Researchers find link between burden of genetic risk factors and reduction of cardiovascular death and heart attacks with statin therapy

Research has demonstrated that the risk for developing coronary heart disease depends on a host of risk factors that are related both to lifestyle and genetics. In a new study from Brigham and Women's Hospital (BWH), Washington University School of Medicine in St. Louis, and Massachusetts General Hospital (MGH), researchers tested whether a composite of genetic variants could identify the risk of cardiovascular death and heart attacks as well as identify individuals who derived greater clinical benefit from statin therapy.

Researchers found that a genetic risk score identified individuals at increased risk for cardiovascular death or a heart attack, both in individuals with and without known coronary disease, with individuals in the highest genetic risk score group having more than a 70 percent increase in the risk of cardiovascular death or a heart attack compared to the lowest risk group. Moreover, the individuals with the highest burden of genetic risk had the largest benefit with statin therapy in terms of reducing the risk of cardiovascular death or heart attacks, with three times the absolute risk reduction seen in the low risk group. These findings are published in the March 3 issue of The Lancet.

"These findings could play an important role in helping physicians understand which patients will benefit the most from statin therapy," said Jessica L. Mega, MD, MPH, first author of the research paper and a cardiologist and Senior Investigator in the TIMI Study Group at BWH.

"Current clinical guidelines base treatment indications, in part, on the estimated 10-year risk of having an event," added Nathan Stitziel, MD, PhD, co-first author of the report and a cardiologist at Washington University in St. Louis. "It is possible that a genetic score such as this one might help refine these risk estimates in the future."

Researchers examined data from 48,421 individuals who experienced 3,477 cardiac events during the study period, and evaluated the association of a genetic risk score, based on 27 known genetic variants, with a first time or repeat cardiac event. After grouping patients by genetic risk, researchers then evaluated the role of statin therapy in reducing the risk of a cardiac event in each group.

They report that those with the lowest genetic risk score had the lowest risk of a first-time or recurring cardiac event, such as heart attack or stroke. In terms of the benefit of statin therapy, researchers observed an increase in both absolute and relative risk reduction across the low, intermediate and high genetic risk categories.

"Over the last five years, we have identified more than two dozen genetic variants that increase risk for heart attack," said Sekar Kathiresan, MD, director of Preventive Cardiology at MGH and co-senior author of the paper. "We wondered if those at highest genetic risk would enjoy the greatest benefit from statin therapy with respect to preventing a first heart attack. This looks to be the case."

"This knowledge will allow us, as cardiologists, to provide more personalized treatment for our patients," said Marc S. Sabatine, MD, MPH, a cardiologist at BWH, chairman of the TIMI Study Group and co-senior author of the paper.

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Genetic risk linked to clinical benefit of statin therapy

The order in which genetic mutations are acquired determines how an individual cancer behaves, according to research from the University of Cambridge, published today in the New England Journal of Medicine.

Most of the genetic mutations that cause cancer result from environmental 'damage' (for example, through smoking or as a result of over-exposure to sunlight) or from spontaneous errors as cells divide. In a study published today, researchers at the Department of Haematology, the Cambridge Institute for Medical Research and the Wellcome Trust/Medical Research Council Stem Cell Institute show for the first time that the order in which such mutations occur can have an impact on disease severity and response to therapy.

The researchers examined genetically distinct single stem cells taken from patients with myeloproliferative neoplasms (MPNs), a group of bone marrow disorders that are characterised by the over-production of mature blood cells together with an increased risk of both blood clots and leukaemia. These disorders are identified at a much earlier stage than most cancers because the increased number of blood cells is readily detectable in blood counts taken during routine clinical check-ups for completely different problems.

Approximately one in ten of MPN patients carry mutations in both the JAK2 gene and the TET2 gene. By studying these individuals, the research team was able to determine which mutation came first and to study the effect of mutation order on the behaviour of single blood stem cells.

Using samples collected primarily from patients attending Addenbrooke's Hospital, part of the Cambridge University Hospitals, researchers showed that patients who acquire mutations in JAK2 prior to those in TET2 display aberrant blood counts over a decade earlier, are more likely to develop a more severe red blood cell disease subtype, are more likely to suffer a blood clot, and their cells respond differently to drugs that inhibit JAK2.

Dr David Kent, one of the study's lead authors, says: "This surprising finding could help us offer more accurate prognoses to MPN patients based on their mutation order and tailor potential therapies towards them. For example, our results predict that targeted JAK2 therapy would be more effective in patients with one mutation order but not the other."

Professor Tony Green, who led the study, adds: "This is the first time that mutation order has been shown to affect any cancer, and it is likely that this phenomenon occurs in many types of malignancy. These results show how study of the MPNs provides unparalleled access to the earliest stages of tumour development (inaccessible in other cancers, which usually cannot be detected until many mutations have accumulated). This should give us powerful insights into the origins of cancer."

Work in the Green Lab is supported in party by Leukaemia and Lymphoma Research and Cancer Research UK.

Dr Matt Kaiser, Head of Research at Leukaemia & Lymphoma Research, said: "We are becoming more and more aware that a cancer's genetic signature can vary from patient to patient, and we are becoming better at personalising treatment to match this. The discovery that the order in which genetic errors occur can have such a big impact on cancer progression adds an important extra layer of complexity that will help tailor treatment for patients with MPNs. The technology to do this sort of study has been available only recently and it shows once again how pioneering research into blood cancers can reveal fundamental insights into cancer in general."

Dr ine McCarthy, Science Information Officer at Cancer Research UK, says: "The methods used in this pioneering research could help improve our understanding of how cancer cells develop mutations and when they do so. This interesting study suggests that the order in which genetic faults appear can affect how patients respond to different drugs - this insight could help doctors personalise treatment to make it more effective for each patient."

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Order matters: Sequence of genetic mutations determines how cancer behaves

(Boston)--A new genetic discovery in the field of Huntington's disease (HD) could mean a more effective way in determining severity of this neurological disease when using specific treatments. This study may provide insight for treatments that would be effective in slowing down or postponing the death of neurons for people who carry the HD gene mutation, but who do not yet show symptoms of the disease.

The work was led by researchers at Boston University School of Medicine (BUSM) and currently appears in BMC Medical Genomics.

HD is a fatal, inherited neurological disease that usually manifests between 30 and 50 years of age. The disease is caused by a genetic defect that is passed from parent to child in the huntingtin gene. Having too many repeated elements in the gene sequence causes the disease and an increasing number of repeats leads to earlier onset and increased severity of the disease.

The researchers studied the brains of people who died from HD and those who died of other, non-neurological diseases and identified a very specific genetic signal that strongly correlates disease severity and extent of neuronal, or brain cell death. The genetic signal, also called a microRNA, silences certain genes in the DNA. Genes that lead to the toxic effects of the huntingtin gene may be silenced by these microRNAs, in particular the miR-10b-5p microRNA.

"The findings that we found most interesting were the microRNAs that reflect the extent of the neuron death in the brain, since it is this process that causes the debilitating symptoms of the disease and eventually leads to the death of the individual," explained senior author Richard H. Myers, PhD, Director of the Genome Science Institute at BUSM.

According to the researchers these findings may represent a more effective way to tell whether or not HD treatments may be slowing down the pace of the death of brain cells. "If miR-10b-5p measurements can provide a faster and more effective way to determine whether or not a specific treatment is protecting brain neurons, it may be possible to study more potential treatments for HD more quickly. Equally importantly, it may become feasible to perform these trials in people who are HD gene carriers, but who do not yet show symptoms, by giving evidence for which trials may postpone onset and provide more healthy years of life," added Myers.

These findings also suggest that other microRNAs may also be important markers of severity for other neurological diseases such as Parkinson's disease and Alzheimer's disease. Further research is already being conducted in Parkinson's Disease by Myers and his colleagues.

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This research was supported by the Jerry McDonald Huntington Disease Research Fund, the National Institutes of Health and the National Institute of Neurological Disorders and Stroke.

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Genetic discovery may help determine effectiveness of Huntington's disease treatments