Genome-wide methylation patterns in Marfan syndrome.
Aortic diameters
Clinical events
EWAS
Marfan syndrome
Methylation loci
Journal
Clinical epigenetics
ISSN: 1868-7083
Titre abrégé: Clin Epigenetics
Pays: Germany
ID NLM: 101516977
Informations de publication
Date de publication:
11 12 2021
11 12 2021
Historique:
received:
17
09
2021
accepted:
27
11
2021
entrez:
13
12
2021
pubmed:
14
12
2021
medline:
1
2
2022
Statut:
epublish
Résumé
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. 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. 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 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.
Sections du résumé
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
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.
Identifiants
pubmed: 34895303
doi: 10.1186/s13148-021-01204-4
pii: 10.1186/s13148-021-01204-4
pmc: PMC8665617
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
217Informations de copyright
© 2021. The Author(s).
Références
J Am Heart Assoc. 2018 Mar 7;7(6):
pubmed: 29514810
Arterioscler Thromb Vasc Biol. 2019 Sep;39(9):1859-1873
pubmed: 31315432
Eur Heart J. 2016 Nov 14;37(43):3285-3290
pubmed: 26787436
Science. 2020 Oct 2;370(6512):113-116
pubmed: 33004519
Circulation. 2017 Oct 17;136(16):1528-1544
pubmed: 28838933
PLoS One. 2016 May 17;11(5):e0154856
pubmed: 27187494
Circulation. 2010 Jun 1;121(21):2302-9
pubmed: 20479155
Front Mol Neurosci. 2020 Jun 30;13:117
pubmed: 32694982
Mol Cell Proteomics. 2015 Mar;14(3):456-70
pubmed: 25616866
Circulation. 2019 Aug 20;140(8):645-657
pubmed: 31424985
BMC Bioinformatics. 2012 May 08;13:86
pubmed: 22568884
Ther Adv Endocrinol Metab. 2020 Oct 4;11:2042018820958331
pubmed: 33088475
PLoS One. 2016 Jul 29;11(7):e0160168
pubmed: 27472518
Circ Res. 2014 Mar 14;114(6):957-65
pubmed: 24478334
Birth Defects Res. 2017 Jan 20;109(1):8-15
pubmed: 28009100
Gene. 2016 Dec 20;595(1):62-68
pubmed: 27693370
Med Sci Monit. 2019 Oct 09;25:7581-7590
pubmed: 31595884
Nat Genet. 2015 Nov;47(11):1282-1293
pubmed: 26390057
Heart. 2017 Nov;103(22):1795-1799
pubmed: 28468757
J Hypertens. 2016 Nov;34(11):2206-19
pubmed: 27512969
Am J Hypertens. 2010 Jan;23(1):70-7
pubmed: 19851296
Proc Natl Acad Sci U S A. 2019 Sep 10;116(37):18455-18465
pubmed: 31451669
Atherosclerosis. 2015 Nov;243(1):30-7
pubmed: 26343869
Nat Commun. 2019 Dec 20;10(1):5828
pubmed: 31862885
Curr Med Sci. 2018 Dec;38(6):989-996
pubmed: 30536060
Circulation. 2020 Oct 6;142(14):1374-1388
pubmed: 33017217
Hum Mutat. 2003 Sep;22(3):199-208
pubmed: 12938084
J Am Acad Orthop Surg. 2017 Sep;25(9):603-609
pubmed: 28837453
Circulation. 2019 Aug 6;140(6):500-513
pubmed: 31163988
Circ Res. 2021 Mar 5;128(5):e84-e101
pubmed: 33508947
Oncotarget. 2017 Dec 4;8(67):112152-112165
pubmed: 29340119
Genomics. 2017 Oct;109(5-6):391-400
pubmed: 28648597
J Am Heart Assoc. 2019 Oct 15;8(20):e013743
pubmed: 31595818
PLoS Genet. 2011 Nov;7(11):e1002344
pubmed: 22072978
Ann N Y Acad Sci. 2021 Apr;1490(1):57-76
pubmed: 32880985
Eur J Hum Genet. 2018 Dec;26(12):1759-1772
pubmed: 30087447
Pediatr Cardiol. 2019 Oct;40(7):1410-1418
pubmed: 31399780
Arterioscler Thromb Vasc Biol. 2015 Apr;35(4):960-72
pubmed: 25593132
Genes (Basel). 2019 Feb 11;10(2):
pubmed: 30754709
Pediatr Cardiol. 2018 Aug;39(6):1069-1081
pubmed: 29569026
J Biol Chem. 2010 Aug 13;285(33):25677-85
pubmed: 20562105
Thromb Haemost. 2015 Oct;114(4):748-56
pubmed: 26063524
Free Radic Biol Med. 2017 Aug;109:125-131
pubmed: 27993729
J Med Genet. 2010 Jul;47(7):476-85
pubmed: 20591885
Trials. 2010 Jan 12;11:3
pubmed: 20067609
Genet Med. 2021 Jul;23(7):1296-1304
pubmed: 33731877
Virchows Arch. 2000 Jan;436(1):12-9
pubmed: 10664157
J Clin Invest. 2013 Mar;123(3):1359-70
pubmed: 23434587
Int J Cardiol. 2013 Oct 3;168(3):2441-6
pubmed: 23582687
Nat Genet. 2011 Mar 06;43(4):333-8
pubmed: 21378990
Reprod Sci. 2018 Apr;25(4):523-539
pubmed: 28693373
Epigenetics. 2021 Jan 25;:1-17
pubmed: 33487124
Circ Res. 2020 Jan 31;126(3):377-394
pubmed: 31999538
Ann Hum Genet. 2008 Jul;72(Pt 4):443-53
pubmed: 18318786
Circ Cardiovasc Genet. 2015 Apr;8(2):383-8
pubmed: 25613431
J Cell Sci. 2021 Feb 17;134(4):
pubmed: 33597154
Eur Heart J. 2013 Dec;34(45):3491-500
pubmed: 23999449
Curr Genomics. 2021 Feb;22(2):79-87
pubmed: 34220295
Arterioscler Thromb Vasc Biol. 2020 Sep;40(9):2195-2211
pubmed: 32698686
Tumour Biol. 2016 Nov;37(11):14687-14699
pubmed: 27623942
Hypertension. 2014 Feb;63(2):397-403
pubmed: 24166750
Clin Genet. 2019 Jan;95(1):85-94
pubmed: 29767458
Eur Heart J. 2020 Nov 14;41(43):4181-4187
pubmed: 32548624
Mech Dev. 2019 Apr;156:8-19
pubmed: 30796970
Exp Dermatol. 2020 Jan;29(1):39-50
pubmed: 31602702
Front Physiol. 2018 Aug 21;9:965
pubmed: 30246778
EMBO Rep. 2017 Jul;18(7):1166-1185
pubmed: 28588072
J Reprod Dev. 2017 Apr 21;63(2):157-165
pubmed: 28111381
Circ Res. 2015 Apr 10;116(8):1448-61
pubmed: 25858068
Dis Markers. 2015;2015:657570
pubmed: 25802477
Nat Genet. 2015 Oct;47(10):1206-11
pubmed: 26301497
Heart Vessels. 2014 Jul;29(4):478-85
pubmed: 23852405
J Bone Joint Surg Am. 1995 Jun;77(6):867-76
pubmed: 7782359
Clin Epigenetics. 2021 Feb 25;13(1):43
pubmed: 33632303
Curr Top Dev Biol. 2017;122:223-243
pubmed: 28057265
Heart Fail Rev. 2010 Mar;15(2):133-42
pubmed: 19107595
Nat Commun. 2020 Aug 21;11(1):4187
pubmed: 32826901
Am J Med Genet A. 2021 Mar;185(3):889-893
pubmed: 33369061
Am J Cardiol. 2010 Oct 1;106(7):1048-53
pubmed: 20854973
Hum Mol Genet. 2015 May 15;24(10):2764-70
pubmed: 25652400
Histochem Cell Biol. 2015 Jul;144(1):39-48
pubmed: 25744490