Office of Research & Development

VA research on

Genomics


Introduction

A gene is the basic unit of heredity. Genes act as instructions to make molecules called proteins.

The Human Genome Project (HGP) was an international research effort to sequence and map all of the genes of humans, which are together known as the genome. When the HGP was completed in 2003, this gave scientists the ability, for the first time, to read nature's complete genetic blueprint for the human organism.

HGP has estimated that every human has between 20,000 and 25,000 genes.

New knowledge about the role of genes in health and disease holds the promise of developing safer, more effective, personalized treatments for many conditions. The completion of the genome map has created the emerging field of "precision medicine"(also known as "personalized medicine"), which will allow health care providers to better optimize therapies for each individual patient in the future.

VA is well-equipped to study genomics. The department has a large and diverse patient population; an integrated network of basic research and clinical programs; and an electronic medical record system that offers a rich source of health and clinical data.

Among the areas in which VA already uses genomics-based approaches to provide care are tests to confirm hemochromatosis, a hereditary condition in which iron builds up in the body. VA also uses genomic medicine to predict Veterans' responses to cholesterol-lowering statin drugs and to help diagnose and treat breast, colon, and other cancers.

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Selected Major Accomplishments

  • 2006: Launched a genomic medicine initiative to advance knowledge of how genes affect health and to promote personalized medicine for Veterans
  • 2007: Established a laboratory in Little Rock, Arkansas. to conduct diagnostic or treatment-related genetic tests for Veterans and to serve as a genetic research lab
  • 2011: Launched the Million Veteran Program (MVP) to establish one of the world's largest databases of health and genetic information
  • 2014: Found that an alteration in a common gene could help predict how well patients with lung cancer respond to chemotherapy
  • 2015: Recognized for MVP by the federal working group on the Precision Medicine Initiative, which recommends that the governance of its new PMI Cohort Program include VA representation
  • 2016:
    • Developed a test to determine whether a respiratory illness is caused by an infection from a virus or bacteria
    • Announced a collaboration with the Department of Energy (DoE) to apply the powerful computing assets available at DoE National Labs to the MVP program
    • Began the APOLLO Network, a new tri-agency coalition with the Department of Defense (DoD) and the National Cancer Institute (NCI) that will enable oncologists to more rapidly and accurately identify effective drugs to treat cancer based on their patients' unique genomic profiles

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New, Ongoing, and Published Research<

Genomic medicine has the potential to launch the world into a new era of personalized medical care. VA researchers are working to developed personalized treatments based on patients' genes and other individual factors.

A Genomic Medicine Program Advisory Committee, which advises the Secretary of Veterans Affairs, lays the groundwork for the VA Research Genomic Medicine Program. Members include leaders in the public and private sectors and academia in the fields of genetic research and medical genetics; genomic technology; health information technology; and health care delivery, policy, and program administration. The committee also includes a Veterans Service Organization representative.

➤ Genomic medicine implementation

Genomic medicine implementation is focused on the improvement of Veteran's health through genomics and is focused on development of processes and methodologies that enable genomic research-to-practice tests to become sufficiently validated, and ultimately implemented within routine care settings. This includes the assessment of current research within the Office of Research and Development, as well as development of novel approaches to evaluate and implement genomic testing in health care. This may include leveraging and analyzing large-scale data maintained within the Million Veterans Program and other sources, clinical validity/utility of genomic tests in clinical care settings, and implementing the return of genomic test results in routine care, taking into account health system, provider, and patient factors associated with clinical deployment and spread.

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➤ Million Veteran Program

MVP was conceived and implemented to foster genomic discoveries and to bring precision medicine to the forefront of VA health care.

MVP's aim is to build one of the world's largest databases of genetic, military exposure, lifestyle, and health information. VA researchers are partnering with Veterans to study how genes affect health.

MVP is now more than halfway past its enrollment goal of 1 million Veterans, whose coded DVA samples and health information will provide an unprecedented resource for researchers. DNA, or deoxyribonucleic acid, is a self-replicating material present in nearly all living organisms. It is the carrier of genetic information.

Veterans who volunteer to be part of the program are asked to fill out surveys about their health and health-related behaviors, and to complete an optional health assessment. They are also asked permission to allow VA researchers to confidentially access information from their medical records, and to allow VA researchers to contact them in the future.

The program has extensive safeguards in place to ensure that information security and participant confidentiality are top priorities. As of August 2016, more than 500,000 Veterans had enrolled in MVP. The program is expected to reach its goal of having information about participants' DNA (or genes) and environment and health data from 1 million Veterans in the next few years.

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➤ Genomics and mental health

Schizophrenia—An international group of researchers, including researchers at the Washington, D.C., VA Medical Center, identified 108 genetic locations in 2014 where the DNA of people with schizophrenia tends to differ from those who do not have the disease. Many of these genes have important roles in the immune system, providing support for a possible link between the immune system and schizophrenia.

While schizophrenia has long been known to run in families, scientists have identified specific genetic changes linked to the disease only in the past few years. Many of these changes have very small effects on their own, but they can significantly increase risk if they act together.

The study could eventually lead to new ways to identify and treat the disease.

Traumatic brain injury and PTSD—In 2015, researchers at the James J. Peters VA Medical Center in the Bronx and VA's War-Related Illness and Injury Study Center in East Orange, New Jersey, learned that four specific RNA molecules, known by the designations ACA48, U35, U55, and U83A, were found at significantly lower than normal levels in Veterans who had had traumatic brain injuries (TBIs) and also suffered from posttraumatic stress disorder (PTSD).

RNA, or ribonucleic acid, is a nucleic acid present in all living cells. Its principal role is to act as a messenger carrying instructions from DNA for controlling the synthesis of proteins.

The researchers tested blood samples from 58 Iraq and Afghanistan Veterans. Some of the Veterans had a combination of TBI and PTSD, some had only one of the illnesses, and others had neither problem.

Veterans who had only PTSD had significantly lower levels of only the U55 RNA module, and Veterans who only had a TBI and not PTSD had normal levels of all four modules.

The team hopes that their study will eventually result in a simple blood test to help diagnose the two issues in Veterans.

Depression—The Office of Research and Development will soon be funding a project led by the Genomic Medicine Implementation, HSR&D, and QUERI programs to study the genomics of major depressive disorder in Veterans. The project will examine strategies to use patients' genetic information to prescribe the best antidepressants and discover the most effective dosage.

Until now, there have not been many studies of genomic testing implementation in the clinical care setting. This program will actually return genomic test results to providers and patients, which may subsequently influence treatment. The study will look at at the most effective way return results to clinicians and patients to directly guide treatment. This type of study could serve as a primer for similar studies going forward.

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➤ Genomics and Alzheimer's disease

Hippocampus size and memory—The hippocampus is a small region of the brain that plays an important role in memory and spatial navigation. VA researchers and others have shown that the smaller a person's hippocampus is, the greater the chances of cognitive decline and Alzheimer's disease late in life.

In 2014, a team of researchers from VA's Geriatric Research, Education, and Clinical Center in Nashville and Vanderbilt and Duke universities found that variants in a gene responsible for regulating blood pressure may also cause shrinking of the hippocampus.

The team found that three variants of the AGTR1 gene, part of a hormone system responsible for regulating blood pressure and fluid balance, were associated with greater change in hippocampal volume and memory problems. This shrinkage occurred only in the right side of the hippocampus, which is related more to navigation.

The study looked at gene variants in 138 adults older than age 60. The team hopes that the gene variant can serve as a biomarker for future risk of memory loss and depression, and possibly for other psychiatric illnesses. It may also provide clues to guide future treatments.

Nerve growth factor gene therapy—Researchers at the VA San Diego Healthcare System and the University of California, San Diego, found, in 2015 that injecting nerve growth factor directly into the brains of patients with Alzheimer's disease can reactivate dying brain cells. Nerve growth factor is a protein that promotes the growth, organization, and maintenance of nerve cells,

The team's findings were based on postmortem analyses of 10 patients who participated in clinical trials, begun in 2001, to assess whether injected nerve growth factor might safely slow or prevent the degeneration of neurons in patients with Alzheimer's disease. The patients lived between 1 and 10 years following the injections before dying. All of the brains showed anatomical evidence of a growth response.

The researchers said that the findings indicate that nerve growth factor is safe over extended periods, and that it merits continued testing as a potential treatment for Alzheimer's disease.

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➤ Genomics and Parkinson's disease

Researchers with the VA Pittsburgh Healthcare System and the University of Pittsburgh School of Medicine found, in 2015, that gene therapy to reduce the production of a brain protein could successfully prevent the development of Parkinson's disease (PD) in rats.

PD is a chronic neurological disease that is commonly referred to as a movement disorder. The disease can cause muscle rigidity, delayed movement, poor balance, and tremors. PD is caused by aggregates or deposits of a protein called alpha-synuclein (α-synuclein) within neurons. It is also linked to a dysfunction of mitochondria, the powerhouses of the cell that produce energy for the body.

According to the research team, their study was the first to show that mitochondria and α-synuclein can interact in a damaging way in vulnerable cells, and that targeting α-synuclein might be an effective way to treat the disease.

In their study, the team blocked the expression of α-synuclein in rats' brains by injecting the rats with a harmless virus called AAV2. They then exposed the rats to a naturally occurring pesticide called rotenone, which creates Parkinson-like body chemistry changes in rats exposed to it.

They found that their gene therapy protected the rats from the effects of rotenone, and concluded that gene therapy aimed at reducing α-synuclein production has a protective effect and successfully prevented the development of PD in a rat model.

The team will now work to identify the pathways by which α-synuclein affects the mitochondrial function and will work to develop potential drug therapies that target this mechanism. They hope to be able to translate their approach into human clinical trials soon.

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➤ Genomics and cancer

Predicting chemotherapy outcomes through genes—According to a 2014 study by researchers at the Atlanta VA Medical Center and Emory University School of Medicine, a variation in a common gene called caveolin-1 could help predict how well patients with lung cancer respond to chemotherapy.

Patients with that variation tended to respond better to chemotherapy, and tended to have higher survival rates. Because cancer patients and their doctors are often battling against both the disease and time, the ability to quickly identify which treatments will and will not be effective allows patients and doctors the ability to change treatment options sooner rather than later.

Effect of microRNAs on bladder cancer—In 2015, researchers at the VA Northern California Health Care System and the University of California, Davis, found that microRNAs (small RNA modules that help regulate genes in the body) could help suppress cancer cells in the bladder.

The team found that in cancer cells in the bladder, there tended to be a shortage of the microRNA module miR-148a. This module can be reproduced in laboratories, raising the possibility that if it can be introduced into cancer cells in a targeted way, it can help suppress the growth of those cells.

Bladder cancer is the fourth most common cancer in men, and the ninth most common in women.

Two RNA molecules may suppress tumor growth—Another study of RNA, this one published in 2016 by researchers at the VA Palo Alto Healthcare System and Stanford University School of Medicine, found that two RNA molecules, SNORD50A and SNORD50B, are missing in 10 to 40 percent of tumors in patients with 12 common cancers—and that patients whose tumors do not have these molecules have poorer survival rates than their peers.

The two molecules directly inhibit a well-known cancer-associated protein called K-Ras. In the absence of those molecules, K-Ras becomes hyperactive and emits continued signals to cancer cells to divide.

According to the research team, this is the first time an RNA molecule of this kind has been shown to act as a powerful tumor suppressor. K-ras mutation is an essential step in the development of nearly all human cancers. Understanding how the two molecules block the ability of K-Ras to be activated may open new doors to blocking its function in cancer.

New lung cancer clinical program—In 2015, VA's New England Healthcare System and the Massachusetts Veterans Epidemiology Research and Information Center instituted a clinical program to help Veterans who have been newly diagnosed with non-small cell lung center.

As Veterans are diagnosed, VA physicians will take a specimen of their tumor and send it to qualified laboratories for targeted genomic sequencing, a process that determines the DNA sequence of genes that are considered important in lung cancer.

The sequencing will identify specific mutations, or changes, that are causing the lung cancer to grow, allowing the Veterans to benefit from drugs that are targeted to those mutations, and to take part in clinical trials of new drugs targeted toward their specific mutations.

This precision oncology program is currently underway at VA facilities throughout New England. VA hopes to expand it nationally in the future.

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➤ Genomics and respiratory ailments

Researchers at the Durham VA Medical Center, Johns Hopkins University, and Duke University are now fine-tuning a test that can determine whether a respiratory illness is caused by an infection from a virus or bacteria.

The team has identified gene signatures that reflect which of a patient's genes are turned on or off, to indicate the cause of an infection. These gene signatures can be derived from a small blood sample.

The signatures were tested in a study, published in 2016, and were found to be 87 percent effective in classifying more than 300 patients with flu viruses, rhinovirus, several strep bacteria, and other common infections. The signatures also indicated when no infection was present.

The team hopes to develop a blood test that can be used in clinics to distinguish between bacterial and viral infections in an hour or less (the current test takes about 10 hours to evaluate), and to guide appropriate treatment. Such a test should reduce excess use of antibiotics, which is a risk to both the patient and to public health.

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More on Our Website

 

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Selected Scientific Articles by Our Researchers

Delivery of genomic medicine for common chronic adult diseases: a systematic review, Scheuner MT, Sieverding P, Shekelle PG. Many gaps in knowledge about organization, clinician, and patient needs must be filled to translate basic and clinical science advances in genomics of common chronic diseases into practice. JAMA, 2008 Mar 19;299(11):1320-34.

Veterans' attitudes regarding a database for genomic research. Kaufman D, Murphy J, Erby L, Hudson K, Scott J. Majorities of Veterans Affairs health patients in a broad range of demographic groups supported the establishment of a genomic database and showed willingness to participate. Genet Med, 2009 May;11(5):329-37.

Preferences regarding genetic research results: comparing veterans and nonveterans responses. Arar N, Seo J, Lee S, Abboud HE, Copeland LA, Noel P, Parchman M. Participants believed they would prefer receiving their genetic research results. Veterans are similar to non-Veterans in their preferences. Public Health Genomics, 2010;13(7-8);431-9.

The VA Hypertension Primary Care Longitudinal Cohort: Electronic medical records in the post-genomic era. Salem RM, Pandey B, Richard E, Fung MM, Garcia EP, Brophy VH, Schork NJ, O'Connor DT, Bhatnegar V. The coupling of detailed medical databases with genetic information has the potential to facilitate the genetic study of hypertension and other complex diseases. Health Informatics J, 2010 Dec;16(4):274-86.

Biological insights from 108 schizophrenia-associated genetic loci.Schizophrenia Working Group of the Psychatric Genomics Consortium. A multi-stage schizophrenia genome wide association study of up to 36,989 cases and 113,075 controls identified 128 independent associations, 83 of which have not been previously reported. Nature, 2014 Jul 24;511(7510):421-7.

Aberrant promoter methylation of caveolin-1 is associated with favorable response to taxane-platinum combination chemotherapy in advanced NSCLC. Brodie SA, Lombardo C, Li G, Kowalski J, Gandhi K, You S, Khuri FR, Marcus A, Vertino PM, Brandes JC. CAV1 methylation, an alteration in a common gene, can help predict how well patients with non-small cell lung cancer respond to chemotherapy. PLoS One, 2014 Sep 15;9(9):e107124.

Association of gene variants of the renin-angiotensin system with accelerated hippocampal volume loss and cognitive decline in old age. Zannas AS, McQuoid DR, Payne ME, MacFall JR, Ashley-Koch A, Steffens DC, Potter GG, Taylor WD. Risk genetic variants of the renin-angiotensin system may accelerate memory decline in older adults. Am J Psychiatry, 2014 Nov 1;171(11):1214-21.

Select small nucleolar RNAs in blood components as novel biomarkers for improved identification of comorbid traumatic brain injury and post-traumatic stress disorder in veterans of the conflicts in Afghanistan and Iraq. Ho L, Lange G, Zhao W, Wang J, Rooney R, Patel DH, Fobler MM, Helmer DA, Elder G, Shaughess MC, Ahlers ST, Russo SJ, Pasinetti GM. Biological interactions between TBI and PTSD may contribute to the clinical features of veterans with comorbid mild TBI and PTSD. Am J Neurodegener Dis, 2014 Dec 5;3(3):170-81.

miR-148a dependent apoptosis of bladder cancer cells is mediated in part by the epigenetic modifier DNMT1. Lombard AP, Mooso BA, Libertini SJ, Lim RM, Nakagawa RM, Vidallo KD, Costanzo NC, Ghosh PM, Mudryj M. The microRNA R-148a is a tumor suppressor in urothelial cell carcinoma of the bladder and could potentially serve as a novel therapeutic for this malignancy. Mol Carcinog, 2015 Apr 11. (Epub ahead of print.)

shRNA targeting α-synuclein prevents neurodegeneration in a Parkinson's disease model. Zharikov AD, Cannon JR, Tapias V, Bai Q, Horowitz MP, Shah V, El Ayadi A, Hastings TG, Greenamyre JT, Burton EA. Short hairpin RNA targeting the SNCA transcript should be further evaluated as a possible neuroprotective therapy in Parkinson's disease. J Clin Invest, 2015 Jul 1;125(7):2721-35.

Nerve growth factor gene therapy: activation of neuronal responses in Alzheimer disease. Tuszynski MH, Yang JH, Barba D, U HS, Bakay RA, Pay MM, Masliah E, Conner JM, Kobalka P, Roy S, Nagahara AH. Growth factor therapy appears safe over extended periods and merits continued testing as a means of treating neurodegenerative disorders. JAMA Neurol, 2015 Oct;72(10):1139-47.

The noncoding RNAs SNORD50A and SNORD50B bind K-Ras and are recurrently deleted in human cancer. Shiprashvili Z, Webster DE, Johnston D, Shenoy RM, Ungewickell AJ, Bhaduri A, Flockhart R, Zamegar BJ, Che Y, Meschi F, Puglisi JD, Khavari PA. Two short "housekeeping" RNA molecules block cancer growth by binding to an important cancer-associated protein called K-Ras. Nat Genet, 2016 Jan;48(1):53-8.

Host gene expression classifiers diagnose acute respiratory illness etiology. Tsalik EL, Henao R, Nichols M, Burke T, Ko ER, McClain MT, Hudson LL, Mazur A, Freeman DH, Veldman T, Langley RJ, Quackenbush EB, Glickman SW, Cairns CB, Jaehne AK, Rivers EP, Otero RM, Zaas AK, Kingsmore SF, Lucas J, Fowler VG Jr, Carin L, Ginsburg GS, Woods CW. Host gene expression classifiers can be used as diagnostic platforms to combat inappropriate antibiotic use and emergency antibiotic resistance. Sci Transl Med, 2016 Jan 20;8(322):322ra11.

SKA2 methylation is associated with decreased prefrontal cortical thickness and greater PTSD severity among trauma-exposed veterans. Sadeh N, Spielberg JM, Logue MW, Wolf EJ, Smith AK, Lusk J, Hayes JP, Sperbeck E, Milberg WP, McGlinchey RE, Salat DH, Carter WC, Stone A, Schichman SA, Humphries DE, Miller MW. DNA methylation of the SKA2 gene in blood indexes points to its potential value as a biomarker of stress exposure and susceptibility. Mol Psychiatry, 2016 Mar;21(3):357-63.

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Genomics Fact Sheet

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VA Research in the News

Gene therapy prevents Parkinson's disease in animal model, says Pitt study, University of Pittsburgh Medical Center press release, June 15, 2015

Degenerating neurons respond to gene therapy treatment for Alzheimer's disease, UC San Diego Health press release, Aug. 27, 2015

Gene may predict severity of post-traumatic stress disorder, Boston University Medical Center press release, Sept. 1, 2015

Inside the drive to collect DNA from 1 million Veterans and revolutionize medicine, Stat, Nov. 11, 2015

New class of RNA tumor suppressors identified, Stanford University press release, Nov. 23, 2015

Not 'junk' anymore: Obscure DNA has key role in stroke damage, University of Wisconsin-Madison press release, Dec. 15, 2015

Do you need antibiotics? A new test may tell, CBS News, Jan. 20, 2016

Genes identified that may predispose some individuals to getting sick, MedicalResearch.com, Jan. 24, 2016

Work begins on precision medicine healthcare data standards, HealthIT Interoperability, Feb. 17, 2016

VA and other U.S. Government Online Resources

Genomic medicine program advisory committee, Department of Veterans Affairs

MAVERIC (Massachusetts Veterans Epidemiology Research and Information Center), Department of Veterans Affairs

Providence VA Medical Center Genomics Laboratory, Department of Veterans Affairs

The VA precision oncology program and a learning healthcare system—wearing the short white coat, VA VAntage Point Blog, Aug. 25, 2015

National Human Genome Research Institute, National Institutes of Health

Public Health Genomics, Centers for Disease Control and Prevention

genomics.energy.gov, U.S. Department of Energy

Drugs: Genomics, U.S. Food and Drug Administration

The Precision Medicine Initiative, The White House


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