Center for Perioperative Genomics

Body Lab

Dr. Simon Body's laboratory focuses on the genetics of atrial fibrillation and the elucidation of the genetic causes and consequences of bicuspid aortic valve disease.

The CABG Genomics Program is a two-institution study that provides patient data and genomics resources to the investigators. Since 2001, ~2,500 patients undergoing cardiac surgery have enrolled in the Program. Clinical data, patient outcomes, and DNA, buffy coat mRNA, plasma, and serum, are collected and stored for subsequent genotyping and measurement of circulating biomarkers. Specifically, the Program seeks to identify the relationships between genetic variation and major adverse cardiac events, bleeding and other patient outcomes after CABG surgery. The Program has been, and will continue to be, a vital resource for our individual research goals and has resulted in multiple studies and publications. In addition, it has been a vehicle for collaboration with other US and International research groups with similar resources and goals. To understand the genetic impact upon adverse outcomes after cardiac surgery, the CABG Genomics Program collaborates across three institutions (Brigham and Women's Hospital (Drs. Simon Body and J. Daniel Muehlschlegel), Texas Heart Institute (Dr. C. David Collard) and University of Texas Southwestern Medical Center (Dr. Amanda Fox). At Brigham and Women's Hospital and collaborating Centers, subjects are enrolled from the population of patients undergoing cardiac surgery. A total of 5,000 patients will be enrolled.

Objectives

The objective of our study is to understand the impact of genetic variation on the prevalence and severity of adverse outcomes after cardiac surgery. Furthermore, we wish to identify biological networks involved in the generation of atherosclerosis. Cardiac surgical outcomes of particular interest include:

  • Postoperative atrial fibrillation
  • Postoperative myocardial injury
  • Postoperative ventricular dysfunction

For each of these outcomes, we hypothesize an underlying role for one or more elements of genetic variation, to be identified by genotyping, DNA sequencing, or studies of transcriptional activity. The genetic variation that causes these outcomes is often multifaceted and frequently includes environmental or epigenetic dynamics. In order to access each of these etiologic factors, we use methods that identify sources of variation and then investigate their statistical associations with the outcome of interest.

Atrial Fibrillation

Atrial fibrillation (AF) is a frequent cause of stroke, other morbidity, mortality and cost; >20% of Americans will suffer from it in their lifetimes. Thus AF is an important and costly disease with an identified heritable locus. There is strong evidence for heritability of AF, with an off-spring risk ratio of ~2. Recently, a frequent chromosome 4q25 haplotype has been associated with AF in several Caucasian and non-Caucasian ambulatory populations. This haplotype has a remarkably high population-attributable risk for AF of 23.7%. However, the biological mechanisms responsible for this association between the 4q25 haplotype and AF have not yet been identified.

AF is also a frequent adverse outcome after cardiac surgery and is associated with significant short and long-term patient morbidity and mortality. We have recently demonstrated that the same genetic variants in the 4q25 locus detailed above, are also associated with new-onset postoperative AF in over 1000 Caucasian patients undergoing cardiac surgery, replicated using a separately collected cohort. We have narrowed this region to a single haplotype encompassing 66,000 bp of chromosome 4. The concordance of variants in two similar phenotypes strongly supports a common biological mechanism for AF in the ambulatory and post-surgical environment, that allows examination of the genetic mechanisms of AF using surgically-collected atrial tissue. We therefore use the perioperative cardiac surgical environment, with its ready availability of atrial tissue and frequent AF phenotype, as a model to determine the biological mechanisms of the association between the AF-associated 4q25 haplotype and AF. Our overall goal is to identify the genetic and molecular mechanisms whereby genetic variation in the 4q25 locus causes atrial fibrillation.

Bicuspid Aortic Valve Disease

The International Bicuspid Aortic Valve Consortium, a 16-institution consortium investigating the genetic etiology of bicuspid aortic valve disease, is lead by Dr. Simon Body. The consortium was started in 2011 and encompasses investigators from Europe, Canada and the U.S.

Bicuspid Aortic Valve
Bicuspid Aortic Valve, Short Axis View at the Aortic Level

source: Patrick J. Lynch, medical illustrator

Bicuspid aortic valve (BAV) is the most frequent congenital cardiac malformation, occurring in 0.5-1.2% of the US population. In young adults, it is generally a benign abnormality; but in older adults it is associated with thoracic aortic aneurysm or dissection in 20-30% of those with BAV. BAV is strongly associated with early development of aortic valve calcification or incompetence in >50% of BAV patients, and accounts for ~40% of the >30,000 aortic valve replacements (AVR) performed in the US each year. Yet, we know little of the etiology, cellular events and modifiers of progression of BAV to calcific aortic valve disease and we still do not understand the genetic cause(s) of BAV despite evidence for its high heritability. In a few families, highly-penetrant dominant mutations of NOTCH1 have been associated with BAV. Additional susceptibility loci have also been identified but not replicated. However, a majority of individuals with BAV do not report family members with BAV and do not have NOTCH1 mutations. Furthermore, even though aortic disease warranting surgery occurs much earlier with BAV than TAV, there is a wide variation in disease severity and progression of aortic valve disease, epitomized by the range of age of presentation for AVR, implying that this variation may be of genetic etiology, independent of the altered blood flow patterns of BAV. Because of the previously small collected cohorts, modifiers of disease have been difficult to identify.

Our goals are to elucidate the genetic pathways involved in BAV etiology and the subsequent progression of aortic valve calcification; work that has been hampered by the low numbers of patients enrolled in individual centers, the uncertain genetic model and the few animal models of BAV that are relevant to human disease. Our Specific Aims are to: Identify genetic etiologies of BAV through exome sequencing and GWAS analyses. Prioritize candidate BAV genes for re-sequencing in BAV cohorts, via high-throughput zebrafish functional and anatomical assays and by in-situ hybridization. Define BAV pathways of calcific aortic stenosis through transcriptional analyses of the aging aortic valve in GATA5-/- BAV mice, and in diseased aortic valve tissue derived from humans undergoing AVR.