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Unraveling the Genetic Predisposition for Aortic
Aneurysms: Is it Time for Tailored Medicine?
Debabrata Mukherjee1
A
neurysms and dissections are the major pathologies affecting the thoracic aorta. Based on available data, up to 20% of individuals with thoracic
aortic aneurysms (TAAs) may have a first-degree
relative with aortic aneurysms or dissection, indicating a strong genetic predisposition.1 Within families, TAAs
are inherited primarily in an autosomal dominant manner, with
decreased penetrance and variable expression.2 Moreover, they
are often asymptomatic until a catastrophic event occurs,2 which
may be prevented if family members can be identified prior to
such events. Based on this premise, recent studies have begun
to elucidate the genetic factors that predispose an individual
to TAA.
The first genetic predisposition for TAA was detected by
use of families with multiple members with the disorder. The
locus was mapped to the long arm of chromosome 5 (5q13-14),
termed the TAAD1 locus.3 Genetic heterogeneity was indicated
by the fact that only one-half of the identified families mapped
to this locus and was confirmed by mapping another gene causing TAA to the long arm of chromosome 11, 11q23-24 (termed
the FAAl locus).4 Hasham et al. also mapped another locus for
TAA to 3p24-25, termed the TAAD2 locus, by using a family
with multiple affected members.3 Having mapped a TAA locus
to 3p24-25, they sequenced the gene for transforming growth
factor-β receptor type 2 (TGFBR2) and demonstrated that germline TGFBR2 mutations are responsible for the predisposition
to familial TAA in 5% of these cases.5
In this issue of the Journal, Kato et al. performed an association study for 142 polymorphisms of 119 candidate genes
and TAA in 1,351 hypertensive Japanese individuals to identify
genetic variants that confer susceptibility to TAA. They report
that the variant G allele of THBS2 was a risk factor for TAA,
whereas the variant C allele of HSPA8, T allele of GPX1, A allele
of AGT, and T allele of TNF were protective against this condition. The authors suggest that the determination of genotypes for
these polymorphisms may prove informative for assessment of
the genetic risk for TAA and may contribute to the personalized
prevention of this condition.
Although a particular combination of polymorphisms may
predispose to TAA, any individual gene is likely to have only
a limited effect. The role of hypertension, smoking, gender,
and age must be taken into consideration when considering
the likelihood of TAA in a given patient. The true mechanism
underlying TAA probably involves the interplay between genetic
predisposition and acquired risk factors listed above. The study
by Kato et al. is important because understanding the genetic
predisposition to TAA development will provide a better understanding of the pathophysiology and may help identify potential
new targets for therapeutic intervention. However at this point
in time, genetic predisposition studies should be considered for
research, and clinicians should focus on appropriate history,
physical examination, and imaging tests to diagnose TAA. In
individuals with a family history of TAA, it is extremely important to control blood pressure optimally and convince individuals who smoke to quit. Additional studies with larger cohorts
will be required to verify and better characterize the actual magnitude of the risk/benefit of the individual alleles reported, and
we hope that in the future genetic makeup of an individual may
help quantify their risk of developing TAA and other disease
conditions.
Disclosure: The author declared no conflict of interest.
1. Albornoz G, Coady MA, Roberts M, Davies RR, Tranquilli M, Rizzo JA,
Elefteriades JA. Familial thoracic aortic aneurysms and dissections—incidence,
modes of inheritance, and phenotypic patterns. Ann Thorac Surg 2006; 82:
1400–1405.
2. Milewicz DM, Chen H, Park ES, Petty EM, Zaghi H, Shashidhar G, Willing M,
Patel V. Reduced penetrance and variable expressivity of familial thoracic aortic
aneurysms/dissections. Am J Cardiol 1998; 82:474–479.
3. Hasham SN, Lewin MR, Tran VT, Pannu H, Muilenburg A, Willing M, Milewicz DM.
Nonsyndromic genetic predisposition to aortic dissection: a newly recognized,
diagnosable, and preventable occurrence in families. Ann Emerg Med 2004;
43:79–82.
4. Vaughan CJ, Casey M, He J, Veugelers M, Henderson K, Guo D, Campagna R,
Roman MJ, Milewicz DM, Devereux RB, Basson CT. Identification of a
chromosome 11q23.2-q24 locus for familial aortic aneurysm disease, a
genetically heterogeneous disorder. Circulation 2001; 103:2469–2475.
5. Pannu H, Fadulu VT, Chang J, Lafont A, Hasham SN, Sparks E, Giampietro PF,
Zaleski C, Estrera AL, Safi HJ, Shete S, Willing MC, Raman CS, Milewicz DM.
Mutations in transforming growth factor-beta receptor type II cause familial
thoracic aortic aneurysms and dissections. Circulation 2005; 112:513–520.
1Gill Heart Institute, University of Kentucky, Lexington, Kenticky, USA.
Correspondence: Debabrata Mukherjee ([email protected])
doi:10.1038/ajh.2008.232
© 2008 American Journal of Hypertension, Ltd.
AMERICAN JOURNAL OF HYPERTENSION | VOLUME 21 NUMBER 9 | 967 | september 2008
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