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Abstract
Aim: This study aims to assess whether epigenetic changes may account for high-density lipoprotein cholesterol (HDL-C) level variability in familial hypercholesterolemia (FH), a recognized human model to study cardiovascular disease risk modulators. Materials & methods: A genome-wide DNA methylation analysis (Infinium HumanMethylation27 BeadChip, Illumina) was performed on peripheral blood DNA samples obtained from men with FH with low (n = 10) or high (n = 11) HDL-C concentrations. The initial association with one of the top differentially methylated loci located in the promoter of the TNNT1 gene was replicated in a cohort of 276 FH subjects using pyrosequencing. Results: According to the Ingenuity Pathway Analysis software, the HDL-C differentially methylated loci identified were significantly associated with pathways related to lipid metabolism and cardiovascular disease. TNNT1 DNA methylation levels were positively correlated with mean HDL particle size, HDL-phospholipid, HDL-apolipoprotein AI, HDL-C and TNNT1 expression levels. Conclusion: These results suggest that epigenome-wide changes account for interindividual variations in HDL particle metabolism and that TNNT1 is a new candidate gene for dyslipidemia.
Authors‘ contributions
S-P Guay contributed to the study design, performed the data collection, the data analysis/interpretation and wrote the manuscript. G Voisin performed the epigenome-wide study data analysis and revised the manuscript. D Brisson conceived the study design, participated to the data analysis/interpretation process and revised the manuscript. J Munger and B Lamarche participated to the data collection and revised the manuscript. D Gaudet contributed to the study design, supplied the 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.
Acknowledgements
The authors are thankful to all participants and the staff of the ECOGENE-21 Laboratory and Clinical Research Center. Particularly, the authors warmly acknowledge the contribution of S Claveau, N Mior, J Landry and C Aubut for their dedicated work in this study. The authors also express their gratitude to C Bélanger for her thoughtful revision of the manuscript.
Financial & competing interests disclosure
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 FRSQ and the Banting Research Foundation. During this research, S-P Guay was recipient of a doctoral research award from the Canadian Institutes for Health and Research (CIHR), and a master‘s award from the Fonds de la recherche en santé du Québec (FRSQ). D Gaudet held the Canada Research Chair in preventive genetics and community genomics (www.chairs.qc.ca). L Bouchard is a junior research scholar from the FRSQ and a member of the FRSQ-funded Centre de recherche clinique Étienne-Le Bel. The authors have no other relevant affiliations 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 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.