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Category Archives: Genetic Medicine

Cancer researchers across the UK join forces to find drugs for rare cancers – The University of Manchester

Cancer Research UK, The University of Manchester and Roche, today (Monday 20th), announce a partnership to run a multi-drug, precision medicine platform trial for adults and children with rare cancers who have run out of other treatment options.

The DETERMINE* trial will be one of the largest precision medicine platform trials targeting these populations and it will enrol patients who have an identifiable genetic alteration in their cancer that can be targeted by treatments that are already approved for use in other cancer types.

Its unique design means that any treatment shown to benefit patients on the trial could be fast-tracked towards approval on the NHS**.

The University of Manchester will lead the trial which will be run in collaboration with the Royal Marsden NHS Foundation Trust, The University of Birmingham, and the Christie NHS Foundation Trust***, with contribution from the adult and paediatric Experimental Cancer Medicine Centres (ECMC) network****.

Under the terms of the partnership, Cancer Research UKs Centre for Drug Development will sponsor and manage the trial, with Roche providing 7***** of their targeted therapies to be evaluated in the first instance. More pharmaceutical partners are expected to join and contribute their drugs as the trial progresses.

The trial is aiming to recruit patients with rare adult and paediatric cancers, as well as more common cancers with rare genetic alterations that could be targeted by the drugs being studied in the trial.

Worldwide, rare cancers make up 22 out of every 100 (22%) cancers that are diagnosed each year****** which is more than any single type of cancer. If we were to define all rare cancers as a single type, they would top the list of the most prevalent cancers worldwide, above lung, breast and colorectal cancer.

But despite their prevalence, fewer treatment options exist for patients with rare cancers.

The DETERMINE trial aims to find out whether existing licensed drugs, meaning those which are already prescribed by doctors for more common types of cancer, could also benefit patients with rare cancer types that the drug isnt currently licensed for.

The medicines being used in the trial are targeted to specific genetic faults that occur in cancer. Genetic testing is increasingly being undertaken for cancer patients in the UK either on the NHS or as part of other research trials. The genetic testing will help assess whether a patient is eligible for the study and which drug is most likely to benefit the patient.

Any drug in that is shown to benefit patients, even if only in a small group of patients with rare cancers, could be submitted for review by the Cancer Drug Fund (CDF)*******. They would then decide whether to collect more data to assess if the drug could be used more routinely for patients with this cancer type as a treatment option potentially available in an NHS setting.

Ultimately the study will create a roadmap to help establish new treatment options for patients with some types of rare cancer.

This precision medicine trial is set to open to recruitment nationwide in early summer 2022, with the entire length of the trial spanning 5 years.

Dr Matthew Krebs, Chief Investigator for the DETERMINE trial at The University of Manchester and The Christie NHS Foundation Trust, said:

Patients with rare cancer often have few treatment options available and its vitally important we increase our research efforts for these patients.

With technological advances in genetic testing weve learned that some rare tumours contain genetic abnormalities which may benefit from targeted treatment currently only available for more common cancer types. We will undertake in-depth research to understand which patients with rare cancers could benefit from these treatments

With the potential to change outcomes for adults, teenagers and children with rare cancers, this trial will be ground-breaking for a patient population who often feel neglected by current cancer research.

Iain Foulkes, Executive Director of Research and Innovation at Cancer Research UK, said:

With numerous researchers involved nationwide and potentially around 850 people with rare cancers taking part, this trial represents a significant undertaking by Cancer Research UK and our partners.

But what makes this even more exciting is that we will be able to fast track the approval of any promising drugs, opening the door to treatments for patients who have historically been left with limited options.

Richard Erwin, General Manager, Roche Products Ltd, said:

We are committed to helping find ways to identify the right treatment for the right person at the right time. This study will help in identifying novel treatments for adults and children living with rare cancers.

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Cancer researchers across the UK join forces to find drugs for rare cancers - The University of Manchester

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Intellia Therapeutics Appoints Derek Hicks as Chief Business Officer – BioSpace

CAMBRIDGE, Mass., Dec. 20, 2021 (GLOBE NEWSWIRE) -- Intellia Therapeutics (NASDAQ: NTLA), a leading genome editing company focused on developing curative therapeutics using CRISPR/Cas9 technology both in vivo and ex vivo, today announced the appointment of Derek Hicks to a newly created position as Executive Vice President, Chief Business Officer.

Mr. Hicks joins Intellia with more than 25 years of combined business, leadership and biotechnology experience, having most recently served as Head of Business Development at Spark Therapeutics. While at Spark, he was responsible for business development strategy, search and evaluation, licensing and key partnership activities. Prior to this role, Mr. Hicks spent 18 years at Pfizer in a variety of business and corporate development roles culminating with his position as Vice President, Corporate Development, World-Wide Business Development.

As Intellia continues to expand its leadership position in the field of genome editing, our ability to grow our pipeline, imagine new therapeutic possibilities and collaborate with leading organizations will be key to our future success. I am thrilled to welcome Derek to Intellias executive team as we enter the next chapter in our evolution, said Intellia President and Chief Executive Officer John Leonard, M.D. Derek is an accomplished business leader who shares Intellias values and commitment to bringing forth life-changing therapies for patients. He has a long, successful history of leading corporate and business development efforts in the biotechnology and pharmaceutical industry. I am confident his expertise will complement Intellias strong legacy of identifying and executing upon value-adding partnerships and corporate development opportunities critical to our mission of building the industrys most innovative genome editing company.

I could not be more excited to join Intellia at this transformational time as the team is just beginning to realize the full potential of genome editing, said Mr. Hicks. Intellia has clearly been a pioneer in the space, and I look forward to working with the Intellia team and our partners in maximizing the impact of its world-class science for the benefit of patients.

Mr. Hicks earned both a Bachelors and Masters of Science degree in mechanical engineering from the University of Connecticut and an MBA in finance from Indiana University Kelly School of Business.

About Intellia Therapeutics

Intellia Therapeutics, a leading clinical-stage genome editing company, is developing novel, potentially curative therapeutics using CRISPR/Cas9 technology. To fully realize the transformative potential of CRISPR/Cas9, Intellia is pursuing two primary approaches. The companys in vivo programs use intravenously administered CRISPR as the therapy, in which proprietary delivery technology enables highly precise editing of disease-causing genes directly within specific target tissues. Intellias ex vivo programs use CRISPR to create the therapy by using engineered human cells to treat cancer and autoimmune diseases. Intellias deep scientific, technical and clinical development experience, along with its robust intellectual property portfolio, have enabled the company to take a leadership role in harnessing the full potential of CRISPR/Cas9 to create new classes of genetic medicine. Learn more at intelliatx.com. Follow us on Twitter@intelliatweets.

Forward-Looking Statements

This press release contains forward-looking statements of Intellia Therapeutics, Inc. (Intellia) within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements include, but are not limited to, express or implied statements regarding Intellias ability to advance and expand the CRISPR/Cas9 technology to develop into human therapeutic products, as well as our CRISPR/Cas9 intellectual property portfolio; achieve stable or effective genome editing; the timing and potential achievement of milestones to advance our pipeline and grow as a company; and the anticipated contribution of the members of our board of directors and our executives to our operations and progress.

Any forward-looking statements in this press release are based on managements current expectations and beliefs of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to: risks related to Intellias ability to protect and maintain its intellectual property position; risks related to Intellias relationship with third parties, including its licensors and licensees; risks related to the ability of its licensors to protect and maintain their intellectual property position; uncertainties related to the authorization, initiation and conduct of studies and other development requirements for its product candidates; the risk that any one or more of Intellias product candidates will not be successfully developed and commercialized; the risk that the results of preclinical studies or clinical studies will not be predictive of future results in connection with future studies; and the risk that Intellias collaborations with Regeneron or its other collaborations will not continue or will not be successful. For a discussion of these and other risks and uncertainties, and other important factors, any of which could cause Intellias actual results to differ from those contained in the forward-looking statements, see the section entitled Risk Factors in Intellias most recent annual report on Form 10-K as well as discussions of potential risks, uncertainties, and other important factors in Intellias other filings with the Securities and Exchange Commission (SEC). All information in this press release is as of the date of the release, and Intellia undertakes no duty to update this information unless required by law.

Intellia Contacts:

Investors:Ian KarpSenior Vice President, Investor Relations and Corporate Communications+1-857-449-4175ian.karp@intelliatx.com

Lina LiDirector, Investor Relations+1-857-706-1612lina.li@intelliatx.com

Media:Matt CrensonTen Bridge Communications+1-917-640-7930media@intelliatx.commcrenson@tenbridgecommunications.com

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Montefiore Health System and Albert Einstein College of Medicine Announce New Chair of Otorhinolaryngology-Head and Neck Surgery – Yahoo Finance

BRONX, N.Y., Dec. 20, 2021 /PRNewswire/ -- Richard V. Smith, M.D., FACS, has been named professor and university chair of the department of otorhinolaryngology-head and neck surgery at Montefiore Health System and Albert Einstein College of Medicine. Dr. Smith assumed his new position on October 1 and had been the interim chair of the department since February 2020.

Richard V. Smith, M.D., FACS, professor and university chair of the department of otorhinolaryngology-head and neck surgery at Montefiore Health System and Albert Einstein College of Medicine

Dr. Smith, an accomplished thyroid/parathyroid surgeon, was the first to develop transoral robotic total laryngectomy, a complicated, but minimally invasive surgery for head and neck cancers that results in improved outcomes, such as shorter hospital stays. His research on genetic biomarkers in head and neck cancers to predict disease progression and develop personalized treatments has also been widely published.

"Dr. Smith's significant accomplishments as a surgeon and researcher, including the pioneering of new robotic surgery techniques, reflects his unwavering commitment to patient-centered care," said Philip O. Ozuah, M.D., Ph.D., president and chief executive officer at Montefiore. "We are excited about his vision for the department and are confident in his ability to lead it with empathy and an eye to the future."

As interim chair, Dr. Smith streamlined patient scheduling for appointments and ensured the completion of necessary medical testing prior to subspecialty visits. This has led to a decrease in patient no-show rates and better, more productive in-person visits. In this role, he also spearheaded a new hospitalist service at the Moses campus and a new rotation for the residents in the department.

"Dr. Smith has proved himself an exceptional leader over the past 10 months and we're immensely pleased he will be taking the helm," said Gordon F. Tomaselli, M.D., the Marilyn and Stanley M. Katz Dean at Einstein and executive vice president and chief academic officer at Montefiore Medicine. "His commitment to our medical students and to advancing care through research has enriched the College of Medicine and our greater enterprise."

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Earlier this year, the American Academy of Otolaryngology-Head and Neck Surgery honored Dr. Smith with their Board of Governors' Practitioner Excellence Award, which recognizes an otolaryngologist that others wish to emulate and who is sought out by other physicians because of his personal and effective care.

In addition to this honor, Dr. Smith has held leadership positions in regional and national organizations, including the president of the New York Laryngological Society and the New York Head and Neck Society. He has also earned the Distinguished Academic Achievement Award from the University of Vermont College of Medicine.

Smith received his B.A. cum laude from Middlebury College and his M.D. from the University of Vermont. He completed his general surgery internship and his otolaryngology-head and neck surgery residency at the Georgetown University Hospital in Washington, DC. After completing his training, he joined Montefiore and Einstein in 1995.

About Montefiore Health SystemMontefiore Health System is one of New York's premier academic health systems and is a recognized leader in providing exceptional quality and personalized, accountable care to approximately three million people in communities across the Bronx, Westchester and the Hudson Valley. It is comprised of 10 hospitals, including the Children's Hospital at Montefiore, Burke Rehabilitation Hospital and more than 200 outpatient ambulatory care sites. The advanced clinical and translational research at its medical school, Albert Einstein College of Medicine, directly informs patient care and improves outcomes. From the Montefiore-Einstein Centers of Excellence in cancer, cardiology and vascular care, pediatrics, and transplantation, to its preeminent school-based health program, Montefiore is a fully integrated healthcare delivery system providing coordinated, comprehensive care to patients and their families. For more information please visit http://www.montefiore.org. Follow us on Twitter and view us on Facebook and YouTube.

About Albert Einstein College of MedicineAlbert Einstein College of Medicine is one of the nation's premier centers for research, medical education and clinical investigation. During the 2020-21 academic year, Einstein is home to 732 M.D. students, 190 Ph.D. students, 120 students in the combined M.D./Ph.D. program, and approximately 250 postdoctoral research fellows. The College of Medicine has more than 1,900 full-time faculty members located on the main campus and at its clinical affiliates. In 2020, Einstein received more than $185 million in awards from the National Institutes of Health. This includes the funding of major research centers at Einstein in cancer, aging, intellectual development disorders, diabetes, clinical and translational research, liver disease, and AIDS. Other areas where the College of Medicine is concentrating its efforts include developmental brain research, neuroscience, cardiac disease, and initiatives to reduce and eliminate ethnic and racial health disparities. Its partnership with Montefiore, the University Hospital and academic medical center for Einstein, advances clinical and translational research to accelerate the pace at which new discoveries become the treatments and therapies that benefit patients. For more information, please visit einsteinmed.org, read our blog, follow us on Twitter, like us on Facebook, and view us on YouTube.

Montefiore (PRNewsfoto/Montefiore/Albert Einstein College of Medicine)

Albert Einstein College of Medicine Logo (PRNewsfoto/Albert Einstein College of Medicine)

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Genetics, Epigenetics, and Cancer: What Data Are We Missing? – AJMC.com Managed Markets Network

During the discussion of disparities in cancer care, one panelist explained that the National Institutes of Health definition of precision medicine is broader than most people realize.

A flashpoint in the discussion of disparities in cancer care concerns data:If most of the data collected on genetic mutations come from White Europeans, what insights might we have missed? Will approved therapies offer the same level of efficacy in patients of color?

More importantly, what data beyond a persons genetics are not accounted for in todays clinical trials that could affect cancer outcomes? And how can artificial intelligence (AI) enable these factors to be part of the care equation?

During the discussion on cancer care disparities at Patient-Centered Oncology Care, Karen Winkfield, MD, PhD, executive director of the Meharry-Vanderbilt Alliance, asked John Carpten, PhD, of the Keck Schoolof Medicine at the University of Southern California Norris Comprehensive Cancer Center the following question: If we are talking about getting the right treatment to the right patient at the right time, what are some of thedata points that were currently missing?

The answer, Carpten replied, starts with the basic concept of precision medicine itself. And this is broader than most people realize if one looks at the definition given by the National Institutes of Health (NIH), he said.

"Im going to say this sensitivelyits consistently dumbed down to performing a genetic assay and trying to understand how to manage disease based on the individuals genetics," Carpten pointed out. "But if youlook at the NIH definition, it broadens it: it talks about lifestyle [and] environmental factors that can also [have] a significant impact on individual exposures."

These can include stresses, the built environment, and other factors that affect a persons living condition, Carpten said, in addition to their genetic ancestry. This area, epigenetics, involves individual behaviors and external factors that can alter how genes work. Epigenetics plays a huge role in cancer because if these other factors are not taken into account, targeting a patients mutation wont bring about the expected result.

"There are so many aspects of managing disease that go beyond just, 'Theres an alteration, its linked to this drug, so that drug should be effective in that setting. And we know that thats not always the case because there are so many other things that can impact that individuals response,' " Carpten said.

The future, he continued, should involve building cancer care models that would take both genetic and epigenetic factors into account. Winkfield used the example of smoking and how a mothers smoking during pregnancy can affect multiple generations of a family.

The more data we generate, the more we learn, and the more we can contribute to the model," Carpten said. "My hope is that it wont be about one measurement, it will be about a model. And in order to develop those models, we have to perform the studies that generate the data."

An opportunity exists for trauma, poverty, and institutional racism, for example, to finally be factored into such a model. "Im starting to be more vocal about the fact that racism is trauma, right? Its generational trauma," said Winkfield.

According to Carpten, models are beginning to take structural racism into account, including how exposure to environmental and social stressors affected the rate of reactive oxygen species development. This, in turn, led to effects such as chronic inflammation that are known to increase cancer risk. For all his excitement over the possibilities of AI, Carpten offered a warning: disparities could be exacerbated if not everyone has access. We have to take it one step at a time," he said. "[but] I think weve made a lotof progress."

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$11.5 million commitment supports new Alzheimer’s prevention clinical trial Washington University School of Medicine in St. Louis – Washington…

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Major international initiative renamed in honor of Knight family

Longtime St. Louis benefactor Joanne Knight has committed up to $11.5 million to Washington University School of Medicine in St. Louis to support an innovative clinical trial aimed at preventing Alzheimers disease by treating people before the first signs of the illness appear in the brain.

Longtime St. Louis benefactor Joanne Knight has committed up to $11.5 million to Washington University School of Medicine in St. Louis to support an innovative clinical trial aimed at preventing Alzheimers disease by treating people before the first signs of the illness appear in the brain.

In recognition of this gift and the Knight familys generous history of support for Alzheimers research, the universitys long-running Alzheimers prevention initiative will be named the Knight Family Dominantly Inherited Alzheimer Network-Trials Unit (Knight Family DIAN-TU).

The gift as well as any funds raised by Washington University through a $6.5 million matching challenge will help support the new trial, designed to determine whether early treatment can forestall the cascade of molecular brain changes that eventually lead to memory loss and cognitive decline. Such changes typically begin two decades before the onset of dementia.

The new trial differs from other Alzheimers prevention trials at Washington University and elsewhere in that it begins treatment even before brain changes become evident via scans and tests. The study involves people genetically predisposed to develop the disease at a young age because its easier to evaluate the effectiveness of drugs in people whose path toward disease is so clearly marked.

Joanne Knight and her late husband, Chuck, have provided indispensable support for Alzheimers research at Washington University through many generous gifts over the years, said Chancellor Andrew D. Martin. Her most recent gift will aid in understanding this devastating illness and bring us closer to finding a much-needed preventive treatment.

Joanne Knight has had intimate experiences with Alzheimers through the years. Chuck Knight died from complications of Alzheimers in 2017, and Chucks father and Joannes mother both died of the illness.

I have coped with the realities of Alzheimers disease in my family for the majority of my adult life, Joanne Knight said. Chuck always believed that if you didnt like something, you do something about it and he didnt like Alzheimers. Thats why we first started funding Alzheimers research at Washington University. Chuck would be so thrilled by the trials going on now. I am glad to have the opportunity to support clinical trials to preemptively halt Alzheimers disease in people.

The trial will recruit participants with a rare genetic mutation that all but guarantees they will develop the disease as early as their 50s, 40s or even 30s. A parent with such a mutation has a 50% chance of passing the genetic mutation to a child, and any child who inherits the mutation is nearly certain to develop symptoms of dementia near the same age as his or her parent. This timeline gives researchers an opportunity to evaluate the effectiveness of drugs designed to prevent Alzheimers. Many of these individuals and families participate in the Dominantly Inherited Alzheimer Network, an international research network led by Washington University to study this strongly inherited form of the disease.

Our Alzheimers team has been at the forefront in understanding how this disease progresses and in developing better diagnostic tests and novel treatment approaches, said David H. Perlmutter, MD, executive vice chancellor for medical affairs, the George and Carol Bauer Endowed Dean of the School of Medicine, and the Spencer T. and Ann W. Olin Distinguished Professor.

This new funding will permit them to continue the unique and bold clinical trial design addressing the central question of early intervention. The generosity of Joanne Knight and the Knight family has been critical to this groundbreaking research effort.

The new trial involves young adults who have inherited a mutation for early-onset Alzheimers but whose brains still appear normal and have not yet started to collect plaques of the toxic protein amyloid beta. It is believed that amyloid plaques set off a cascade of brain changes that lead to the death of brain tissue, resulting in memory loss and confusion. Family members without the mutation will be studied for comparison.

During the four-year study, participants will receive a drug designed to block the buildup of amyloid in the brain, or a placebo. The trial will be conducted in people with rare, early-onset forms of the disease, but the results also could benefit the 5 million Americans living with the more common form, which starts later in life. The processes that lead to memory loss and cognitive impairment are thought to be highly similar, whether the disease is caused by a dominant mutation or by the complex combination of genetics and environment that causes most Alzheimers cases.

Washington Universitys first Alzheimers prevention trial, the DIAN-TU-001 (ClinicalTrials.gov identifier NCT01760005), launched in 2012. That study evaluates whether drug treatment can protect people who have some amyloid plaques, but who are still cognitively sharp, from developing dementia. The new study involves even younger people who carry the risky genes but whose brains have not yet begun changing.

Beginning with their support for the Charles F. and Joanne Knight Alzheimers Disease Research Center at Washington University and continuing today, the Knight familys contributions have been key to seeding the success of Alzheimers research at the university, enabling us to lead the DIAN-TU trials worldwide, said Randall J. Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology and director of the Knight Family DIAN-TU. With the Knight familys latest commitment, the Knight Family DIAN-TU is enabled to launch bold and potentially world-changing trials in the fight against Alzheimers disease.

As part of the Knight familys $11.5 million commitment, the family worked with Washington University to establish theKnight Alzheimers Primary Prevention Challenge. Through the challenge, the family will match up to $6.5 million in gifts and pledges raised by the university for the Knight Family DIAN-TU. Altogether, contributions from the Knight family and the matching challenge could total $18 million.

In addition to the Knight family, the new prevention trial is supported by two grants totaling an estimated $97.5 million from the National Institute on Aging of the National Institutes of Health (NIH), awarded to the trials principal investigator, Eric McDade, DO, an associate professor of neurology at the School of Medicine and associate director of the Knight Family DIAN-TU, as well as $14 million from the Alzheimers Association and GHR Foundation.

Washington University School of Medicines 1,700 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, and is among the top recipients of research funding from the National Institutes of Health (NIH). Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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Very important pharmacogene variants in the Blang population | PGPM – Dove Medical Press

Introduction

The use of drugs should be different among diverse ethnic groups because of differences in ethnicity, age, sex, environmental factors and genetic factors. If these differences are ignored, then drug sensitivity, metabolic rate, and adverse reactions are affected, which influences the curative effect of drugs and aggravates the illness of patients.

Genetic factors can explain up to 2095% of the variability in drug response.1 Variations in genes can affect the pharmacokinetics/pharmacodynamics of drugs, as well as their absorption and metabolism. Pharmacogenes are genes that decide the fate of drug pharmacology in a biological system. In general, pharmacogenes correspond to specific gene superfamilies. Among numerous gene superfamilies, the cytochrome P450 superfamily is the most widely researched in pharmacogenomics studies. It has been reported that polymorphisms of cytochrome P450 account for the most frequent variations in the phase-I metabolism of drugs.2 Variations in most gene superfamilies can affect the metabolism of drugs and disease risk.

The single-nucleotide polymorphism (SNP) is the most common variation of very important pharmacogenes (VIPs). Usually, SNPs are employed to analyze the pharmacogenomic information in different populations.3,4 Pharmacogenomics is an emerging approach to precision medicine. Pharmacogenomics plays a major part in precision medicine by tailoring the selection and dosing to the patients genetic features.5 The Pharmacogenomics Knowledge Base (PharmGKB; http://www.pharmgkb.org/) is one of the most commonly used databases on primary pharmacogenomics. PharmGKB contains information on gene-variant annotations, drug-centered pathways, VIPs and diverse diseases. PharmGKB aims to share genotype, phenotype, or other data on genetic variations among researchers.6

It has been demonstrated that pharmacogenomic analysis of a specific population can aid the efficacious, accurate use of drugs in a population.7,8 For example, Bader et al found that variants of the vitamin K epoxide reductase complex gene (VKORC) and cytochrome P450 family 2 subfamily C member 9 gene (CYP2C9), which encode enzymes for warfarin metabolism, were the strongest predictors of variability in the warfarin dose among different populations in Middle East and North Africa.7 In addition, Kim et al demonstrated that adverse drug reactions could be avoided if preemptive genotyping was employed in a South Korean population.8

The US Food and Drug Administration (www.fda.gov/) have recognized >250 biomarkers with known pharmacogenomic value, and provided recommendations for therapeutic management.9 Recently, pharmacogenomics information on increasing numbers of ethnic minorities in China has been explored. For example, Liu et al found that, compared with 11 populations in a dataset from the International HapMap Project (www.genome.gov/), differences in expression between the rs2070676 of the cytochrome P450 family 2 subfamily E member 1 gene (CYP2E1) and rs1065852 of cytochrome P450 family 2 subfamily D member 6 gene (CYP2D6) in people of Zhuang nationality were the greatest according to genotyping of samples of 105 people of Zhuang nationality.3 Besides, He et al concluded that expression of rs4291 of the angiotensin I-converting enzyme gene (ACE), rs1051296 of the solute carrier family 19 member 1 gene (SLC19A1) and rs1065852 of CYP2D6 differed significantly in a Tibetan population compared with that of 26 other populations after genotyping of 200 samples from a Tibetan population. They also found that the allele frequency in this Tibetan population differed least from that of an East Asian population, and differed most from that of a North American population.4

China has 56 ethnic groups. The Blang ethnic group is found in Yunnan Province in China. According to the Sixth National Census in 2010, the total number of people of Blang ethnicity was 119,639. Among them, >30,000 people live in Mount Blang, Xiding, Bada, Daluo, Mengman, Menggang and other towns in Menghai County in Xishuangbanna Dai Autonomous Prefecture.10 People of Blang ethnicity live in mountainous areas with a mild climate and abundant rainfall, which is very conducive to plant growth. The area in which Blang populations live is one of the main raw material-producing areas of Puer tea and Mengku tea. Even though genetic studies on Blang populations have been conducted,1012 pharmacogenomics information of the Blang population is lacking. Cheng et al explored the pharmacogenomics information of a Blang population.13

Here, we shed light on the pharmacogenomic information of a Blang population by genotyping 55 different loci of 27 VIPs using 200 samples from Yunnan Province. These samples are different from those investigated by Cheng and collaborators. We also compared the distribution of genotype frequency and minor allele frequency (MAF) differences (55 loci of 27 VIPs) with a Blang population and 26 other populations. The genetic variations of the 15 gene superfamilies involved in the present study were related mainly to changes in drug metabolism and disease risk.2,1427 We wished to enrich the pharmacogenomics information of a Blang population and provide a theoretical foundation for promoting the development of personalized precise medication for Blang populations in the future.

The study protocol was approved by the Clinical Research Ethics Committee of Xizang Minzu University (Xianyang, China). Written informed consent was obtained from each study participant before a blood sample was given.

Two-hundred randomly selected healthy, unrelated individuals of Blang ethnicity from Yunnan Province were recruited. Whole-blood samples were collected according to the study protocol. Candidate participants were healthy individuals and had exclusive Blang ancestry for 3 previous generations. People suffering from cancer, infectious diseases, drug/alcohol addiction, severe dysfunction of the heart, liver, or kidney or immune disorders were excluded, as were women who were pregnant or lactating. Thus, the recruited individuals were representative of a Blang population.

PharmGKB was used for selection of genetic variants from published polymorphisms associated with VIP variants. Assays for the loci of 55 genetic variants in 27 VIPs were designed. Loci that could not be designed for an assay were excluded.

We extracted the genomic DNA from the peripheral blood of participants using the GoldMag-Mini Whole Blood Genomic DNA Purification Kit (GoldMag. Xian, China) according to manufacturer protocols. The DNA concentration was measured using the NanoDrop 2000C spectrophotometer (Thermo Scientific, Waltham, MA, USA). MassARRAY Assay Design 3.0 (Sequenom, San Diego, CA, USA) was employed to design multiplexed SNP MassEXTEND assays.28 SNP genotyping was done using MassARRAY RS1000 (Sequenom) according to manufacturer protocols. Sequenom Typer 4.0 was employed to manage and analyze the data on SNP genotyping.29 The basic information on the selected 55 loci related to 27 VIPs of the Blang population are listed in Table 1. The polymerase chain reaction (PCR) primers designed for the selected SNPs are shown in Supplemental Table 1. The basic information comprised the gene name, SNP ID, positions, functional consequence, genotype frequencies and MAF in the Blang population. All samples from the Blang population were genotyped with respect to these variants. PharmGKB was also used for the clinical and variant annotations for seven significantly different SNPs in the Blang population compared with 26 other populations.

The genotype data of individuals from 26 populations was obtained from the International HapMap Project Internet website (www.genome.gov/10001688/international-hapmap-project/). The 26 populations were as follows: 1) Chinese Dai in Xishuangbanna, China (CDX); 2) Han Chinese in Beijing, China (CHB); 3) Southern Han Chinese, China (CHS); 4) Japanese in Tokyo, Japan (JPT); 5) Kinh in Ho Chi Minh City, Vietnam (KHV); 6) African Caribbeans in Barbados (ACB); 7) African Ancestry in Southwest USA (ASW); 8) Esan in Nigeria (ESN); 9) Gambian in Western Divisions, The Gambia (GWD); 10) Luhya in Webuye, Kenya (LWK); 11) Mende in Sierra Leone (MSL); 12) Yoruba in Ibadan, Nigeria (YRI); 13) Colombian in Medellin, Colombia (CLM); 14) Mexican Ancestry in Los Angeles, Colombia (MXL); 15) Peruvian in Lima, Peru (PEL); 16) Puerto Rican in Puerto Rico (PUR); 17) Utah residents with Northern and Western European ancestry (CEU); 18) Finnish in Finland (FIN); 19) British in England and Scotland (GBR); 20) Iberian populations in Spain (IBS); 21) Toscani in Italy (TSI); 22) Bengali in Bangladesh (BEB); 23) Gujarati Indian in Houston, Texas (GIH); 24) Indian Telugu in the UK (ITU); 25) Punjabi in Lahore, Pakistan (PJL); 26) Sri Lankan Tamil in the UK (STU).

An exact test was used to test the frequency validity of each VIP variant by assessing the departure from the HardyWeinberg equilibrium. The comparison of genotype frequencies between the Blang population and 26 other populations was conducted using the 2 test. SPSS 17.0 (Armonk, NY, USA) and Excel (Microsoft, Redmond, WA, USA) were used to analyze the distribution of genotypes and MAFs. The Bonferroni correction was applied to p < 0.05 (two-sided).

The VIPs corresponding to 55 loci could be classified into 15 gene superfamilies (Table 1): cytochrome P450 superfamily; dihydropyrimidine dehydrogenase; prostaglandin-endoperoxide synthase; calcium voltage-gated channel; ryanodine receptor; alcohol dehydrogenase; potassium voltage-gated ion channel; N-acetyltransferase; angiotensin I-converting enzyme; potassium inwardly rectifying channel; G-protein coupled receptor family; solute carrier organic anion transporter family; nuclear receptor family; sulfotransferase family; solute carrier family. The sequence function of these 55 loci was classified mainly into eight types: intron variant; upstream transcript variant; downstream transcript variant; coding sequence variant; missense; 3 untranslated region (UTR) variant; non-coding transcript variant; 5 UTR variant.

All selected loci met the HardyWeinberg equilibrium (p>0.05) with a call rate >99.9%. Among the 26 populations studied, GWD, YRI, GIH, ESN, MSL, TSI, PJL, ACB, FIN and IBS were the top-10 populations which showed significant differences compared with the Blang population (>35 loci) (Table 2). Conversely, CHB, JPT, CDX, CHS and KHV populations showed the most similarities with the Blang population (genotype distribution <20 loci). The genotype distribution of 2734 loci in the Blang population showed a significant difference from that of 11 other populations, (LWK, CEU, ITU, STU, PUR, CLM, GBR, ASW, BEB, MXL and PEL). On the one hand, among 26 populations, the GWD population had the greatest number of significantly different loci after Bonferroni correction compared with that in the Blang population, indicating that GWD was the most different population from the Blang population. This significant difference may have resulted from a difference in the genetic background between them. On the other hand, the KHV population showed the least number of different loci after Bonferroni correction. The relatively greater number of similar loci was probably caused by a similar geographic location (East Asian) between them. The distribution of genotypes and allele frequencies of the seven significantly different SNPs are shown in Supplemental Table 2 and Supplemental Figures 17.

Table 2 The Genotype Distribution Difference Between Blang and 26 Other Populations After Bonferronis Multiple Adjustments

Among 55 loci, after Bonferroni correction between the Blang population and 26 other populations, the distribution of genotype frequencies was significantly different in five loci: rs750155 of sulfotransferase family 1A member gene (SULT1A1), rs4291 of ACE, rs1051298, rs1131596 and rs1051296 of SLC19A1. Besides, the genotype distribution of rs1800764 (ACE) and rs1065852 (CYP2D6) was different in all populations except for PEL and LWK, respectively. Conversely, the genotype distribution of rs1801028 of the dopamine receptor D2 gene (DRD2) was significantly different only in the GIH population compared with that in the Blang population. In addition to the eight loci mentioned above, the genotype distribution of the remaining loci in the Blang population also showed a significant difference compared with that in the other 26 populations, but to different degrees.

The MAF distribution of seven significantly different SNPs is shown in Table 3 and Figure 1. The MAFs of rs1065852 (CYP2D6) and rs750155 (SULT1A1) showed the greatest similarities among SAS, EUR, AFR and AMR populations, but also showed the largest fluctuation between the Blang population and SAS, EUR, AFR and AMR populations. The MAFs of rs1800764 (ACE) and rs1131596 (SLC19A1) among the seven subpopulations of AFR showed distinct differences when compared with those of the Blang population. However, the MAFs of rs4291 (ACE), rs1051298 (SLC19A1), and rs1051296 (SLC19A1) showed relatively less fluctuation between the Blang population and the other 26 populations. Besides, the MAFs of rs1800764 (ACE) and rs750155 (SULT1A1) in the Blang population were close to those of the PEL population, even though most of other populations showed distinct differences on it. To better observe the phenotypes of these seven significantly different SNPs in the Blang population, their clinical and variant annotations were retrieved from PharmGKB (Supplemental Table 3 and Supplemental Table 4, respectively).

Table 3 The Minor Allele Frequency Distribution of Seven SNPs Among 27 Populations

Figure 1 The minor allele frequency (MAF) distribution of seven significantly different SNPs between Blang population and other 26 populations. The value of the Y axis represents the MAF.

We genotyped 55 VIP variants from PharmGKB and compared the genotype distribution and MAF of variants in a Blang population with those of 26 other populations. Among 55 loci, the genotype distribution of five SNPs (rs750155 (SULT1A1), rs4291 (ACE), rs1051298 (SLC19A1), rs1051296 (SLC19A1) and rs1131596 (SLC19A1)) was significantly different in the Blang population compared with that in the other 26 populations. Two SNPs (rs1800764 (ACE) and rs1065852 (CYP2D6)) showed a significantly different genotype distribution in the Blang population compared with that in the other 25 populations but, compared with PEL and LWK populations, respectively, a significant difference was not observed. In addition, the MAFs of rs1065852 (CYP2D6) and rs750155 (SULT1A1) showed the greatest fluctuation between the Blang population and SAS, EUR, AFR and AMR populations.

SULT1A1, encoded by SULT1A1, is an isoform of sulfotransferases. The latter are phase-II detoxification enzymes and have a crucial role in the metabolism of several xenobiotics and endogenous compounds (eg, tamoxifen).30,31 High polymorphism of SULT1A1 has been reported among Caucasian, Chinese, AfricanAmerican and Korean populations.32,33 Moyer et al reported that the genetic variation in SULT1A1, including rs750155, which is located in the promoter region (the short arm of chromosome 16) of SULT1A1, could explain (at least in part) the interindividual variability in the onset of menopause and symptoms before initiation of hormone therapy, and may represent a step towards individualizing decisions for hormone therapy.34 Besides, Innocenti et al demonstrated that allele T of rs750155 is not associated with the pharmacokinetic parameters of ABT-751 (novel anticancer agent) in people with neoplasms as compared with allele C.35 In our study, the genotype frequency distribution of rs750155 (SULT1A1) in the Blang population was significantly different from that of the other 26 populations. Also, the MAF distribution of rs750155 (SULT1A1) showed the greatest difference between the Blang population and SAS, EUR, AFR and AMR populations. Besides, the allele T frequency of rs750155 was far higher than that of allele C [T (76.7%) vs C (23.3%)], which indicated that the T allele of rs750155 in members of the Blang population with neoplasms could metabolize ABT-751 more readily.

ACE, encoded by ACE, is an enzyme that can affect the reninangiotensin system and regulation of blood pressure.36,37 ACE inhibitors are first-line treatment for hypertension. They can favorably affect the vascular remodeling of patients with myocardial infarction and heart failure, and reduce its risk and mortality.38 The functional SNPs rs1800764 (ACE) and rs4291 (ACE) are located in the promoter region (chromosome 17) of ACE.39 Linkage disequilibrium has been identified between these two SNPs in ACE in multiple populations.40,41 These two SNPs possess the same pharmacokinetic characteristics and are associated with the risk of breast cancer, end-stage renal disease and Alzheimers disease.4244 The SNPs rs1800764 (ACE) and rs4291 (ACE) show different drug responses in different populations.4547 In the present study, the genotype frequency distribution of SNPs rs1800764 (ACE) and rs4291 (ACE) in the Blang population was different from that of the other populations studied, even though rs1800764 (ACE) was not significantly different in the Blang population compared with that in the PEL population. Besides, the MAF of rs1800764 (ACE) in the AFR population showed a distinct difference compared with that in the Blang population. However, rs4291 (ACE) showed relatively less fluctuation of MAF between the Blang population and the other 26 populations. Although the association between SNPs rs1800764 (ACE) and rs4291 (ACE) and the risk of breast cancer, end-stage renal disease and Alzheimers disease have not been elucidated in the Blang population, our pharmacogenomics study of the SNPs rs1800764 (ACE) and rs4291 (ACE) in the Blang population is important for disease prevention and safe use of drugs.

Reduced folate carrier protein 1 (RFC1), encoded by SLC19A1, is a high-capacity, bidirectional transporter of 5-methyl-tetrahydrofolate and thiamine monophosphate. RFC1 is involved in the uptake, homeostasis, folate deficiency as well as the transportation and sensitivity of antifolate chemotherapeutic agents, such as methotrexate.4850 The SNPs rs1051298 and rs1051296 are intron variants, and rs1131596 is the missense variant of SLC19A1. Scholars have postulated genotype (AA + AG) of rs1051298 to be associated with reduced overall survival upon treatment with pemetrexed in people with non-small-cell lung cancer or mesothelioma compared with that with genotype GG.51 In addition, allele G of rs1051298 has been reported to be associated with longer progression-free survival after treatment with bevacizumab and pemetrexed in patients with lung neoplasms compared with that with allele A of rs1051298.52 Besides, the SNP rs1051296 is associated with higher plasma concentrations of methotrexate in pediatric patients with acute lymphoblastic leukemia.53 Evidence suggests that rs1131596 variants have a positive effect on methotrexate toxicity.54 Research has shown that the SNP rs1131596-G is not associated with alteration of the concentration or side-effects of methotrexate treatment compared with that of the SNP rs1131596-A in Chinese children with precursor cell lymphoblastic leukemia/lymphoma and people with rheumatoid arthritis.55 In our study, the genotype distribution of rs1051298, rs1051296, and rs1131596 in the Blang population was significantly different from that of the other 26 populations. MAF analyses showed that rs1051298 (SLC19A1), and rs1051296 (SLC19A1) showed relatively less fluctuation between the Blang population and the other 26 populations, even though the MAF of rs1131596 (SLC19A1) in the AFR population showed a distinct difference when compared with that of the Blang population. These observations suggested that pharmacogenomic research of variants of rs1051298, rs1051296 and rs1131596 may help to provide guidance for individualized drug use for the Blang population.

CYP2D6, encoded by CYP2D6, is an enzyme of the cytochrome P450 superfamily. It is involved in the metabolism of 25% of drugs in common use in the clinic.56 Debrisoquine and sparteine are CYP2D6 variation-related drugs.57 The genetic variation of CYP2D6 has been reported to be closely related to the metabolism of antipsychotic, antiarrhythmic and antiepileptic drugs.5860 The SNP rs1065852 is an intron variant of CYP2D6. It is related to alteration of the encoded amino acids of CYP2D6 protein, reduction of CYP2D6 activity and to have a poor metabolizer phenotype.61 In addition, the genotype GG of rs1065852 (CYP2D6) is a factor of increased corrected QT (QTc) interval after treatment with iloperidone in people suffering from schizophrenia.61 The distribution of rs1065852 (CYP2D6) has been shown to be significantly different in a Zhuang population as compared with that in 11 other ethnic groups by Liu et al.3 In the present study, the genotype distribution of rs1065852 (CYP2D6) was different in the Blang population when compared with that in all other ethnic groups except for the LWK population, and the MAF distribution showed the largest fluctuation between the Blang population and SAS, EUR, AFR and AMR populations. Hence, the different corrected QTc interval may occur in schizophrenia patients of Blang ethnicity upon treatment with iloperidone. All the above evidence indicated the non-negligible roles of CYP2D6 (rs1065852) in effective drug usage and normal drug metabolism in Blang individuals.

We provided information on the genetic polymorphisms of VIP variants in the Blang population from Yunnan Province. Nevertheless, the sample size was small: a much larger sample size is needed to verify our results.

The genotype distribution of five SNPs (rs750155 (SULT1A1), rs4291 (ACE), rs1051298 (SLC19A1), rs1051296 (SLC19A1) and rs1131596 (SLC19A1)) was significantly different in the Blang population compared with that in the other 26 populations tested. Two SNPs (rs1800764 (ACE) and rs1065852 (CYP2D6)) showed a significantly different genotype distribution in the Blang population as compared with all other populations tested except for PEL and LWK populations, respectively. The MAF of rs1065852 (CYP2D6) and rs750155 (SULT1A1) showed the largest fluctuation between the Blang population and SAS, EUR, AFR and AMR populations. Our data can provide theoretical guidance for safe and efficacious personalized drug use in the Blang population.

VIPs, very important pharmacogenes; BP, Blang population; GD, genotype distribution; CDX, Chinese Dai in Xishuangbanna, China; CHB, Han Chinese in Beijing, China; CHS, Southern Han Chinese, China; JPT, Japanese in Tokyo, Japan; KHV, Kinh in Ho Chi Minh City, Vietnam; BEB, Bengali in Bangladesh; GIH, Gujarati Indian in Houston, Texas; ITU, Indian Telugu in the UK; PJL, Punjabi in Lahore, Pakistan; STU, Sri Lankan Tamil in the UK; CEU, Western European ancestry; FIN, Finnish in Finland; GBR, British in England and Scotland; IBS, Iberian populations in Spain; TSI, Toscani in Italy; ACB, African Caribbeans in Barbados; ASW, African Ancestry in Southwest USA; ESN, Esan in Nigeria; GWD, Gambian in Western Divisions, The Gambia; LWK, Luhya in Webuye, Kenya; MSL, Mende in Sierra Leone; YRI, Yoruba in Ibadan, Nigeria; CLM, Colombian in Medellin, Colombia; MXL, Mexican Ancestry in Los Angeles, Colombia; PEL, Peruvian in Lima, Peru; PUR, Puerto Rican in Puerto Rico; LD, linkage disequilibrium; MTX, methotrexate; SULT1A1, sulfotransferase family 1A member 1; ACE, angiotensin I-converting enzyme; SLC19A1,solute carrier family 19 Member 1; CYP2D6, cytochrome P450 family 2 subfamily D member 6; VKORC, vitamin K epoxide reductase complex; CYP2C9, cytochrome P450 family 2 subfamily C member 9; DRD2, dopamine receptor D2; RFC1, reduced folate carrier protein 1; PCR, polymerase chain reaction; MAF, minor allele frequency; SNP, single-nucleotide polymorphism; PharmGKB, Pharmacogenomics Knowledge Base; SAS, South Asian; EUR, European; AFR, African; AMR, American.

All relevant data are available within the manuscript. Scholars interested in other information from this study should contact the corresponding author.

All experiments were conducted in accordance with the Declaration of Helsinki 1964 and its later amendments. Each participant provided written informed consent before study commencement. The study protocol was approved (2019-12) by the Ethics Committee of Xizang Minzu University.

We express our thanks to all study participants. We also thank the clinicians and hospital staff who worked on sample/data collection in this study.

This work was performed in collaboration between all authors. YLW and LNP carried out the draft and improvement of the manuscript. HYL, ZHZ and SSX designed the tables and figures. DDL and CJH performed the SNP genotyping analysis. TBJ and LW conceived of the study, worked on associated data collection and statistical analysis, participated in the coordination and funded of the study. All authors contributed to data analysis, drafting or revising the article, have agreed on the journal to which the article will be submitted, gave final approval of the version to be published, and agree to be accountable for all aspects of the work. YLW and LNP contributed equally to this article. Yuliang Wang and Linna Peng are co-first authors.

The study was supported by the Talent Development Supporting Project entitled Tibet-Shaanxi Himalaya of Xizang Minzu University (2020 Plateau Scholar), Major Science and Technology Research Projects of Xizang (Tibet) Autonomous Region (2015XZ01G23), and Natural Science Foundation of Tibet Autonomous Region (2015ZR-13-19).

The authors declare that they have no competing interests.

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Very important pharmacogene variants in the Blang population | PGPM - Dove Medical Press

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