Genome-wide methylation patterns in Marfan syndrome

Mitzi M Van Andel,Maarten Groenink,Maarten P Van Den Berg,Janneke Timmermans,Vivian De Waard,Aeilko H Zwinderman,Arthur J H A Scholte,Barbara J M Mulder

doi:10.1186/s13148-021-01204-4

Abstract

BackgroundMarfan 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.MethodsThe 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.ResultsWe 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.ConclusionThis 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.

Highlights

Marfan syndrome (MFS) is a dominant autosomal disorder caused by mutations in the Fibrillin-1 (FBN1) gene, which results in a connective tissue defect
Description of the MFS patient population Patient characteristics and disease phenotypes are summarized in Tables 1 and 2
Regarding the differentially methylated positions (DMP), it was striking that a number of the underlying genes had a known cardiovascular function, since these DMPs are identified in DNA of peripheral whole-blood samples, DNA of white blood cells

Summary

Introduction

Marfan syndrome (MFS) is a dominant autosomal disorder caused by mutations in the Fibrillin-1 (FBN1) gene, which results in a connective tissue defect. The multitude in FBN1-mutations, leading to for example defining dominant negative or haploinsufficient FBN1expression phenotypes, have been implicated in disease severity and response to pharmaceutical treatments [2,3,4,5,6]. Genetic variations in other genes at other chromosomal loci have been reported to be associate with enhanced aorta pathology MFS, such as COL4A1 and PRKG1, which are considered genetic modifiers [9]. Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the Fibrillin-1 gene (FBN1). 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

Results

Discussion

Conclusion