Coronary artery disease

Scientists have moved a step closer to understanding how our genetic make-up can lead us to develop heart disease and to predicting who is most at risk.

In a study published in the 18 July issue of the New England Journal of Medicine, they have confirmed six new genetic variants that increase the likelihood of developing coronary artery disease.

The research was jointly carried out by researchers at the University of Leicester and the University of Leeds, in collaboration with colleagues in Germany at the Universities of Lubeck and Regensburg.

The first important clues to the identities of these variants came from a genome-wide analysis conducted in almost 2,000 people with coronary artery disease and 3,000 healthy controls as part of the Wellcome Trust Case Control Consortium (WTCCC), the largest ever study of the genetics of common disease. The findings were then compared with the German MI Family Study, with almost 900 additional cases and 1,600 additional controls.

The researchers found that changes in our DNA on chromosomes 2, 6, 10 and 15 and two on chromosome 1 were associated with increased risk of developing coronary artery disease and heart attacks. The study also confirmed the importance of a variant on chromosome 9, previously identified in an independent study.

“We are not talking about rare genetic variants here, but rather variants that are very common in our population,” says Professor Nilesh Samani, British Heart Foundation Chair of Cardiology at the University of Leicester, and lead author on the paper. “Many of these genetic variants are carried by between a quarter and three-quarters of white Europeans. They are clearly very important and explain a significant proportion of the heart attacks that occur.”

Genetic information is inherited from each parent and may include variants that influence the likelihood of developing disease. Carrying one copy of the newly-identified variants increases the chances of developing heart disease by at least 20%; carrying two such copies would increase the risk by over 40%. A person who carries copies of more than one of the genetic variants may be at a substantially higher risk, therefore.

“Understanding the genetics that lead to heart disease is a powerful tool to tell us how much risk a person faces,” says Professor Samani.

“However, it's important to emphasise that even if a person carries one or more of the risk variants, they can still do a lot to reduce their risk by adopting a healthy lifestyle, not smoking and if they have high blood pressure or raised cholesterol levels, to have these treated.”

Left hand

An international group of scientists, led by a team from the Wellcome Trust Centre for Human Genetics at Oxford University, have discovered a gene that increases an individual’s chances of being lefthanded. A report of the study is published in the journal Molecular Psychiatry.

The research, which involved over 40 scientists from 20 research centres around the world, revealed a gene called LRRTM1; the first to be discovered which has an effect on handedness. Although little is known about LRRTM1, the Oxford team suspects that it modifies the development of asymmetry in the human brain. Asymmetry is an important feature of the human brain, with the left side usually controlling speech and language, and the right side controlling emotion. In lefthanders this pattern is often reversed. There is also evidence that asymmetry of the brain was an important feature during human evolution; the brains of our closest relatives, the apes, are more symmetrical than those of humans – and apes do not show a strong handedness.

The researchers also discovered that LRRTM1 might slightly increase the risk of developing schizophrenia. People with schizophrenia often have unusual patterns of brain asymmetry and handedness, so the researchers were not surprised when LRRTM1 also showed a possible effect on the risk of developing schizophrenia.

The study leader, Dr Clyde Francks pointed out that there are many factors which make individuals more likely to develop schizophrenia and the vast majority of left-handers will never develop a problem.

“We don’t yet know the precise role of this gene.”

Asthma

Scientists have discovered a gene mutation that could up the risk of developing asthma by as much as 80%. A study of more than 2,000 children has pinpointed a single gene that may be at the core of the debilitating lung disease.

The gene, known as ORMDL3, is located on chromosome 17 (of the 23 chromosome pairs in the human genome); elevated levels of the protein for which it codes were found in the white blood cells of asthmati. The team reports in Nature that a single mutation in the script of nucleotides that form this gene may markedly increase a person's chances of developing the illness.

“The most strongly associated polymorphism [(variation in DNA)] … increased the risk of asthma by 80% and potentially contributed to the disease in 30% of asthmatic children,” says senior author William Cookson, professor of respiratory genetics at Imperial College London.

Cookson and colleagues compared the genetic profiles of 994 sufferers of childhood-onset asthma with those of 1,243 healthy children. They combed through more than 317,000 single-base mutations before they zeroed in on ORMDL3 as a possible risk factor. The genetic analysis was further bolstered by the hyperactivity of the gene in the blood cells of the asthmatics.

Even though the gene's role remains a mystery, researchers still believe it has therapeutic potential. “Its structure suggests that it may be a drug target,” Cookson says. “We will now be investigating this possibility, but it will take a few years before any new treatments are likely.”

Gallstones

Scientists at the University of Bonn, Germany, with colleagues from Romania, have discovered a gene variant that significantly increases the risk of developing gallstones. For those who have this gene variant the likelihood of developing a gallstone in the course of their life is two to three times higher. The relevant gene contains the instructions for building a molecular pump which transports cholesterol from the liver into the bile ducts – cholesterol being the substance from which most gallstones are formed. The genetic modification appears to cause this pump to work permanently at high speed.

Gallstones tend to be found at high levels within certain families. In particular, studies of twins provide evidence of a genetic component that boosts risk levels. However the researchers say they reckon that environmental influences, like the wrong diet, are 70% to 80% responsible for the disorder, the rest is caused by genes.

Reference: Hepatology No. 46, 11 July 2007, DOI 10.1002/hep.21847

On-off switch

Biologists have long thought that a simple on/off switch controls most genes in human cells. Flip the switch and a cell starts or stops producing a particular protein. But new evidence suggests that this model is too simple and that our genes are more ready for action than previously thought.

Scientists in the lab of Whitehead Member Richard Young have discovered that many human genes hover between 'on' and 'off' in any given cell. According to the study, which appears online in Cell, these genes begin making RNA templates for proteins – a process termed transcription – but fail to finish. The templates never materialise, and the proteins never appear.

“Surprisingly, about onethird of our genes, including all the regulators of cell identity, fall into this new class,” says Young, who is also an MIT professor of biology. “It seems awfully risky for an adult cell to leave genes primed that could change its identity.”

The human body comprises more than 200 types of cells. Each cell contains the same complete set of genes, but expresses only a unique fraction of them, churning out proteins that make it a nerve or skin or white blood cell. Scientists have known for years that a cell hides the genes it doesn't need by coiling the dormant DNA tightly around protein spools called histones. The new study, however, suggests that DNA packaging stays loose at the beginning of many inactive genes, contrary to textbook models.

Whitehead postdoctoral researchers Matthew Guenther and Stuart Levine screened the entire human genome for a chemical signature ‘a landmark’ that corresponds with this looser DNA packaging configuration and thus with transcription initiation. They worked with embryonic stem cells, liver cells and white blood cells.

“We expected to find the landmark on 30% to 40% of the genes because that's how many are active in each cell,” Guenther says. “We were shocked when it showed up on more than 75% of the genes in both unspecialised embryonic stem cells and specialised adult cells.”

Pancreatic cancer

The University of Texas MD Anderson Cancer Center reports in Cancer Cell that researchers have developed a molecularly engineered therapy that selectively embeds a gene in pancreatic cancer that shrinks or eradicates tumours, inhibits metastasis, and prolongs survival with virtually no toxicity.

“This vehicle, or vector, is so targeted and robust in its cancer-specific expression that it can be used for therapy and perhaps for imaging,” notes senior author Mien-Chie Hung, PhD, professor and chair of MD Anderson's Department of Molecular and Cellular Oncology.

The researchers call the system a versatile expression vector – nicknamed VISA. It includes a targeting agent, also called a promoter, two components that boost gene expression in the target tissue, and a payload – in this case a gene known to kill cancer cells. It's all packaged in a fatty ball called a liposome and delivered intravenously.

Researchers are working with MD Anderson clinicians to move the system, developed and tested in mouse models of pancreatic cancer, to a Phase I clinical trial.

“This looks like a promising approach to gene therapy for pancreatic cancer and we are working to bring it to a clinical trial,” says James Abbruzzese, MD, professor and chair of the MD Anderson Department of Gastrointestinal Oncology.

He estimates that it will take between one and two years to complete US Food and Drug Administration requirements for a Phase I trial.

                                  
                                                           Copyright © 2007 MiddleEastHealthMag.com. All Rights Reserved.