The potential role of DNA methylation in the pathogenesis of abdominal aortic aneurysm


      • AAA is a chronic degenerative disease of the aorta with several risk factors.
      • Genetic studies have identified multiple loci that increase disease susceptibility.
      • Changes in DNA methylation status are associated with every major hallmark of AAA.
      • Hallmarks include proteolysis, inflammation, vascular cell death, smoking and ageing.
      • There is no conclusive evidence of this link and future research is recommended.


      Abdominal aortic aneurysm (AAA) is characterised by the chronic degradation and gradual, irreversible dilation of the abdominal aorta. Smoking, genetics, male sex and increased age are major factors associated with developing AAA. Rupture contributes to around 2% of deaths in all Caucasians over 65, and there is no pharmaco-therapeutic treatment. Methylation is an epigenetic modification to DNA, where a methyl group is added to a cytosine base 5′ to a guanine (CpG dinucleotide). Methylation patterns are long term, inherited signatures that can induce changes in gene transcription, and can be affected by both genetic and environmental factors. Methylation changes are involved in hypertension and atherosclerosis, both of which are risk factors of, and often coexist with AAA. Extra-cellular matrix degradation and inflammation, both important pathological hallmarks of AAA, are also promoted by changes in CpG methylation in other diseases. Additionally, the adverse effects of smoking and ageing take place largely through epigenetic manipulation of the genome. Every factor associated with AAA appears to be associated with DNA methylation, yet no direct evidence confirms this. Future work to identify a link between global methylation and AAA, and differentially methylated regions may reveal valuable insight. The identification of a common epigenetic switching process may also signify a promising future for AAA pharmaco-therapeutic strategies. Epigenetic therapies are being designed to target pathogenic CpG methylation changes in other diseases, and it is feasible that these therapies may also be applicable to AAA in the future.


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        • Abraha I.
        • Romagnoli C.
        • Montedori A.
        • et al.
        Thoracic stent graft versus surgery for thoracic aneurysm.
        Cochrane Database Syst. Rev. 2009; : Cd006796
        • Lu H.
        • Rateri D.L.
        • Bruemmer D.
        • et al.
        Novel mechanisms of abdominal aortic aneurysms.
        Curr. Atheroscler. Rep. 2012; 14: 402-412
        • Earnshaw J.J.
        Triumphs and tribulations in a new national screening programme for abdominal aortic aneurysm.
        Acta Chir. Belg. 2012; 112: 108-110
        • Thompson S.G.
        • Ashton H.A.
        • Gao L.
        • et al.
        Screening men for abdominal aortic aneurysm: 10 year mortality and cost effectiveness results from the randomised multicentre aneurysm screening Study.
        BMJ. 2009; 338: b2307
        • Moll F.L.
        • Powell J.T.
        • Fraedrich G.
        • et al.
        Management of abdominal aortic aneurysms clinical practice guidelines of the European society for vascular surgery.
        Eur. J. Vasc. Endovasc. Surg. 2011; 41: S1-s58
        • Kuivaniemi H.
        • Ryer E.J.
        • Elmore J.R.
        • et al.
        Update on abdominal aortic aneurysm research: from clinical to genetic studies.
        Sci. (Cairo). 2014; 2014: 564734
        • Harrison S.C.
        • Kalea A.Z.
        • Holmes M.V.
        • et al.
        Genomic research to identify novel pathways in the development of abdominal aortic aneurysm.
        Cardiol. Res. Pract. 2012; 2012: 852829
        • Saratzis A.
        • Bown M.J.
        The genetic basis for aortic aneurysmal disease.
        Heart (Br. Card. Soc.). 2014; 100: 916-922
        • Bown M.J.
        • Sweeting M.J.
        • Brown L.C.
        • et al.
        Surveillance intervals for small abdominal aortic aneurysms: a meta-analysis.
        JAMA. 2013; 309: 806-813
        • Liyanage V.R.
        • Jarmasz J.S.
        • Murugeshan N.
        • et al.
        DNA modifications: function and applications in normal and disease States.
        Biol. (Basel). 2014; 3: 670-723
        • Zaina S.
        • Heyn H.
        • Carmona F.J.
        • et al.
        A DNA methylation map of human atherosclerosis, circulation.
        Cardiovasc. Genet. 2014; 7: 692-700
        • Participants, TUSAT
        Mortality results for randomised controlled trial of early elective surgery or ultrasonographic surveillance for small abdominal aortic aneurysms. The UK small aneurysm trial participants.
        Lancet. 1998; 352: 1649-1655
        • Davis F.M.
        • Rateri D.L.
        • Daugherty A.
        Mechanisms of aortic aneurysm formation: translating preclinical studies into clinical therapies.
        Heart (Br. Card. Soc. 2014; 100: 1498-1505
        • Campbell W.B.
        Mortality statistics for elective aortic aneurysms.
        Eur. J. Vasc. Surg. 1991; 5: 111-113
        • Participants, UKSAT
        Long-term outcomes of immediate repair compared with surveillance of small abdominal aortic aneurysms.
        N. Engl. J. Med. 2002; 346: 1445-1452
        • Svensjo S.
        • Bjorck M.
        • Gurtelschmid M.
        • et al.
        Low prevalence of abdominal aortic aneurysm among 65-year-old Swedish men indicates a change in the epidemiology of the disease.
        Circulation. 2011; 124: 1118-1123
        • Earnshaw J.J.
        • Shaw E.
        • Whyman M.R.
        • et al.
        Screening for abdominal aortic aneurysms in men.
        BMJ. 2004; 328: 1122-1124
        • Eckroth-Bernard K.
        • Garvin R.
        • Ryer E.
        Current status of endovascular devices to treat abdominal aortic aneurysms.
        Biomed. Eng. Comput Biol. 2013; 5: 25-32
        • Holt P.J.
        • Poloniecki J.D.
        • Gerrard D.
        • et al.
        Meta-analysis and systematic review of the relationship between volume and outcome in abdominal aortic aneurysm surgery.
        Br. J. Surg. 2007; 94: 395-403
        • Ketelsen D.
        • Thomas C.
        • Schmehl J.
        • et al.
        Endovascular aneurysm repair of abdominal aortic aneurysms: standards, technical options and advanced indications.
        RoFo. 2014; 186 (Fortschritte auf dem Gebiete der Rontgenstrahlen und der Nuklearmedizin): 337-347
        • Saratzis A.
        • Abbas A.A.
        • Kiskinis D.
        • et al.
        Abdominal aortic aneurysm: a review of the genetic basis.
        Angiology. 2011; 62: 18-32
        • Wahlgren C.M.
        • Larsson E.
        • Magnusson P.K.
        • et al.
        Genetic and environmental contributions to abdominal aortic aneurysm development in a twin population.
        J. Vasc. Surg. 2010; 51 (discussion 7): 3-7
        • Golledge J.
        • Kuivaniemi H.
        Genetics of abdominal aortic aneurysm.
        Curr. Opin. Cardiol. 2013; 28: 290-296
        • Kuivaniemi H.
        • Elmore J.R.
        Opportunities in abdominal aortic aneurysm research: epidemiology, genetics, and pathophysiology.
        Ann. Vasc. Surg. 2012; 26: 862-870
        • Majumder P.P.
        • St Jean P.L.
        • Ferrell R.E.
        • et al.
        On the inheritance of abdominal aortic aneurysm.
        Am. J. Hum. Genet. 1991; 48: 164-170
        • Powell J.T.
        • Greenhalgh R.M.
        Multifactorial inheritance of abdominal aortic aneurysm.
        Eur. J. Vasc. Surg. 1987; 1: 29-31
        • Bown M.J.
        • Jones G.T.
        • Harrison S.C.
        • et al.
        Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1.
        Am. J. Hum. Genet. 2011; 89: 619-627
        • Jones G.T.
        • Bown M.J.
        • Gretarsdottir S.
        • et al.
        A sequence variant associated with sortilin-1 (SORT1) on 1p13.3 is independently associated with abdominal aortic aneurysm.
        Hum. Mol. Genet. 2013; 22: 2941-2947
        • Bradley D.T.
        • Hughes A.E.
        • Badger S.A.
        • et al.
        A variant in LDLR is associated with abdominal aortic aneurysm.
        Circ. Cardiovasc. Genet. 2013; 6: 498-504
        • Goldberg A.D.
        • Allis C.D.
        • Bernstein E.
        Epigenetics: a landscape takes shape.
        Cell. 2007; 128: 635-638
        • Conaway J.W.
        Introduction to theme “Chromatin, epigenetics, and transcription.
        Annu. Rev. Biochem. 2012; 81: 61-64
        • Roth T.L.
        • Sweatt J.D.
        Annual research review: epigenetic mechanisms and environmental shaping of the brain during sensitive periods of development.
        J. Child Psychol. Psychiatry Allied Discip. 2011; 52: 398-408
        • Jaenisch R.
        • Bird A.
        Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals.
        Nat. Genet. 2003; 33: 245-254
        • Clark C.
        • Palta P.
        • Joyce C.J.
        • et al.
        A comparison of the whole genome approach of MeDIP-seq to the targeted approach of the infinium HumanMethylation450 BeadChip((R)) for methylome profiling,.
        PLoS One. 2012; 7: e50233
        • Michels K.B.
        • Binder A.M.
        • Dedeurwaerder S.
        • et al.
        Recommendations for the design and analysis of epigenome-wide association studies.
        Nat. Methods. 2013; 10: 949-955
        • Bannister A.J.
        • Kouzarides T.
        Regulation of chromatin by histone modifications.
        Cell Res. 2011; 21: 381-395
        • Jeltsch A.
        Reading and writing DNA methylation.
        Nat. Struct. Mol. Biol. 2008; 15: 1003-1004
        • Bird A.
        DNA methylation patterns and epigenetic memory.
        Genes Dev. 2002; 16: 6-21
        • Tsaprouni L.G.
        • Yang T.P.
        • Bell J.
        • et al.
        Cigarette smoking reduces DNA methylation levels at multiple genomic loci but the effect is partially reversible upon cessation.
        Epigenet. Off. J. DNA Methylation Soc. 2014; 9: 1382-1396
        • Glier M.B.
        • Green T.J.
        • Devlin A.M.
        Methyl nutrients, DNA methylation, and cardiovascular disease.
        Mol. Nutr. Food Res. 2014; 58: 172-182
        • Wongtrakoongate P.
        Epigenetic therapy of cancer stem and progenitor cells by targeting DNA methylation machineries.
        World J. Stem Cells. 2015; 7: 137-148
        • Egger G.
        • Liang G.
        • Aparicio A.
        • et al.
        Epigenetics in human disease and prospects for epigenetic therapy.
        Nature. 2004; 429: 457-463
        • Kawasaki H.
        • Taira K.
        Induction of DNA methylation and gene silencing by short interfering RNAs in human cells.
        Nature. 2004; 431: 211-217
        • Cao Q.
        • Wang X.
        • Jia L.
        • et al.
        Inhibiting DNA methylation by 5-aza-2'-deoxycytidine ameliorates atherosclerosis through suppressing macrophage inflammation.
        Endocrinology. 2014; 155: 4925-4938
        • Yang X.
        • Han H.
        • De Carvalho D.D.
        • et al.
        Gene body methylation can alter gene expression and is a therapeutic target in cancer.
        Cancer Cell. 2014; 26: 577-590
        • Robertson A.K.
        • Geiman T.M.
        • Sankpal U.T.
        • et al.
        Effects of chromatin structure on the enzymatic and DNA binding functions of DNA methyltransferases DNMT1 and Dnmt3a in vitro.
        Biochem. Biophys. Res. Commun. 2004; 322: 110-118
        • Chuang L.S.
        • Ian H.I.
        • Koh T.W.
        • et al.
        Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for p21WAF1.
        Sci. (N. Y., N. Y.). 1997; 277: 1996-2000
      1. Kroeze, LI, van der Reijden, BA and Jansen, JH, 5-Hydroxymethylcytosine: an epigenetic mark frequently deregulated in cancer, Biochim. Biophys. Acta (BBA) – Rev. Cancer 1855 (2), 144–154.

        • Drong A.W.
        • Nicholson G.
        • Hedman A.K.
        • et al.
        The presence of methylation quantitative trait loci indicates a direct genetic influence on the level of DNA methylation in adipose tissue,.
        PLoS One. 2013; 8: e55923
        • Zhi D.
        • Aslibekyan S.
        • Irvin M.R.
        • et al.
        SNPs located at CpG sites modulate genome-epigenome interaction.
        Epigenet. Off. J. DNA Methylation Soc. 2013; 8: 802-806
        • Robertson K.D.
        DNA methylation and human disease, nature reviews.
        Genetics. 2005; 6: 597-610
        • Marian A.J.
        • Belmont J.
        Strategic approaches to unraveling genetic causes of cardiovascular diseases.
        Circ. Res. 2011; 108: 1252-1269
        • Wang X.
        • Falkner B.
        • Zhu H.
        • et al.
        A genome-wide methylation study on essential hypertension in young African American males,.
        PLoS One. 2013; 8: e53938
        • Hur K.
        • Han T.S.
        • Jung E.J.
        • et al.
        Up-regulated expression of sulfatases (SULF1 and SULF2) as prognostic and metastasis predictive markers in human gastric cancer.
        J. Pathol. 2012; 228: 88-98
        • Baccarelli A.
        • Wright R.
        • Bollati V.
        • et al.
        Ischemic heart disease and stroke in relation to blood DNA methylation.
        Epidemiol. (Camb. Mass). 2010; 21: 819-828
        • Krishna S.M.
        • Dear A.
        • Craig J.M.
        • et al.
        The potential role of homocysteine mediated DNA methylation and associated epigenetic changes in abdominal aortic aneurysm formation,.
        Atherosclerosis. 2013; 228: 295-305
        • Krishna S.M.
        • Dear A.E.
        • Norman P.E.
        • et al.
        Genetic and epigenetic mechanisms and their possible role in abdominal aortic aneurysm.
        Atherosclerosis. 2010; 212: 16-29
        • Diehm N.
        • Dick F.
        • Schaffner T.
        • et al.
        Novel insight into the pathobiology of abdominal aortic aneurysm and potential future treatment concepts.
        Prog. Cardiovasc. Dis. 2007; 50: 209-217
        • Ailawadi G.
        • Knipp B.S.
        • Lu G.
        • et al.
        A nonintrinsic regional basis for increased infrarenal aortic MMP-9 expression and activity,.
        J. Vasc. Surg. 2003; 37: 1059-1066
        • Pearce W.H.
        • Shively V.P.
        Abdominal aortic aneurysm as a complex multifactorial disease: interactions of polymorphisms of inflammatory genes, features of autoimmunity, and current status of MMPs.
        Ann. N. Y. Acad. Sci. 2006; 1085: 117-132
        • Dobrin P.B.
        • Mrkvicka R.
        Failure of elastin or collagen as possible critical connective tissue alterations underlying aneurysmal dilatation.
        Cardiovasc. Surg. Lond. Engl. 1994; 2: 484-488
        • Wassef M.
        • Baxter B.T.
        • Chisholm R.L.
        • et al.
        Pathogenesis of abdominal aortic aneurysms: a multidisciplinary research program supported by the National Heart, Lung, and Blood Institute,.
        J. Vasc. Surg. 2001; 34: 730-738
        • Thompson R.W.
        • Liao S.
        • Curci J.A.
        Vascular smooth muscle cell apoptosis in abdominal aortic aneurysms.
        Coron. Artery Dis. 1997; 8: 623-631
        • Sakalihasan N.
        • Delvenne P.
        • Nusgens B.V.
        • et al.
        Activated forms of MMP2 and MMP9 in abdominal aortic aneurysms.
        J. Vasc. Surg. 1996; 24: 127-133
        • Longo G.M.
        • Buda S.J.
        • Fiotta N.
        • et al.
        MMP-12 has a role in abdominal aortic aneurysms in mice.
        Surgery. 2005; 137: 457-462
        • Zhang S.
        • Zhong B.
        • Chen M.
        • et al.
        Epigenetic reprogramming reverses the malignant epigenotype of the MMP/TIMP axis genes in tumor cells.
        Int. J. Cancer J. Int. du cancer. 2014; 134: 1583-1594
        • Stenvinkel P.
        • Karimi M.
        • Johansson S.
        • et al.
        Impact of inflammation on epigenetic DNA methylation - a novel risk factor for cardiovascular disease?.
        J. Intern. Med. 2007; 261: 488-499
        • Fuggle N.R.
        • Howe F.A.
        • Allen R.L.
        • et al.
        New insights into the impact of neuro-inflammation in rheumatoid arthritis.
        Front. Neurosci. 2014; 8: 357
        • Pereira I.T.
        • Ramos E.A.
        • Costa E.T.
        • et al.
        Fibronectin affects transient MMP2 gene expression through DNA demethylation changes in non-invasive breast cancer cell lines.
        PLoS One. 2014; 9 (e105806)
        • Yuan C.
        • Zhang L.
        • Gao Y.
        • et al.
        DNA demethylation at the promoter region enhances the expression of MMP-9 in ectopic endometrial stromal cells of endometriosis.
        Xi bao yu fen zi mian yi xue za zhi = Chin. J. Cell. Mol. Immunol. 2014; 30: 1258-1261
        • Liu Y.
        • Aryee M.J.
        • Padyukov L.
        • et al.
        Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis.
        Nat. Biotechnol. 2013; 31: 142-147
        • St-Pierre Y.
        • Van Themsche C.
        • Esteve P.O.
        Emerging features in the regulation of MMP-9 gene expression for the development of novel molecular targets and therapeutic strategies, current drug targets.
        Inflamm. Allergy. 2003; 2: 206-215
        • Xue M.
        • Le N.T.
        • Jackson C.J.
        Targeting matrix metalloproteases to improve cutaneous wound healing.
        Expert Opin. Ther. Targets. 2006; 10: 143-155
        • Amar S.
        • Engelke M.
        Periodontal innate immune mechanisms relevant to atherosclerosis.
        Mol. Oral Microbiol. 2014; 30: 171-185
        • Parks W.C.
        • Wilson C.L.
        • Lopez-Boado Y.S.
        Matrix metalloproteinases as modulators of inflammation and innate immunity.
        Nat. Rev. Immunol. 2004; 4: 617-629
        • Golledge J.
        • Norman P.E.
        Atherosclerosis and abdominal aortic aneurysm: cause, response, or common risk factors?, Arteriosclerosis.
        Thromb. Vasc. Biol. 2010; 30: 1075-1077
        • Shimizu K.
        • Mitchell R.N.
        • Libby P.
        Inflammation and cellular immune responses in abdominal aortic aneurysms, Arteriosclerosis.
        Thromb. Vasc. Biol. 2006; 26: 987-994
        • Golledge J.
        • Karan M.
        • Moran C.S.
        • et al.
        Reduced expansion rate of abdominal aortic aneurysms in patients with diabetes may be related to aberrant monocyte-matrix interactions.
        Eur. Heart J. 2008; 29: 665-672
        • Samadzadeh K.M.
        • Chun K.C.
        • Nguyen A.T.
        • et al.
        Monocyte activity is linked with abdominal aortic aneurysm diameter.
        J. Surg. Res. 2014; 190: 328-334
        • Chatzizisis Y.S.
        • Coskun A.U.
        • Jonas M.
        • et al.
        Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular, and vascular behavior.
        J. Am. Coll. Cardiol. 2007; 49: 2379-2393
        • Cutolo M.
        • Paolino S.
        • Pizzorni C.
        Possible contribution of chronic inflammation in the induction of cancer in rheumatic diseases.
        Clin. Exp. Rheumatol. 2014; 32: 839-847
        • Gunawardhana L.P.
        • Gibson P.G.
        • Simpson J.L.
        • et al.
        Characteristic DNA methylation profiles in peripheral blood monocytes are associated with inflammatory phenotypes of asthma.
        Epigenet. Off. J. DNA Methylation Soc. 2014; 9: 1302-1316
        • Nordon I.M.
        • Hinchliffe R.J.
        • Loftus I.M.
        • et al.
        Pathophysiology and epidemiology of abdominal aortic aneurysms, nature reviews.
        Cardiology. 2011; 8: 92-102
        • Cornuz J.
        • Sidoti Pinto C.
        • Tevaearai H.
        • et al.
        Risk factors for asymptomatic abdominal aortic aneurysm: systematic review and meta-analysis of population-based screening studies.
        Eur. J. Public Health. 2004; 14: 343-349
        • Sweeting M.J.
        • Thompson S.G.
        • Brown L.C.
        • et al.
        Meta-analysis of individual patient data to examine factors affecting growth and rupture of small abdominal aortic aneurysms.
        Br. J. Surg. 2012; 99: 655-665
        • Norman P.E.
        • Curci J.A.
        Understanding the effects of tobacco smoke on the pathogenesis of aortic aneurysm, Arteriosclerosis.
        Thromb. Vasc. Biol. 2013; 33: 1473-1477
        • Wan E.S.
        • Qiu W.
        • Baccarelli A.
        • et al.
        Cigarette smoking behaviors and time since quitting are associated with differential DNA methylation across the human genome.
        Hum. Mol. Genet. 2012; 21: 3073-3082
        • Lee K.W.
        • Pausova Z.
        Cigarette smoking and DNA methylation.
        Front. Genet. 2013; 4: 132
        • Bergoeing M.P.
        • Arif B.
        • Hackmann A.E.
        • et al.
        Cigarette smoking increases aortic dilatation without affecting matrix metalloproteinase-9 and -12 expression in a modified mouse model of aneurysm formation.
        J. Vasc. Surg. 2007; 45: 1217-1227
        • Horvath S.
        DNA methylation age of human tissues and cell types.
        Genome Biol. 2013; 14 (R115)
        • Zykovich A.
        • Hubbard A.
        • Flynn J.M.
        • et al.
        Genome-wide DNA methylation changes with age in disease-free human skeletal muscle.
        Aging Cell. 2014; 13: 360-366
        • Johnson A.A.
        • Akman K.
        • Calimport S.R.
        • et al.
        The role of DNA methylation in aging, rejuvenation, and age-related disease,.
        Rejuvenation Res. 2012; 15: 483-494
        • Guay S.P.
        • Legare C.
        • Houde A.A.
        • et al.
        Acetylsalicylic acid, aging and coronary artery disease are associated with ABCA1 DNA methylation in men.
        Clin. Epigenet. 2014; 6: 14
        • Alcazar O.
        • Achberger S.
        • Aldrich W.
        • et al.
        Epigenetic regulation by decitabine of melanoma differentiation in vitro and in vivo.
        Int. J. Cancer J. Int. du cancer. 2012; 131: 18-29
        • Chouliaras L.
        • van den Hove D.L.
        • Kenis G.
        • et al.
        Histone deacetylase 2 in the mouse hippocampus: attenuation of age-related increase by caloric restriction.
        Curr. Alzheimer Res. 2013; 10: 868-876
        • Martin S.L.
        • Hardy T.M.
        • Tollefsbol T.O.
        Medicinal chemistry of the epigenetic diet and caloric restriction.
        Curr. Med. Chem. 2013; 20: 4050-4059
        • Shukeir N.
        • Stefanska B.
        • Parashar S.
        • et al.
        Pharmacological methyl group donors block skeletal metastasis in vitro and in vivo.
        Br. J. Pharmacol. 2015; ([Epub ahead of print])