BAK1 gene variation and abdominal aortic aneurysms

Gottlieb, Bruce; Chalifour, Lorraine E.; Mitmaker, Benjamin; Sheiner, Nathan; Obrand, Daniel; Abraham, Cherrie; Meilleur, Melissa; Sugahara, Tomoko; Bkaily, Ghassan; Schweitzer, M.

doi:10.1002/humu.21046

Cited by 30 publications

(24 citation statements)

References 36 publications

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“…In particular, studies have focused on associating single nucleotide polymorphisms (SNPs) with AAA (examples shown in Table 4). 125–130…”

Section: 0 Future Prospects Of Aaa Diagnosis and Monitoringmentioning

confidence: 99%

“…On the other hand, genetic studies have great potential in unraveling the mechanisms behind AAA formation. Furthermore, a genetic marker will be present within all nucleated diploid cells (although there is some evidence to suggest that different polymorphisms may be tissue-specific),125 and are thus easily accessed and sampled in a relatively non-invasive manner. Thus, genetic screening may be useful to determine AAA susceptibility in at-risk populations, and this may prompt firm diagnosis through measurement of dynamic biological systems which more actively reflect current aortic phenotype.…”

Section: 0 Future Prospects Of Aaa Diagnosis and Monitoringmentioning

confidence: 99%

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Diagnosis and Monitoring of Abdominal Aortic Aneurysm: Current Status and Future Prospects

Moxon

Parr²,

Emeto³

et al. 2010

Current Problems in Cardiology

125

148

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Abdominal aortic aneurysm (AAA) remains an important cause of morbidity and mortality in elderly men, and prevalence is predicted to increase in parallel with a global ageing population. AAA is commonly asymptomatic, and in the absence of routine screening, diagnosis is usually incidental when imaging to assess unrelated medical complaints. In the absence of approved diagnostic and prognostic markers, AAAs are monitored conservatively via medical imaging until aortic diameter approaches 50-55mm and surgical repair is performed. There is currently significant interest in identifying molecular markers of diagnostic and prognostic value for AAA. Here we outline the current guidelines for AAA management, and discuss modern scientific techniques currently employed to identify improved diagnostic and prognostic markers. KeywordsAbdominal aortic aneurysm; diagnosis; prognosis; biomarker INTRODUCTIONAn abdominal aortic aneurysm (AAA) is a dilation of the infra-renal aorta, which appears to result from chronic weakening of the arterial wall, increasing the risk of fatal rupture.1 -3 AAA is also associated with an increased risk of other major cardiovascular events in aneurysmal patients. For example the UK small aneurysm trial (UKSAT), demonstrated that only 16% of deaths in patients with 40-55mm AAAs was related to AAA repair or rupture while ~50% were due to other cardiovascular causes (mainly myocardial infarction and stroke).4 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access AAA pathologyMacroscopically, an AAA can be considered a dilatation of the infrarenal aorta, giving rise to a permanent vessel diameter >30mm (typical abdominal aortic diameter ranges from 15 to 25mm). 23-27 AAA vessel dilation is commonly progressive, and is often accompanied by the formation of a laminated, non-occlusive, intraluminal thrombus.28 -29 Thrombus size and location varies between patients, and the arterial wall may be partially or completely covered by the thrombus ( Figure 1A and B). 30 The thrombus remains in permanent contact with circulating blood and is continually remodeled, 31,32 and thrombus size increases in parallel with aortic dilation. Due to constant remodeling the thrombus is a laminated structure comprising a red blood cell-rich luminal layer in contact with the flowing blood, progressing to a brown fibrinolysed layer at the aortic wall. 29 Localised hypoxia has been demonstrated in regions of the aorta covered by the thrombus and this has been suggested to contribute to physiological stresses within the arterial wall. 33 Similar to other vascular dise...

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“…In particular, studies have focused on associating single nucleotide polymorphisms (SNPs) with AAA (examples shown in Table 4). 125–130…”

Section: 0 Future Prospects Of Aaa Diagnosis and Monitoringmentioning

confidence: 99%

Section: 0 Future Prospects Of Aaa Diagnosis and Monitoringmentioning

confidence: 99%

Diagnosis and Monitoring of Abdominal Aortic Aneurysm: Current Status and Future Prospects

Moxon

Parr²,

Emeto³

et al. 2010

Current Problems in Cardiology

125

148

View full text Add to dashboard Cite

show abstract

“…However, a few recent studies including our own study of BAK1 and abdominal aortic aneurysms (Gottlieb et al 2009) have suggested that it indeed may be more widespread than previously imagined. Indeed, it has been suggested that a number of neurodegenerative diseases, such as amyotrophic lateral sclerosis may be due to somatic mutations occurring during development resulting in highly variable genetic mosaicism (Frank 2010).…”

Section: Evect Of "Minority" Dna Variants On Genetic Paradigmsmentioning

confidence: 94%

Selection and mutation in the “new” genetics: an emerging hypothesis

et al. 2010

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It has been anticipated that new, much more sensitive, next generation sequencing (NGS) techniques, using massively parallel sequencing, will likely provide radical insights into the genetics of multifactorial diseases. While NGS has been used initially to analyze individual human genomes, and has revealed considerable differences between healthy individuals, we have used NGS to examine genetic variation within individuals, by sequencing tissues "in depth", i.e., oversequencing many thousands of times. Initial studies have revealed intra-tissue genetic heterogeneity, in the form of multiple variants of a single gene that exist as distinct "majority and "minority" variants. This highly specialized form of somatic mosaicism has been found within both cancer and normal tissues. If such genetic variation within individual tissues is widespread, it will need to be considered as a significant factor in the ontogeny of many multifactorial diseases, including cancer. The discovery of majority and minority gene variants and the resulting somatic cell heterogeneity in both normal and diseased tissues suggests that selection, as opposed to mutation, might be the critical event in disease ontogeny. We, therefore, are proposing a hypothesis to explain multifactorial disease ontogeny in which pre-existing multiple somatic gene variants, which may arise at a very early stage of tissue development, are eventually selected due to changes in tissue microenvironments.

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“…However, there do appear to be cases where modifications of disease phenotypes are related to RNA editing [27,28]. …”

Section: Introductionmentioning

confidence: 99%

Changing genetic paradigms: creating next-generation genetic databases as tools to understand the emerging complexities of genotype/phenotype relationships

2014

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Understanding genotype/phenotype relationships has become more complicated as increasing amounts of inter- and intra-tissue genetic heterogeneity have been revealed through next-generation sequencing and evidence showing that factors such as epigenetic modifications, non-coding RNAs and RNA editing can play an important role in determining phenotype. Such findings have challenged a number of classic genetic assumptions including (i) analysis of genomic sequence obtained from blood is an accurate reflection of the genotype responsible for phenotype expression in an individual; (ii) that significant genetic alterations will be found only in diseased individuals, in germline tissues in inherited diseases, or in specific diseased tissues in somatic diseases such as cancer; and (iii) that mutation rates in putative disease-associated genes solely determine disease phenotypes. With the breakdown of our traditional understanding of genotype to phenotype relationships, it is becoming increasingly apparent that new analytical tools will be required to determine the relationship between genotype and phenotypic expression. To this end, we are proposing that next-generation genetic database (NGDB) platforms be created that include new bioinformatics tools based on algorithms that can evaluate genetic heterogeneity, as well as powerful systems biology analysis tools to actively process and evaluate the vast amounts of both genomic and genomic-modifying information required to reveal the true relationships between genotype and phenotype.

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BAK1 gene variation and abdominal aortic aneurysms

Cited by 30 publications

References 36 publications

Diagnosis and Monitoring of Abdominal Aortic Aneurysm: Current Status and Future Prospects

Diagnosis and Monitoring of Abdominal Aortic Aneurysm: Current Status and Future Prospects

Selection and mutation in the “new” genetics: an emerging hypothesis

Changing genetic paradigms: creating next-generation genetic databases as tools to understand the emerging complexities of genotype/phenotype relationships

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