Category Archives: Genetic Medicine

The massive international effort to map the entire human genome, completed in 2003, opened a new field we now know as personalized medicine.

The breakthrough, which identified the location and function of every human gene, offered the promise of medical care tailored specifically to individual patients, based on their personal genetic makeup.

When researchers identified a gene associated with a 44 per cent risk of breast cancer in women, for example, it seemed that protecting them might be as simple as deactivating that gene.

But the promise of such personalized medicine has not fully materialized, say two McMaster researchers, because the full sophistication of the genetic blueprint has a more complex and far-reaching influence on human health than scientists had first realized.

In the hope of integrating genetics more closely with medical practice, McMaster evolutionary biologists Rama Singh and Bhagwati Gupta have carried out an exhaustive and critical review of decades of research in their field. They lay out their conclusions inan articlepublished today in the Nature Partner JournalGenomic Medicine.

The biochemical pathway that shapes evolution is dense with inherited redundancies, they explain. Genetic information from our ancestors trails along forever in an incremental physical record that interacts significantly with our own most recently evolved and internally complex genetic network, which in turn interacts with the environment, creating almost infinite combinations and potential health outcomes.

Individual genes do not determine sickness or health on their own, the authors say, but act in concert with groups of other genes all in various stages of mutation in ways that are just beginning to be understood.

Our bodies have an immense ability to change and to cope with issues that arise. Context matters in our genome, Gupta says. Even a simple single mutation can have a profound effect on the body, when acting in combination with others.

The scientists conclude that precision medicine is still critical to the future of medicine, but that the same technology that identified the necessary complexity of the genome also needs to be applied to the entire blueprint including the unnecessary elements creating a longer, more complicated road to the same destination.

Any disease we see is a result of the interactions between necessary and unnecessary complexity, says Gupta.

Nature does not go back in time. It goes forward, and as it encounters challenges, it comes up with solutions.

Our genes carry the history of all the changes that have occurred over many generations. It may not be necessary to our function today, but it is embedded in our genes.

Complexity is not a curse. Its a reflection of our evolutionary history, and it needs to be recognized as an important part of the body that medicine is trying to treat, Singh says. Beyond personalized medicine, complexity bears on the evolution of life itself.

Reference:Rama S. Singh, Bhagwati P. Gupta. Genes and genomes and unnecessary complexity in precision medicine. npj Genomic Medicine, 2020; 5 (1) DOI: 10.1038/s41525-020-0128-1.

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Personalized Medicine Complicated by Overlapping Versions of Our Genetic History - Technology Networks

As with any medical procedure, to undergo genetic testing, informed consent must be given.According to the National Institutes of Health, informed consent (in the context of genetic testing) is the process of making sure that, wherever possible, a patient fully understands:

With this information, a patient can make an educated, voluntary choice i.e. they are informed to a level such that they can provide consent. This is usually a legal and ethical requirement in medicine.Whilst this might seem like a relatively simple concept, for genetic testing, informed consent suddenly becomes a whole lot more complex. Bioethicists, experts in the ethical practice of biology and medicine, often use case studies to explore these complexities and to discuss potential solutions to the dilemmas arising from them.

Jodie is a 28-year-old woman who is thinking about having children. However, she has a family history of limb-girdle muscular dystrophy and is considering undergoing genetic screening to determine if she is a carrier of any variants (a.k.a. mutations in her genome) associated with the disease.

Genetic Counselor Margarita Raygada, Ph.D., explains the role of a genetic counselor in cancer care and shares the benefits and implications of genetic testing for patients and their families.Genetic counselors are individuals educated in both medical genetics and counseling. This gives them the expertise to provide patients with the knowledge required to give consent, but also to offer guidance and support. As such, they are most likely the person who will be responsible for gaining informed consent from the patient.

Laura Hercher, Director of Research in Human Genetics at Sarah Lawrence College, has almost 20 years experience working as a genetic counselor. She emphasizes that the role of counseling goes far beyond testing alone:

Genetic counseling is about more than genetic testing. It can obviously be about that, and a genetic counselor would be a good person to discuss genetic testing with, but we meet with people where genetic testing isn't on the table at all.

I think that there is an element of education in many genetic counseling sessions or interpretation but also in many circumstances, theres what we call establishing a therapeutic relationship, where you do the counseling side of it.

Continuing on this theme, Hercher points out a key aspect of genetic counseling and something which is crucial to the consent process but often forgotten amongst the hype surrounding genetic testing.

We [genetic counselors] don't take for granted that somebody will want genetic testing. They have the right to say no these are shared norms in genetics in the UK and the US.

However, in Jodies case, she has expressed interest in genetic testing. How does a genetic counselor go about establishing informed consent for this?

You have to consider both of these two very basic things, Hercher begins. Make sure the person has an understanding of what genetic testing may tell them and also have an understanding of what genetic testing may not tell them.

These are very important to understand because, number one, you don't want someone to walk away from the experience saying, "Okay, great, I've been tested. I don't have a disease, if that isn't comprehensive.

Number two, we want to talk about what the test will show the patient, both in terms of setting up correct expectations that's consent but also by identifying additional things they might find out that are not necessarily the goals of testing.

The blood sample provided by Jodie undergoes whole exome sequencing. Upon sequence analysis, its found that Jodie does not have any of the variants currently associated with limb-girdle muscular dystrophy. However, the person analyzing the data also checks for other common disease-associated variants. They discover that Jodie has a mutation in BRCA2 that puts her at a higher risk of developing breast and/or ovarian cancer.

The discovery described above is known as a secondary finding, meaning that whilst its identification may not have been the main goal of the test, its presence was actively sought. This is different to an incidental finding, although the terms are often used interchangeably.The potential for secondary findings demonstrates how consent in genetic testing isnt as simple as a single yes or no answer. The decision to actively look for other variants and have them reported back provides an additional layer of consideration to the consent process.

In 2013, the American College of Medical Genetics and Genomics (AMCG) published recommendations for the responsible handling of incidental findings emerging from clinical exome or genome sequencing. This includes clinicians being responsible for alerting patients to the possibility that sequencing could result in incidental findings, and that these may warrant further investigation.1A proper informed consent for genetic testing would give the person a notion of what they might encounter as a part of testing, and what choices they have, about what [testing or results] they can get and what not to get, if there are choices available in the setting in which you're operating.

Jodie doesnt just have a decision to make about whether or not she wants the test, she also has to consider what results she would want reported back to her. The availability of choice is an important one because of the potential implications, both physically and mentally, of being given information you werent expecting or didnt want to receive.

Jodies results show that she, and potentially her first-degree relatives, are at a high risk of developing breast and/or ovarian cancer. Although it isnt a guarantee that she would develop those diseases, this knowledge could impact upon decisions she makes about her healthcare. For people carrying a disease-associated BRCA mutation, preventative, albeit drastic, surgical measures may be available, including mastectomies and oophorectomies.

Preventative surgery, or even just knowing that you may develop a disease can also take an emotional toll. In addition, a patient could find out that they have variation that means they will develop a condition at some point in their lifetime, such as Huntingtons disease. This may have an impact on mental health if there are currently very limited or no treatment options for the condition diagnosed, although further and continual research needs to be conducted to assess the extent of such an impact.

Secondary findings can also emerge with advances in research; a variant that may not have been considered a pathogenic variant before could be considered so in the future, or vice versa. Patients like Jodie would need to think about whether they would want to be re-contacted with new or updated information.

Thats a lot of factors for someone to consider before consenting. How can we simplify consent to account for all of those decisions and outcomes, if its even possible?

This requires time something which the healthcare system doesnt always have enough of. How do we create a process that works for both clinicians and patients?

The answers people are coming up with tend to be that we need better tools, Hercher tells me. And that includes online or digital tools that would allow people to interact with the information. You know, if you sit somebody down and spout off 15 minutes worth of information, dense information, you're not doing anything for them.

So, what's needed to improve the situation is new tools that allow people to tackle it over time, at their own pace, exploring what they want to and when. That would optimize the situation for both the caregiver and the patient. And allow them to go back to it [the information] to refresh their memory and so on. The optimal consent process is not "let's decide everything we can fit into this space of time consent, optimally, is an ongoing process.

Research conducted in the UK seems to agree. A recent report from the Joint Committee on Genomics in Medicine sums it up nicely:Consent may be more appropriately seen as an ongoing conversation that needs updating and clarifying where necessary, rather than as a single historical event that needs to be revisited.Reference

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Exploring the Ethics of Genetic Testing: What Does Consent Mean? - Technology Networks

Glaucoma is an eye disease affecting almost 80 million people and is the second leading cause of blindness worldwide.

Glaucoma results in progressive damage to the optic nerve head, which leads to a corresponding visual field loss and when severe, blindness. The pressure within the eye (intraocular pressure) is the only modifiable risk factor for glaucoma.

Glaucoma has a clear genetic component and tens of common genetic variants affecting intraocular pressure and/or glaucoma risk have been identified. The clinical impact of these results has, however, thus far been negligible.

In this study, published in the journal PLOS Genetics, researchers searched for less common genetic variants which might lower intraocular pressure and protect from glaucoma and focused on those with a clear effect on the function of the corresponding protein product. Such variants have particularly high therapeutic potential since they would highlight a specific gene and a genetic modification that protects from disease.

The results of the study are based on two big European cohorts with large-scale genome and health information data available. Altogether more than 514,000 individuals from the UK Biobank and the FinnishFinnGenstudies were examined. Both cohorts include thousands of individuals with a glaucoma diagnosis. Furthermore, over 120 000 UK Biobank participants have participated in the intraocular pressure measurement tests.

Both study cohorts provided independent, complementary and convincing evidence for the role of theANGPTL7gene in glaucoma. UK Biobank participants carried several rare genetic changes that were shown to reduce intraocular pressure, while FinnGen study provided very strong evidence of another variant specific to the Finnish population which significantly decreased glaucoma risk.

The variant we identified is more than 50 times more common in the Finnish population than elsewhere in the world. In fact, more than 8% of Finns carry it and have a substantially reduced risk of glaucoma. This again demonstrates how the population history of the Finns makes it much easier to identify clinically important genetic variants, said ProfessorMark Dalyfrom the Institute for Molecular Medicine Finland (FIMM), University of Helsinki who co-led the study.

With clinic-based recruitment focused on several areas including ophthalmology, and with more than 30 % of the participants being above age 70, FinnGen is particularly well-powered for aging-associated endpoints.

We often think of the body as a machine whereby taking a single bolt out of that machine and something could go wrong. In this study that hypothetical bolt made the machine work even better by protecting human individuals from glaucoma. Our results highlight the benefits of multi-cohort analysis for the discovery of rare protein-altering variants in common diseases, and ANGPTL7 provides the best therapeutic hypothesis out there for glaucoma, saidManuel Rivas,assistant professor of biomedical data science, Stanford Universitys School of Medicine, who co-led the study.

Importantly, cohorts such as FinnGen and UK Biobank make it possible for the researchers to assess whether the identified protective variants increase the risk of some other condition.

Using the comprehensive health information in the two population cohorts, we assessed the potential impacts of rare genetic variants inANGPTL7on a spectrum of human disorders. We did not find any severe medical consequences that would be of obvious concern in developing a therapeutic to mimic the effect of these alleles, saidYosuke Tanigawa,doctoral student, Stanford Universitys School of Medicine, the first author of the study.

Better understanding of the genetic and pathological mechanism behind intraocular pressure can open up new ways of preventing or treating glaucoma. In this case, the genetic findings support inhibition or lowering the amount of ANGPTL7 as a potentially safe and effective therapeutic strategy for glaucoma.

Our results position angiopoietin like 7 as an appealing and safe target for glaucoma therapies. If a drug can be developed that mimics the protective effect of these mutations, intraocular pressure in at-risk individuals could be lowered, saidMark Daly.

Reference:Tanigawa et al. (2020).Rare protein-altering variants in ANGPTL7 lower intraocular pressure and protect against glaucoma. PLOS Genetics. DOI: https://doi.org/10.1371/journal.pgen.1008682.

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Gene Variants That Protect Against Glaucoma Discovered - Technology Networks

New research suggests the prevalence of infection has links to the development of some types of cancer.

A new study has suggested that before developing some forms of cancer, people experienced increased rates of infectious diseases, such as influenza and pneumonia.

The study, published in the journal Cancer Immunology Research, might help develop diagnostic methods for detecting cancers.

Previous research has indicated that there is a link between immunity, inflammation, and cancer.

Inflammation can promote the development of cancers. This can compromise a persons immune system, which can, in turn, increase inflammation.

Dr. Shinako Inaida, a visiting researcher at the Graduate School of Medicine at Kyoto University in Japan and the corresponding author of the study, explains. Cancer can develop in an inflammatory environment caused by infections, immunity disruption, exposure to chemical carcinogens, or chronic or genetic conditions.

An individuals immunity is thought to be a factor in the development of cancer, but additional research is needed to understand the relationship [between] precancerous immunity, infections, and cancer development. This information may contribute to efforts to prevent or detect cancer.

Consequently, it may be valuable to investigate the relationship between immunity, inflammation, and cancers.

The researchers wanted to understand the relationship between the prevalence of specific infectious diseases that could cause inflammation and cancer development.

To investigate, the authors took their information from a 7-year Japanese social health insurance system database.

The researchers looked at data from 50,749 participants. All the participants were over the age of 30 and did not have any detected immunodeficiency.

The case group comprised 2,354 participants who had developed a form of cancer in the 7th year of the study. The control group consisted of 48,395 people who had no cancer diagnosis during the 7 years of the study, plus an additional final year.

The authors then calculated the prevalence of influenza, gastroenteritis, hepatitis, and pneumonia infections for the two groups.

The authors found a clear link between the prevalence of the four illnesses and the later development of cancer.

The case group experienced significantly higher infection rates than the control group in the 6 years before cancer diagnosis.

Members of the case group experienced higher rates of infection in the year before their cancer diagnosis than those in the control group. During this year, the case group experienced an 18% greater infection of influenza, 46.1% of gastroenteritis, 232.1% of hepatitis, and 135.9% for pneumonia than the control group.

The authors also noted that there was a relationship between different infections and different cancers.

For example, people who developed male germ cell cancers were more likely to have experienced influenza. People who developed stomach cancer were more likely to have had pneumonia, and people who developed blood or bone cancers were more likely to have had hepatitis.

However, as Dr. Inaida points out, [i]nterestingly, we found that infection afflicting a specific organ did not necessarily correlate with increased risk of cancer in the same organ.

The authors point out that the study had some limitations. For example, the data provided limited information on underlying genetic and medical conditions, as well as environmental exposures and different lifestyles. These may have affected the chances of infection and developing cancer.

Nonetheless, by making clear an association between infections, inflammation, immunity, and the development of cancers, future research can look in more detail at the precise mechanisms that govern these relationships.

This may then open the door to better diagnostic methods.

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Infection rates may have links to cancer - Medical News Today

Higher alcohol consumption was shown to be associated with an increased risk of having a stroke or developing peripheral artery disease, according to new research published in Circulation: Genomic and Precision Medicine.While observational studies have consistently shown that heavy alcohol consumption is associated with an increased risk of certain cardiovascular diseases, they often use self-reported data and are unable to determine cause. Researchers in this study used a different technique called Mendelian randomization that identifies genetic variants with a known association to potential risk factors to determine the potential degree of disease risk.

Since genetic variants are determined at conception and cannot be affected by subsequent environmental factors, this technique allows us to better determine whether a risk factor in this case, heavy alcohol consumption is the cause of a disease, or if it is simply associated, said Susanna Larsson, Ph.D., senior researcher and associate professor of cardiovascular and nutritional epidemiology at Karolinska Institutet in Stockholm, Sweden. To our knowledge, this is the first Mendelian randomization study on alcohol consumption and several cardiovascular diseases.

Researchers analyzed the genetic data from several large-scale consortia and the UK Biobank, which follows the health and well-being of 500,000 United Kingdom residents. Results indicate that with higher alcohol consumption:

Higher alcohol consumption is a known cause of death and disability, yet it was previously unclear if alcohol consumption is also a cause of cardiovascular disease. Considering that many people consume alcohol regularly, it is important to disentangle any risks or benefits, Larsson said.Researchers noted that this study suggested the mechanism by which higher consumption was associated with the risk of stroke and PAD may be blood pressure.

According to a statement on dietary health, the American Heart Association believes that alcohol intake can be a component of a healthy diet if consumed in moderation (no more than one alcoholic drink per day for women and 2 alcohol drinks per day for men) and only by nonpregnant women and adults when there is no risk to existing health conditions, medication-alcohol interaction, or personal safety and work situations. One drink is equivalent to 12 ounces of beer (5% alcohol); 5 ounces of wine (12% alcohol); or 1.5 ounces of 80-proof distilled spirits (40% alcohol).

The study has some limitations. According to Dr. Larsson, the prevalence of heavy drinking in the UK Biobank was low, and it is unlikely that the burden of increased risk of cardiovascular disease is restricted to heavy drinkers alone. Also, the exact amount and frequency of alcohol consumed could not be quantified for this study. The researchers said the causal role of alcohol consumption on cardiovascular diseases other than stroke and peripheral artery disease requires further research.ReferenceLarsson et al. (2020). Alcohol Consumption and Cardiovascular Disease: A Mendelian Randomization Study. Circulation: Genomic and Precision Medicine. DOI: https://doi.org/10.1161/CIRCGEN.119.002814

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Genetic Study Links Higher Alcohol Consumption to Increased Stroke and PAD Risk - Technology Networks

The new study, released today on Biorxiv sought to identify genetic risk factors for sepsis especially in the context of COVID-19, and to use these insights to identify existing drugs that might be used to treat life-threatening late-stage disease.

"Ours is the first study looking at host genomics and opportunities to treat later stage severe disease where host immune processes take over,"said Dr Steve Gardner CEO of PrecisionLife.

Like the initial genomic studies on COVID-19 patients, previous analyses of sepsis patients have failed to identify more than a handful of genetic variants that predispose individuals to developing the disease. By providing deeper insights, this study identifies novel approaches and hope for new therapies.

PrecisionLife analyzed patient datasets compiled by UK Biobank to identify genes associated with sepsis, which are also found in severe COVID-19 patients. Sepsis is observed in 60% of severe COVID-19 patients and is a life-threatening condition with a mortality rate of approximately 20%.

The team identified mutations in 70 sepsis risk genes, 61% of which were also present specifically in severe COVID-19 patients. Several of the disease associated genetic signatures found in both sepsis and severe COVID-19 patients have previously been linked to cancer, immune response, endothelial and vascular inflammation and neuronal signalling.

13 of the sepsis risk genes, which the study shows are also COVID risk genes, are known to be druggable i.e. targeted by active chemical compounds used to treat these other diseases and therefore represent potential drug repurposing opportunities. The study went on to identify 59 compounds and drugs that are known to be active against these 13 targets. These could form the basis for future drug trials and repurposing projects. They could also offer potential as COVID-19 high risk biomarkers.

"Our high-resolution genomic analysis tools have allowed us to develop new insights into two serious and complex diseases for which new therapeutic options are urgently required. We hope that these will lead to better understanding of what drives sepsis in COVID-19 patients and result in new ways to treat seriously ill patients," said Dr Gardner.

PrecisionLife is disclosing its new insights and will be working with international collaborators to investigate therapeutic strategies that may help to reduce the high mortality rates in patients who develop sepsis with or without the context of COVID-19.

As more COVID-19 patient data become available in UK Biobank and other patient data sources, PrecisionLife will be able to analyze the clinical impact of these disease signatures in a larger group of patients.

For more information, please see http://www.precisionlife.com, or email covid-19@precisionlife.com.

Follow us on Twitter @precisionlifeAI and on LinkedIn http://www.linkedin.com/company/precisionlifeai

About PrecisionLife

PrecisionLife Ltd started in 2015, built on a shared vision to bring a new level of analytical capability to computational biology, genomic medicine and healthcare. Its powerful data analytics platform is built on a unique mathematical framework and over 30 years' experience in delivering new technologies and products to enable the discovery of richer and more useful links between patients, disease, targets and drugs.

Headquartered in the UK, PrecisionLife also has operations in the US, Denmark and Poland.

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AI Precision Medicine Company, PrecisionLife, Have Identified 59 Repurposing Drug Candidates That Could Be Used to Increase the Survival Rate of...