Download PDF
CC BY-NC-ND 4.0 · Aorta (Stamford) 2023; 11(03): 125-134
DOI: 10.1055/s-0043-57266
State-of-the-Art-Review

Comparison of Genes Associated with Thoracic and Abdominal Aortic Aneurysms

Argyrios Gyftopoulos
1   National Kapodistrian University of Athens, School of Medicine, Athens, Greece
,
Bulat A. Ziganshin
2   Aortic Institute, Yale University School of Medicine, New Haven, Connecticut
,
John A. Elefteriades 
2   Aortic Institute, Yale University School of Medicine, New Haven, Connecticut
,
Cassius I. Ochoa Chaar
3   Division of Vascular Surgery and Endovascular Therapy, Department of Surgery, Yale University School of Medicine, New Haven, Connecticut
› Author Affiliations Funding None.
› Further Information
   Permissions and Reprints

Abstract

Aneurysms impacting the ascending thoracic aorta and the abdominal aorta affect patient populations with distinct clinical characteristics. Through a literature review, this paper compares the genetic associations of ascending thoracic aortic aneurysm (ATAA) with abdominal aortic aneurysms (AAA). Genes related to atherosclerosis, lipid metabolism, and tumor development are associated specifically with sporadic AAA, while genes controlling extracellular matrix (ECM) structure, ECM remodeling, and tumor growth factor β function are associated with both AAA and ATAA. Contractile element genes uniquely predispose to ATAA. Aside from known syndromic connective tissue disease and poly-aneurysmal syndromes (Marfan disease, Loeys–Dietz syndrome, and Ehlers–Danlos syndrome), there is only limited genetic overlap between AAA and ATAA. The rapid advances in genotyping and bioinformatics will elucidate further the various pathways associated with the development of aneurysms affecting various parts of the aorta.

Keywords

abdominal aortic aneurysm - thoracic aortic aneurysm - genetics - mutation - polymorphism


Publication History

Received: 23 June 2022

Accepted: 09 December 2022

Article published online:
06 June 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Cornuz J, Sidoti Pinto C, Tevaearai H, Egger M. Risk factors for asymptomatic abdominal aortic aneurysm: systematic review and meta-analysis of population-based screening studies. Eur J Public Health 2004; 14 (04) 343-349
    CrossrefPubMedGoogle Scholar
  • 2 Wahlgren CM, Larsson E, Magnusson PKE, Hultgren R, Swedenborg J. Genetic and environmental contributions to abdominal aortic aneurysm development in a twin population. J Vasc Surg 2010; 51 (01) 3-7 , discussion 7
    CrossrefPubMedGoogle Scholar
  • 3 Achneck H, Modi B, Shaw C. et al. Ascending thoracic aneurysms are associated with decreased systemic atherosclerosis. Chest 2005; 128 (03) 1580-1586
    CrossrefPubMedGoogle Scholar
  • 4 Saeyeldin AA, Velasquez CA, Mahmood SUB. et al. Thoracic aortic aneurysm: unlocking the “silent killer” secrets. Gen Thorac Cardiovasc Surg 2019; 67 (01) 1-11
    CrossrefPubMedGoogle Scholar
  • 5 Elefteriades JA, Farkas EA. Thoracic aortic aneurysm clinically pertinent controversies and uncertainties. J Am Coll Cardiol 2010; 55 (09) 841-857
    CrossrefPubMedGoogle Scholar
  • 6 Vinholo TF, Brownstein AJ, Ziganshin BA. et al. Genes associated with thoracic aortic aneurysm and dissection: 2019 update and clinical implications. Aorta (Stamford) 2019; 7 (04) 99-107
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Rohde S, Zafar MA, Ziganshin BA, Elefteriades JA. Thoracic aortic aneurysm gene dictionary. Asian Cardiovasc Thorac Ann 2021; 29 (07) 682-696
    CrossrefPubMedGoogle Scholar
  • 8 Jones GT, Tromp G, Kuivaniemi H. et al. Meta-analysis of genome-wide association studies for abdominal aortic aneurysm identifies four new disease-specific risk loci. Circ Res 2017; 120 (02) 341-353
    CrossrefPubMedGoogle Scholar
  • 9 Visscher PM, Brown MA, McCarthy MI, Yang J. Five years of GWAS discovery. Am J Hum Genet 2012; 90 (01) 7-24
    CrossrefPubMedGoogle Scholar
  • 10 Klarin D, Verma SS, Judy R. et al; Veterans Affairs Million Veteran Program†. Genetic architecture of abdominal aortic aneurysm in the million veteran program. Circulation 2020; 142 (17) 1633-1646
    CrossrefPubMedGoogle Scholar
  • 11 Ye Z, Austin E, Schaid DJ, Kullo IJ. A multi-locus genetic risk score for abdominal aortic aneurysm. Atherosclerosis 2016; 246: 274-279
    CrossrefPubMedGoogle Scholar
  • 12 Eriksson P, Jones KG, Brown LC, Greenhalgh RM, Hamsten A, Powell JT. Genetic approach to the role of cysteine proteases in the expansion of abdominal aortic aneurysms. Br J Surg 2004; 91 (01) 86-89
    CrossrefPubMedGoogle Scholar
  • 13 Thompson AR, Cooper JA, Jones GT. et al. Assessment of the association between genetic polymorphisms in transforming growth factor beta, and its binding protein (LTBP), and the presence, and expansion, of abdominal aortic aneurysm. Atherosclerosis 2010; 209 (02) 367-373
    CrossrefPubMedGoogle Scholar
  • 14 Bellamkonda KS, Nassiri N, Sadeghi MM, Zhang Y, Guzman RJ, Ochoa Chaar CI. Characteristics and outcomes of small abdominal aortic aneurysm rupture in the American College of Surgeons National Surgical Quality Improvement Program database. J Vasc Surg 2021; 74 (03) 729-737
    CrossrefPubMedGoogle Scholar
  • 15 Tcheandjieu C, Xiao K, Tejeda H. et al; Regeneron Genetics Center, VA Million Veterans Program, FinnGen Project. High heritability of ascending aortic diameter and trans-ancestry prediction of thoracic aortic disease. Nat Genet 2022; 54 (06) 772-782
    CrossrefPubMedGoogle Scholar
  • 16 Li Y, Song L, Rong W. et al. Exome risk score for predicting susceptibility to and severity of isolated thoracic aortic aneurysm. Hum Mol Genet 2022; 31 (21) 3672-3682
    CrossrefPubMedGoogle Scholar
  • 17 Pirruccello JP, Chaffin MD, Chou EL. et al. Deep learning enables genetic analysis of the human thoracic aorta. Nat Genet 2022; 54 (01) 40-51
    CrossrefPubMedGoogle Scholar
  • 18 Hultgren R, Larsson E, Wahlgren CM, Swedenborg J. Female and elderly abdominal aortic aneurysm patients more commonly have concurrent thoracic aortic aneurysm. Ann Vasc Surg 2012; 26 (07) 918-923
    CrossrefPubMedGoogle Scholar
  • 19 Dombrowski D, Long GW, Chan J, Brown OW. Screening chest computed tomography is indicated in all patients with abdominal aortic aneurysm. Ann Vasc Surg 2020; 65: 190-195
    CrossrefPubMedGoogle Scholar
  • 20 Dobrin PB, Baker WH, Gley WC. Elastolytic and collagenolytic studies of arteries. Implications for the mechanical properties of aneurysms. Arch Surg 1984; 119 (04) 405-409
    CrossrefPubMedGoogle Scholar
  • 21 Ashvetiya T, Fan SX, Chen YJ. et al. Identification of novel genetic susceptibility loci for thoracic and abdominal aortic aneurysms via genome-wide association study using the UK Biobank Cohort. PLoS One 2021; 16 (09) e0247287
    CrossrefPubMedGoogle Scholar
  • 22 MacSweeney STR, Skidmore C, Turner RJ. et al. Unravelling the familial tendency to aneurysmal disease: popliteal aneurysm, hypertension and fibrillin genotype. Eur J Vasc Endovasc Surg 1996; 12 (02) 162-166
    CrossrefPubMedGoogle Scholar
  • 23 van 't Hof FNG, Ruigrok YM, Lee CH. et al; Aneurysm Consortium; Vascular Research Consortium of New Zealand. Shared genetic risk factors of intracranial, abdominal, and thoracic aneurysms. J Am Heart Assoc 2016; 5 (07) e002603
    CrossrefPubMedGoogle Scholar
  • 24 Kontusaari S, Tromp G, Kuivaniemi H, Ladda R, Prockop D. Inheritance of an RNA splicing mutation (G+ 1 IVS20) in the type III procollagen gene (COL3A1) in a family having aortic aneurysms and easy bruisability: phenotypic overlap between familial arterial aneurysms and Ehlers-Danlos syndrome type IV. J Clin Invest 1990; 86 (05) 1465-1473
    PubMedGoogle Scholar
  • 25 Kontusaari S, Tromp G, Kuivaniemi H, Romanic AM, Prockop DJ. A mutation in the gene for type III procollagen (COL3A1) in a family with aortic aneurysms. J Clin Invest 1990; 86 (05) 1465-1473
    CrossrefPubMedGoogle Scholar
  • 26 Tromp G, Wu Y, Prockop DJ. et al. Sequencing of cDNA from 50 unrelated patients reveals that mutations in the triple-helical domain of type III procollagen are an infrequent cause of aortic aneurysms. J Clin Invest 1993; 91 (06) 2539-2545
    CrossrefPubMedGoogle Scholar
  • 27 Saracini C, Bolli P, Sticchi E. et al. Polymorphisms of genes involved in extracellular matrix remodeling and abdominal aortic aneurysm. J Vasc Surg 2012; 55 (01) 171-179.e2
    CrossrefPubMedGoogle Scholar
  • 28 Jelsig AM, Urban Z, Hucthagowder V, Nissen H, Ousager LB. Novel ELN mutation in a family with supravalvular aortic stenosis and intracranial aneurysm. Eur J Med Genet 2017; 60 (02) 110-113
    CrossrefPubMedGoogle Scholar
  • 29 Renard M, Francis C, Ghosh R. et al. Clinical validity of genes for heritable thoracic aortic aneurysm and dissection. J Am Coll Cardiol 2018; 72 (06) 605-615
    CrossrefPubMedGoogle Scholar
  • 30 Lee VS, Halabi CM, Hoffman EP. et al; Brigham Genomic Medicine. Loss of function mutation in LOX causes thoracic aortic aneurysm and dissection in humans. Proc Natl Acad Sci U S A 2016; 113 (31) 8759-8764
    CrossrefPubMedGoogle Scholar
  • 31 Tilson MD, Reilly JM, Brophy CM, Webster EL, Barnett TR. Expression and sequence of the gene for tissue inhibitor of metalloproteinases in patients with abdominal aortic aneurysms. J Vasc Surg 1993; 18 (02) 266-270
    CrossrefPubMedGoogle Scholar
  • 32 Ogata T, Shibamura H, Tromp G. et al. Genetic analysis of polymorphisms in biologically relevant candidate genes in patients with abdominal aortic aneurysms. J Vasc Surg 2005; 41 (06) 1036-1042
    CrossrefPubMedGoogle Scholar
  • 33 Hinterseher I, Tromp G, Kuivaniemi H. Genes and abdominal aortic aneurysm. Ann Vasc Surg 2011; 25 (03) 388-412
    CrossrefPubMedGoogle Scholar
  • 34 Tang W, Saratzis A, Pattee J. et al. Replication of newly identified genetic associations between abdominal aortic aneurysm and SMYD2, LINC00540, PCIF1/MMP9/ZNF335, and ERG. Eur J Vasc Endovasc Surg 2020; 59 (01) 92-97
    CrossrefPubMedGoogle Scholar
  • 35 Loeys BL, Schwarze U, Holm T. et al. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med 2006; 355 (08) 788-798
    CrossrefPubMedGoogle Scholar
  • 36 Baas AF, Medic J, van't Slot R. et al. Association study of single nucleotide polymorphisms on chromosome 19q13 with abdominal aortic aneurysm. Angiology 2010; 61 (03) 243-247
    CrossrefPubMedGoogle Scholar
  • 37 Guo DC, Grove ML, Prakash SK. et al; GenTAC Investigators, BAVCon Investigators. Genetic variants in LRP1 and ULK4 are associated with acute aortic dissections. Am J Hum Genet 2016; 99 (03) 762-769
    CrossrefPubMedGoogle Scholar
  • 38 Guo DC, Regalado E, Casteel DE. et al; GenTAC Registry Consortium, National Heart, Lung, and Blood Institute Grand Opportunity Exome Sequencing Project. Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections. Am J Hum Genet 2013; 93 (02) 398-404
    CrossrefPubMedGoogle Scholar
  • 39 Golledge J, Norman PE. Atherosclerosis and abdominal aortic aneurysm: cause, response, or common risk factors?. Arterioscler Thromb Vasc Biol 2010; 30 (06) 1075-1077
    CrossrefPubMedGoogle Scholar
  • 40 Gretarsdottir S, Baas AF, Thorleifsson G. et al. Genome-wide association study identifies a sequence variant within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm. Nat Genet 2010; 42 (08) 692-697
    CrossrefPubMedGoogle Scholar
  • 41 Bradley DT, Hughes AE, Badger SA. et al. A variant in LDLR is associated with abdominal aortic aneurysm. Circ Cardiovasc Genet 2013; 6 (05) 498-504
    CrossrefPubMedGoogle Scholar
  • 42 Harrison SC, Smith AJP, Jones GT. et al; Aneurysm Consortium. Interleukin-6 receptor pathways in abdominal aortic aneurysm. Eur Heart J 2013; 34 (48) 3707-3716
    CrossrefPubMedGoogle Scholar
  • 43 Bradley DT, Badger SA, McFarland M, Hughes AE. Abdominal aortic aneurysm genetic associations: mostly false? A systematic review and meta-analysis. Eur J Vasc Endovasc Surg 2016; 51 (01) 64-75
    CrossrefPubMedGoogle Scholar
  • 44 Fatini C, Sofi F, Sticchi E. et al. eNOS G894T polymorphism as a mild predisposing factor for abdominal aortic aneurysm. J Vasc Surg 2005; 42 (03) 415-419
    CrossrefPubMedGoogle Scholar
  • 45 Jones GT, Thompson AR, van Bockxmeer FM. et al. Angiotensin II type 1 receptor 1166C polymorphism is associated with abdominal aortic aneurysm in three independent cohorts. Arterioscler Thromb Vasc Biol 2008; 28 (04) 764-770
    CrossrefPubMedGoogle Scholar
  • 46 Giusti B, Saracini C, Bolli P. et al. Genetic analysis of 56 polymorphisms in 17 genes involved in methionine metabolism in patients with abdominal aortic aneurysm. J Med Genet 2008; 45 (11) 721-730
    CrossrefPubMedGoogle Scholar
  • 47 Liu J, Jia X, Li H. et al. Association between MTHFR C677T polymorphism and abdominal aortic aneurysm risk: a comprehensive meta-analysis with 10,123 participants involved. Medicine (Baltimore) 2016; 95 (36) e4793
    CrossrefPubMedGoogle Scholar
  • 48 Strauss E, Waliszewski K, Pawlak AL. [The normotensive carriers of the MTHFR 677T allele, displaying the increased risk of development of the abdominal aortic aneurysm (AAA), occur at the highest frequency among the smoking patients]. Przegl Lek 2004; 61 (10) 1086-1089
    PubMedGoogle Scholar
  • 49 Baas AF, Medic J, van't Slot R. et al. The intracranial aneurysm susceptibility genes HSPG2 and CSPG2 are not associated with abdominal aortic aneurysm. Angiology 2010; 61 (03) 238-242
    CrossrefPubMedGoogle Scholar
  • 50 Bown MJ, Jones GT, Harrison SC. et al; CARDIoGRAM Consortium, Global BPgen Consortium, DIAGRAM Consortium, VRCNZ Consortium. Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1. Am J Hum Genet 2011; 89 (05) 619-627
    CrossrefPubMedGoogle Scholar
  • 51 Sampson UKA, Norman PE, Fowkes FGR. et al. Estimation of global and regional incidence and prevalence of abdominal aortic aneurysms 1990 to 2010. Glob Heart 2014; 9 (01) 159-170
    CrossrefPubMedGoogle Scholar
  • 52 Elmore JR, Obmann MA, Kuivaniemi H. et al. Identification of a genetic variant associated with abdominal aortic aneurysms on chromosome 3p12.3 by genome wide association. J Vasc Surg 2009; 49 (06) 1525-1531
    CrossrefPubMedGoogle Scholar
  • 53 Jones GT, van Rij AM. Regarding “Identification of a genetic variant associated with abdominal aortic aneurysms on chromosome 3p12.3 by genome wide association”. J Vasc Surg 2009; 50 (05) 1246-1247 , author reply 1247
    CrossrefPubMedGoogle Scholar
  • 54 Biros E, Norman PE, Jones GT. et al. Meta-analysis of the association between single nucleotide polymorphisms in TGF-β receptor genes and abdominal aortic aneurysm. Atherosclerosis 2011; 219 (01) 218-223
    CrossrefPubMedGoogle Scholar