The Biobank provides DNA specimens for personalized medicine treatments and research. Photo: Getty Images.

A fundamental financial concept is that banks should be well capitalized with diversified investment portfolios. These two elements are the foundation of their economic strength.

In genetics, a different kind of bank must adhere to a similar set of principles in its own unique way.

On the Anschutz Medical Campus, thats the Biobank, which is part of the Colorado Center for Personalized Medicine. The Biobank is a repository of DNA specimens from UCHealth and Childrens Hospital Colorado patients. Researchers use the samples for research, genetic analysis and clinical care. The bank is one key element in efforts to advance personalized or precision medicine that aims to tailor medical care to the specific genetic makeup of patients.

But as with the banks with teller windows and ATMs, the Biobank and other biorepositories like it need deposits and the more the better, says Dr. David Kao, medical director of the Colorado Center for Personalized Medicine. The deeper the biorepository, the greater the evidence on which to learn from and draw reliable conclusions about, for example, specific genetic mutations and the health conditions linked to them.

The fewer the people, the more generic the treatments, Kao said. The more people, the more targeted or personalized are the treatments.

In addition, Kao said, biobanks grow stronger as they diversify genetically. A repository that accurately reflects a communitys makeup is well positioned to assist clinicians and researchers in serving that community. Call it a well-diversified genetic portfolio.

For these reasons, Kao and his colleagues are working to reach out to UCHealth patients and the wider Colorado community to encourage people to participate in the Biobank. In an interview with UCHealth Today, Kao explained what the Biobank is, how it operates, and how it benefits both patients and providers. He also addressed questions about how the Biobank protects patient privacy.

The Biobank is essentially a large research study that aims to collect DNA specimens from a set of UCHealth and Childrens Hospital Colorado patients who voluntarily agree to participate.

The fundamental goal is to understand how genetics fits into everyday health, Kao said. We can learn how patients genes are associated with different facets of health, whether that is risk of developing certain conditions, or responses to treatment, or ways to prevent disease, Kao said.

To do that, biobanks strive to increase the number of specimens in the repository. Doing so enriches the genetic diversity of the specimens. That, in turn, helps researchers and clinicians learn more about the unique characteristics of patients in different racial and ethnic groups, for example.

A surprising amount of what we know about genes and diseases has come from a relatively narrow population of people white males, Kao explained. That is not the world, so we have discovered that the diversity that exists is important to study in order to know if the recommendations we are making are appropriate in different populations.

There are several reasons that it makes sense to have a local biobank, Kao said.

The first is that having a unique, local biobank helps with the practical goal of incorporating genetics into health care. The Biobank at the Colorado Center for Personalized Medicine contains samples and genetic information derived from UCHealth patients. That can enrich the knowledge their providers use to treat them.

We are able to assess how genetics are important to treating our patients here, Kao said. We can tell providers what the best things to do are, with confidence that it applies to the person in front of them.

For example, Kao said, Hispanics make up about 15% of UCHealths patient population. Genetic information from a biobank of patients from, say, the United Kingdom, with a much smaller Hispanic population, would not make an ideal match.

You know youre going to miss something, he said.

In addition, the Biobank specimen data links to a deep reservoir of clinical data stored in the Epic electronic health record (EHR), a capability many other institutions lack, Kao said.

Finally, the Biobank is set up to return certain clinical results from DNA specimens to patients. To our knowledge, we are the only biobank that does that, Kao said. Genetic research benefits everyone, but here you can get an individual benefit.

There are three main ways that the Biobank can help individual patients, Kao said.

First, there are a set of about 75 genes with significant health implications, most notably breast and other cancers and heart failure caused by organ deterioration that begins at a young age.

These are conditions that the genetics community has said, If you see this, you really need to tell the person, Kao said.

About 60 UCHealth patients with these genes have been identified, with about half so far contacted directly to notify them and help them make further decisions, he said.

Second, data about genes that affect how certain medications work or dont work go directly into a patients medical record in the EHR. If a provider tries to prescribe one of these medications, a message pops up with a warning about the patients genetic risk.

One example, Kao said, is statins, a frequently prescribed class of medications that protect against heart disease. In patients with a specific genetic abnormality, the drugs can cause muscle aches and soreness. Without understanding the genetic cause, the patient might stop taking the drug and increase their risk of heart problems. On the other hand, if the provider knows a specific drug has those side effects, theyll simply choose a different one.

We can make sure the person gets the medication they need without being misled by side effects, Kao said. He added that as of recently, the Biobank provides genetically driven advice for all statins because they are so commonly prescribed.

Third, genetic data has been used to flag other conditions, such as risk of hemochromatosis, or iron overload. The condition generally doesnt produce symptoms early, but over time, it can cause deposits of the mineral in the liver, heart and joints. A specific gene is usually present in people who have hemochromatosis, Kao said, although not everyone who has the gene will develop problems. But with knowledge of the gene, again embedded in the EHR, providers can advise patients to get screened early and, if necessary, get treatments, which are effective.

Without the genetic information, most patients wouldnt think to check about iron levels at an early age, Kao said.

Specimens are protected through the same protocols used to store other research specimens across the University of Colorado Anschutz Medical Campus, Kao said. They are placed in tubes with no patient identifying information and stored in deep freezers behind multiple locked doors, with access limited to very specific personnel, he added.

The data lives in a highly secured, cloud storage environment that is more secure than the electronic health record, Kao said. The specific genetic data is stored without patient identifying information attached to it.

It is true that for people with the specific genes discussed earlier (and others), the Biobank has a matching process used to regenerate the connection between them and their samples, Kao said. So we do have a path to trace genetic data back to an individual, because that is how we are able to put specific results back into the medical record. However, he added, that path involves several steps that are each secure in their own right. A hacker would have to breach all the systems involved and then know the protocols to rematch genetic data to an individual, and there are a number of safeguards to protect that from happening, Kao said.

Some researchers on campus use the results of the Biobanks analysis of DNA specimens, Kao said. Others may use samples for further testing in pursuit of their own research. But they have no access to patient-identifying information, he added.

Yes, some do. But, there is always rigorous protection of patient privacy, Kao said.

We collaborate with a number of national and international consortia of biobanks for research and innovation, he said. One purpose is to study conditions that might be seen infrequently in a place like Colorado or another state, region or country. With a much larger pool of biobank data, we can make some conclusions about relatively rare conditions, Kao said.

Dr. Chris Gignoux, director of research for the Colorado Center for Personalized Medicine, said the Biobank is part of consortia that include the Covid-19 Human Genetics Initiative, the Global Biobank Meta-analysis Initiative, and the Biobank Rare Variant Analysis consortium. Gignoux added that the Biobank works frequently with UCLA (ATLAS) and Mount Sinai (BioMe), and is now collaborating with those two biorepositories on three major grants. The Biobank also shares data with the Million Veteran Program and Vanderbilt University (BioVU), among others, he said.

The simplest way is to sign in to your My Health Connection account (or create one). Click the UCHealth Research Opportunities button on the main page to read more about the Biobank and view the consent form. After reading the form, you can sign it, decline to or elect to decide at a later time.

At your next clinic or hospital visit that requires a blood draw, a provider will draw at least one extra tube of blood. Kao said the Biobank has started more recently to use saliva-based collection, and mailed out 250 kits in early June. We may be ramping that up, he said.

Its important to be part of the research because the more different people that we have, both in terms of genes and their entire life course, the better we can understand how to customize, select and choose with each person how they want to treat disease or manage their health over time, Kao said.

Kao added that as medical director of the Biobank, he wants genetic medicine to become an accepted part of all medicine. I want more patients and providers to be aware of it and expect it, just like getting your blood sugar checked, he said. Part of that is empowering patients to learn about and figure out how to use the Biobank, how it matters to them and how they want to engage with it.

The rest is here:
Biobanking makes genetics a fundamental part of health care - UCHealth Today

We have long been baffled as to why men live around five years less than women, on average. But now a new study suggests that, beyond the age of 60, the main culprit is a genetic defect: the loss of the Y chromosome, which determines sex at birth.

Its clear that men are more fragile, the question is why, explains Lars Forsberg, a researcher at Uppsala University in Sweden.

For decades it was thought that the male Y chromosomes only function was to generate sperm that determine the sex of a newborn. A boy carries one X chromosome from the mother and one Y from the father, while a girl carries two Xs, one from each parent.

In 1963, a team of scientists discovered that as men age, their blood cells lose the Y chromosome due to a copying error that happens when the mother cell divides to produce a daughter cell. In 2014, Forsberg analyzed the life expectancy of older men based on whether their blood cells had lost the Y chromosome, a mutation called mLOY. The effect recorded was mindblowing, the researcher recalls.

Men with fewer Y chromosomes had a higher risk of cancer and lived five and a half years less than those who retained this part of the genome. Three years later, Forsberg discovered that this mutation makes getting Alzheimers three times as likely. What is most worrying is the enormous prevalence of this defect. Twenty percent of men over the age of 60 have the mutation. The rate rises to 40% in those over 70 and 57% in those over 90, according to Forsbergs previous studies. It is undoubtedly the most common mutation in humans, he says.

Until now, nobody knew whether the gradual disappearance of the Y chromosome in the blood played a pivotal role in diseases associated with aging. In a study just published in the journal Science, Forsberg and scientists from Japan and the US demonstrate for the first time that this mutation increases the risk of heart problems, immune system failure and premature death.

The researchers have created the first animal model without a Y chromosome in their blood stem cells: namely, mice modified with the gene-editing tool CRISPR. The study showed that these rodents develop scarring of the heart in the form of fibrosis, one of the most common cardiovascular ailments in humans, and die earlier than normal mice. The authors then analyzed the life expectancy recorded in nearly 15,700 patients with cardiovascular disease whose data are stored in the UK public biobank. The analysis shows that loss of the Y chromosome in the blood is associated with a 30% increased risk of dying from cardiovascular disease.

This genetic factor can explain more than 75% of the difference in life expectancy between men and women over the age of 60, explains biochemist Kenneth Walsh, a researcher at the University of Virginia in the US and co-author of the study. In other words, this mutation would explain four of the five years lower life expectancy in men. Walshs estimate links to a previous study in which men with a high mLOY load live about four years less than those without it.

It is well known that men die earlier than women because they smoke and drink more and are more prone to recklessness. But, beyond the age of 60, genetics becomes the main culprit in the deterioration of their health: It seems as if men age earlier than women, Walsh points out.

The study reveals the molecular keys to the damage associated with the mLOY mutation. Within the large group of blood cells can be found the immune systems white blood cells responsible for defending the body against viruses and other pathogens. The loss of the Y chromosome triggers aberrant behavior in macrophages, a type of white blood cell, causing them to scar heart tissue, which in turn increases the risk of heart failure. Researchers have shown that the damage can be reversed if they give mice pirfenidone, a drug approved to treat humans with idiopathic pulmonary fibrosis, a condition in which the lungs become scarred and breathing becomes increasingly difficult.

There are three factors that increase the risk of Y chromosome loss. The first is the inevitable ageing process. The longer one lives, the more cell divisions occur in the body and the greater the likelihood of mutations occurring in the genome copying process. The second is smoking. Smoking causes you to lose the Y chromosome in your blood at an accelerated rate; if you stop smoking, healthy cells once again become the majority, says Walsh. But the third is also inevitable: other inherited genetic mutations can increase the gradual loss of the Y chromosome in the blood by a factor of five, explains Forsberg.

Both Forsberg and Walsh believe that this study opens up an enormous field of research. Still to be studied is whether men with this mutation also have cardiac fibrosis and whether this is behind their heart attacks and other cardiac ailments. We also need to better understand why losing the Y chromosome damages health. For now, we have shown that the Y chromosome is not just there for reproduction, but is is also important for our health, says Forsberg. The next step is to identify which genes are responsible for the phenomenon.

The loss of this chromosome has been detected in all organs and tissues of the body and at all ages, although it is more evident after 60. It is abundant in the blood because this is a tissue that produces millions of new cells every day from blood stem cells. Healthy stem cells produce healthy daughter cells and mutated ones produce daughter cells with mLOY.

A previous study showed that this mutation of the Y chromosome disrupts the function of up to 500 genes located elsewhere in the genome. It has also been shown to damage lymphocytes and natural killer cells, evident in men with prostate cancer and Alzheimers disease, respectively.

There are hardly any tests for mLOY at present. But Forsberg and his colleagues have designed a PCR test that measures the level of this mutation in the blood and could serve to determine which levels of this mutation are harmful to health. Right now, we see people in their 80s with 80% of their blood cells mutated, but we dont know what impact this has on their health, says Walsh.

Another unanswered question is why men lose the genetic mark of the male with age. The evolutionary logic, argue the authors of the paper, is that men are biologically designed to have offspring as soon as possible and to live 40 to 50 years at most. The spectacular increase in life expectancy in the last century has meant that men and women live to an advanced age 80 and 86 years in Spain, respectively which makes the effect of these mutations more evident. Another fact which possibly has some bearing on the issue: the vast majority of people who reach 100 are women.

To transform all these discoveries into treatments, we first need to better understand this phenomenon, says Forsberg. We men are not designed to live forever, but perhaps we can increase our life expectancy by a few more years.

Biochemist Jos Javier Fuster, who studies pathological mutations in blood cells at the National Center for Cardiovascular Research, stresses the importance of the work. Until now it was not clear whether the loss of Y was the cause of cancer, Alzheimers disease and heart failure, he explains. This is the first demonstration in animals that it has a causal role. The human Y chromosome is different from the mouse chromosome, so the priority now is to accumulate more data in humans. This is a great first step in understanding this new mechanism behind aging-linked diseases, he adds.

The cells of the human body group their DNA into 23 pairs of chromosomes that pair up one by one when a cell copies its genome to generate a daughter cell. The Y is the only one that does not have a symmetrical partner to pair up with: instead, it does so with an X chromosome; and the entire Y chromosome is often lost, explains Luis Alberto Prez Jurado from Pompeu Fabra University in Barcelona. For now, six genes have been identified within the Y chromosome that would be responsible for an impact on health, he says. All of them are related to the proper functioning of the immune system. In part, this would also explain the greater vulnerability of males to viral infections, including Covid-19.

Originally posted here:
mLOY: The genetic defect that explains why men have shorter lives than women - EL PAS USA

Media Advisory

Thursday, July 14, 2022

Researchers from the National Cancer Institute, part of the National Institutes of Health, and their collaborators have discovered that people of European and African ancestries who were hospitalized for COVID-19 are more likely to carry a particular combination of genetic variants in a gene known as OAS1 than patients with mild disease who were not hospitalized. People with this combination of genetic variants also remain positive for SARS-CoV-2 infection longer. However, interferon treatment may reduce the severity of COVID-19 in people with these genetic factors. Interferons are a type of protein that can help the bodys immune system fight infection and other diseases, such as cancer.

The study appears July 14 in Nature Genetics.

These findings build on previous studies that have suggested that genetic factors, such as genetic variants affecting OAS antiviral proteins that facilitate the detection and breakdown of the SARS-CoV-2 virus, may influence the risk of SARS-CoV-2 infection.

The NCI researchers and their collaborators found that treatment of cells with an interferon decreased the viral load of SARS-CoV-2. The researchers also analyzed data from a clinical trial in which patients with COVID-19 who were not hospitalized were treated with the recombinant interferon pegIFN-1 and found that treatment improved viral clearance in all patients; those with the OAS1 risk variants benefitted the most. The results suggest that interferon treatment may improve COVID-19 outcomes and specifically in patients with certain OAS1 genetic variants who have impaired ability to clear infection.

Ludmila Prokunina-Olsson, Ph.D., and Oscar Florez-Vargas, Ph.D., Division of Cancer Epidemiology and Genetics, National Cancer Institute

Genetic regulation of OAS1 nonsense-mediated decay underlies association with COVID-19 hospitalization in patients of European and African ancestries appears July 14 in Nature Genetics.

About the National Cancer Institute (NCI): NCI leads the National Cancer Program and NIHs efforts to dramatically reduce the prevalence of cancer and improve the lives of people with cancer. NCI supports a wide range of cancer research and training extramurally through grants and contracts. NCIs intramural research program conducts innovative, transdisciplinary basic, translational, clinical, and epidemiological research on the causes of cancer, avenues for prevention, risk prediction, early detection, and treatment, including research at the NIH Clinical Centerthe worlds largest research hospital. Learn more about NCIs intramural research from the Center for Cancer Research and the Division of Cancer Epidemiology and Genetics. For more information about cancer, please visit the NCI website at cancer.gov or call NCIs contact center at 1-800-4-CANCER (1-800-422-6237).

About the National Institutes of Health (NIH):NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

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Interferon treatment may reduce severity of COVID-19 in people with certain genetic factors - National Institutes of Health (.gov)