Closer Look at Heart Attack Medications Required Owing to Racial Difference in Blood Clotting
A new understanding of the effects of race on heart disease has been provided by Thomas Jefferson University (PA, USA) researchers who have discovered that blood clot formation in African–Americans and European–Americans follows a different molecular route. The research, published online in Nature Medicine, could potentially aid doctors in providing more individualized treatment of heart disease and other blood-clot-related illnesses.
An additional explanation for the difference in outcomes seen in black and white patients with heart disease may be provided by these findings. Black patients have a twofold increased incidence of heart disease and a lower long-term survival when compared with white patients. There are complex reasons behind this racial disparity, including racial bias, a higher prevalence of traditional risk factors in black patients, and differences in socioeconomic status, management and environment. However, the survival of black heart attack patients is 2.5-times lower than white patients even when these factors are taken into account, suggesting that there are as yet unidentified factors contributing to the racial disparity in heart disease.
“We may need to consider our patient‘s race when using certain heart disease therapies,” said lead author of the research Paul Bray, Director of Thomas Jefferson University‘s Cardeza Foundation for Hematologic Research.
In order to prevent heart attack or stroke antiplatelet medications, such as aspirin, are commonly prescribed. These medications act on platelets, small cells that normally circulate in the blood stream and stick to damaged or atherosclerotic blood vessels, preventing this clot-forming activity. Rupture of these plaques in atherosclerotic vessels can result in the formation of a platelet plug, which can block blood vessels and lead to a heart attack or stroke. Patient response to these medications is, however, highly variable, which presents difficulties for physicians who must chose the appropriate drug and most effective dose for individual patients. Doctors could be helped in treating racial groups in a more personalized and effective way as a result of this research from Thomas Jefferson University, which identifies some of the genetic differences behind these variations.
“Differences in platelet biology could be part of the explanation of the disparity,” says Bray.
Platelets from blood samples of 154 young healthy subjects, including 70 black patients and 84 white patients, were analyzed by Bray and collaborators from Baylor Medical College, Harvard Medical School (MA, USA) and the New York and Puget Sounds Blood Centers (NY, USA and WA, USA) in order to investigate the racial component of variation among different individuals. Genetic tests that verified geographic ancestry were used to confirm self-reported race. Platelets from black donors were unexpectedly found to clot faster and to a greater extent in response to the naturally occurring clotting agent thrombin that specifically activated PR4, a platelet-activating receptor. Other clotting agents did not show racial differences.
As the most potent platelet activator in the body, a number of blood-thinning medications target thrombin. Newer drugs targeting thrombin, however, inhibit members of the PAR receptor family. An example is vorapaxar, which specifically inhibits the PAR1 receptor and is in development for the treatment of patients with heart disease. The only route through which thrombin can activate platelets, when PAR1 is blocked by vorapaxar, is PAR4, and it was shown by Jefferson scientists that in this situation platelets were more potently activated by thrombin in black patients. How these results relate to drugs that are currently described or that are in development remains to be determined.
A novel gene called PCTP, which mediates platelet activation though PAR4, was identified by molecular studies. PCTP appears to be a major contributor to the difference in blood clotting as it was expressed at higher levels in platelets from black patients. In addition, a miRNA that silenced the expression of PCTP was identified. This miRNA may contribute to the lower levels of thrombin activation through the PAR4 receptor in white patients as it was found to be expressed at higher levels in platelets from white patients than from black patients.
The researchers found that, in platelets, many silencing miRNAs were more actively expressed in white patients than in black patients, suggesting other aspects of platelet biology may be race dependent. Individual differences in platelet function could be elucidated by uncovering the genes that these miRNAs suppress, which could eventually lead to an understanding of how these differences contribute to disease and response to anticlotting medications.
“In this age where there is such a focus on delivering personalized medicine, we should embrace these differences to try to give our patients better care,” says Bray.
Source: Edelstein LC, Simon LM, Montoya RT et al. Racial differences in human platelet PAR4 reactivity reflect expression of PCTP and miR-376c. Nat. Med. doi:10.1038/nm.3385 (2013) (Epub ahead of print).
Using Tumor Genomics to Customize Treatments for Deadly Prostate Cancer
Genomic sequencing is being used in a new study at the Mayo Clinic (MN, USA) to allow individualized treatments for men with castration-resistant prostate cancer. At this stage of prostate cancer, there is no longer a response to hormone therapies that stop or slow testosterone production, and the disease becomes progressive and incurable.
“Men with castration-resistant prostate cancer have abysmal survival rates, typically living an average of 2 years once hormone therapies fail,” says Manish Kohli, a Mayo Clinic oncologist and principal investigator of the Prostate Cancer Medically Optimized Genome-Enhanced Therapy (PROMOTE) study. Owing to the poor prognosis for men with this cancer, Kohli says, there is a need for studies like PROMOTE, which use the genomic characteristics of a patient‘s tumor to tailor new targeted drugs.
New hope for men with this castration-resistant prostate cancer is offered by several new therapies that have recently been approved by the US FDA for use in this disease. There are, however, still questions as to which medications to use in individual cases. The PROMOTE study matched a particular patient to the best drug using exome sequencing and RNA profiling to establish the molecular fingerprint of their tumor. As well as allowing for these individualized treatment plans, the study will result in the development of new therapies through the identification of new targets in the cancer genome. Identification of these new targets will occur largely through the use of mouse ‘avatars‘, which will carry individual study participant‘s tumors. New drugs will also be tested in these avatars against the patients tumors before giving the potentially harmful agents to the patients themselves.
“The approach we are taking with PROMOTE is exactly what we are working toward across Mayo Clinic through our Center for Individualized Medicine,” says Gianrico Farrugia, director of the Mayo Clinic Center for Individualized Medicine. “We‘re offering individualized care and tailored treatment options for our patients.”
There are more than 238,000 new diagnoses of prostate cancer in the USA annually and the disease is the most commonly diagnosed solid organ malignancy in the USA. It is also the second leading cause of cancer deaths in America, with 29,720 deaths annually, according to the Surveillance Epidemiology and End Results Program of the National Cancer Institute.
Source: Customizing Treatments for Deadly Prostate Cancer With Tumor Genomics: www.sciencedaily.com/releases/2013/11/131106113839.htm
Identification of Mutation Associated with Breast Cancer Treatment Resistance
A type of mutation that develops in breast cancer patients taking antiestrogen therapies has been revealed by research at the University of Michigan Comprehensive Cancer Center (MI, USA). Identification of these mutations sheds light on one reason why patients often become resistant to antiestrogen therapies. The results appear online in Nature Genetics.
The research grew out of a program at the University of Michigan Comprehensive Cancer Center called Mi-ONCOSEQ, which involved the sequencing of DNA and RNA from patients with advanced tumors in a bid to identify genetic mutations that may play a role in the cancer. The findings are used by researchers to help direct therapies that they think will work best, but can also be used to identify new genetic links. Anomalies among a small number of patients can be identified through the detailed analysis.
Eleven patients with metastatic breast cancer that was estrogen-receptor positive were examined. This type of tumor is influenced by the hormone estrogen and is the most common type for breast cancer.
Six patients were found to have mutations in the estrogen receptor. All of them had been treated with the estrogen-blocking class of drugs known as aromatase inhibitors.
Interestingly, it was the treatment that caused the mutations to develop or be selected as they were not present before the patients started therapy.
“This is the tumor‘s way of evading hormonal therapy. These mutations activate the estrogen receptor when there is no estrogen – as is the case when a patient takes an aromatase inhibitor. It‘s essentially an on-switch for the estrogen receptor,” says lead study author, Dan Robinson, Research Assistant Professor of Pathology at the University of Michigan Medical School.
The on-switch prevents the estrogen-receptor signaling from being shut down by circumventing the effects of the aromatase inhibitor. Patients then become resistant to therapy, which leaves very few other treatment options open. In the USA, there will be 40,000 deaths this year from breast cancer, and the majority of these will have the estrogen-receptor positive form of the disease.
“We‘ve been trying for a long time to understand why people become resistant to antihormone therapy. This finding sheds an entirely new light onto the problem. Now, we can look at how these estrogen receptors function and begin to develop drugs to shut down or attack this mutation,” says study coauthor Anne F Schott, Associate Professor of Internal Medicine at the University of Michigan Medical School.
Monitoring and detection of these mutations could be performed by blood tests that would allow treatment to be shifted before the development of resistance. The frequency with which these mutations occur is not yet known and no targeted treatment currently exists.
“Precision medicine approaches will allow us to understand how targeted therapies are working, but another important challenge is to understand the mechanisms by which tumors become resistant to these treatments so that we can prevent the resistance or develop strategies to overcome it,” says senior study author Arul Chinnaiyan, director of the Michigan Center for Translational Pathology and SP Hicks Professor of Pathology at the University of Michigan Medical School.
Source: Robinson DR, Wu YM, Vats P et al. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat. Genet. doi:10.1038/ng.2823 (2013) (Epub ahead of print).
New Study to Examine the Genomics of Antiplatelet Medication
The question of which antiplatelet medication is best after a coronary stent is still one that faces doctors who perform the 600,000 angioplasties carried out each year in the USA. It is possible the answer may reside in your genetic make up. However, professional cardiovascular societies and many working cardiologists question the recent recommendation from the US FDA that patients undergo genetic testing before taking clopidogrel.
Launched this summer by the Individualized Medicine and the Division of Cardiovascular Diseases at Mayo Clinic (MN, USA), the Tailored Antiplatelet Therapy to Lessen Outcomes after Percutaneous Coronary Intervention (TAILOR-PCI) study looks at whether using CYP2C19 genotype to determine heart medication prescribing will help prevent heart attack, stroke, unstable angina and cardiovascular death in patients who undergo percutaneous coronary intervention, commonly called angioplasty.
“The current standard of care after angioplasty is to prescribe clopidogrel for 1 year, regardless of a person‘s individual genotype, even though we have known for several years that variation in the CYP2C19 gene may diminish the benefit from the drug,” says Naveen Pereira, a Mayo Clinic cardiologist and principal investigator of TAILOR-PCI. “What we don‘t know – and why there is such confusion in the cardiovascular community – is how these genetic changes affect long-term clinical outcomes and whether we can decrease overall healthcare costs.”
By reducing the possibility of blood clots around the surgical site, antiplatelet medication reduces the risk of heart attack, unstable angina, stroke and cardiovascular death after stent placement.
The liver enzyme CYP2C19 is, however, required to convert clopidogrel to its active form. There are medications that do not require activation through this genetic pathway, such as ticagrelor.
“Ticagrelor has its own risks, including serious or life-threatening bleeding. Additionally, this alternative therapy costs approximately six- to eight-times as much and must be taken twice a day,” says Pereira. “Ultimately, what we‘re trying to do with TAILOR is use pharmacogenomics to determine whether choosing medication based on individual genotype will help patients live longer and whether the benefits will outweigh the risks of alternative therapies.”
Potential cost impacts to the healthcare system will be studied by Nilay Shah, a Mayo Clinic Health Sciences Research Professor.
“This study examines as much as an US$8 billion question in healthcare,” says Shah. “Clopidogrel is the second-most prescribed medication in the USA; and although ticagrelor costs much more, the costs of taking patients into the emergency room and performing a second angioplasty are much higher.”
The study will also result in the creation of a coronary artery disease biobank with DNA samples from the 5300 participants enrolled in the study. Through the use of genomic sequencing technologies, these samples can be mined by researchers to further our knowledge of the origins of and risk factors for coronary artery disease.
Gianrico Farrugia, director of the Center for Individualized Medicine, Mayo Clinic (MN, USA), says, “TAILOR-PCI is exactly the type of research we do every day –the kind that translates into better health for our patients and improves the delivery of care for millions of patients around the world.”
Up to one-third of patients taking clopidogrel carry a genomic variant implicated in diminished drug response. The enrollment of 5300 patients into TAILOR-PCI will be undertaken by study teams at 15 hospitals in three countries, and results are expected in 3 years.
Source: Genomics of Antiplatelet Heart Medication Being Studied: www.sciencedaily.com/releases/2013/11/131113132137.htm
– All stories written by Sarah Jones