Variations in genes involved in normal bone development are associated with an 8- to 15-fold increased risk for osteonecrosis in young patients with acute lymphoblastic leukaemia (ALL), according to research led by St. Jude Children’s Research Hospital and Children’s Oncology Group investigators.
Osteonecrosis is a major side effect of ALL treatment with chemotherapy. About 15 percent of ALL patients develop the complication, which is caused by reduced blood flow to bones in the hips and other joints and leads bone to break down faster than it is replaced. For patients, the results may include stiffness, pain, disability and joint-replacement surgery. ALL patients aged 10 to 20 years old are at particularly high risk for osteonecrosis.
This study is the first to focus on genetic risk factors for osteonecrosis in ALL patients less than 10 years old, an age group that accounts for about 75 percent of newly identified ALL patients and about half of ALL patients who develop osteonecrosis. Researchers used genome-wide association studies to check the DNA of 1,186 ALL patients less than 10 years old for single changes in the 3.2 billion “letters” or chemical bases that make up the human genetic code.
Researchers checked for genetic variations that were more common in 82 young ALL patients who developed osteonecrosis than in 287 who did not. The screening was then repeated with an additional 817 ALL patients younger than 10 years old. The patients were treated in clinical trials of the Children’s Oncology Group, an international clinical trials group focused exclusively on paediatric cancer.
Patients with osteonecrosis were eight to 15 times more likely to have genetic variations located near BMP7, a gene important for normal bone development.
“The goal of this and earlier studies is to identify and understand genetic and other risk factors for osteonecrosis so we can identify patients at high risk for the side effect and develop interventions to prevent the disease,” said first author Seth Karol, M.D., a St. Jude Physician Scientist Training Program fellow. Karol works with the study’s senior author Mary Relling, Pharm.D., chair of the St. Jude Department of Pharmaceutical Sciences.
A variation in the glutamate receptor gene GRID2 was also associated with a greater likelihood of osteonecrosis in ALL patients younger than 10. GRID2 belongs to a family of genes that carries instructions for assembling receptor proteins on the cell membrane that cells rely on to respond to the chemical messenger glutamate. The finding confirms previous research that reported variations in other glutamate receptor genes were associated with an elevated risk of osteonecrosis, with the prior study primarily identifying the risk in patients aged 10 and older.
“The finding that the genetic variations that affect osteonecrosis risk differ by age was unexpected,” Karol said. “The results suggest that as children age, particularly when bone growth is accelerated during adolescence, certain gene variants may become more or less important.”
Additional research is planned to expand the search for osteonecrosis genetic risk factors to include additional ALL treatment regimens and subtypes of the disease. Working in laboratory models, researchers also plan to study how gene variants affect osteonecrosis risk in order to help lay the groundwork for intervention to prevent the disease.
St. Jude Children’s Research Hospital
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The leading cause of epilepsy-related death is a poorly understood phenomenon known as sudden unexpected death in epilepsy (SUDEP). The risk factors and causes of SUDEP remain unclear but researchers have proposed explanations ranging from irregular heart rhythm to genetic predisposition to accidental suffocation during sleep. Three studies to be presented at the American Epilepsy Society’s (AES) 69th Annual Meeting parse the contributions of genetics to SUDEP in hopes of uncovering new strategies for prevention.
Researchers from the Universities of Melbourne and Sydney report that genetic variants associated with cardiac sudden death may be to blame for SUDEP. The authors examined DNA samples from 62 people who died from SUDEP, searching for mutations in genes known to contribute to cardiac arrhythmia, respiratory function and epilepsy.
Their results reveal that nearly a quarter of people who experienced SUDEP carried mutations linked to cardiac sudden death, suggesting that irregular heart rhythms may underlie a significant number of deaths in epilepsy. Furthermore, one-quarter of the cases had genetic mutations associated with epilepsy.
‘These findings raise the possibility that SUDEP might be prevented in some cases by avoiding the use of anti-epileptic drugs known to alter the heart’s electrical activity’ says Douglas Crompton, M.D., Ph.D., a neurologist at the University of Melbourne. ‘In some cases, it may be advisable to recommend beta blockers, pacemakers or implantable defibrillators.’
In a second study, researchers from New York University’s Langone Medical Center find that genetic mutations altering the transmission of electrical impulses in the heart and brain may raise the risk of SUDEP in people.
The authors searched for genetic mutations that might explain the disproportionately high risk of SUDEP in people with poorly controlled focal epilepsy, which, by definition stems from a specific area of the brain. To identify genetic risk factors for SUDEP, the authors analysed brain tissue that had been removed during epilepsy surgery from 8 people who later experienced SUDEP and from seven living people with similar histories.
The study found mutations in 607 genes in brain tissue from patients who died from SUDEP that were not seen in the tissue from the living people. Analysis of affected genes revealed possible functional effects from 532 of the mutations. Three of people who experienced SUDEP had mutations in six genes linked to cardiac arrhythmia. The other five people who died from SUDEP had mutations in seven genes involved in GABA/Glutamate pathways.
‘Genetic testing for these mutations could potentially allow for the early identification of people with epilepsy who are at high risk of sudden death,’ notes author Daniel Friedman, M.D., an assistant professor of neurology at NYU.
A third study pinpoints a specific genetic mutation that may raise the risk of SUDEP in patients with early-infantile epileptic encephalopathy — a severe, drug-resistant disorder that manifests in the first 3 months of life. Researchers from the University of Michigan set out to explore whether genetic mutations in voltage-gated Na+ channels (VGSCs), which promote the transmission of electrical impulses in the heart and brain, increase the risk of SUDEP in patients with early-infantile epileptic encephalopathy.
The authors reproduced this disorder in mice to explore whether mutations in a particular VGSC, encoded by the SCN8A gene, increase the risk of cardiac arrhythmia, which might, in turn, influence susceptibility to SUDEP. Animal experiments revealed that mice carrying a mutated SCN8A gene had reduced heart rate compared with their healthy littermates, and that administration of caffeine produced an abnormal heart rhythm known as accelerated idioventricular rhythm. Examination of cardiac cells revealed a number of molecular changes that further altered the heart rhythm.
‘Taken together, our results suggest that SCN8A mutations in people with early-infantile epileptic encephalopathy may increase the risk of SUDEP by creating an environment in which the heart has a higher susceptibility to arrhythmias,’ explains author Chad Frasier, Ph.D., a postdoctoral researcher at the University of Michigan.
American Epilepsy Society
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In the first study to run a genome-wide analysis of Short Tandem Repeats (STRs) in gene expression, a large team of computational geneticists led by investigators from Columbia Engineering and the New York Genome Center have shown that STRs, thought to be just neutral, or ‘junk,’ actually play an important role in regulating gene expression.
“Our work expands the repertoire of functional genetic elements,” says the study’s leader Yaniv Erlich, who is an assistant professor of computer science at Columbia Engineering, a member of Columbia’s Data Science Institute, and a core member of the New York Genome Center. “We expect our findings will lead to a better understanding of disease mechanisms and perhaps eventually help to identify new drug targets.”
Genomic variants are what makes our DNA different from each other, and come,
Erlich explains, “like spelling errors in different flavours.” The most common
variants are SNPs (single nucleotide polymorphisms). Computational geneticists
have been focused mostly on SNPs that look like a single letter typo—mother vs.
muther—and their effect on complex human traits.
Erlich’s study looked at Short Tandem Repeats (STRs), variants that create what
look like typos: stutter vs. stututututututter. Most researchers, assuming that
STRs were neutral, dismissed them as not important. In addition, these variants
are extremely hard to study. “They look so different to analysis algorithms,” Erlich notes, “that they just usually classify them as noise and skip these positions.”
Erlich used a multitude of statistical genetic and integrative genomics analyses to
reveal that STRs have a function: they act like springs or knobs that can expand
and contract, and fine-tune the nearby gene expression. Different lengths
correspond to different tensions of the spring and can control gene expression and disease traits. He is calling these variants eSTRs, or expression STRs, to note that they regulate gene expression. He and his team also discovered that these eSTRs can be associated with a range of conditions including Crohn’s diseases, high blood pressure, and a range of metabolites. These eSTRs explain on average 10 to 15% the genetic differences of gene expression between individuals.
“We’ve known that STRs are known to play a role in these diseases, but no one has ever conducted a genome-wide scan to find their effect on complex traits,” Erlich adds. “If we want to do personalized medicine, we really need to understand every part of the genome, including repeat elements—there’s a lot of exciting biologyahead.”
New York Genome Centre
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Genes that act as brakes to stop the development of an aggressive form of leukaemia have been identified by researchers. Their findings offer fresh insights into how to tackle the disease and could lead to new therapies that prevent relapses.
Scientists have found that two molecules – Hif-1alpha and Hif-2alpha – work together to stop the formation of leukemic stem cells in an aggressive type of blood cancer called Acute Myeloid Leukaemia (AML). The cancer occurs when production of new blood cells by the bone marrow goes awry. This leads to the formation of leukemic stem cells, which fuel the disease and provide a constant flow of abnormal leukaemia cells.
The University of Edinburgh study shows that blocking Hif-2alpha – or both Hif-1alpha and Hif-2alpha – accelerates the development of leukaemia. The findings are surprising because previous research had suggested that blocking Hif-1alpha or Hif-2alpha may stop leukaemia progression.
Researchers say that their new results suggest that therapies designed to block these molecules may have no impact or could even worsen disease.
Conversely, designing new therapies that promote the activity of Hif-1alpha and Hif-2alpha could help to treat AML or stop the disease from recurring after chemotherapy.
University of Edinburgh
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According to the World Health Organization, in 2014, there was an estimated 9.6 million new cases of tuberculosis (TB). TB is one of the leading, potentially-fatal infectious diseases caused by a bacterium known as Mycobacterium tuberculosis (MTB) that commonly affects the lungs. In 2014, nearly 500,000 people developed resistance to the two most powerful, anti-TB drugs known as isoniazid (INH) and rifampicin (RIF). These drug therapies have been used for decades to treat TB, but resistance is becoming widespread from inappropriate or incorrect use. Today, molecular tests from Abbott are available to help doctors diagnose tuberculosis and to detect resistance to INH and RIF. The first test, Abbott’s Realtime MTB (CE-marked), is designed to qualitatively detect MTB in samples from individuals suspected of having tuberculosis. The second test, the RealTime MTB RIF/INH Resistance, was recently CE-marked and is designed to identify single resistance to INH or RIF as well as resistance to both drugs. At this year’s 46th Union World Conference on Lung Health (Cape Town, South Africa), Abbott hosted a satellite symposium titled “Advancing to the Next Level of Molecular Testing for Mycobacterium Tuberculosis (MTB)”.
www.abbottmolecular.com
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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.
www.randoxqc.com
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MEDLAB Middle East attracts more than 25,000 unique visitors and the exhibition floor area has grown considerably in recent years. MEDLAB is expanding its exhibition even further with two new halls, housing more than 500 exhibitors dedicated to sharing the most recent technology available in the IVD-, and medical laboratory market. The exhibition is open Monday 25 January to Thursday 28th January in Dubai International Convention and Exhibition Centre.
Over the years, attendance has increased considerably, and in 2015, MEDLAB hosted 519 exhibitors from 37 countries. The MEDLAB Congress is also enjoying massive growth with more than 6,500 delegates in attendance in 2015, making it the largest gathering to date and resulting in many of the conference tracks completely selling out.
MEDLAB exhibition space will also host new conference rooms to accommodate the growth of the popular MEDLAB congress, where more than 7,000 delegates will gather to find out about the latest diagnostics developments.
The MEDLAB Congress comprises of six tracks dedicated to the field of laboratory medicine and diagnostics where pathologists and laboratory professionals can share their knowledge and experiences. By providing access to education and networking opportunities, the congress hopes to improve laboratory practices and patient care as well as developing the laboratory medicine community.
The conference tracks will cover the areas of Laboratory management, Molecular diagnostics, Clinical microbiology & Immunology, Hispatology, Clinical chemistry, and Haematologym that will provide CME Credits, unparalleled education and management solutions to help labs excel in today’s competitive market.
There is also a dedicated dealers and distributers lounge. The purpose of the lounge is for healthcare dealers and distributors to conduct meetings with clients and network with colleagues.
MEDLAB will host 13 country pavilions further enhancing the range of hospital equipment, medical equipment, medical devices and medical technology on display at the exhibition. Some of the leaders in the field of clinical laboratories exhibiting at MEDLAB will include Roche Diagnostics, Abbott, al Borge Medical Laboratories, Cleveland Clinic Laboratories, Randox, Thermo Fisher Scientific, Bio-Rad, Cepheid and Pure Health to name a few.
Click here to register and get your pass for MEDLAB 2016.
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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
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Humans evolved unique gene variants that protect older adults from neurodegenerative disease, thus preserving their valuable contributions and delaying dependency
Many human gene variants have evolved specifically to protect older adults against neurodegenerative and cardiovascular diseases, thus preserving their contributions to society, report University of California, San Diego School of Medicine researchers.
“We unexpectedly discovered that humans have evolved gene variants that can help protect the elderly from dementia,” said Ajit Varki, MD, Distinguished Professor of Medicine and Cellular and Molecular Medicine at UC San Diego School of Medicine, adjunct professor at the Salk Institute for Biological Studies and co-director of the UC San Diego/Salk Center for Academic Research and Training in Anthropogeny (CARTA). “Such genes likely evolved to preserve valuable and wise grandmothers and other elders, as well as to delay or prevent the emergence of dependent individuals who could divert resources and effort away from the care of the young.” Varki led the study, along with Pascal Gagneux, PhD, associate professor of pathology and associate director of CARTA.
The standard model of natural selection predicts that once the age of reproduction ends, individuals die. That’s because selection early in life strongly favours variants that benefit reproductive success, even at the cost of negative consequences late in life — one major reason we age. This is indeed the case in almost all vertebrates. Humans (and certain whales) are an exception to this rule, living decades beyond reproductive age. Such elders contribute to the fitness of younger individuals by caring for grandchildren and also by passing down important cultural knowledge. Age-related cognitive decline compromises these benefits, and eventually burdens the group with the need to care for dependent older members.
In this first-of-its kind discovery, Varki, Gagneux and their teams initially focused on the gene that encodes the CD33 protein. CD33 is a receptor that projects from the surface of immune cells, where it keeps immune reactions in check, preventing “self” attack and curtailing unwanted inflammation. Previous studies suggested that a certain form of CD33 suppresses amyloid beta peptide accumulation in the brain. Amyloid beta accumulation is thought to contribute to late-onset Alzheimer’s disease, a post-reproductive condition that uniquely affects humans and is aggravated by inflammation and cerebral vascular disease.
The researchers compared CD33 regulation in humans and our closest living relatives, chimpanzees. They found that levels of the CD33 variant that protects against Alzheimer’s are four-fold higher in humans than chimpanzees.
They also found human-specific variations in many other genes involved in the prevention of cognitive decline, such as APOE. The ancestral form of the gene, APOE4, is a notorious risk factor for Alzheimer’s and cerebral vascular disease. But this study finds that variants APOE2 and APOE3 seem to have evolved to protect from dementia. All of these protective gene variants are present in Africa, and thus predate the origin of our species. This finding is in keeping with the valuable role of the elderly across human societies.
“When elderly people succumb to dementia, the community not only loses important sources of wisdom, accumulated knowledge and culture, but elders with even mild cognitive decline who have influential positions can harm their social groups by making flawed decisions,” Gagneux said. “Our study does not directly prove that these factors were involved in the selection of protective variants of CD33, APOE and other genes, but it is reasonable to speculate about the possibility. After all, inter-generational care of the young and information transfer is an important factor for the survival of younger kin in the group and across wider social networks or tribes.”
San Diego School of Medicine
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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
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Genetic variants tied to increased risk of bone complications in young leukaemia patients
, /in E-News /by 3wmediaVariations in genes involved in normal bone development are associated with an 8- to 15-fold increased risk for osteonecrosis in young patients with acute lymphoblastic leukaemia (ALL), according to research led by St. Jude Children’s Research Hospital and Children’s Oncology Group investigators.
Osteonecrosis is a major side effect of ALL treatment with chemotherapy. About 15 percent of ALL patients develop the complication, which is caused by reduced blood flow to bones in the hips and other joints and leads bone to break down faster than it is replaced. For patients, the results may include stiffness, pain, disability and joint-replacement surgery. ALL patients aged 10 to 20 years old are at particularly high risk for osteonecrosis.
This study is the first to focus on genetic risk factors for osteonecrosis in ALL patients less than 10 years old, an age group that accounts for about 75 percent of newly identified ALL patients and about half of ALL patients who develop osteonecrosis. Researchers used genome-wide association studies to check the DNA of 1,186 ALL patients less than 10 years old for single changes in the 3.2 billion “letters” or chemical bases that make up the human genetic code.
Researchers checked for genetic variations that were more common in 82 young ALL patients who developed osteonecrosis than in 287 who did not. The screening was then repeated with an additional 817 ALL patients younger than 10 years old. The patients were treated in clinical trials of the Children’s Oncology Group, an international clinical trials group focused exclusively on paediatric cancer.
Patients with osteonecrosis were eight to 15 times more likely to have genetic variations located near BMP7, a gene important for normal bone development.
“The goal of this and earlier studies is to identify and understand genetic and other risk factors for osteonecrosis so we can identify patients at high risk for the side effect and develop interventions to prevent the disease,” said first author Seth Karol, M.D., a St. Jude Physician Scientist Training Program fellow. Karol works with the study’s senior author Mary Relling, Pharm.D., chair of the St. Jude Department of Pharmaceutical Sciences.
A variation in the glutamate receptor gene GRID2 was also associated with a greater likelihood of osteonecrosis in ALL patients younger than 10. GRID2 belongs to a family of genes that carries instructions for assembling receptor proteins on the cell membrane that cells rely on to respond to the chemical messenger glutamate. The finding confirms previous research that reported variations in other glutamate receptor genes were associated with an elevated risk of osteonecrosis, with the prior study primarily identifying the risk in patients aged 10 and older.
“The finding that the genetic variations that affect osteonecrosis risk differ by age was unexpected,” Karol said. “The results suggest that as children age, particularly when bone growth is accelerated during adolescence, certain gene variants may become more or less important.”
Additional research is planned to expand the search for osteonecrosis genetic risk factors to include additional ALL treatment regimens and subtypes of the disease. Working in laboratory models, researchers also plan to study how gene variants affect osteonecrosis risk in order to help lay the groundwork for intervention to prevent the disease. St. Jude Children’s Research Hospital
Unravelling the genetic basis of sudden unexpected death in epilepsy
, /in E-News /by 3wmediaThe leading cause of epilepsy-related death is a poorly understood phenomenon known as sudden unexpected death in epilepsy (SUDEP). The risk factors and causes of SUDEP remain unclear but researchers have proposed explanations ranging from irregular heart rhythm to genetic predisposition to accidental suffocation during sleep. Three studies to be presented at the American Epilepsy Society’s (AES) 69th Annual Meeting parse the contributions of genetics to SUDEP in hopes of uncovering new strategies for prevention.
Researchers from the Universities of Melbourne and Sydney report that genetic variants associated with cardiac sudden death may be to blame for SUDEP. The authors examined DNA samples from 62 people who died from SUDEP, searching for mutations in genes known to contribute to cardiac arrhythmia, respiratory function and epilepsy.
Their results reveal that nearly a quarter of people who experienced SUDEP carried mutations linked to cardiac sudden death, suggesting that irregular heart rhythms may underlie a significant number of deaths in epilepsy. Furthermore, one-quarter of the cases had genetic mutations associated with epilepsy.
‘These findings raise the possibility that SUDEP might be prevented in some cases by avoiding the use of anti-epileptic drugs known to alter the heart’s electrical activity’ says Douglas Crompton, M.D., Ph.D., a neurologist at the University of Melbourne. ‘In some cases, it may be advisable to recommend beta blockers, pacemakers or implantable defibrillators.’
In a second study, researchers from New York University’s Langone Medical Center find that genetic mutations altering the transmission of electrical impulses in the heart and brain may raise the risk of SUDEP in people.
The authors searched for genetic mutations that might explain the disproportionately high risk of SUDEP in people with poorly controlled focal epilepsy, which, by definition stems from a specific area of the brain. To identify genetic risk factors for SUDEP, the authors analysed brain tissue that had been removed during epilepsy surgery from 8 people who later experienced SUDEP and from seven living people with similar histories.
The study found mutations in 607 genes in brain tissue from patients who died from SUDEP that were not seen in the tissue from the living people. Analysis of affected genes revealed possible functional effects from 532 of the mutations. Three of people who experienced SUDEP had mutations in six genes linked to cardiac arrhythmia. The other five people who died from SUDEP had mutations in seven genes involved in GABA/Glutamate pathways.
‘Genetic testing for these mutations could potentially allow for the early identification of people with epilepsy who are at high risk of sudden death,’ notes author Daniel Friedman, M.D., an assistant professor of neurology at NYU.
A third study pinpoints a specific genetic mutation that may raise the risk of SUDEP in patients with early-infantile epileptic encephalopathy — a severe, drug-resistant disorder that manifests in the first 3 months of life. Researchers from the University of Michigan set out to explore whether genetic mutations in voltage-gated Na+ channels (VGSCs), which promote the transmission of electrical impulses in the heart and brain, increase the risk of SUDEP in patients with early-infantile epileptic encephalopathy.
The authors reproduced this disorder in mice to explore whether mutations in a particular VGSC, encoded by the SCN8A gene, increase the risk of cardiac arrhythmia, which might, in turn, influence susceptibility to SUDEP. Animal experiments revealed that mice carrying a mutated SCN8A gene had reduced heart rate compared with their healthy littermates, and that administration of caffeine produced an abnormal heart rhythm known as accelerated idioventricular rhythm. Examination of cardiac cells revealed a number of molecular changes that further altered the heart rhythm.
‘Taken together, our results suggest that SCN8A mutations in people with early-infantile epileptic encephalopathy may increase the risk of SUDEP by creating an environment in which the heart has a higher susceptibility to arrhythmias,’ explains author Chad Frasier, Ph.D., a postdoctoral researcher at the University of Michigan. American Epilepsy Society
Repetitive DNA provides a hidden layer of functional information
, /in E-News /by 3wmediaIn the first study to run a genome-wide analysis of Short Tandem Repeats (STRs) in gene expression, a large team of computational geneticists led by investigators from Columbia Engineering and the New York Genome Center have shown that STRs, thought to be just neutral, or ‘junk,’ actually play an important role in regulating gene expression.
“Our work expands the repertoire of functional genetic elements,” says the study’s leader Yaniv Erlich, who is an assistant professor of computer science at Columbia Engineering, a member of Columbia’s Data Science Institute, and a core member of the New York Genome Center. “We expect our findings will lead to a better understanding of disease mechanisms and perhaps eventually help to identify new drug targets.”
Genomic variants are what makes our DNA different from each other, and come,
Erlich explains, “like spelling errors in different flavours.” The most common
variants are SNPs (single nucleotide polymorphisms). Computational geneticists
have been focused mostly on SNPs that look like a single letter typo—mother vs.
muther—and their effect on complex human traits.
Erlich’s study looked at Short Tandem Repeats (STRs), variants that create what
look like typos: stutter vs. stututututututter. Most researchers, assuming that
STRs were neutral, dismissed them as not important. In addition, these variants
are extremely hard to study. “They look so different to analysis algorithms,” Erlich notes, “that they just usually classify them as noise and skip these positions.”
Erlich used a multitude of statistical genetic and integrative genomics analyses to
reveal that STRs have a function: they act like springs or knobs that can expand
and contract, and fine-tune the nearby gene expression. Different lengths
correspond to different tensions of the spring and can control gene expression and disease traits. He is calling these variants eSTRs, or expression STRs, to note that they regulate gene expression. He and his team also discovered that these eSTRs can be associated with a range of conditions including Crohn’s diseases, high blood pressure, and a range of metabolites. These eSTRs explain on average 10 to 15% the genetic differences of gene expression between individuals.
“We’ve known that STRs are known to play a role in these diseases, but no one has ever conducted a genome-wide scan to find their effect on complex traits,” Erlich adds. “If we want to do personalized medicine, we really need to understand every part of the genome, including repeat elements—there’s a lot of exciting biologyahead.” New York Genome Centre
Leukaemia study reveals therapy clues
, /in E-News /by 3wmediaGenes that act as brakes to stop the development of an aggressive form of leukaemia have been identified by researchers. Their findings offer fresh insights into how to tackle the disease and could lead to new therapies that prevent relapses.
Scientists have found that two molecules – Hif-1alpha and Hif-2alpha – work together to stop the formation of leukemic stem cells in an aggressive type of blood cancer called Acute Myeloid Leukaemia (AML). The cancer occurs when production of new blood cells by the bone marrow goes awry. This leads to the formation of leukemic stem cells, which fuel the disease and provide a constant flow of abnormal leukaemia cells.
The University of Edinburgh study shows that blocking Hif-2alpha – or both Hif-1alpha and Hif-2alpha – accelerates the development of leukaemia. The findings are surprising because previous research had suggested that blocking Hif-1alpha or Hif-2alpha may stop leukaemia progression.
Researchers say that their new results suggest that therapies designed to block these molecules may have no impact or could even worsen disease.
Conversely, designing new therapies that promote the activity of Hif-1alpha and Hif-2alpha could help to treat AML or stop the disease from recurring after chemotherapy. University of Edinburgh
Innovative Abbott tests help in detecting tuberculosis and drug resistance
, /in E-News /by 3wmediaAccording to the World Health Organization, in 2014, there was an estimated 9.6 million new cases of tuberculosis (TB). TB is one of the leading, potentially-fatal infectious diseases caused by a bacterium known as Mycobacterium tuberculosis (MTB) that commonly affects the lungs. In 2014, nearly 500,000 people developed resistance to the two most powerful, anti-TB drugs known as isoniazid (INH) and rifampicin (RIF). These drug therapies have been used for decades to treat TB, but resistance is becoming widespread from inappropriate or incorrect use. Today, molecular tests from Abbott are available to help doctors diagnose tuberculosis and to detect resistance to INH and RIF. The first test, Abbott’s Realtime MTB (CE-marked), is designed to qualitatively detect MTB in samples from individuals suspected of having tuberculosis. The second test, the RealTime MTB RIF/INH Resistance, was recently CE-marked and is designed to identify single resistance to INH or RIF as well as resistance to both drugs. At this year’s 46th Union World Conference on Lung Health (Cape Town, South Africa), Abbott hosted a satellite symposium titled “Advancing to the Next Level of Molecular Testing for Mycobacterium Tuberculosis (MTB)”.
www.abbottmolecular.comRandox announces 8 new external quality assurance programmes
, /in E-News /by 3wmediaRandox 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.
www.randoxqc.comMEDLAB Middle East expands in 2016
, /in E-News /by 3wmediaMEDLAB Middle East attracts more than 25,000 unique visitors and the exhibition floor area has grown considerably in recent years. MEDLAB is expanding its exhibition even further with two new halls, housing more than 500 exhibitors dedicated to sharing the most recent technology available in the IVD-, and medical laboratory market. The exhibition is open Monday 25 January to Thursday 28th January in Dubai International Convention and Exhibition Centre.
Over the years, attendance has increased considerably, and in 2015, MEDLAB hosted 519 exhibitors from 37 countries. The MEDLAB Congress is also enjoying massive growth with more than 6,500 delegates in attendance in 2015, making it the largest gathering to date and resulting in many of the conference tracks completely selling out.
MEDLAB exhibition space will also host new conference rooms to accommodate the growth of the popular MEDLAB congress, where more than 7,000 delegates will gather to find out about the latest diagnostics developments.
The MEDLAB Congress comprises of six tracks dedicated to the field of laboratory medicine and diagnostics where pathologists and laboratory professionals can share their knowledge and experiences. By providing access to education and networking opportunities, the congress hopes to improve laboratory practices and patient care as well as developing the laboratory medicine community.
The conference tracks will cover the areas of Laboratory management, Molecular diagnostics, Clinical microbiology & Immunology, Hispatology, Clinical chemistry, and Haematologym that will provide CME Credits, unparalleled education and management solutions to help labs excel in today’s competitive market.
There is also a dedicated dealers and distributers lounge. The purpose of the lounge is for healthcare dealers and distributors to conduct meetings with clients and network with colleagues.
MEDLAB will host 13 country pavilions further enhancing the range of hospital equipment, medical equipment, medical devices and medical technology on display at the exhibition. Some of the leaders in the field of clinical laboratories exhibiting at MEDLAB will include Roche Diagnostics, Abbott, al Borge Medical Laboratories, Cleveland Clinic Laboratories, Randox, Thermo Fisher Scientific, Bio-Rad, Cepheid and Pure Health to name a few.
Click here to register and get your pass for MEDLAB 2016.
Small changes in DNA can affect nicotine consumption
, /in E-News /by 3wmediaNicotine 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
Newly evolved, uniquely human gene variants protect older adults from cognitive decline
, /in E-News /by 3wmediaHumans evolved unique gene variants that protect older adults from neurodegenerative disease, thus preserving their valuable contributions and delaying dependency
Many human gene variants have evolved specifically to protect older adults against neurodegenerative and cardiovascular diseases, thus preserving their contributions to society, report University of California, San Diego School of Medicine researchers.
“We unexpectedly discovered that humans have evolved gene variants that can help protect the elderly from dementia,” said Ajit Varki, MD, Distinguished Professor of Medicine and Cellular and Molecular Medicine at UC San Diego School of Medicine, adjunct professor at the Salk Institute for Biological Studies and co-director of the UC San Diego/Salk Center for Academic Research and Training in Anthropogeny (CARTA). “Such genes likely evolved to preserve valuable and wise grandmothers and other elders, as well as to delay or prevent the emergence of dependent individuals who could divert resources and effort away from the care of the young.” Varki led the study, along with Pascal Gagneux, PhD, associate professor of pathology and associate director of CARTA.
The standard model of natural selection predicts that once the age of reproduction ends, individuals die. That’s because selection early in life strongly favours variants that benefit reproductive success, even at the cost of negative consequences late in life — one major reason we age. This is indeed the case in almost all vertebrates. Humans (and certain whales) are an exception to this rule, living decades beyond reproductive age. Such elders contribute to the fitness of younger individuals by caring for grandchildren and also by passing down important cultural knowledge. Age-related cognitive decline compromises these benefits, and eventually burdens the group with the need to care for dependent older members.
In this first-of-its kind discovery, Varki, Gagneux and their teams initially focused on the gene that encodes the CD33 protein. CD33 is a receptor that projects from the surface of immune cells, where it keeps immune reactions in check, preventing “self” attack and curtailing unwanted inflammation. Previous studies suggested that a certain form of CD33 suppresses amyloid beta peptide accumulation in the brain. Amyloid beta accumulation is thought to contribute to late-onset Alzheimer’s disease, a post-reproductive condition that uniquely affects humans and is aggravated by inflammation and cerebral vascular disease.
The researchers compared CD33 regulation in humans and our closest living relatives, chimpanzees. They found that levels of the CD33 variant that protects against Alzheimer’s are four-fold higher in humans than chimpanzees.
They also found human-specific variations in many other genes involved in the prevention of cognitive decline, such as APOE. The ancestral form of the gene, APOE4, is a notorious risk factor for Alzheimer’s and cerebral vascular disease. But this study finds that variants APOE2 and APOE3 seem to have evolved to protect from dementia. All of these protective gene variants are present in Africa, and thus predate the origin of our species. This finding is in keeping with the valuable role of the elderly across human societies.
“When elderly people succumb to dementia, the community not only loses important sources of wisdom, accumulated knowledge and culture, but elders with even mild cognitive decline who have influential positions can harm their social groups by making flawed decisions,” Gagneux said. “Our study does not directly prove that these factors were involved in the selection of protective variants of CD33, APOE and other genes, but it is reasonable to speculate about the possibility. After all, inter-generational care of the young and information transfer is an important factor for the survival of younger kin in the group and across wider social networks or tribes.” San Diego School of Medicine
New genetic clues to age-related macular degeneration
, /in E-News /by 3wmediaResearchers 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