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Genetics of Aortic Diseases

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Diseases of the Aorta

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Abstract

The clinically most important aortic diseases are those that cause aneurysms and dissections in the aortic wall. Aortic aneurysms and/or dissections are sometimes subject to sudden rupture, which often causes sudden death. Currently the biggest problem in addressing sudden rupture is, that early stage aneurysm, which can be successfully treated by surgery, remains often undetected because it is not associated with clearly detectable symptoms.

Aortic aneurysmal diseases include thoracic aortic aneurysms (TAAs) and abdominal aortic aneurysms (AAAs). TAAs have a strong and well-characterized genetic component. In the western world, TAA occurs with an incidence of about 12 per 100,000 per year in all age groups, shows little gender bias and does not show strict association with cardiovascular risk factors (Saratzis A, Bown MJ, Heart 100:916–922, 2014). In contrast, AAA is generally diagnosed in people over the age of 65, has a prevalence rate of about 8% for men and 1% for women (Miner GH, Faries PL, Costa KD, Hanss BG, Marin ML, Expert Rev Cardiovasc Ther 13:1079–1090, 2015), and shows strong association with male gender, smoking, and cardiovascular disease.

We summarize here the most important facts about the known TAA and AAA types, with emphasis on known genetic cause(s) and risk factors and how they relate to cellular pathology and clinical treatment. For each type we describe in detail the relevant genetic animal model(s) and how these may inform current pharmacological management and surgical treatment as well as future drug development and gene/cell therapy. Importantly, we show how animal models of genetic TAA and AAA also strongly inform treatment and drug development for non-genetic TAA and AAA, which indeed comprise at least 70% of all aneurysmal disease. We also illustrate how genetic testing can help predict risk of aneurysmal disease at birth and also describe efforts to devise blood tests that reliably predict development of TAA and AAA well before they rupture.

These are clearly exciting times for the field of aneurysmal disease as we move toward unprecedented personalized and effective treatment of patients based on very detailed knowledge of the genetic and non-genetic causes. Ultimately early detection combined with novel drugs as well as cell/gene therapies may significantly reduce the need for surgery.

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Abbreviations

TAA:

Thoracic aortic aneurysm

AAA:

Abdominal aortic aneurysm

FTAAD:

Familial thoracic aortic aneurysm and dissection

LDS:

Loeys–Dietz syndrome

MFS:

Marfan syndrome

vEDS:

Vascular Ehlers–Danlos syndrome

BAV:

Bicuspid aortic valve syndrome

ATS:

Arterial tortuosity syndrome

ECM:

Extracellular matrix

VSMC:

Vascular smooth muscle cell

AngII:

Angiotensin II

NAD+ :

Nicotinamide adenine dinucleotide

MI:

Myocardial infarction

CAD:

Coronary artery disease

SNP:

Single nucleotide polymorphism (the associated rs number unambiguously identifies both the SNP’s exact genetic location and specific nucleotide change)

NGS:

Next-generation sequencing

GWAS:

Genome-wide association study

WES:

Whole exome sequencing

Exon:

Protein coding DNA sequences of a gene

Intron:

Non-protein coding DNA sequences of a gene, usually larger than exons

Promoter:

Short DNA sequence located upstream of the transcription start site of a gene that induces production of the mRNA and protein encoded by the gene

Enhancer:

Short DNA sequence located up to 100kB away from a gene; interacts with a gene’s promoter to enhance protein production of the gene

OMIM:

Online Mendelian Inheritance in Man database

kB:

Kilobases of DNA

kD:

Kilodalton of protein

miRNA:

microRNA, short ~20 nucleotide long RNA produced by a short gene, it regulates activity of other genes

lncRNA:

Long non-coding RNA, a long RNA (produced from a long gene) that cannot be translated into a protein but nevertheless regulates the activity of other genes

FBN1:

Fibrillin 1

TGFbeta:

Transforming growth factor beta

TGFBR1:

Transforming growth factor beta receptor 1

TGFBR2:

Transforming growth factor beta receptor 2

TGFB2:

Transforming growth factor beta 2

TGFB3:

Transforming growth factor beta 3

MYH11:

Myosin heavy chain 11

ACTA2:

Alpha 2 actin, smooth muscle cell specific

MYLK:

Myosin light chain kinase

PRKG1:

cGMP-dependent protein kinase 1

MFAP5:

Microfibril-associated protein 5

LOX:

Lysil oxidase

FOXE3:

Forkhead box E3 gene

NOTCH1:

NOTCH1 gene

SMAD2:

SMAD family member 2 gene

SMAD3:

SMAD family member 3 gene

SKI:

SKI proto oncogene

LDLR:

Low-density lipoprotein receptor

SORT1:

sortilin 1

IL6R:

Interleukin 6 receptor

MMP9:

Metalloproteinase 9

9p21:

Chromosome 9 locus 21

ANRIL:

Long non-coding RNA ANRIL

SMYD2:

SET and MYND Domain containing 2 (protein lysine N methyl transferase)

ERG:

ETS-related gene

DAB2IP:

DAB2 interacting protein

LINC00540:

Long non-coding RNA LINC00540

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Acknowledgments

We thank Reed E. Pyeritz and Jeffrey T. Billheimer from the Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, for careful review of the text and very helpful comments.

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Authors and Affiliations

  1. Surgical Pathology and Laboratory Medicine, University of Southern California (USC), Keck School of Medicine (Emeritus), Chatsworth, CA, USA

    Arno A. Roscher

  2. Cardiovascular and Thoracic Surgery, Northwestern University at Cadence Health Emeritus, Winfield, IL, USA

    Raymond A. Dieter Jr.

  3. Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Tobias D. Raabe

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  1. Interventional Cardiology, Vascular and Endovascular Medicine, Loyola University Medical Center, Maywood, IL, USA

    Robert S. Dieter

  2. Cardiovascular and Thoracic Surgery, Northwestern University at Cadence Health Emeritus, Winfield, IL, USA

    Raymond A. Dieter Jr.

  3. University of Tennessee Medical Center, Cardiovascular and Thoracic Surgery, Knoxville, TN, USA

    Raymond A. Dieter III

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Roscher, A.A., Dieter, R.A., Raabe, T.D. (2019). Genetics of Aortic Diseases. In: Dieter, R., Dieter Jr., R., Dieter III, R. (eds) Diseases of the Aorta . Springer, Cham. https://doi.org/10.1007/978-3-030-11322-3_5

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