Category Archives: Genetic Medicine

Mapping outcomes: Some genetic mutations can lead to a wide variety of traits, including those associated with autism.

People with mutations in distant chromosomal regions often share a range of autism traits, even if they do not meet the diagnostic threshold for autism, according to a new study.

Mutations called copy number variations (CNVs) involve duplications or deletions of large stretches of DNA. Having a CNV in the 16p11.2 or 22q11.2 chromosomal region increases a persons likelihood of being diagnosed with autism, but previous studies have found significant variability in the traits associated with mutations in either location.

The new work shows that deletions or duplications in 16p11.2 or 22q11.2 track with distinct profiles of cognitive abilities and autism traits, and that each type of variant is linked to a different probability of being diagnosed with autism.

These profiles overlap, which suggests that the different CNVs have similar impacts on developmental pathways involved with autism, says lead investigator Marianne van den Bree, professor of psychological medicine at Cardiff University in the United Kingdom. The findings also support the idea that other factors such as the environment or other genes shape a persons autism traits.

Van den Bree and her colleagues across eight institutions pooled data from 547 people with a deletion or duplication in 16p11.2 or 22q11.2. They compared the data with similar information from the Autism Genome Project, looking at 2,027 autistic people who do not have these CNVs.

Pulling these datasets together provided an in-depth look at patterns of outcomes. The four groups of people with CNVs a deletion or duplication in either chromosomal region differ the most in motor function, van den Bree and her colleagues found. And people with 22q11.2 deletions are less likely to have an autism diagnosis than those with any of the other CNVs, but they still have a higher autism prevalence than the general population.

People with a duplication in 22q11.2 or 16p11.2 tend to have more severe autism traits than people with deletions, the researchers found. And people with a 16p11.2 duplication or 22q11.2 deletion have greater cognitive impairment than those with one of the other two variants do.

Despite these differences between groups, people within each group show even greater variability, the team found, which suggests that other factors contribute to a persons traits. The work appeared in January in the American Journal of Psychiatry.

These four CNVs have not previously been compared in this way, but the study feels more confirmatory than it feels like its carving out something new, says Elliott Sherr, professor of neurology at University of California, San Francisco, who was not involved in the new work.

Many people, however, including some clinicians, are unaware that these genetic conditions are often linked to autism, says study investigator Samuel Chawner, research fellow in psychology at Cardiff University. He says he hopes that the profiles he and his colleagues identified will inform how genetic conditions are treated. For instance, 54 percent of people carrying one of the CNVs who do not have an autism diagnosis still have significant autism-like difficulties.

Whats missing from the new work is an examination of what else besides the CNVs contributes to the diversity of traits seen in people with these mutations, such as environment and other genes, says David Ledbetter, chief clinical officer at Dascena, a personalized medicine company. Ledbetter was not involved in the study.

For example, people with a 22q11.2 deletion have an increased likelihood of having schizophrenia, but information from the rest of their genome can help to accurately forecast outcomes, according to a study published in November. This same technique could be used to predict traits in people with the other CNVs, Ledbetter says.

A persons environment including their ability to access medical support and early education may also play a role in this variability, Chawner says. Van den Bree, Chawner and their colleagues at the Genes to Mental Health consortium plan to study how these factors in particular contribute to traits in people with CNVs.

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Copy number variations linked to autism have diverse but overlapping effects - Spectrum

Jan. 29, 2021 12:00 UTC

Program to screen for congenital, monogenic hearing loss in children diagnosed with auditory neuropathy

BOSTON--(BUSINESS WIRE)-- Decibel Therapeutics, a clinical-stage biotechnology company dedicated to discovering and developing transformative treatments to restore and improve hearing and balance, today announced a partnership with Invitae, a leading medical genetics company, to launch AmplifyTM, a no-charge genetic testing program to screen for the genetic cause of congenital hearing loss in children diagnosed with auditory neuropathy.

We are pleased to collaborate with Invitae to introduce AmplifyTM, which is designed to bring patients one step closer to molecular diagnosis and clinical management of auditory neuropathy, a disorder that affects approximately 10 percent of children who are born with hearing loss, said Jonathon Whitton, Au.D., Ph.D., Vice President of Clinical Research at Decibel. This program seeks to provide much-needed answers to patients and families of patients who experience congenital, monogenic hearing loss. We hope that AmplifyTM will provide those patients with a better understanding of their diagnosis and their treatment options.

Auditory neuropathy is a hearing disorder in which the cochlea, the hearing organ located in the inner ear, receives sound normally, yet the transmission of sound to the brain is interrupted. The most common genetic cause of auditory neuropathy is insufficient production of a protein called otoferlin, which facilitates communication between the inner ear sensory cells and the auditory nerve. When this protein is lacking, the ear cannot communicate with the auditory nerve and the brain, resulting in profound hearing loss. Decibels lead investigational gene therapy program, DB-OTO, is designed to treat congenital, monogenic hearing loss caused by a deficiency in the otoferlin gene.

Amplify Program Eligibility

AmplifyTM is available to individuals who meet the following criteria:

AmplifyTM is a no-charge program that offers genetic testing for those who qualify. Although genetic testing can confirm a potential diagnosis, the absence of a genetic alteration does not preclude a diagnosis of genetic hearing loss. For more information about the program, please visit the Amplify program page.

About DB-OTO

DB-OTO is Decibels investigational gene therapy to restore hearing in children with congenital hearing loss due to a deficiency in the otoferlin gene. The program, developed in collaboration with Regeneron Pharmaceuticals, uses a proprietary, cell-selective promoter to precisely control gene expression in cochlear hair cells. DB-OTO is in preclinical studies, and Decibel expects to initiate clinical testing in 2022.

About Invitae

Invitae Corporation (NYSE: NVTA) is a leading medical genetics company whose mission is to bring comprehensive genetic information into mainstream medicine to improve healthcare for billions of people. Invitae's goal is to aggregate the world's genetic tests into a single service with higher quality, faster turnaround time, and lower prices. For more information, visit the company's website.

About Decibel Therapeutics

Decibel Therapeutics is a clinical-stage biotechnology company dedicated to discovering and developing transformative treatments to restore and improve hearing and balance, one of the largest areas of unmet need in medicine. Decibel has built a proprietary platform that integrates single-cell genomics and bioinformatic analyses, precision gene therapy technologies and expertise in inner ear biology. Decibel is leveraging its platform to advance gene therapies designed to selectively replace genes for the treatment of congenital, monogenic hearing loss and to regenerate inner ear hair cells for the treatment of acquired hearing and balance disorders. Decibels pipeline, including its lead investigational gene therapy program, DB-OTO, to treat congenital, monogenic hearing loss, is designed to deliver on our vision of a world in which the privileges of hearing and balance are available to all. For more information about Decibel Therapeutics, please visit http://www.decibeltx.com or follow @DecibelTx.

View source version on businesswire.com: https://www.businesswire.com/news/home/20210129005089/en/

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Decibel Therapeutics and Invitae Announce Launch of Amplify Genetic Testing Program - BioSpace

Today marked some wheeling and dealing in the life sciences industry as several companies licensed products or invested in other companies. Heres a look.

Eli Lillyand Asahi Kasei Pharma Eli Lilly and Company inked a license agreement with Tokyos Asahi Kasei Pharma Corporation. In it, Lilly picks up exclusive rights to AK1780 from Asahi. The drug is an oral P2X7 receptor antagonist that recently finished a Phase I dosing study. P2X7 receptors are associated with neuroinflammation that drives chronic pain conditions.

Under the terms of the deal, Lilly will handle future global development and regulatory activities. Lilly is paying Asahi Kasei Pharma $20 million up front and the Japanese company is eligible for up to $210 million in development and regulatory milestones. Asahi Kasei will retain the rights to promote the drug in Japan and China, including Hong Kong and Macau. If it makes it to market, Asahi Kesei will also be eligible for up to $180 million in sales milestones and tiered royalties from the mid-single to low-double digits.

Lilly is committed to developing novel medicines that may provide relief for patients suffering with various pain conditions, said Mark Mintun, vice president of pain and neurodegeneration research at Lilly. We are pleased to license this molecule from Asahi Kasei Pharma, and look forward to developing it further as a potential treatment for neuroinflammatory pain conditions.

Artiva Biotherapeutics and Merck San Diego-based Artiva Biotherapeutics announced an exclusive global collaboration and license agreement with Merck to develop novel chimeric antigen receptor (CAR)-NK cell therapies against solid tumor-associated antigens. They will leverage Artivas off-the-shelf allogeneic NK cell manufacturing platform and its proprietary CAR-NK technology. At first, the collaboration will include two CAR-NK programs with an option for a third. None of them are currently part of Artivas current or planned pipeline. Artiva will develop the programs through the first GMP manufacturing campaign and to preparation for the Investigational New Drug (IND) application, where Merck will take over clinical and commercial development.

Merck is paying Artiva $30 million upfront for the first two programs and another $15 million if Merck chooses to go ahead with the third. Artiva will be up for development and commercial milestones up to $612 million per program and royalties on global sales. Merck also is ponying up research funding for each program.

Our NK platform has been developed to be truly off-the-shelf and we believe it will be further validated by this exclusive collaboration with Merck, as we work together to bring cell therapies to all patients who may benefit, said Peter Flynn, chief operating officer of Artiva.

NeuBase Therapeutics and Vera Therapeutics Pittsburgh-based NeuBase Therapeutics announced a binding agreement to acquire infrastructure, programs and intellectual property for several peptide-nucleic acid (PNA) scaffolds from Vera Therapeutics, formerly called TruCode Gene Repair. Vera is based in South San Francisco. On January 19, Vera announced its launch with a $80 million Series C financing led by Abingworth LLP and joined by Sofinnova Investments, Longitude Capital, Fidelity Management & Research Company, Surveyor Capital, Octagon Capital, Kliner Perkins, GV and Alexandria Venture Investments. Veras lead clinical candidate is atacicept, a novel B cell and plasma cell inhibitor being developed for patients with IgA nephropathy (IgAN).

The technology acquired by NeuBase has shown the ability to resolve disease in genetic models of several disease indications. NeuBase is focused on genetic medicine.

With this acquisition, we enhance our PATrOL platform, furthering our unique ability to directly engage and correct malfunctioning genes with exquisite precision to address the root causes of a wide variety of human diseases, said Dietrich A. Stephan, chief executive officer of NeuBase. These assets extend and refine our PATrOL platforms capabilities and accelerates, through our Company, to bring the rapidly growing genetic medicines industry toward a single high-impact focal point. We are committed to advancing our pipeline and candidates to the clinic and to exploiting the full potential of PNA technology to continue creating value for our shareholders and importantly, for patients.

Bio-Techne Corporation and Changzhou Eminence Biotechnology Co Minneapolis-based Bio-Techne Corporation announced an initial minority strategic equity investment in Chinas Changzhou Eminence Biotechnology Co. Eminence plans to use the financing to expand its manufacturing capacity and increase the service capabilities of its China-based GMP media production facility. Eminence, based in Changzhou City, Jiangsu, China, launched in 2016 and initially focused on manufacturing and selling best-in-class media to life science companies, including Chinese Hamster Ovary (CHO) cells and other serum-free media products and services. The company is currently finishing and scaling its GMP production facility, which it plans to complete by the end of this year.

With our protein analysis instruments and expanding GMP protein capabilities, Bio-Techne continues to expand its offering of products and tools critical for bioprocessing, said Chuck Kumeth, president and chief executive officer of Bio-Techne. Investing in Eminence not only gives Bio-Techne a foothold in providing additional products and services to support the critical needs of the rapidly growing Chinese biopharmaceutical industry, but also fits extremely well with our existing high-growth product portfolio in China. We look forward to working with the Eminence team.

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4 New Life Sciences Licensing Deals and Investments to Watch - BioSpace

BETHESDA, Md., Jan. 27, 2021 /PRNewswire/ --The ACMG Annual Clinical Genetics Meeting will be a fully virtual meeting in 2021 and continues to provide groundbreaking research and the latest advances in medical genetics, genomics and personalized medicine. To be held April 1316, experience four days of professional growth, education, networking and collaboration with colleagues from around the world and discover what's shaping the future of genetics and genomics, including several sessions on COVID-19. The 2021 ACMG Meeting Virtual Experience is designed to offer a variety of engaging and interactive educational formats and types of sessionsfrom Scientific Sessions and Workshops to TED-Style Talks, Case-based Sessions, Platform Presentations and Short Courses. The 2021 ACMG Meeting Virtual Experience has something for everyone on the genetics healthcare team and will be available to participate in from the convenience of your home or office.

Interview those at the forefront in medical genetics and genomics, connect with new sources, and get story ideas on the clinical practice of genetics and genomics in healthcare today and for the future. Learn how genetics and genomics research is being integrated and applied into medical practice. Topics include COVID-19, gene editing, cancer genetics, molecular genomics, exome sequencing, pre- and perinatal genetics, diversity/equity and inclusion, biochemical/metabolic genetics, genetic counseling, health services and implementation, legal and ethical issues, therapeutics and more.

Credentialed media representatives on assignment are invited to cover the ACMG Annual Meeting A Virtual Experience on a complimentary basis. Contact Kathy Moran, MBA at [emailprotected]for the Press Registration Invitation Code, which will be needed to register at http://www.acmgmeeting.net.

Abstracts of presentations will be available online in February.

A few 2021 ACMG Annual Meeting highlights include:

Program Highlights:

Two Short Courses Available Starting on Tuesday, April 13:

Cutting-Edge Scientific Concurrent Sessions:

Social Media for the 2021 ACMG Meeting Virtual Experience: As the ACMG Annual Meeting approaches, journalists can stay up to date on new sessions and information by following the ACMG social media pages on Facebook,Twitterand Instagramand by usingthe hashtag #ACMGMtg21 for meeting-related tweets and posts.

The ACMG Annual Meeting website has extensive information at http://www.acmgmeeting.net and will be updated as new information becomes available.

About the American College of Medical Genetics and Genomics (ACMG) and the ACMG Foundation for Genetic and Genomic Medicine (ACMGF)

Founded in 1991, the American College of Medical Genetics and Genomics (ACMG) is the only nationally recognized medical society dedicated to improving health through the clinical practice of medical genetics and genomics and the only medical specialty society in the US that represents the full spectrum of medical genetics disciplines in a single organization. The ACMG is the largest membership organization specifically for medical geneticists, providing education, resources and a voice for more than 2,400 clinical and laboratory geneticists, genetic counselors and other healthcare professionals, nearly 80% of whom are board certified in the medical genetics specialties. ACMG's mission is to improve health through the clinical and laboratory practice of medical genetics as well as through advocacy, education and clinical research, and to guide the safe and effective integration of genetics and genomics into all of medicine and healthcare, resulting in improved personal and public health. Four overarching strategies guide ACMG's work: 1) to reinforce and expand ACMG's position as the leader and prominent authority in the field of medical genetics and genomics, including clinical research, while educating the medical community on the significant role that genetics and genomics will continue to play in understanding, preventing, treating and curing disease; 2) to secure and expand the professional workforce for medical genetics and genomics; 3) to advocate for the specialty; and 4) to provide best-in-class education to members and nonmembers. Genetics in Medicine, published monthly, is the official ACMG journal. ACMG's website (www.acmg.net) offers resources including policy statements, practice guidelines, educational programs and a 'Find a Genetic Service' tool. The educational and public health programs of the ACMG are dependent upon charitable gifts from corporations, foundations and individuals through the ACMG Foundation for Genetic and Genomic Medicine.

Kathy Moran, MBA[emailprotected]

SOURCE American College of Medical Genetics and Genomics

http://www.acmg.net

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Press Registration Is Now Open for the 2021 ACMG Annual Clinical Genetics Meeting - A Virtual Experience - PRNewswire

Introduction

Calcium channel blockers (CCBs) are widely used in the treatment of hypertension. In addition to their antihypertensive effects, CCBs may also lead to many adverse reactions, including peripheral edema, dizziness, flushing, fatigue, headache, palpitations, and gingival enlargement.14 Peripheral edema, particularly of lower limbs, is the most common side effect of CCBs. CCBs-induced peripheral edema is more common in women and is related to age, upright posture and duration of CCBs therapy.2,5 Although it has been known for decades that CCBs could cause peripheral edema, there are still very few genetic markers that could be used in clinical treatment.

Amlodipine is a first-line antihypertensive drug and a long-acting 1,4-dihydropyridine calcium channel blocker.6 It became the fifth most prescribed medication in the United States in 2018.7 However, therapy trials report that the incidence of amlodipine-induced peripheral edema is about 19%, which also probably serves as the main reason behind the limited use of this drug.8,9 To our knowledge, factors that increase the serum concentration of drugs may also increase the risk of side effect. Accordingly, genetic factors affecting the metabolism of amlodipine will consequently influence its clearance, thus possibly resulting in peripheral edema. In recent years, numerous studies have focused on identifying genetic factors determining the responses to amlodipine therapy, including aspects of efficacy and safety.1012 Nevertheless, the genetic predisposition to amlodipine-induced peripheral edema remains unclear. However, some studies shine light on CYP genes, which are involved in the metabolism of amlodipine.13,14

CYP3A is a subfamily of cytochrome P450 and is involved in the metabolism of many compounds.10,1517 CYP3A4 and CYP3A5 are the two major enzymes of CYP3A family and play important roles in the dehydrogenation of amlodipine.18 However, it has been reported that CYP3A4, rather than CYP3A5, plays a more important role in amlodipine clearance in vivo.16 However, according to our observations, almost all SNPs of CYP3A4 are very rare in Chinese Han or East Asian.1921 A recent study evaluated the influence of CYP3A polymorphisms on the pharmacokinetic (PK) parameters of 10 CYP3A substrates including amlodipine, and it turned out CYP3A4 polymorphisms did not show a pronounced influence on PK of amlodipine.22 So, as far as we know, CYP3A4 does not suffice as an explanation towards the incidence of amlodipine-induced adverse responses. Additionally, the contribution of CYP3A5 in amlodipine metabolism is still controversial. CYP3A5 expression varies among individuals due to gene polymorphisms that result in non-productive mRNA splicing and lower or undetectable expression of the protein.14,23,24 Pharmacogenomics studies have found that CYP3A5 gene polymorphisms have significant impact on drug metabolism, efficacy, and toxicity.25,26 Recent studies have reported a possible relationship between CYP3A5 and amlodipine. CYP3A5*3/*3 genotypes might be associated with blood pressure response to amlodipine,27 and CYP3A5*3 may affect the disposition of amlodipine.13 In Chinese hypertensive patients who underwent renal transplantation, researchers have demonstrated that CYP3A5*3 polymorphism affects the antihypertensive efficacy of amlodipine. In such patients with CYP3A5*3/*3, the reduction in diastolic blood pressure (DBP) was significantly higher than those with other genotypes.28 Additionally, compared with CYP3A5*1/*1, CYP3A5*1/*3 patients exhibit a lower metabolic ratio of amlodipine in vivo and hypertensive patients with CYP3A5*1/*3 genotypes show a higher decrease in blood pressure.14 These findings suggest that CYP3A5 genetic variants are really involved in amlodipine response, having an impact on treatment effectivity of amlodipine.

Although studies have identified that CYP3A5 polymorphisms do play a role in blood pressure control and treatment responses of amlodipine, the effect of a particular genotype in amlodipine-induced peripheral edema remains unclear. Here, we aim to test whether any genetic variants associate with amlodipine-induced peripheral edema. For this, we used the targeted region sequencing method to genotype the SNPs in all known haplotypes of CYP3A5, and evaluated their effect on amlodipine-induced peripheral edema in Chinese Han hypertensive patients.

We recruited a total of 240 patients with essential hypertension who have ever been treated with amlodipine or L-amlodipine for more than 4 weeks. The participants were outpatients from Beijing Chaoyang Hospital of Capital Medical University and the Second Hospital of Jilin University. The demographic characteristics and baseline data were collected, including gender, age, body mass index (BMI), smoking and drinking status, blood pressure, heart rate and use of medications. Participants were also questioned about peripheral edema symptoms (leg or ankle edema). Two trained physicians evaluated the adverse drug reactions caused by the amlodipine or L-amlodipine based on the WHO-UMC scale.29 We classified the participant as a peripheral edema case if WHO-UMC causality categories were certain, probable, or possible. The others were grouped as controls.

The DNA Sampling Swabs (Taitong Gene Testing Equipments Co., Ltd., Suzhou, China) were used for collecting oral buccal mucosa cells. Genomic DNA was isolated from the swabs, using Hi-Swab DNA kit (TIANGEN, Beijing, China) according to the manufacturers instructions. Quantification of the DNA concentration was performed using the manufacturers protocol with the Qubit dsDNA HS Assay Kit (Yeasen, Shanghai, China). Methods for targeted region capture and NGS have been reported previously.30 Illumina HiSeq X was used to sequence the captured DNA with paired-end reads of 150 bp length. Table S1 lists the targeted regions of sequencing and the 24 SNPs of CYP3A5.

High-quality sequencing reads were obtained from the raw data by removing reads that contained adapters, were with unknown bases, or had a low-quality using the Trimmomatic (v0.36)31 program. The high-quality reads were aligned to human reference genome hg19 using the Burrows-Wheeler Aligner (BWA, v0.7.15)32 using the default parameters. The Genome Analysis ToolKit (GATK, v3.8)33 was used for indels realignment, quality score recalibration, variant calling, and genotyping (using Haplotype Caller).

Demographic and clinical characteristics of different groups were compared by t-test or Chi-square (2) test according to the data category. The associations between gene polymorphisms and the risk of peripheral edema were assessed by codominant model, dominant model, recessive model and allele model by calculating the odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression with or without adjustment by gender and alcohol status. Stratification was done by gender. Analyses above were carried out on R-4.03. PLINK 1.934 was used to calculate the minor allele frequency and assess HardyWeinberg equilibrium (HWE) for each SNP. Additionally, linkage disequilibrium (LD) block and haplotype were assessed by Haploview35 software. The D and r2 values for all pairs of SNPs were calculated. P value<0.05 was considered as the significant level.

Two hundred and forty enrolled patients were separated into 64 cases and 176 controls. The general characteristics of the study population are summarized in Table 1. In agreement with previous reports, a higher incidence of CCB-induced peripheral edema was observed in women. A significant difference was found in the sex ratio between cases and controls (P=0.00048). In addition, the frequency of drinkers was 29.69% in the case group and 46.02% in the control group (P=0.034). There was no significant difference between the two groups regarding other characteristics.

Table 1 Characteristics of the Study Population

All the observed SNPs and the minor allele frequencies (MAF) in two groups are listed in Table 2. Except rs15524, rs4646453 and rs776746, the other SNPs were rare or not detected in the studied population. Therefore, we focused on these three SNPs (MAF>0.05) for further studies. Distributions of genotype frequencies of the SNPs did not show any deviation in HardyWeinberg equilibrium (P>0.05).

Table 2 Observed CYP3A5 Variations and Frequencies

The genotype and allele allocations of the test polymorphisms differed considerably between cases and controls (Table 3). In more detail, the frequencies of alleles rs15524 G, rs4646453 A, and rs776746 T were significantly lower in cases than those in the control group (G vs A: OR=0.53, P=0.011; A vs C: OR=0.54, P=0.019; T vs C: OR=0.58, P=0.03; respectively). Furthermore, there was a statistically significant difference in genotype of the rs15524 and rs4646453 between the two groups in dominant model with or without adjustment by gender and alcohol status (GG+AA vs AA: OR=0.5, P=0.021; AA+AC vs CC: OR=0.54, P=0.04). As for rs776746, the presence of TT+CT genotype demonstrated a significantly lower risk after gender and alcohol status adjustment (TT+CT vs CC: OR=0.57, adjusted P=0.044).

Table 3 Genotype Frequencies of Study SNPs in Case and Control Groups

Stratified analyses were performed to access the differential effect of gender on the association between amlodipine-induced edema and the polymorphisms. No significant differences were identified, but the relevant genotypes still showed lower risk in all subgroups. The details are presented in Table 4.

Table 4 Stratified Analyses Between SNPs and Risk of Amlodipine-Induced Peripheral Edema

We employed Haploview program to assess the Linkage disequilibrium (LD) block and haplotype of the three SNPs of CYP3A5. The LD analysis indicated that these SNPs were in strong LD with each other (Figure 1, rs15524 and rs4646453 D=0.965, r2=0.821; rs15524 and rs776746 D=0.979, r2=0.919; rs776746 and rs4646453 D=0.989, r2=0.898). Frequencies of four haplotypes were found to be more than 1% in the haplotype analysis (Table 5). The most represented haplotype in the whole cohort of controls and cases was ACC, followed by GAT, GCC and GCT. Two haplotypes (ACC and GAT) were significantly associated with the risk of amlodipine-induced peripheral edema. The frequency of the ACC haplotype was higher in the cases than controls (79.7% vs 67.9%, P=0.012), whereas the frequency of the GAT haplotype was lower in the cases (17.2% vs 28.1%, P=0.015).

Figure 1 Linkage disequilibrium coefficients (|D|) and LD block among the three polymorphisms of CYP3A5.

Table 5 Haplotype Frequencies of CYP3A5 Gene and the Association with the Amlodipine-Induced Peripheral Edema Risk

Studies have demonstrated that genetic polymorphisms may influence the gene function, thus causing alterations in the pharmacokinetics (PK) and pharmacodynamics (PD) of the gene-associated drugs. Moreover, genetic variants have been confirmed for their association with appearance of adverse reactions to drugs, such as ACE inhibitors-induced cough36 and rosuvastatin-induced myotoxicity.37 To our knowledge, this is the first study to investigate the relationships of CYP3A5 polymorphisms and amlodipine-induced peripheral edema by using a casecontrol retrospective study in the Chinese population. Our study reveals that amlodipine-induced peripheral edema may associate with genetic polymorphisms in CYP3A5 gene. We find that the distribution of allele and genotype frequencies of the three SNPs are significantly different between cases and controls. Specifically, the alleles rs15524 G, rs4646453 A, and rs776746 T reduce the risk of amlodipine-induced peripheral edema. On the other hand, A, C, and C increase the risk and haplotype analysis also confirms this. These findings support the hypothesis that genetic variation in CYP3A5 is involved in the development of amlodipine-induced peripheral edema.

CYP3A5 is highly polymorphic with significant inter-individual variation in the enzyme activity contributing to the absorption, metabolism and tissue distribution of drugs.24,38 Genetic polymorphisms of CYP3A5 may potentially alter its proteins expression and function, and subsequently influence the clearance of any drugs metabolized by CYP3A5.38 The most studied SNP related to CYP3A5 functional variation is rs776746 (also known as CYP3A5*3 or CYP3A5*3C). Homozygous carriers of this SNP (*3/*3 or CC) lack functional CYP3A5 protein because of the frameshift mutation and truncation of the translated protein.39 Previous studies have confirmed that CYP3A5*3 is associated with drug metabolism, and CYP3A5*3/*3 carriers have decreased metabolism of nifedipine40 and tacrolimus,41 compared to CYP3A5*1/*1 and CYP3A5*1/*3 carriers. Patients with CYP3A5*3/*3 who are treated with tacrolimus may have an increased risk of nephrotoxicity as compared to patients without it.25,26 These findings suggest that the CYP3A5 *3/*3 carriers have low activity of CYP3A5 enzyme and decreased metabolism for certain drugs dependent on it, resulting in the appearance of an adverse reaction to the drug. Conforming to these findings, our study also indicates that there is an association between CYP3A5*3 and the occurrence of amlodipine-induced peripheral edema and that *3/*3 (CC) carriers have a higher risk of peripheral edema.

CYP3A5*1D (rs15524) is another frequently studied SNP in CYP3A5, which is in the 3-untranslated region (UTR). CYP3A5*1D is differentially distributed among populations ranging from 77.5% in Americans to 71.4% in East Asians, 40.6% in Africans, and even rarer in Europeans (less than 8%) (GnomAD).21 SNPs in UTRs may influence the stability of mRNA, thus affecting the expression and activity of the enzyme.42,43 According to a study identifying the potential SNPs related to miRNA, rs15524 may influence the hsa-miR-500a-5p that targets CYP3A5, affecting its expression.44 In addition, studies have found that CYP3A5*1D influences the pharmacokinetics of many drugs, including tacrolimus45 and carbamazepine.46 Therefore, rs15524 may act as a genetic marker and should be considered while studying or prescribing drugs metabolized by CYP3A5. Here, we find that the frequencies of rs15524 G allele and GA+GG genotypes in cases are lower than controls, which indicates that this SNP is associated with reduced risk of incidence of amlodipine-induced peripheral edema. In other words, CYP3A5*1D/*1D carriers may have an increased risk than others.

As for CYP3A5*1E (rs4646453), it is associated with a decreasing risk of amlodipine-induced peripheral edema. However, there is litter information about the function of the rs4646453. To some extent, this is possible because the SNP locates in the intron region. Studies have revealed that CYP3A5 rs4646453 is in LD with rs776746,47 and there is a strong LD between rs15524 and rs776746.39,46 Our findings are consistent with these studies and further promote that the presence of LDs with rs776746 may partly explain the role of rs15524 and rs4646453 in amlodipine-induced peripheral edema.

Given all these findings, there are some limitations in our present study that we would like to acknowledge. First, the population in our study is Chinese Han, and it is known that the frequency of mutations differs among ethnic groups. Hence, our results may apply well to Chinese population but are probably not suitable for populations of other ethnic groups. Second, we have performed a retrospective study and not a prospective one. The study is also limited by the smaller number of samples. The third limitation is not involving other genes contributing to amlodipine metabolism, such as CYP3A4. As we mentioned before, polymorphisms of CYP3A4 are rare in Chinese, and the evidence so far that CYP3A4 polymorphisms influence amlodipine metabolism is scarce. So, we took no account of them currently. But it would be better for future studies to include these related genes to better explain the connection between genetic factors and amlodipine-induced peripheral edema. Hence, more casecontrol studies with large number of polyethnic samples and involvement of diversified factors are necessary.

None the less, our study does investigate the novel relationship between the genetic variants and amlodipine-induced peripheral edema. In conclusion, we provide evidence that CYP3A5 polymorphisms are involved in the occurrence of amlodipine-induced peripheral edema, and the three genetic variants of CYP3A5 have the potential to serve as novel biomarkers for amlodipine-induced adverse reactions. Our findings thus provide new insights into amlodipine-induced peripheral edema and are of importance in developing and prescribing personalized and precise medicine for hypertension.

The raw data are available on reasonable request to the correspondence author Songnian Hu.

All the participants have signed the written informed consent, and approval was obtained from the Research Ethics Board of Beijing Chaoyang Hospital of Capital Medical University and the Research Ethics Board of the Second Hospital of Jilin University. This study has been conducted in accordance with the World Medical Association Declaration of Helsinki.

We thank all the participants included in this study.

All authors declare that they have no conflicts of interest for this work.

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2. Sica DA. Pharmacotherapy review: calcium channel blockers. J Clin Hypertens (Greenwich). 2006;8(1):5356. doi:10.1111/j.1524-6175.2005.04140.x

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[Full text] Association of CYP3A5 Gene Polymorphisms and Amlodipine-Induced Periph | PGPM - Dove Medical Press

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As researchers around the world scramble to understand the dangers of several newly discovered variants of the deadly coronavirus, the US remains woefully behind in its ability to track the mutations, scientists say.

The federal government has had its head in the sand, failing to develop a coordinated surveillance system for tracking the genetic footprints of the virus, according to academic researchers, scientific panelists and private entrepreneurs, who say they have been urging US officials for months to make better use of the hi-tech resources already sitting in labs around the country.

Genomic sequencing looks at the entire genetic code or genome of viruses obtained from samples from infected patients. The technique allows researchers to watch for dangerous mutations and to track movements of specific variants, like detectives following footprints.

Most genetic variations are inconsequential. But to discover those with functional differences, like more transmissible variants first identified in the UK (B117) and in South Africa (B1351), the research is essential. Yet by Friday the US had only plotted and shared the genetic sequences of 0.3% of its coronavirus cases, ranking 30th in the world, behind countries including Portugal, Latvia and Sierra Leone, according to a tracker developed by scientists at the Broad Institute of MIT and Harvard. Some US states have had virtually no surveillance at all.

Were used to being No 1 and this technology is all over the country, said Jeremy Kamil, a virologist at the Louisiana State University Health Sciences Center Shreveport, who heads a coronavirus sequencing effort there. Instead, he said, when alarms were raised about the new mutation spreading rapidly in the UK, we were in the dark. With so few samples, the detective work becomes more like seeing a mirage in the desert.

As viruses replicate, small copying errors lead to changes in their genetic material. These mutations are one of the central features of how viruses function, mutating as they infect more and more hosts. Following the different changes can be like tracking fingerprints or footprints for homicide detectives. By watching for a sudden increase in a certain version of the virus, researchers can raise an alarm if one particular variant appears to be more transmissible than the dominant strain, as happened in December with the variant discovered in the United Kingdom, known as B117.

The UK has been a world leader in the field of genomic sequencing, budgeting 20m ($27m) at the beginning of the pandemic to fund and coordinate research by a large network of laboratories around the country. So far, it has examined 186,000 genetic samples of its coronavirus cases more than twice as many as the US, despite a caseload thats one-seventh the size of that of the US, according to data from the worldwide open repository of genetic information, known as Gisaid.

The US offered its scientists no such budget and coordination.

In December, as scientists around the world scrambled to understand the potential dangers of the new variant rapidly spreading around London, the US had no way of knowing whether it was also thriving there, as many states had done no genetic sampling at all.

The US also severely lagged behind when it came to sharing the few sequencing results it had with the global network of scientists tracking the pandemic through a global repository of genomic data. It has taken the US a median of 72 days to process and share each genetic sequence, compared with 23 days for the UK researchers, according to figures compiled by the Broad Institute with data from Gisaid.

Its just been a head-in-the-sand approach, said Dr Diane Griffin, a virologist at the Johns Hopkins University School of Public Health. It was really a failure of leadership.

Griffin chaired a national panel of scientists that warned the federal government in a National Academies of Science report last summer that the US genomic research response to the virus was patchy, typically passive, and reactive due to poor funding, coordination and capacity.

Yet, she said, the government never did anything.

The Trump administrations attitude towards testing and tracking mutations of the coronavirus seemed to be reflected by Donald Trumps remarks in May that if we didnt do any testing, we would have very few cases.

The Centers for Disease Control and Prevention finally began to ramp up genetic surveillance of the virus in mid-December, after alarms were raised about the UK variant, and contracted with several private testing companies to check at least some genetic samples from every state.

Contributing to the chaos was the USs lack of the type of centralized healthcare model that allowed the UK to streamline its genetic research. Weve yoked testing to insurance reimbursement, said Dr Alex Greninger, the assistant director of the clinical virology laboratories at the University of Washingtons medical center. But, while it is crucial to public health, genetic sequencing does not help the individual patient, making it hard to figure out who should pay for it.

Dr Phil Febbo, the chief medical officer of Illumina, an American company that makes some of the machines used to do the sequencing, said he had been urging US officials to develop a coordinated approach to tracking the virus since the beginning of the pandemic only to be politely ignored.

His company finally started getting calls for help from federal officials around 18 December and now is working to scale up a laboratory that can sequence 3,000 samples a week, under a federal contract.

I try not to take it personally, but I spent six to eight months being less effective trying to get people motivated to do genetic surveillance than a small virus variant [in the UK] was in a few weeks, he said.

The CDC did not respond to a request for comment.

Researchers at many of the academic research centers that have worked on their own to keep track of the genetic changes in the virus for months said they were still looking for federal leadership and funding, and hoping that the new administration would offer more of it.

We dont need the Manhattan Project, said Dr David Relman, a microbiology professor at Stanford Universitys medical school, who also sat on the national panel. Even if we cant do a perfect job, lets just do an OK job so we have some information. We cant keep playing catch-up.

The Biden administrations American Rescue Plan for addressing the pandemic says the discoveries of the UK and South African variants highlight a key vulnerability in our nations Covid response.

Scientists believe the new variant discovered in the UK spreads about 50% more easily than the coronavirus variants currently dominant in the US. Researchers have already discovered at least one vaccine under development is less effective against the variant first discovered in South Africa (B1351.) That variant was found this week in two samples from South Carolina, but it remains unclear how prevalent it might be in the US.

We simply do not have the kind of robust surveillance capabilities that we need to track outbreaks and mutations, says the Biden administrations rescue plan, which promises to dramatically increase funding. Tracking the way the virus is changing and moving through the population is essential to understanding outbreaks, generating treatments and vaccines, and controlling the pandemic.

Researchers at the University of Washingtons school of medicine said their understaffed labs were now squeezing in the time to do statewide surveillance on top of their other duties. They obtain their samples from leftover genetic materials from the other coronavirus testing work they do.

A lot of us are stretched really thin, said Pavitra Roychoudhury, an acting instructor of laboratory medicine at the university, who runs a virology lab that was involved in some of the earliest genetic sleuthing on the virus. She said she wakes up at 4am and often works until 11 at night, hoping she can somehow make a difference in fighting the pandemic. I feel weve been running a marathon at a sprint pace, she said.

Her supervisor, Dr Alex Greninger, said getting funding to do the surveillance still comes down to which billionaire do you know?

Philanthropies run by wealthy tech entrepreneurs have indeed provided much of the money to keep an eye out for dangerous changes in the virus.

California has organized a network of public health agencies, university researchers and laboratories, funded in part by the Chan Zuckerberg Biohub to do surveillance of coronavirus genomes spreading in the state. The Biohub, a non-profit research center, founded by the Facebook CEO, Mark Zuckerberg, and his wife, the pediatrician Priscilla Chan, offered no cost genetic sequencing for all California counties. But it had to negotiate a thicket of regulatory hurdles before it could get that started, according to Patrick Ayscue, an epidemiologist who is the senior biosecurity fellow for the center.

The center and the academic laboratories associated with the project had the equipment and expertise to do the genetic testing, but they didnt have the samples of the virus from the infected patients. County health departments had the samples, but werent allowed to share them under privacy rules. The Biohub has had to negotiate more than 20 separate contracts with individual counties to get the work going with anonymized testing of the virus samples, Ayscue said. But many of Californias other counties still have no way of tracking the genetic variants of coronavirus flowing through their communities.

Ayscue said he hopes the Biden administration will coordinate a centralized federal system for genetic surveillance to make sure a balanced sample of cases from around the country are examined on a regular basis.

A lot of things are going to get done now that werent in place previously, said Ayscue. But many of those things are so obvious that they could have been put in place nine or 10 months ago and things would be very different right now.

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'We were in the dark': why the US is far behind in tracking Covid-19 variants - The Guardian