Australian researchers have demonstrated a strong association between the FTO (fat and obesity) gene and hip fracture in women. While the gene is already well known to affect diabetes and body fat, this is the first study to show that its high-risk variant can increase the risk of hip fracture by as much as 82%.
The study, undertaken by Dr Bich Tran and Professor Tuan Nguyen from Sydney’s Garvan Institute of Medical Research, examined six gene variants (single nucleotide polymorphisms, or SNPs) of the FTO gene, taken from the DNA of 943 women in the Dubbo Osteoporosis Epidemiology Study (DOES). The women were all over 60, and their bone health was followed between 1989 and 2007. During that period, 102 women had hip fractures.
On average, the risk of fracture is about 11%. The study showed that if a woman has a low-risk genotype, or gene variant, the risk of fracture is 10%. If she has a high-risk genotype, it is 16%.
The authors believe that the findings have the potential to improve prediction of hip fracture. Known risk factors, also to be taken into account, include advancing age, falls, history of fracture, low bone mineral density, low body mass index (BMI) and genetic make-up.
‘We found that for a woman of the same age and same clinical risk factors, those with the high-risk genotype have an increased risk of fracture of 82% – a very high effect in genetic terms,’ said Professor Tuan Nguyen.
‘A genome-wide association study published in 2007 suggested that genetic variants in the FTO gene were associated with variation in BMI. This led us to hypothesise that they might also be associated with variation in hip fracture risk.’
‘The present study tested our hypothesis by examining the association between common variants in the FTO gene and hip fracture.’
‘Our results showed a strong association with hip fracture, with some gene variants doubling the risk of fracture. Interestingly, this was independent of both the bone density and BMI of the women we studied.’
‘We also found that the FTO gene expresses in bone cells, and may have something to do with bone turnover, or remodelling, although its exact mechanisms are unclear.’
‘It’s important to emphasise that, while promising, our finding is a first step. It will need to be replicated in other studies, and its mechanisms clearly understood before it is useful in drug development.’
Garvan Institute of Medical Research
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:35:232021-01-08 11:12:33Fat and obesity gene also affects hip fracture
A recent study by members of the Children’s Oncology Group reports results of a large trial showing that children whose leukaemia cells have amplification of a portion of chromosome 21 may require more aggressive treatment for Acute Lymphoblastic Leukaemia (ALL) than children without this gene amplification.
‘This helps identify patients who need more therapy than they may otherwise get,’ says Stephen Hunger, MD, investigator at the University of Colorado Cancer Center, professor of paediatrics at the University of Colorado School of Medicine, and director of the Center for Cancer and Blood Disorders at Children’s Hospital Colorado.
Hunger notes that this genetic abnormality was first described in 2003 and has subsequently been found in about 2 percent of pediatric ALL patients. Initial reports described poor outcomes for small groups of children with this abnormality, but the current study is by far the largest and shows the importance of this genetic abnormality even with modern treatments. The study documents the treatments and outcomes of more than 8,000 cases of pediatric ALL.
‘What we found is that when this genetic abnormality is present in children with good risk features who get a standard level of treatment, there is more treatment failure than with similar, low-risk kids who don’t have this genetic marker. But with kids whose risk features already dictate more aggressive treatment, this genetic abnormality doesn’t seem to be associated with a worse outcome, because kids are already getting the appropriate treatment. Recognising this abnormality could help us treat even otherwise low-risk kids more aggressively up front leading to improved cure rates,’ Hunger says.
Specifically, the genetic abnormality is defined as four or more copies of the gene RUNX1, located on an abnormal chromosome 21. And this amplification is already detected as a by-product of another genetic test standard in pediatric ALL, namely a test for fusion of this RUNX1 gene with the gene ETV6.
‘In a sense, the testing comes for free with other testing you’re already doing,’ Hunger says.
A study published by the same group in 2012 showed that pediatric ALL cure rates are at or above 90.4 percent.
‘In early 1960s this disease was incurable,’ Hunger says. ‘Then in the late 1960s, the cure rate was 10 percent. Now 90 percent of children and adolescents diagnosed with ALL will be cured. Still, a 90-percent survival rate is little consolation to the 10 percent of families whose child doesn’t survive. There’s still more work to be done.’
University of Colorado Cancer Center
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:35:232021-01-08 11:12:40Chromosome 21 abnormality tells oncologists to treat pediatric ALL more aggressively
Researchers with the UC Davis MIND Institute and Agilent Laboratories have found that Prader-Willi syndrome — a genetic disorder best known for causing an insatiable appetite that can lead to morbid obesity — is associated with the loss of non-coding RNAs, resulting in the dysregulation of circadian and metabolic genes, accelerated energy expenditure and metabolic differences during sleep.
The research was led by Janine LaSalle, a professor in the UC Davis Department of Medical Microbiology and Immunology who is affiliated with the MIND Institute. It is published online in Human Molecular Genetics.
‘Prader-Willi syndrome children do not sleep as well at night and have daytime sleepiness,’ LaSalle said. ‘Parents have to lock up their pantries because the kids are rummaging for food in the middle of the night, even breaking into their neighbours’ houses to eat.’
The study found that these behaviours are rooted in the loss of a long non-coding RNA that functions to balance energy expenditure in the brain during sleep. The finding could have a profound effect on how clinicians treat children with Prader-Willi, as well as point the way to new, innovative therapies, LaSalle said.
The leading cause of morbid obesity among children in the United States, Prader-Willi involves a complex, and sometimes contradictory, array of symptoms. Shortly after birth children with Prader-Willi experience failure to thrive. Yet after they begin to feed themselves, they have difficulty sleeping and insatiable appetites that lead to obesity if their diets are not carefully monitored.
The current study was conducted in a mouse model of Prader-Willi syndrome. It found that mice engineered with the loss of a long non-coding RNA showed altered energy use and metabolic differences during sleep.
Prader-Willi has been traced to a specific region on chromosome 15 (SNORD116), which produces RNAs that regulate gene expression, rather than coding for proteins. When functioning normally, SNORD116 produces small nucleolar (sno) RNAs and a long non-coding RNA (116HG), as well as a third non-coding RNA implicated in a related disorder, Angelman syndrome. The 116HG long non-coding RNA forms a cloud inside neuronal nuclei that associates with proteins and genes regulating diurnal metabolism in the brain, LaSalle said.
‘We thought the cloud would be activating transcription, but in fact it was doing the opposite,’ she said. ‘Most of the genes were dampened by the cloud. This long non-coding RNA was acting as a decoy, pulling the active transcription factors away from genes and keeping them from being expressed.’
As a result, losing snoRNAs and 116HG causes a chain reaction, eliminating the RNA cloud and allowing circadian and metabolic genes to get turned on during sleep periods, when they should be dampened down. This underlies a complex cycle in which the RNA cloud grew during sleep periods (daytime for nocturnal mice), turning down genes associated with energy use, and receded during waking periods, allowing these genes to be expressed. Mice without the 116HG gene lacked the benefit of this neuronal cloud, causing greater energy expenditure during sleep.
The researchers said that the work provides a clearer picture of why children with Prader-Willi syndrome can’t sleep or feel satiated and may change therapeutic approaches. For example, many such children have been treated with growth hormone because of short stature, but this actually may boost other aspects of the disease.
‘People had thought the kids weren’t sleeping at night because of the sleep apnea caused by obesity,’ said LaSalle. ‘What this study shows is that the diurnal metabolism is central to the disorder, and that the obesity may be as a result of that. If you can work with that, you could improve therapies, for example figuring out the best times to administer medications.’
UC Davis Department of Medical Microbiology and Immunology
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:35:232021-01-08 11:12:47Symptoms of Prader-Willi syndrome associated with interference in circadian, metabolic genes
Researchers from Yale School of Medicine and Celera Diagnostics have confirmed and extended the significance of a genetic variant that substantially increases the risk of a frequently fatal thoracic aortic dissection or full rupture.
Thoracic aortic aneurysms, or bulges in the artery wall, can develop without pain or other symptoms. If they lead to a tear — dissection — or full rupture, the patient will often die without immediate treatment. Therefore, better identification of patients at risk for aortic aneurysm and dissection is considered essential.
The research team, following up on a previous genome-wide association study by researchers at Baylor College of Medicine, investigated genetic variations in a protein called FBN-1, which is essential for a strong arterial wall. After studying hundreds of patients at Yale, they confirmed what was found in the Baylor study: that one variation, known as rs2118181, put patients at significantly increased risk of aortic tear and rupture. In addition, the Yale team was able to show that this increased risk of tear was powerful enough to be significant even independently of aortic size.
‘Although surgical therapy is remarkable and effective, it is incumbent on us to move to a higher genetic level of understanding of these diseases,’ said senior author Dr. John Elefteriades, the William W. L. Glenn Professor of Surgery (Section of Cardiac Surgery) at Yale School of Medicine, and director of the Aortic Institute at Yale-New Haven Hospital. ‘Such studies represent important steps along that path.’
The researchers hope their confirmation of the earlier study may help lead to better clinical care of patients who may be at high risk of this fatal condition. ‘Patients with this mutation may merit earlier surgical therapy, before aortic dissection has a chance to occur,’ Elefteriades says. Yale cardiothoracic surgeons will now begin assessing this gene in clinical patients with aneurysm disease.
Yale University
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:35:032021-01-08 11:12:04Gene variant raises risk for aortic tear and rupture
A team of cardiovascular researchers from the Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai, Sanford-Burnham Medical Research Institute, and University of California, San Diego have identified a small, but powerful, new player in the onset and progression of heart failure. Their findings also show how they successfully blocked the newly discovered culprit to halt the debilitating and chronic life-threatening condition in its tracks.
In the study, investigators identified a tiny piece of RNA called miR-25 that blocks a gene known as SERCA2a, which regulates the flow of calcium within heart muscle cells. Decreased SERCA2a activity is one of the main causes of poor contraction of the heart and enlargement of heart muscle cells leading to heart failure. Using a functional screening system developed by researchers at Sanford-Burnham, the research team discovered miR-25 acts pathologically in patients suffering from heart failure, delaying proper calcium uptake in heart muscle cells.
‘Before the availability of high-throughput functional screening, our chance of teasing apart complex biological processes involved in disease progression like heart failure was like finding a needle in a haystack,’ says study co-senior author Mark Mercola, PhD, professor in the Development, Aging, and Regeneration Program at Sanford-Burnham and professor of Bioengineering at UC San Diego Jacobs School of Engineering. ‘The results of this study validate our approach to identifying microRNAs as potential therapeutic targets with significant clinical value.’
Dr. Mercola’s laboratory has pioneered the use of robotic high-throughput methods of drug discovery to identify new targets for heart failure. According to co-lead study authors Christine Wahlquist and Agustin Rojas Muñoz, PhD, developers of the approach and researchers in Mercola’s lab at Sanford-Burnham, they used high-throughput robotics to sift through the entire genome for microRNAs involved in heart muscle dysfunction.
Subsequently, the researchers at the Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai found that injecting a small piece of RNA to inhibit the effects of miR-25 dramatically halted heart failure progression in mice. In addition, it also improved their cardiac function and survival.
‘In this study, we have not only identified one of the key cellular processes leading to heart failure, but have also demonstrated the therapeutic potential of blocking this process,’ says co-lead study author Dongtak Jeong, PhD, a post-doctoral fellow at the Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai in the laboratory of the study’s co-senior author Roger J. Hajjar, MD.
Nearly 6 million Americans suffer from heart failure, which is when the heart becomes weak and cannot pump enough blood and oxygen throughout the body. Heart failure is a leading cause of hospitalisation in the elderly. Often, a variety of medications are used to provide heart failure patients temporary relief of their debilitating symptoms. However, these medications do not improve cardiac function or halt the progression of the disease.
Mount Sinai Health System
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:35:032021-01-08 11:12:11Study shows blocking microRNA miR-25 halts progression of heart failure, improves cardiac function, and may increase survival.
A study done by researchers at Fox Chase Cancer Center shows that many relatives of patients who undergo testing for a gene linked to breast and ovarian cancers misinterpret the results, and less than half of those who could benefit from genetic testing say they plan to get tested themselves—despite the fact that knowing your genetic status may help catch the disease in its earliest stages.
‘People don’t always understand genetic information, so there’s confusion,’ says study author Mary B. Daly, MD, PhD, chair of the Department of Clinical Genetics at Fox Chase. ‘Family members are either not understanding what they’re hearing, not realising it has implications for them, or they’re not hearing it at all.’
For a long time, Daly says she ‘naively’ assumed that, once one family member knew whether or not they carried genes linked to breast and ovarian cancers—known as BRCA1/2—their entire family would understand the result, and what it meant for their own genetic risk. ‘Over time, we realised that wasn’t happening, or it wasn’t happening very well.’
Some genetic information is straightforward, says Daly. For example, when a woman learns she carries BRCA1/2 that means her parents, siblings and children may also carry the gene. But there are more ‘indeterminate’ results, which are harder to interpret, she adds. If a woman with a strong family history of breast and ovarian cancers tests negative for the BRCA1/2 genes, that does not mean her relatives are not at risk, says Daly—her siblings could still carry the gene, or there could be additional genes present that predispose them to cancer that clinicians don’t yet know how to test for.
‘When you look at some of these families who are so full of breast and ovarian cancer, and the person tests negative, you think there’s got to be something going on here. We just can’t find it. That’s a difficult thing for someone to explain to a relative,’ says Daly.
To understand better what was (and was not) being communicated after people underwent genetic testing, Daly and her team called 438 relatives of 253 people who had undergone genetic testing and said they’d shared their results. More than one-quarter of family members reported the test result incorrectly. They were most likely to understand positive results—like their family member carries the BRCA1/2 gene. But only 60% understood the so-called ‘indeterminate’ results, where their relative tested negative for the gene but they and other family members could still be at risk. Nearly one-third said they had trouble understanding the result.
Concerningly, only half (52%) of family members whose relative tested positive for the BRCA1/2 gene said they planned to get tested themselves. Among those whose relative tested negative for the BRCA1/2 gene, but knew the gene was present in their families (meaning they could still carry the gene), only 36% said they were going to find out their own genetic risk. ‘These findings imply the family members did not fully understand the significance of these results for their own risk,’ says Daly.
People were more likely to share their results with adult children than parents or siblings, and particularly with female relatives. ‘Over and over you hear people say ‘I’m doing this for my children’s sake,” says Daly.
As part of the study, Daly and her colleagues had asked half of the people getting tested to participate in two coaching sessions to help them communicate their results to relatives, such as through role playing. However, these people were no more likely to communicate the result of their tests than people who had simply sat through educational sessions about overall health. ‘It didn’t matter which group they were in, unfortunately,’ says Daly. ‘That disappointed me.’
But it also inspired her to develop the next project—exploring the effect of directly reaching out to the relatives of someone who underwent genetic testing (with that person’s permission), to see if hearing the results from an expert who’s not personally involved in the situation helps family members understand what they mean.
Fox Chase Cancer Center
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:35:032021-01-08 11:12:18Families don’t understand genetic test results or their implications
Thermo Fisher Scientific and the Department of Systems Biology at the Technical University of Denmark (DTU) have formed a collaboration to pursue breakthroughs in the understanding of how cellular protein networks drive important diseases. Under the collaboration, Thermo Fisher will provide early access to new technology and designs, and DTU proteomics scientists will provide feedback and collaborate on new applications. The centerpiece of this collaboration is a new proteomics laboratory in Lyngby, Denmark equipped with the latest liquid chromatography- mass spectrometry (LC-MS) technology. This includes the unique Thermo Scientific Orbitrap Fusion Tribrid LC-MS system that offers unprecedented depth of analysis of biological samples. ‘Studying the dynamic rewiring of cellular signaling networks requires state-of-the-art mass spectrometry,” said DTU professor Rune Linding. “The Orbitrap Fusion system enables us to push the boundaries and analyse completely new avenues of cellular decision processes, and perform genome-scale studies of how the dynamics in these networks affect cell behaviour. This is crucial, as it is now clear that the progression of complex diseases such as cancer is due to changes in these molecular networks. We were extremely excited to see, only a few days aft er installation, the Orbitrap Fusion system generate the best MS/MS data we have ever seen for the characterization of phosphorylation sites on critical tumour samples.” DTU is establishing the state-of-the-art laboratory to develop new experiments to dig deeper into the core machinery of the cell.
www.dtu.dk/english
www.thermofisher.com
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:35:032021-01-08 11:12:28Thermo Fisher Scientific and the Technical University of Denmark form systems biology collaboration
Some women with endometriosis, a chronic inflammatory disease, are predisposed to ovarian cancer, and a genetic screening might someday help reveal which women are most at risk, according to a University of Pittsburgh Cancer Institute (UPCI) study, in partnership with Magee-Womens Research Institute (MWRI).
Monday at the American Association for Cancer Research (AACR) Annual Meeting 2014, UPCI and MWRI researchers will present the preliminary results of the first comprehensive immune gene profile exploring endometriosis and cancer.
‘A small subset of women with endometriosis go on to develop ovarian cancer, but doctors have no clinical way to predict which women,’ said senior author Anda Vlad, M.D., Ph.D., assistant professor of obstetrics, gynecology and reproductive sciences at MWRI. ‘If further studies show that the genetic pathway we uncovered is indicative of future cancer development, then doctors will know to more closely monitor certain women and perhaps take active preventative measures, such as immune therapy.’
Endometriosis is a painful, often invasive and recurrent condition that happens when the tissue that lines the uterus grows outside of the uterus, causing inflammation. It affects approximately one in 10 women.
By screening tissue samples from women with benign endometriosis, endometriosis with pre-cancerous lesions and endometriosis-associated ovarian cancer, Dr. Vlad and her colleagues identified the complement pathway, which refers to a series of protein interactions that trigger an amplified immune response, as the most prominent immune pathway that is activated in both endometriosis and endometriosis-associated ovarian cancer.
‘If, as our study indicates, a problem with the immune system facilitates cancer growth through chronic activation of the complement pathway, then perhaps we can find ways to change that and more effectively prime immune cells to fight early cancer, while controlling the complement pathway,’ said lead author Swati Maruti Suryawanshi, Ph.D., a post-doctoral research fellow at MWRI.
EurekAlert
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:35:032021-01-08 11:12:06Screening reveals additional link between endometriosis and ovarian cancer
Before doctors like Matthias Kretzler can begin using the results of molecular research to treat patients, they need science to find an effective way to match genes with the specific cells involved in disease. As Kretzler explains, finding that link would eventually let physicians create far more effective diagnostic tools and treatments.
‘Among many uses, it would allow us to develop cell-type targeted therapies,’ said Kretzler, a University of Michigan professor of internal medicine and computational medicine and bioinformatics. He recently collaborated with Princeton University professor Olga Troyanskaya on a way to match genes to cells. ‘If you identify a [disease] that is in the liver or in the kidney, you could target those areas and not affect other parts of the body,’ he said.
Although scientists have decoded the human genome — the list of all the genes in human cells — they still have great difficulty determining the specific genes that are activated to make a kidney cell as opposed to a liver or heart cell.
In theory, an easy way to link genes to cells would be to isolate a cell and test it. However, solid human tissue is so closely packed that even the finest surgical techniques cannot separate types of cells efficiently enough for analysis. A kidney biopsy, for example, produces a mix of several different types of cells that Kretzler dismisses as ‘kidney soup.’
Princeton University and University of Michigan researchers have developed a system that allows computers to ‘virtually dissect’ a kidney in a way that surgery cannot. The machine uses data from an array of gene-activity measurements in patients’ kidney biopsies to mathematically separate cells and identify genes that are turned on in a specific cell type. The researchers identified 136 genes involved in the creation of a critical kidney cell called a podocyte, tiny cells that serve as filters in the kidneys and are frequently involved in kidney disease.
‘We call it in-silico nano-dissection,’ said Troyanskaya, a professor of computer science and the Lewis-Sigler Institute for Integrative Genomics. Using a large database of such gene-activity measurements to track genetic lineage allows scientists to refine their analysis through thousands of measurements, something that would be impossible with individual cell cultures, she said.
The method has proven far faster and significantly more effective than current techniques. Researchers from Kretzler’s lab at Michigan and Troyanskaya’s at Princeton reported that they had identified 136 genes involved in the creation of a critical kidney cell called a podocyte. In decades of research, only 46 had been previously identified.
‘The potential for this is huge,’ said Behzad Najafian, a University of Washington assistant professor of pathology who specializes in renal pathology. ‘I believe this novel technique, which is a significant improvement in cell lineage-specific gene-expression analysis, will not only help us understand the pathophysiology of kidney diseases better through biopsy studies, but also provides a strong tool for discovery or validation of cell-specific urine or plasma biomarkers.’
Princeton University
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:35:032021-01-08 11:12:13Tracking genes on the path to genetic treatment
By linking antibodies to certain diseases, researchers at UC Santa Barbara have found a way to uncover and confirm environmental triggers
By cross referencing the amino acid sequence of peptides strongly associated with illnesses with a library of known peptides, researchers may be able to map antigens with identical sequences to their environment, thus uncovering and confirming environmental triggers for diseases such as Type-1 diabetes, schizophrenia, and autism.
You may be sensitive to gluten, but you’re not sure. Perhaps you can’t put your finger on a recurring malaise, and your doctor is at a loss to figure it out. A diagnostic method recently developed by UC Santa Barbara professor Patrick Daugherty can reveal — on a molecular level — the factors behind conditions thought to have environmental triggers. By decoding an individual’s immune system, this elegant and accurate method can demystify, diagnose and provide further insight into conditions like celiac disease, multiple sclerosis, pre-eclampsia and schizophrenia.
‘We have two goals,’ said Daugherty, a researcher with the Department of Chemical Engineering at UCSB and the campus’s Center for BioEngineering. ‘We want to identify diagnostic tests for diseases where there are no blood diagnostics … and we want to figure out what might have given rise to these diseases.’
The process works by mining an individual’s immunological memory — a veritable catalogue of the pathogens and antigens encountered by his or her immune system.
‘Every time you encounter a pathogen, you mount an immune response,’ said Daugherty. The response comes in the form of antibodies that are specific to the antigens — molecular, microbial, chemical — your body is resisting, and the formation of ‘memory cells’ that are activated by subsequent encounters with the antigen. Responses can vary, from minor reactions — a cough, or a sneeze — to serious autoimmune diseases in which the body turns against its own tissues and its immune system responds by destroying them, such as in the case of Type 1 diabetes and celiac disease.
‘The trick is to determine which antibodies are linked to specific diseases,’ said Daugherty. Celiac disease sufferers, for example, will have certain antibodies in their blood that bind to specific peptides — short chains of amino acids — present in wheat, barley and rye. These peptides are the gluten that is the root of allergies and sensitivities in some people. Like a lock and key, these antibodies — the locks — bind only to certain sequences of amino acids that comprise the peptides — the keys.
‘People with celiac disease have two particular antibody types in their blood, which have proved to be enormously useful for diagnosis,’ said Daugherty.
However, sheer variety and number of antibodies present in a person’s blood at any given time has been a challenge for researchers trying to link specific illnesses with specific antibody molecules. One antigen can stimulate the production of many antibodies in response. What’s more, each individual’s antibodies to even the same antigen differ slightly in their form. The idea of using molecular separation to find the disease antibodies has been around for over 20 years, said Daugherty, but no one had figured quite how to sift through the vast amount of molecules.
To sort through perhaps tens of thousands of antibody molecules present in a person’s blood, the research team — including John T. Ballew from UCSB’s Biomolecular Science and Engineering graduate program, now a postdoctoral associate with the Koch Institute for Integrative Cancer Research at MIT — mixed a sample of a subject’s blood, which contains the antibody molecules, with a vast number of different peptides (about 10 billion).
‘All the keys associate with their preferred lock,’ said Daugherty. ‘The peptides that can bind to an antibody, do so.’ The researchers then pull out the disease-bound pairs, in a process that progressively decreases the number of antibodies-peptide pairs that are most unique to a particular disease. Repeated with subsequent patients who may have the same symptoms, phenotypes or genetic dispositions, continues to whittle down the size of the peptide pool. Further in vitro evolution of the best draft peptides can identify the particular sequence of amino acid keys that fit into the antibody locks. This sequence can be used to confirm the antibodies in question as the biomarkers specifically associated with the disease.
‘The diagnostic performance of the reagents generated with this approach is excellent,’ said Daugherty. ‘We can discover biomarkers with as little as a drop of blood, and the peptides discovered can be adapted into preferred low cost testing platforms widely used in clinical practice.’
The amino acid sequence of the evolved peptides, when cross-referenced with a database of known proteins, can identify the antigens (that contain the same peptide sequence). This, in turn, can then yield clues into what factors in the patient’s environment may have contributed to the disease. The process may be used to gain insight on diseases that are thought to have environmental triggers, including Type-1 diabetes, autism, schizophrenia/bipolar disorder, Crohn’s disease, Parkinson’s disease, and perhaps even Alzheimers disease. In cases, such as Graves’ disease, where an antibody is identified as the cause (as opposed to simply an indicator) knowing the antibody’s structure can lead to more effective therapies.
‘If you can get rid of the antibody, you can treat the disease,’ said Daugherty. ‘By finding these keys, you can block the antibody.’
University of California – Santa Barbara
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:35:032021-01-08 11:12:21Breaking the Code
We may ask you to place cookies on your device. We use cookies to let us know when you visit our websites, how you interact with us, to enrich your user experience and to customise your relationship with our website.
Click on the different sections for more information. You can also change some of your preferences. Please note that blocking some types of cookies may affect your experience on our websites and the services we can provide.
Essential Website Cookies
These cookies are strictly necessary to provide you with services available through our website and to use some of its features.
Because these cookies are strictly necessary to provide the website, refusing them will affect the functioning of our site. You can always block or delete cookies by changing your browser settings and block all cookies on this website forcibly. But this will always ask you to accept/refuse cookies when you visit our site again.
We fully respect if you want to refuse cookies, but to avoid asking you each time again to kindly allow us to store a cookie for that purpose. You are always free to unsubscribe or other cookies to get a better experience. If you refuse cookies, we will delete all cookies set in our domain.
We provide you with a list of cookies stored on your computer in our domain, so that you can check what we have stored. For security reasons, we cannot display or modify cookies from other domains. You can check these in your browser's security settings.
.
Google Analytics Cookies
These cookies collect information that is used in aggregate form to help us understand how our website is used or how effective our marketing campaigns are, or to help us customise our website and application for you to improve your experience.
If you do not want us to track your visit to our site, you can disable this in your browser here:
.
Other external services
We also use various external services such as Google Webfonts, Google Maps and external video providers. Since these providers may collect personal data such as your IP address, you can block them here. Please note that this may significantly reduce the functionality and appearance of our site. Changes will only be effective once you reload the page
Google Webfont Settings:
Google Maps Settings:
Google reCaptcha settings:
Vimeo and Youtube videos embedding:
.
Privacy Beleid
U kunt meer lezen over onze cookies en privacy-instellingen op onze Privacybeleid-pagina.