Introduction to VA Palo Alto Health Care System

Epidemiology Research and Information Center (ERIC) for Genomics

VA Palo Alto Health Care System (VAPAHCS) is a long term partner and affiliate of Stanford University. Stanford Center for Genomics and Personalized Medicine (SCGPM) and VA Palo Alto Epidemiology Research and Information Center (ERIC) for Genomics share a common mission in genomics driven precision health. The ERIC center is Directed by Philip Tsao, PhD and co-Directed by Lawrence Leung, MD. Both Directors also hold appointments at Stanford School of Medicine.

Established in 2015, the Palo Alto ERIC for Genomics is located on the campus of the VA Palo Alto Healthcare System. The ERIC is tasked with taking advantage of recent advances in obtaining data from a person's genes and applying it to the rich data associated with the electronic medical record.  ERIC goals are:

  1. To establish a robust infrastructure for large-scale genomics efforts. The ERIC is dedicated to develop an accurate, efficient, and cost-effective pipeline for analysis of data generated from looking at a person's genes that is scalable to projects as large as the Million Veteran Program. Populated with a multidisciplinary team of geneticists, bioinformaticians, statisticians, biologists and clinicians, this will be a resource for clinical genomics research within the VA network.
  2. To optimize current methodologies as well as develop novel tools to comprehensively analyze whole genome sequence data. The ERIC uses state-of-the-art statistical methodologies to identify genetic signatures and pathways relevant to diseases as well as to integrate existing clinical data to eventually produce information regarding a patient's risk for disease. This will be used to develop novel methodologies to visualize and probe genetic data as well as combine results with other forms of clinically- and biologically-relevant data.

Pilot Million Veteran Program Study

AAA, "ticking time bombs"

Abdominal aortic aneurysms (AAAs) are believed to be related to atherosclerosis as they are often associated with the same type of plaques on the blood vessel wall, but instead of it being an occlusive disease, the wall begins to weaken and bulge from the pressure from the blood inside. Over time as the structural integrity of the blood vessel decreases further, that ballooning will continue until rupture of the blood vessel. Since it's the major highway from your heart to your legs, it carries quite a lot of blood and rupture can be quite catastrophic.

The associated mortality with rupture is 80%, and the lower bound for number of deaths attributed to AAA rupture is nearly 15,000 annually in the US - 60% of patients with AAAs die of other cardiovascular causes, such as myocardial infarction or stroke. It is a fairly common disease among individuals over 65. The prevalence rates can be from 3 to 16 percent for men and about half that for women. The disease is usually asymptomatic until the dilations become large. Currently, there are no specific medical therapies directed for AAAs. If you are diagnosed, the first step is to mitigate risk factors such as smoking cessation and blood pressure medication. Otherwise, you reach a point of watchful waiting, watching it grow over years until it gets to the point where the risk of rupture outweighs the risk of the major surgery (endovascular stenting) needed to repair the AAA. Even though AAA disease is a common cause of morbidity and mortality in our aging society, it remains a somewhat under-studied disease, with a paucity of information available regarding defined mechanisms of initiation and expansion. Importantly, no pharmacological treatment option has been found to prevent the formation of AAAs or effectively slow the growth of these “ticking time bombs”.

AAA Hypothesis

There is significant body of work to show association between AAA and genetics [Golledge2013] and heritability is estimated at 70%. AAA is a complex disease. Tsao lab has taken a comprehensive approach to understanding AAA that includes mouse models, whole genome and transciptome profiling. Tsao lab identified microRNA-21 (miR-21) as a key modulator of proliferation and apoptosis of vascular wall smooth muscle cells during development of AAA in two established murine models [Maegdefessel2012a]. Since then, there have been several high profile publications [Maegdefessel2012b] [Maegdefessel2013] [Maegdefessel2014a] [Maegdefessel2014b] [Maegdefessel2014c]. While it has been quite easy to make lists of genes that are correlated with disease, the questions remain, 'Which ones are causative of the disease?' And If we believe that these complex diseases are regulated by coordinated pathways of genes, then how are those pathways regulated?. 

To answer these questions, Tsao lab has deeply sequenced one of the largest AAA cohorts (DNA-Seq) with the goal to understanding the genetic architecture of AAA. This cohort is a pilot project in the Million Veteran program.

References

  • [Golledge2013] Genetics of abdominal aortic aneurysm, Current Opinion in Cardiology, Issue: Volume 28(3), May 2013, p 290–296
  • [Maegdefessel2012a] MicroRNA-21 blocks abdominal aortic aneurysm development and nicotine-augmented expansion. Sci Transl Med 2012 Feb; 4(122):122ra22
  • [Maegdefessel2012b] Inhibition of microRNA-29b reduces murine abdominal aortic aneurysm development. J. Clin. Invest. 2012 Feb; 122(2):497-50
  • [Maegdefessel2013] Micromanaging abdominal aortic aneurysms. Int J Mol Sci 2013; 14(7):14374-94
  • [Maegdefessel2014a] Pathogenesis of abdominal aortic aneurysms: microRNAs, proteases, genetic associations. Annu. Rev. Med. 2014; 65():49-62
  • [Maegdefessel2014b] MicroRNA-29b regulation of abdominal aortic aneurysm development.Trends Cardiovasc. Med. 2014 Jan; 24(1):1-6 
  • [Maegdefessel2014c] New ways to dismantle a ticking time bomb – miRs-712/-205 and abdominal aortic aneurysm development, Arterioscler Thromb Vasc Biol. 2014 Jul; 34(7): 1339–1340

 

Conference Talks

Precision Medicine World Conference, SV 2017

Talk Title: Million Veteran Program Builds a Mega-biobank for Human Disease Research (Download)

Session Title: Learnings from Precision Medicine Centers

When: Jan 23, 2017, Track 4, 3:15 pm

Session Synopsis: Precision medicine centers are an integral part of research and medical institutions. They are facing many challenges when integrating enabling-technology platforms to achieve throughput goals, build biological repositories, analyze data, or enable translational research. This session will dive into some of the observations and learnings some of these centers encounter.

Talk Abstract: The Veterans Health Administration is America’s largest integrated health care system, serving 8.8 million Veterans each year. Built on top of its longitudinal electronic health record, the Million Veteran Program (MVP) aims to construct a mega-biobank and a large database consolidating their genetic, military exposure, health, and lifestyle information. In August 2015, MVP marked its milestone of 500,000th voluntary enrollment, enabling numerous human health and disease research that are to inform precision medicine for patient care.


Precision Medicine Wolrd Conference, SV 2016

Talk Title: The VA Million Veterans Program (Vimeo video link)

Session Title: Genome: Silos, Hacking Privacy, Collaboration

When: Jan 26, 2016, Track 1, 1:15 pm

Session Synopsis: DNA data is a biometric and hence in theory identifiable even if made “anonymous”. As sequencing costs continue to drop, DNA banks and genomic data silos continue to build up rapidly. Would it accelerate human betterment if we were to build a collaborative genomic analysis platform that protects patient privacy, allows researchers to bring best of breed analysis methods, and provides easy-to-administer access and risk management protocols? Is this a moon shot?

Talk Abstract: The aim of the VA's Million Veteran Program is to produce a resource for better understanding of the inter-relation of genetics, behaviors and environmental factors, and veteran health. Participants provide a blood sample, response to lifestyle questionnaires, and consent to allow access to clinical data from VA electronic medical records.