Common heart disease 'passed on from father to son'

A common heart disease which kills thousands each year may be passed genetically from father to son, according to a study led by the University of Leicester.

A paper published in medical journal The Lancet on February 9, 2012 shows that the Y chromosome, a part of DNA present only in men, plays a role in the inheritance of coronary artery disease (CAD).

The study, called Inheritance of coronary artery disease in men: an analysis of the role of the Y chromosome, was led by researchers at the University's Department of Cardiovascular Sciences and Department of Genetics. The research took four years to complete and was primarily funded by the British Heart Foundation.

It was also supported by the National Institute for Health Research, LEW Cart Charitable Fund, National Health and Medical Research Council of Australia, the European Union, and the Wellcome Trust.

The British Heart Foundation found that coronary artery disease caused 88,236 deaths in 2008 in the United Kingdom, with 49,665 deaths among men and 38,571 among women.

The team at the University of Leicester analysed DNA from over 3,000 men from British Heart Foundation Family Heart Study (BHF-FHS) and the West of Scotland Coronary Prevention Study (WOSCOPS).

They found that 90% of British Y chromosomes belong to one of two major groups – named haplogroup I and haplogroup R1b1b2.

The risk of coronary artery disease among men who carry a Y chromosome from haplogroup I is 50% higher than other men, and the risk is independent of traditional risk factors such as high cholesterol, high blood pressure and smoking.

The researchers believe the increased risk is down to the haplogroup I’s influence on the immune system and inflammation – how our bodies respond to infections.

Principal investigator Dr Maciej Tomaszewski, a clinical senior lecturer at the University's Department of Cardiovascular Sciences, said: “We are very excited about these findings as they put the Y chromosome on the map of genetic susceptibility to coronary artery disease. We wish to further analyse the human Y chromosome to find specific genes and variants that drive this association.

“The major novelty of these findings is that the human Y chromosome appears to play a role in the cardiovascular system beyond its traditionally perceived determination of male sex.

“The University of Leicester has been at the forefront of genetic research for many years. The success of this study builds up on excellence of support for genetic studies in the Department of Cardiovascular Sciences and the Leicester Cardiovascular Biomedical Research Unit.”

The project also included researchers from King’s College, London, the University of Glasgow, the University of Leeds, the Wellcome Trust Sanger Institute, Cambridge, the University of Cambridge, the University of Ballarat and the Garvan Institute for Medical Research in Australia, the University of Lübeck and the University of Regensburg in Germany and the Marie Curie University and Medical School in Paris, France. doi:10.1016/S0140-6736(11)61453-0



Genetic basis for age-related macular degeneration

Age-related macular degeneration (AMD) is one of the leading causes of blindness worldwide, especially in developed countries, and there is currently no known treatment or cure or for the vast majority of AMD patients. New research published in BioMed Central’s open access journal Genome Medicine has identified genes whose expression levels can identify people with AMD, as well as tell apart AMD subtypes.

It is estimated that 6.5% of people over age 40 in the US currently have AMD. There is an inheritable genetic risk factor but risk is also increased for smokers and with exposure to UV light. Genome-wide studies have indicated that genes involved in the innate immune system and fat metabolism are involved in this disease. However none of these prior studies examined gene expression differences between AMD and normal eyes.

In order to address this question, researchers at the University of California Santa Barbara, the University of Utah John Moran Eye Center, and the University of Iowa combined forces and used a human donor eye repository to identify genes up-regulated in AMD. The ability of these genes to recognize AMD was tested on a separate set of samples.

The team discovered over 50 genes that have higher than normal levels in AMD, the top 20 of which were able to ‘predict’ a clinical AMD diagnosis. Genes overexpressed in the RPE-choroid (a tissue complex located beneath the retina) included components of inflammatory responses, while in the retina, the researchers found genes involved in wound healing and the complement cascade, a part of the innate immune system. They found retinal genes with expression levels that matched the disease severity for advanced stages of AMD.

Dr. Monte Radeke, one of the project leaders, explained, "Not only are these genes able to identify people with clinically recognized AMD and distinguish between different advanced types – some of these genes appear to be associated with pre-clinical stages of AMD. This suggests that they may be involved in key processes that drive the disease. Now that we know the identity and function of many of the genes involved in the disease, we can start to look among them to develop new diagnostic methods, and for new targets for the development of treatments for all forms of AMD."

Reference

Aaron M Newman, et al. “Systems-level analysis of age-related macular degeneration reveals global biomarkers and phenotype- specific functional networks”. Genome Medicine (in press)



Scientists find an answer to how brain cells remember memories

Researchers at the RIKEN-MIT Center for Neural Circuit Genetics have discovered an answer to the long-standing mystery of how brain cells can both remember new memories while also maintaining older ones.

They found that specific neurons in a brain region called the dentate gyrus serve distinct roles in memory formation depending on whether the neural stem cells that produced them were of old versus young age.

The study will appear in the March 30 issue of Cell and links the cellular basis of memory formation to the birth of new neurons – a finding that could unlock a new class of drug targets to treat memory disorders.

The findings also suggest that an imbalance between young and old neurons in the brain could disrupt normal memory formation during post-traumatic stress disorder (PTSD) and aging. “In animals traumatic experiences and aging often lead to decline of the birth of new neurons in the dentate gyrus. In humans, recent studies found dentate gyrus dysfunction and related memory impairments during normal aging,” said the study’s senior author Susumu Tonegawa, 1987 Nobel Laureate and Director of the RIKEN-MIT Center.

Other authors include Toshiaki Nakashiba and researchers from the RIKEN-MIT Center and Picower Institute at MIT; the laboratory of Michael S. Fanselow at the University of California at Los Angeles; and the laboratory of Chris J. McBain at the US National Institute of Child Health and Human Development.

In the study, the authors tested mice in two types of memory processes. Pattern separation is the process by which the brain distinguishes differences between similar events, like remembering two Madeleine cookies with different tastes. In contrast, pattern completion is used to recall detailed content of memories based on limited clues, like recalling who one was with when remembering the taste of the Madeleine cookies.

Pattern separation forms distinct new memories based on differences between experiences; pattern completion retrieves memories by detecting similarities. Individuals with brain injury or trauma may be unable to recall people they see every day. Others with PTSD are unable to forget terrible events. “Impaired pattern separation due to the loss of young neurons may shift the balance in favour of pattern completion, which may underlie recurrent traumatic memory recall observed in PTSD patients,” Tonegawa said.

Neuroscientists have long thought these two opposing and potentially competing processes occur in different neural circuits. The dentate gyrus, a structure with remarkable plasticity within the nervous system and its role in conditions from depression to epilepsy to traumatic brain injury – was thought to be engaged in pattern separation and the CA3 region in pattern completion. Instead, the MIT researchers found that dentate gyrus neurons may perform pattern separation or completion depending on the age of their cells.

The MIT researchers assessed pattern separation in mice who learned to distinguish between two similar but distinct chambers: one safe and the other associated with an unpleasant foot shock. To test their pattern completion abilities, the mice were given limited cues to escape a maze they had previously learned to negotiate. Normal mice were compared with mice lacking either young neurons or old neurons. The mice exhibited defects in pattern completion or separation depending on which set of neurons was removed.

“By studying mice genetically modified to block neuronal communication from old neurons – or by wiping out their adultborn young neurons – we found that old neurons were dispensable for pattern separation, whereas young neurons were required for it,” co-author Toshiaki Nakashiba said. “Our data also demonstrated that mice devoid of old neurons were defective in pattern completion, suggesting that the balance between pattern separation and completion may be altered as a result of loss of old neurons.”

The work was supported by the RIKENMIT Center for Neural Circuit Genetics, Howard Hughes Medical Institute, Otsuka Maryland Research Institute, Picower Foundation and the National Institutes of Health.

Reference:

Toshiaki Nakashiba, et al. “Young Dentate Granule Cells Mediate Pattern Separation whereas Old Granule Cells Facilitate Pattern Completion.” Cell, 2012, March 30 issue



US NIH launches open Genetic Testing Registry

An online tool launched in February by the US National Institutes of Health will make it easier to navigate the rapidly changing landscape of genetic tests. The free resource, called the Genetic Testing Registry (GTR), is available at www.ncbi.nlm.nih.gov/gtr

“I’m delighted that NIH has created this powerful, new tool. It is a tremendous resource for all who are struggling to make sense of the complex world of genetic testing,” said NIH Director Francis S. Collins, MD, PhD. “This registry will help a lot of people – from health care professionals looking for answers to their patients’ diseases to researchers seeking to identify gaps in scientific knowledge.”

Genetic tests currently exist for about 2,500 diseases, and the field continues to grow at an astonishing rate. To keep pace, GTR will be updated frequently, using data voluntarily submitted by genetic test providers. Such information will include the purpose of each genetic test and its limitations; the name and location of the test provider; whether it is a clinical or research test; what methods are used; and what is measured. GTR will contain no confidential information about people who receive genetic tests or individual test results.

Genetic tests that the US FDA has cleared or approved as safe and effective are identified in the GTR. However, most laboratory developed tests currently do not require FDA premarket review. Genetic test providers will be solely responsible for the content and quality of the data they submit to GTR. NIH will not verify the content, but will require submitters to agree to a code of conduct that stipulates that the information they provide is accurate and updated on an annual basis. If submitters do not adhere to this code, NIH can take action, including requiring submitters to correct any inaccuracies or to remove such information from GTR.

In addition to basic facts, GTR will offer detailed information on analytic validity, which assesses how accurately and reliably the test measures the genetic target; clinical validity, which assesses how consistently and accurately the test detects or predicts the outcome of interest; and information relating to the test’s clinical utility, or how likely the test is to improve patient outcomes.

“Our new registry features a versatile search interface that allows users to search by tests, conditions, genes, genetic mutations and laboratories,” said Wendy Rubinstein, MD, PhD, director of GTR. “What’s more, we designed this tool to serve as a portal to other medical genetics information, with context-specific links to practice guidelines and a variety of genetic, scientific and literature resources available through the National Library of Medicine at NIH.”

GTR is built upon data pulled from the laboratory directory of GeneTests, a pioneering NIH-funded resource that will be phased out over the coming year. GTR is designed to contain more detailed information than its predecessor, as well as to encompass a much broader range of testing approaches, such as complex tests for genetic variations associated with common diseases and with differing responses to drugs. GeneReviews, which is the section of GeneTests that contains peer-reviewed, clinical descriptions of more than 500 conditions, is also now available through GTR.

Genetic Testing Registry www.ncbi.nlm.nih.gov/gtr To view video tutorials on how to use GTR, go to: http://tinyurl.com/84qaq2m

                                   
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