Genome-wide methylation patterns in Marfan syndrome

Mitzi M van Andel; Maarten Groenink; Maarten P van den Berg; Janneke Timmermans; Arthur J H A Scholte; Barbara J M Mulder; Aeilko H Zwinderman; Vivian de Waard

doi:10.1186/s13148-021-01204-4

Genome-wide methylation patterns in Marfan syndrome

Clin Epigenetics. 2021 Dec 11;13(1):217. doi: 10.1186/s13148-021-01204-4.

Authors

Mitzi M van Andel¹, Maarten Groenink^{2

3}, Maarten P van den Berg⁴, Janneke Timmermans⁵, Arthur J H A Scholte⁶, Barbara J M Mulder², Aeilko H Zwinderman^#⁷, Vivian de Waard^#⁸

Affiliations

¹ Department of Cardiology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. m.m.vanandel@amsterdamumc.nl.
² Department of Cardiology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
³ Department of Radiology, Amsterdam UMC, Amsterdam, The Netherlands.
⁴ Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
⁵ Department of Cardiology, Radboud University Hospital, Nijmegen, The Netherlands.
⁶ Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
⁷ Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam UMC, Amsterdam, The Netherlands.
⁸ Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands.

^# Contributed equally.

Abstract

Background: Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the Fibrillin-1 gene (FBN1). Here, we undertook the first epigenome-wide association study (EWAS) in patients with MFS aiming at identifying DNA methylation loci associated with MFS phenotypes that may shed light on the disease process.

Methods: The Illumina 450 k DNA-methylation array was used on stored peripheral whole-blood samples of 190 patients with MFS originally included in the COMPARE trial. An unbiased genome-wide approach was used, and methylation of CpG-sites across the entire genome was evaluated. Additionally, we investigated CpG-sites across the FBN1-locus (15q21.1) more closely, since this is the gene defective in MFS. Differentially Methylated Positions (DMPs) and Differentially Methylated Regions (DMRs) were identified through regression analysis. Associations between methylation levels and aortic diameters and presence or absence of 21 clinical features of MFS at baseline were analyzed. Moreover, associations between aortic diameter change, and the occurrence of clinical events (death any cause, type-A or -B dissection/rupture, or aortic surgery) and methylation levels were analyzed.

Results: We identified 28 DMPs that are significantly associated with aortic diameters in patients with MFS. Seven of these DMPs (25%) could be allocated to a gene that was previously associated with cardiovascular diseases (HDAC4, IGF2BP3, CASZ1, SDK1, PCDHGA1, DIO3, PTPRN2). Moreover, we identified seven DMPs that were significantly associated with aortic diameter change and five DMP's that associated with clinical events. No significant associations at p < 10^-8 or p < 10^-6 were found with any of the non-cardiovascular phenotypic MFS features. Investigating DMRs, clusters were seen mostly on X- and Y, and chromosome 18-22. The remaining DMRs indicated involvement of a large family of protocadherins on chromosome 5, which were not reported in MFS before.

Conclusion: This EWAS in patients with MFS has identified a number of methylation loci significantly associated with aortic diameters, aortic dilatation rate and aortic events. Our findings add to the slowly growing literature on the regulation of gene expression in MFS patients.

Keywords: Aortic diameters; Clinical events; EWAS; Marfan syndrome; Methylation loci.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
DNA Methylation / genetics*
Female
Genome-Wide Association Study / methods
Genome-Wide Association Study / statistics & numerical data
Humans
Male
Marfan Syndrome / genetics*
Middle Aged