Genome-wide methylation patterns in Marfan syndrome

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.

Genotype-phenotype correlations of marfan syndrome and related fibrillinopathies: Phenomenon and molecular relevance

“…Thus, patients with variants of high risks of aortic events should receive more frequent examinations while those carrying less deleterious variants should not be exempted from follow-up, considering the life-long risks of aortic dissection ( Gaudry et al, 2021 ). Researchers have explored other factors contributing to the phenotypes, including FBN1 expression at mRNA and protein level ( Aoyama et al, 1994 ; Aubart et al, 2015 ), modifying genes ( Aubart et al, 2018 ), and epigenetic factors ( van Andel et al, 2021 ). Thus, a prediction model of phenotype and prognosis is warranted in the future which should incorporate both genotypes and modifying factors.…”

“…Epigenetic factors were found to influence the aortic manifestations and progression in patients with MFS too. Van Andel et al identified 28 differentially methylated regions (DMPs) associated with aortic diameters, 7 DMPs with aortic diameter growth, and 5 DMPs with aortic events by genome-wide DNA-methylation profiling of peripheral whole-blood samples ( van Andel et al, 2021 ). Meanwhile, around 0.64% of MFS patients carried more than one FBN1 gene variant which could be overlooked in routine examinations ( Arnaud et al, 2017 ).…”

Integrated DNA methylation analysis reveals a potential role for PTPRN2 in Marfan syndrome scoliosis

“…[5][6][7] MFS exhibits considerable phenotypic variation, including within families that carry the same genetic mutation. 8 Numerous patient characteristics have been explored to explicate the significant phenotypic variation observed in MFS. 9 A diverse array of mutation types and sites in the FBN1 gene has been linked to disease severity and response to pharmaceutical interventions.…”

“…MFS exhibits considerable phenotypic variation, including within families that carry the same genetic mutation 8 . Numerous patient characteristics have been explored to explicate the significant phenotypic variation observed in MFS 9 .…”

Integrated DNA methylation analysis reveals a potential role for PTPRN2 in Marfan syndrome scoliosis

“…MFS exhibits considerable phenotypic variation, including within families that carry the same genetic mutation [7]. Numerous patient characteristics have been explored to explicate the signi cant phenotypic variation observed in MFS [8].…”