical Research Center and the CRIUCPQ biobank. Authors particularly acknowledge the contribution of S Claveau (MSc), N Mior, D Morin, J Landry (RN), C Aubut (RN), C Bélanger, C Racine and N Gaudreault for their dedicated work. SP Guay contributed to the study design, performed the data collection, the data analysis/interpretation and wrote the manuscript. D Brisson conceived the study design, participated to the data analysis/interpretation process and revised the manuscript. P Mathieu and Bossé participated to the data collection, analysis and interpretation and revised the manuscript. D Gaudet contributed to the study design, supplied the FH patients’ genotype and clinical evaluation, research infrastructure and revised the manuscript. L Bouchard conceived the study design, participated to the data analysis/interpretation process and revised the manuscript.

Financial & competing interests disclosure

SP Guay was the recipient of a doctoral research award from the Canadian Institutes for Health and Research (CIHR). At the time of this study, D Gaudet held the Canada Research Chair in preventive genetics and community genomics. Y Bossé is a Junior 2 Research Scholar from the Fonds de recherché du Québec – Santé (FRQS). P Mathieu is a senior research scholar from the FRQS. L Bouchard is a junior research scholar from the FRQS and a member of the FRQS-funded Centre de recherche clinique du Centre hospitalier universitaire de Sherbrooke (CHUS). This project was supported by ECOGENE-21, the CIHR team in community genetics (grant #CTP-82941), the Fondation des maladies du coeur du Québec, the FRQS and the Banting Research Foundation. The authors have no other relevant affiliation or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the present manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

SP Guay was the recipient of a doctoral research award from the Canadian Institutes for Health and Research (CIHR). At the time of this study, D Gaudet held the Canada Research Chair in preventive genetics and community genomics. Y Bossé is a Junior 2 Research Scholar from the Fonds de recherché du Québec – Santé (FRQS). P Mathieu is a senior research scholar from the FRQS. L Bouchard is a junior research scholar from the FRQS and a member of the FRQS-funded Centre de recherche clinique du Centre hospitalier universitaire de Sherbrooke (CHUS). This project was supported by ECOGENE-21, the CIHR team in community genetics (grant #CTP-82941), the Fondation des maladies du coeur du Québec, the FRQS and the Banting Research Foundation. The authors have no other relevant affiliation or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the present manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.