Randox Quality Control announces the launch of 8 new RIQAS EQA Programmes, with cycles scheduled to begin in March 2016. The new programmes are: CSF, Sweat Testing, Immunosuppressants, Trace Elements in Serum, Trace Elements in Urine, Trace Elements in Blood, Anti-TSH Receptor, Cyfra 21-1. These new RIQAS programmes will provide clinical laboratories with the ability to review calibration issues, systematic errors and monitor accuracy and bias. Furthermore these laboratories will be able to assess their analytical performance in comparison with other laboratories which are employing the same instrument or methods. The new programmes are available in liquid and lyophilized formats, covering the full clinical decision range. Monthly reporting supports the rapid identification of errors and allows implementation of the necessary corrective actions therefore saving the need for expensive and time consuming patient sample retests.  Finally the rapid report turnaround will ensure results are received within 24-72 hours and, if required, corrective actions can then be implemented before the next cycle. RIQAS is the largest international EQA scheme used by more than 32,000 laboratory participants in 123 countries. Such large, international peer groups guarantee the statistical validity of the company’s extensive database of instrument and method results.

Nicotine is an addictive substance and genetic factors are known to play a role in smoking behaviours. Recently, a team of researchers at Penn State and the University of Colorado determined how small differences in a particular region of the mouse genome can alter nicotine consumption.

Nicotine binds to and activates specific receptors on nerve cells in the brain that can also bind the neurotransmitter acetylcholine. These receptors are made up of five subunits, and human genetic studies show that changes in a single subunit can alter nicotine behaviour. In a recent issue of Neuropharmacology, the researchers focused on the gene that encodes the beta-3 subunit, which is found in areas of the brain important in drug behaviour.

‘We know that genes influence nicotine behaviours, but trying to figure out what specific genetic variants do requires different types of tools,’ said Helen Kamens, assistant professor of bio-behavioural health, Penn State. ‘This work was based on associations that were found in human genetic studies. Genetic variants were shown to affect certain nicotine behaviours, but the question was why? Here we focused on trying to figure out what these genetic variants actually do.’

According to Kamens, in humans, two naturally occurring variants in the area of the genome that initiates expression of genes linked to nicotine use have been identified. People carrying the more common version of the beta-3 subunit of nicotinic acetylcholine receptors — the major allele — are more likely to have problems with nicotine use. People with the less common version — the minor allele — are protected against nicotine dependence. The minor allele differs from the major allele in having three differences in the DNA sequence in the area involved in turning on nicotine-related genes. Previous work also shows that expression of the minor allele results in less of the beta-3 protein being made.

The researchers used a mouse model to study how reducing how much of the beta-3 subunit was made, or preventing its production completely, affected nicotine consumption. They used genetic engineering techniques to remove one or both copies of the beta-3 gene. Then, to measure how much the mice wanted the drug, the researchers provided each mouse with two water bottles, one with nicotine and one without nicotine, and recorded how much water the mice drank from each bottle. Mice lacking one or both copies of the gene encoding the beta-3 subunit consumed less nicotine than normal mice. The researchers performed these tests using two different strains of mice, but the lower consumption of nicotine was only seen in one of the strains, indicating that other genetic factors also play a role in nicotine cravings.

Finally, by individually reversing each of the three genetic differences in the minor allele in mouse cells in culture, the researchers found that only one of the three differences reduced the amount of beta-3 protein the cells produced.

‘All three of these single nucleotide changes are inherited together, so in a human population, you get a sequence where all three nucleotides are either major or minor,’ said Kamens. ‘Using a cell culture system, we were able to disentangle which of the nucleotide changes actually has an effect on protein amounts, which is something we could never see in a human population.’

Future work by the researchers will focus on measuring other behaviours that better reflect differences in nicotine addiction to further prove the importance of the beta-3 subunit of nicotinic acetylcholine receptors as well as how changing the DNA in a single location actually reduces expression of the beta-3 gene. Penn State

Researchers from the University of Miami Miller School of Medicine’s John P. Hussman Institute for Human Genomics and Bascom Palmer Eye Institute are part of a consortium that has significantly expanded the number of genetic factors known to play a role in age-related macular degeneration (AMD), a leading cause of vision loss among people age 50 and older. Supported by the National Eye Institute, part of the National Institutes of Health, the findings may help improve our understanding of the biological processes that lead to AMD and identify new therapeutic targets for potential drug development.
AMD is a progressive disease that causes the death of the retinal photoreceptors, the light-sensitive cells at the back of the eye. The most severe damage occurs in the macula, a small area of the retina that is needed for sharp, central vision necessary for reading, driving and other daily tasks. There are currently no FDA -approved treatments for the more common form of advanced AMD, called geographic atrophy or “dry” AMD. While therapies for the other advanced form, neovascular or “wet” AMD, can successfully halt the growth of abnormal, leaky blood vessels in the eye, the therapies do not cure the condition, nor do they work for everyone.

Up to this point, researchers had identified 21 loci that influence the risk of AMD. The new research raises the number of loci to 34. The Miller School’s Margaret A. Pericak-Vance, Ph.D., the Dr. John T. Macdonald Foundation Professor of Human Genomics and Director of the John P. Hussman Institute for Human Genomics, and William K. Scott, Ph.D., professor and Vice Chair for Education and Training at the Dr. John T. Macdonald Foundation Department of Human Genetics and the John P. Hussman Institute for Human Genomics, and professor of public health sciences, were two of the senior authors on the study.

The International AMD Genomics Consortium, which includes 26 centres worldwide, collected and analysed the genetic data from 43,566 people of predominantly European ancestry to systematically identify common and rare variations in genetic coding — called variants — associated with AMD. Pericak-Vance is the co-Principal Investigator of the National Eye Institute-funded consortium. Common variants generally have an indirect association with a disease. Rare variants, by contrast, are more likely to alter protein expression or function and therefore have a direct or causal association with a disease. Rare variants were defined as those found in less than 1 percent of the study population.

The study included about 23,000 participants with AMD and 20,000 without it. Researchers analysed DNA samples from both groups, surveying most of the genome, but also focusing on distinct loci already known or suspected to be associated with AMD. Next, they compared the participants’ DNA to a reference dataset called the 1,000 Genomes project, yielding more than 12 million genetic variants of potential interest. Finally, they went back to the participants’ DNA samples, looking at all 12 million variants, to see if any were found more or less often in people with AMD than those without it.

The study findings also bolster associations between AMD and two genes, CFH and TIMP3, which had each previously been linked to AMD. CFH was the very first disease-linked gene to be found through a genome-wide association study. TIMP3 had earlier been linked to Sorsby’s fundus dystrophy, a rare disease that is similar to AMD clinically, but which tends to affect people before the age of 45.
For the first time the researchers also identified a variant specific to the neovascular form of AMD, which may point to reasons why therapy for this form of AMD is effective for some people but not everyone. Miller School of Medicine

The presence or absence of the CAP2 gene causes sudden cardiac death in mice, according to new research from the Perelman School of Medicine at the University of Pennsylvania. In particular, the absence of the gene interrupts the animal’s ability to send electrical signals to the heart to tell it to contract, a condition called cardiac conduction disease.

“This study proves that the CAP2 gene is directly responsible for cardiac conduction disease in mice,” said senior author Jeffrey Field, PhD, a professor of Systems Pharmacology and Translational Therapeutics. Heart disease is the leading cause of death among men in the United States. There are several risk factors for heart disease, many of which can be controlled with changes in behaviours and medication, but there are also hard-wired genetic factors that play a role. “Since humans have the same CAP2 gene, what we learn from the mice could advance our understanding of heart disease.”

Researchers have known that the CAP2 gene could be implicated in heart disease. However, its effect on cardiac conduction in the mouse heart was a surprise, Field said. The cardiac conduction system is a molecular network that sends electrical signals to the heart, telling it to contract in the correct rhythm to keep blood flowing smoothly.

The CAP2 gene’s class of protein, while known to regulate the structure or cytoskeleton of the heart, is not usually associated with cardiac conduction because this function is governed by a different family of proteins associated with cell communication. “Initially, saying that CAP2 is involved in cardiac conduction is like saying a person with a broken bone isn’t able to talk,” Field said. “The bone’s structural function and the ability to talk are each from entirely different systems. There’s no relationship. This finding merits further study to see how exactly CAP2 regulates conduction. While we don’t understand how, this gene definitely has a role in controlling conduction.”

Using a mouse model in which the team deleted the CAP2 gene, they found that most newborn males died suddenly, soon after weaning. The males were also prone to eye infections, and their eyes developed incorrectly and could not efficiently flush away debris. The knockout mice were also smaller in overall body size.

Though rare, some of the mice also developed hearts that were overly large. “The loss of the CAP2 gene resulted in bigger hearts because the heart had trouble contracting and to compensate, it dilated in order to get more blood flowing,” Field said.

The knockout mice also exhibited arrhythmia that worsened over four to five days. “We were able to monitor the mice as they died. Their hearts beat slower and slower, and they quickly died of heart block,” he said. Heart block happens when the heart atriums contract, but the ventricles do not get the signal to contract. As a result, the mouse hearts missed a few beats at first, and then stopped completely. This condition is called sudden cardiac death, which is distinct from a heart attack caused by clogged arteries impeding blood supply to the heart. In this experiment, there were no observable effects of a missing CAP2 gene on the female newborns.

Studies of some children with a rare developmental problem, called 6p22 syndrome, hint that this gene is associated with similar cardiac issues in people. These children have deep-set eyes and cardiac problems that are not well defined. “Almost all of these children are born with a deletion of one of their copies of the CAP2 gene,” Field noted.

Knowing this connection, the researchers generated mice that would exhibit only cardiac conduction disease (CCD). They reinstated the gene but this time engineered it so they could knock it out again, but this time only in the hearts of the mice. “It took close to five years to perfect this mouse model that exhibited only the heart knockout,” Field said. The researchers could then conduct experiments targeting only the heart problem, because all the other symptoms, such as the eye problems, were out of the picture.

The mice once again developed CCD, leading to sudden cardiac death from complete heart block, but there was an extra surprise this time. The female newborns also died of CCD. “That’s a puzzle for us. We’d be interested in studying why the gender specificity for CAP2-related sudden cardiac death goes away when we knock the gene out just in the heart,” Field said.

The team says that the study increases the understanding of how the CAP2 gene affects heart disease, but it also raises new questions that underline the need for further research heart disease and why it’s a major cause of death in humans. Perelman School of Medicine