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News Article | April 24, 2017
Site: www.eurekalert.org

The largest genomic analysis of puberty timing in men and women conducted to date has identified 389 genetic signals associated with puberty timing, four times the number that were previously known. The study, published today in Nature Genetics and led by researchers from the Medical Research Council (MRC) Epidemiology Unit at the University of Cambridge and other scientists in the international ReproGen consortium, also found new genetic evidence linking earlier timing of puberty to higher risk of several cancers known to be sensitive to sex-hormones in later life, including breast, ovary and endometrial cancers in women, and prostate cancer in men. These influences remained after controlling for body weight, which is important as body weight itself influences both the timing of puberty and the risk of some cancers. Dr John Perry, Senior Investigator Scientist from the MRC Epidemiology Unit and senior author on the paper, says: "Previous studies suggested that the timing of puberty in childhood was associated with risks of disease decades later, but until now it was unclear if those were circumstantial observations, for example secondary to other factors such as body weight. "Our current study identifies direct causal links between earlier puberty timing itself and increased cancer risk. This link could possibly be explained by higher levels of sex hormones throughout life, but we need to do more work to understand the exact mechanisms involved. We aim to understand these disease links and thereby contribute to the prevention of diseases in later life." The timing of puberty varies widely between individuals but tends to run closely within families. Earlier puberty timing may have advantages for some adolescents, for example for boys who engage actively in sports, but it appears to have largely negative effects on later health, such as higher risks of heart disease and some cancers. By performing detailed assessments of genetic variants across the whole genome in 329,345 women, comprising data from 40 studies in the ReproGen consortium, UK Biobank, and consented 23andMe customers, this study identified 389 independent genetic signals for age at puberty in women. This observation was then confirmed in a further 39,543 women from the deCODE study, Iceland. Many of these genetic associations were also found to influence age at voice breaking, a comparable measure of puberty timing in men. These findings shed light on the mechanisms that regulate puberty timing. Dr Perry adds: "These newly identified genetic factors explain one quarter of the estimated heritability of puberty timing. Our findings highlight the remarkable biological complexity of puberty timing, with likely thousands of genetic factors, in combination with numerous environmental triggers, acting together to control the timing of this key transition from childhood to adult life." Dr Ken Ong, also from the MRC Epidemiology Unit and joint senior author on the paper, says: "One of the more remarkable findings concerns the role of certain types of genes called imprinted genes, which are only active in your body when inherited specifically from one parent but not the other. We identified rare variants in two genes, which both lower the age of puberty when inherited from your father, but have no effect when inherited from your mother. This is intriguing as it suggests that mothers and fathers might benefit differently from puberty occurring at earlier or later ages in their children." Felix R. Day, Deborah J. Thompson, Hannes Helgason et al. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk. Nature Genetics; 24 April 2017; DOI: 10.1038/ng.3841


News Article | May 26, 2017
Site: www.sciencedaily.com

Diesel pollution is linked with heart damage, according to research presented today at EuroCMR 2017.1 "There is strong evidence that particulate matter (PM) emitted mainly from diesel road vehicles is associated with increased risk of heart attack, heart failure, and death," said lead author Dr Nay Aung, a cardiologist and Wellcome Trust research fellow, William Harvey Research Institute, Queen Mary University of London, UK. "This appears to be driven by an inflammatory response -- inhalation of fine particulate matter (PM2.5) causes localised inflammation of the lungs followed by a more systemic inflammation affecting the whole body. " The current study examined whether PM2.5 may damage the heart directly. The study included 4 255 participants from the UK Biobank, a large community-based cohort study. Cardiac magnetic resonance imaging was conducted to measure left ventricular volume (structure) and left ventricular ejection fraction (function). Annual average exposure to PM2.5 was calculated based on participants' home address. The association between PM2.5 exposure and heart structure and function was estimated using multivariable linear regression, a form of statistical modelling which adjusts for potential factors that could influence the relationship such as age, gender, diabetes and blood pressure. Participants were 62 years old on average and 47% were men. The annual average PM2.5 level was 10 µg/m3. The investigators found linear relationships between ambient PM2.5 level and heart structure and function. Every 5 µg/m3 increase in exposure was associated with a 4-8% increase in left ventricular volume and a 2% decrease in left ventricular ejection fraction. Dr Aung said: "We found that as PM2.5 exposure rises, the larger the heart gets and the worse it performs. Both of these measures are associated with increased morbidity and mortality from heart disease." The researchers also looked for potential factors that could modify the relationship. They found that people with degree-level education were less prone to having a larger heart and had a smaller reduction in ejection fraction when exposed to PM2.5 than people with a lower level of education. Dr Aung said: "People who were highly educated were less likely to have harmful effects on the heart from pollution. This could be due to a number of factors including better housing and workplace conditions, which reduce pollution exposure. Educated people may also be more aware of their health, have healthier lifestyles, and have better access to healthcare." Regarding how pollution might have these negative effects on the heart, Dr Aung said PM2.5 causes systemic inflammation, vasoconstriction and raised blood pressure. The combination of these factors can increase the pressure in the heart, which enlarges to cope with the overload. The heart chamber enlargement reduces the contractile efficiency leading to reduction in ejection fraction. Dr Aung said: "We found that the average exposure to PM2.5 in the UK is about 10 µg/m3 in our study. This is way below the European target of less than 25 µg/m3 and yet we are still seeing these harmful effects. This suggests that the current target level is not safe and should be lowered." He continued: "Our results suggest that PM2.5 is linked with negative changes in the heart structure and function that are associated with poor outcomes. Reducing PM2.5 emission should be an urgent public health priority and the worst offenders such as diesel vehicles should be addressed with policy measures." In terms of what individuals can do to decrease their risk, Dr Aung said: "Avoid times and places where there is a high level of pollution. If you want to cycle into work and there is heavy traffic around that time then try to find a quieter route. Walk on the part of the pavement furthest from cars to reduce the amount of pollution you breathe in. Those with cardiorespiratory diseases should limit the time spent outdoors during highly polluted periods such as rush hours."


News Article | May 29, 2017
Site: www.sciencedaily.com

Statins are associated with improved heart structure and function, according to research presented at EuroCMR 2017.1 The benefits were above and beyond the cholesterol lowering effect of statins. "Statins are primarily used to lower cholesterol," said lead author Dr Nay Aung, a cardiologist and Wellcome Trust research fellow, William Harvey Research Institute, Queen Mary University of London, UK. "They are highly effective in preventing cardiovascular events in patients who have had a heart attack or are at risk of heart disease." He continued: "Statins have other beneficial, non-cholesterol lowering, effects. They can improve the function of the blood vessels, reduce inflammation, and stabilise fatty plaques in the blood vessels. Studies in mice and small studies in humans have shown that statins also reduce the thickness of heart muscle but this needed to be confirmed in a larger study." This study investigated the association between statins and heart structure and function. The study included 4,622 people without cardiovascular disease from the UK Biobank, a large community-based cohort study. Cardiac magnetic resonance imaging was used to measure left and right ventricular volumes and left ventricular mass. Information on statin use was obtained from medical records and a self-reporting questionnaire. The relationship between statin use and heart structure and function was assessed using a statistical technique called multiple regression which adjusts for potential confounders that can have an effect on the heart such as ethnicity, gender, age, and body mass index (BMI). Nearly 17% of participants were taking statins. Those taking statins were older, had higher BMI and blood pressure, and were more likely to have diabetes and hypertension. "This was not surprising because we prescribe statins to patients at high risk of heart disease and these are all known risk factors," said Dr Aung. Patients taking statins had a 2.4% lower left ventricular mass and lower left and right ventricular volumes. Dr Aung said: "People using statins were less likely to have a thickened heart muscle (left ventricular hypertrophy) and less likely to have a large heart chamber. Having a thick, large heart is a strong predictor of future heart attack, heart failure or stroke and taking statins appears to reverse the negative changes in the heart which, in turn, could lower the risk of adverse outcomes." "It is important to note that in our study, the people taking statins were at higher risk of having heart problems than those not using statins yet they still had positive heart remodelling compared to the healthier control group," added Dr Aung. In terms of how statins might reduce the thickness and volume of the heart, Dr Aung said several studies have demonstrated that statins reduce oxidative stress and dampen the production of growth factors which stimulate cell growth. Statins also increase the production of nitric oxide by the cells lining the blood vessels, leading to vasodilatation, improved blood flow, lower blood pressure, and lower stress on the heart, which is less likely to become hypertrophied. The findings raise the issue of extending statin prescriptions to anyone above the age of 40, but Dr Aung said that was probably not the way to go. "There are clear guidelines on who should receive statins," he said. "There is debate about whether we should lower the bar and the question is when do you stop. What we found is that for patients already taking statins, there are beneficial effects beyond cholesterol lowering and that's a good thing. But instead of a blanket prescription we need to identify people most likely to benefit -- i.e. personalised medicine." Dr Aung said: "A dual approach should be considered to identify people who will benefit most from statins. That means looking at not only clinical risk factors such as smoking and high blood pressure, but also genetic (hereditary) factors which can predict individuals' response to statins. This is an area of growing interest and one that we are also investigating in our lab with our collaborators."


News Article | May 26, 2017
Site: www.eurekalert.org

Prague, Czech Republic - 26 May 2017: Statins are associated with improved heart structure and function, according to research presented today at EuroCMR 2017.1 The benefits were above and beyond the cholesterol lowering effect of statins. "Statins are primarily used to lower cholesterol," said lead author Dr Nay Aung, a cardiologist and Wellcome Trust research fellow, William Harvey Research Institute, Queen Mary University of London, UK. "They are highly effective in preventing cardiovascular events in patients who have had a heart attack or are at risk of heart disease." He continued: "Statins have other beneficial, non-cholesterol lowering, effects. They can improve the function of the blood vessels, reduce inflammation, and stabilise fatty plaques in the blood vessels. Studies in mice and small studies in humans have shown that statins also reduce the thickness of heart muscle but this needed to be confirmed in a larger study." This study investigated the association between statins and heart structure and function. The study included 4,622 people without cardiovascular disease from the UK Biobank, a large community-based cohort study. Cardiac magnetic resonance imaging was used to measure left and right ventricular volumes and left ventricular mass. Information on statin use was obtained from medical records and a self-reporting questionnaire. The relationship between statin use and heart structure and function was assessed using a statistical technique called multiple regression which adjusts for potential confounders that can have an effect on the heart such as ethnicity, gender, age, and body mass index (BMI). Nearly 17% of participants were taking statins. Those taking statins were older, had higher BMI and blood pressure, and were more likely to have diabetes and hypertension. "This was not surprising because we prescribe statins to patients at high risk of heart disease and these are all known risk factors," said Dr Aung. Patients taking statins had a 2.4% lower left ventricular mass and lower left and right ventricular volumes. Dr Aung said: "People using statins were less likely to have a thickened heart muscle (left ventricular hypertrophy) and less likely to have a large heart chamber. Having a thick, large heart is a strong predictor of future heart attack, heart failure or stroke and taking statins appears to reverse the negative changes in the heart which, in turn, could lower the risk of adverse outcomes." "It is important to note that in our study, the people taking statins were at higher risk of having heart problems than those not using statins yet they still had positive heart remodelling compared to the healthier control group," added Dr Aung. In terms of how statins might reduce the thickness and volume of the heart, Dr Aung said several studies have demonstrated that statins reduce oxidative stress and dampen the production of growth factors which stimulate cell growth. Statins also increase the production of nitric oxide by the cells lining the blood vessels, leading to vasodilatation, improved blood flow, lower blood pressure, and lower stress on the heart, which is less likely to become hypertrophied. The findings raise the issue of extending statin prescriptions to anyone above the age of 40, but Dr Aung said that was probably not the way to go. "There are clear guidelines on who should receive statins," he said. "There is debate about whether we should lower the bar and the question is when do you stop. What we found is that for patients already taking statins, there are beneficial effects beyond cholesterol lowering and that's a good thing. But instead of a blanket prescription we need to identify people most likely to benefit - i.e. personalised medicine." Dr Aung said: "A dual approach should be considered to identify people who will benefit most from statins. That means looking at not only clinical risk factors such as smoking and high blood pressure, but also genetic (hereditary) factors which can predict individuals' response to statins. This is an area of growing interest and one that we are also investigating in our lab with our collaborators."


News Article | May 26, 2017
Site: www.eurekalert.org

PM2.5 associated with harmful changes to heart structure and function; higher education protective against the damage Prague, Czech Republic - 26 May 2017: Diesel pollution is linked with heart damage, according to research presented today at EuroCMR 2017.1 "There is strong evidence that particulate matter (PM) emitted mainly from diesel road vehicles is associated with increased risk of heart attack, heart failure, and death," said lead author Dr Nay Aung, a cardiologist and Wellcome Trust research fellow, William Harvey Research Institute, Queen Mary University of London, UK. "This appears to be driven by an inflammatory response - inhalation of fine particulate matter (PM2.5) causes localised inflammation of the lungs followed by a more systemic inflammation affecting the whole body. " The current study examined whether PM2.5 may damage the heart directly. The study included 4 255 participants from the UK Biobank, a large community-based cohort study. Cardiac magnetic resonance imaging was conducted to measure left ventricular volume (structure) and left ventricular ejection fraction (function). Annual average exposure to PM2.5 was calculated based on participants' home address. The association between PM2.5 exposure and heart structure and function was estimated using multivariable linear regression, a form of statistical modelling which adjusts for potential factors that could influence the relationship such as age, gender, diabetes and blood pressure. Participants were 62 years old on average and 47% were men. The annual average PM2.5 level was 10 μg/m3. The investigators found linear relationships between ambient PM2.5 level and heart structure and function. Every 5 μg/m3 increase in exposure was associated with a 4-8% increase in left ventricular volume and a 2% decrease in left ventricular ejection fraction. Dr Aung said: "We found that as PM2.5 exposure rises, the larger the heart gets and the worse it performs. Both of these measures are associated with increased morbidity and mortality from heart disease." The researchers also looked for potential factors that could modify the relationship. They found that people with degree-level education were less prone to having a larger heart and had a smaller reduction in ejection fraction when exposed to PM2.5 than people with a lower level of education. Dr Aung said: "People who were highly educated were less likely to have harmful effects on the heart from pollution. This could be due to a number of factors including better housing and workplace conditions, which reduce pollution exposure. Educated people may also be more aware of their health, have healthier lifestyles, and have better access to healthcare." Regarding how pollution might have these negative effects on the heart, Dr Aung said PM2.5 causes systemic inflammation, vasoconstriction and raised blood pressure. The combination of these factors can increase the pressure in the heart, which enlarges to cope with the overload. The heart chamber enlargement reduces the contractile efficiency leading to reduction in ejection fraction. Dr Aung said: "We found that the average exposure to PM2.5 in the UK is about 10 μg/m3 in our study. This is way below the European target of less than 25 μg/m3 and yet we are still seeing these harmful effects. This suggests that the current target level is not safe and should be lowered." He continued: "Our results suggest that PM2.5 is linked with negative changes in the heart structure and function that are associated with poor outcomes. Reducing PM2.5 emission should be an urgent public health priority and the worst offenders such as diesel vehicles should be addressed with policy measures." In terms of what individuals can do to decrease their risk, Dr Aung said: "Avoid times and places where there is a high level of pollution. If you want to cycle into work and there is heavy traffic around that time then try to find a quieter route. Walk on the part of the pavement furthest from cars to reduce the amount of pollution you breathe in. Those with cardiorespiratory diseases should limit the time spent outdoors during highly polluted periods such as rush hours."


News Article | May 26, 2017
Site: www.greencarcongress.com

« Researchers find that high pressure is key to high-entropy alloys | Main | LA Metro awards multi-year contract for Clean Energy’s renewable natural gas to fuel CNG fleet » Research presented at the annual CMR (cardiovascular magnetic resonance) imaging conference of the European Association of Cardiovascular Imaging (EACVI) links PM pollution to heart damage. Among the sources of urban PM are diesel and gasoline direct injection (GDI) engines (earlier post). There is strong evidence that particulate matter (PM) from road vehicles is associated with increased risk of heart attack, heart failure, and death, said lead author Dr. Nay Aung, a cardiologist and Wellcome Trust research fellow, William Harvey Research Institute, Queen Mary University of London, UK. “This appears to be driven by an inflammatory response—inhalation of fine particulate matter (PM ) causes localized inflammation of the lungs followed by a more systemic inflammation affecting the whole body. “ The current study examined whether PM may damage the heart directly. The study included 4,255 participants from the UK Biobank, a large community-based cohort study. Cardiac magnetic resonance imaging was conducted to measure left ventricular volume (structure) and left ventricular ejection fraction (function). Annual average exposure to PM was calculated based on participants’ home address. The association between PM exposure and heart structure and function was estimated using multivariable linear regression, a form of statistical modeling which adjusts for potential factors that could influence the relationship such as age, gender, diabetes and blood pressure. Participants were 62 years old on average and 47% were men. The annual average PM level was 10 μg/m3. The investigators found linear relationships between ambient PM level and heart structure and function. Every 5 μg/m3 increase in exposure was associated with a 4-8% increase in left ventricular volume and a 2% decrease in left ventricular ejection fraction. The researchers also looked for potential factors that could modify the relationship. They found that people with degree-level education were less prone to having a larger heart and had a smaller reduction in ejection fraction when exposed to PM than people with a lower level of education. People who were highly educated were less likely to have harmful effects on the heart from pollution. This could be due to a number of factors including better housing and workplace conditions, which reduce pollution exposure. Educated people may also be more aware of their health, have healthier lifestyles, and have better access to healthcare. Regarding how pollution might have these negative effects on the heart, Dr Aung said PM causes systemic inflammation, vasoconstriction and raised blood pressure. The combination of these factors can increase the pressure in the heart, which enlarges to cope with the overload. The heart chamber enlargement reduces the contractile efficiency leading to reduction in ejection fraction. We found that the average exposure to PM in the UK is about 10 μg/m3 in our study. This is way below the European target of less than 25 μg/m3 and yet we are still seeing these harmful effects. This suggests that the current target level is not safe and should be lowered. Dr Aung presented the abstract ‘Impact of fine particulate matter air pollutant on cardiac atrial and ventricular structure and function derived from cardiovascular magnetic resonance (CMR) imaging – evidence from the UK Biobank’ during the BEST Oral Abstracts session on 26 May.


An analysis published today in the New England Journal of Medicine (NEJM) showed that people with inactivating mutations of the ANGPTL3 gene have significantly reduced risk of coronary artery disease (CAD) and significantly lower levels of key blood lipids including triglycerides and low-density lipoprotein cholesterol (LDL-C, or "bad cholesterol"). Data also included in this publication showed that blocking ANGPTL3 activity with evinacumab exhibited similar lipid-lowering effects in animal models and a first-in-human clinical study. Separate Phase 2 results presented this past weekend at the National Lipid Association's (NLA) Scientific Sessions showed that, in patients with Homozygous Familial Hypercholesterolemia (HoFH), evinacumab added to current lipid-lowering therapy reduced LDL-C by an additional 49 percent (mean reduction; range 25 percent to 90 percent) at week 4 compared to baseline, the primary endpoint of the study. Mean baseline LDL-C for the nine patients was 376 mg/dL. Data also showed that evinacumab reduced levels of other key lipid parameters including lipoprotein(a) and triglycerides. People with HoFH have serious genetic mutations that result in highly elevated LDL-C levels and often experience early atherosclerotic disease, sometimes suffering cardiac events as early as their teenage years. These patients generally do not respond well to existing therapies. In three patients with homozygous null allele mutations in the LDL receptor, the additional LDL-C reduction was 37 percent at week 4 (mean reduction); these patients had a mean baseline LDL-C of 597 mg/dL. There were no adverse events leading to discontinuation. The most common drug-related adverse events were injection-site reactions (1 patient with 2 events) and hot flush (1 patient with 2 events), which were mild in severity. "Collectively, these findings confirm that the ANGPTL3 pathway is important in regulating lipids and cardiovascular disease," said Robert Pordy, MD, co-author and Vice President of Cardiovascular and Metabolism Therapeutics at Regeneron. "Evinacumab, our antibody to ANGPTL3, has been designated a Breakthrough Therapy by the U.S. Food and Drug Administration for HoFH, and we plan to move to Phase 3 for this indication. We are also planning to initiate additional studies in people with other severe forms of dyslipidemia." Regeneron scientists were the first to clone angiopoietin-1 in the mid-1990s and discovered that angiopoietin-like knockouts in mouse models reduced triglycerides and LDL-C. Angiopoietin-like proteins such as ANGPTL3 inhibit an enzyme called lipoprotein lipase (LPL) that breaks down triglycerides, a form of fat derived from food. ANGPTL3 also plays a fundamental role in the regulation of both types of blood cholesterol: LDL-C and high-density lipoprotein cholesterol (HDL-C or "good cholesterol"). Loss of ANGPTL3 function due to genetic mutations is associated with decreased triglycerides, LDL-C and HDL-C levels. A previous Regeneron NEJM publication showed that genetic inactivation of a similar angiopoietin-like protein, ANGPTL4, decreases triglyceride levels and the risk of CAD, and a separate publication involving investigators from the Regeneron Genetics Center showed that loss of function mutations in LPL that increase triglyceride levels also increase risk of CAD. NEJM Publication Findings In today's NEJM publication, scientists at the Regeneron Genetics Center and a team of international researchers analyzed genetic data and health records from more than 180,000 participants from five studies -- the Geisinger Health System (DiscovEHR study), three major studies in Copenhagen, the Penn Medicine Biobank, the Duke CATHGEN cohort and the TAIwan MetaboCHIp (TAICHI) consortium. The team identified individuals in those studies who had loss of function mutations for ANGPTL3 and found that those who carried loss of function mutations had lower lipid levels and an approximately 40 percent reduction in the risk of CAD. In a related preclinical study, evinacumab was evaluated in animal models of atherosclerosis, resulting in statistically significant reductions in triglyceride levels by 84 percent (p<0.001) and atherosclerotic plaque size by 39 percent (p<0.001). Confirmatory findings from a Phase 1 human study were also included in the paper, showing that responses to treatment were dose dependent, with a maximal reduction at the highest IV dose of 76 percent in triglyceride levels four days after treatment. No participants dropped out of the study due to adverse safety events. Headaches were the most frequently reported adverse event, and two subjects experienced transient elevations of liver enzymes. "The New England Journal of Medicine publication demonstrates the incredible power of an integrated approach to translational medicine and clinical development," said Frederick Dewey, MD, co-author and Senior Director and Head of Translational Genetics at the Regeneron Genetics Center, a wholly-owned subsidiary of Regeneron. "Our team of researchers used large-scale human genetic studies and mouse models to demonstrate that inactivation of ANGPTL3 reduces key lipid levels and cardiovascular disease risk. This human genetics and preclinical validation provide important insight to inform our evinacumab clinical development strategy." About the Regeneron Genetics Center (RGC) The RGC is a fully integrated genomics program that spans early gene discovery and functional genomics and facilitates drug development. The primary goal of the RGC is to improve patient outcomes by identifying novel drug targets, clinical indications for development programs, and genomic biomarkers for pharmacogenomic applications. The RGC is tackling large scale sequencing and analytical approaches and has established numerous collaborations with leading human genetics researchers. To enable this large-scale sequencing and analysis program, the RGC utilizes fully-automated sample preparation and data processing, as well as cutting-edge cloud-based informatics. Through these efforts, the RGC is currently sequencing de-identified samples from patient volunteers at a rate of almost 200,000 unique exomes per year. The RGC has major collaborations with Geisinger Health System and the UK Biobank supporting the goal of sequencing 1,000,000 individuals linked to their comprehensive digital health records, plus many other major initiatives in disease specific-studies, founder populations and family based-studies. About Regeneron Regeneron (NASDAQ: REGN) is a leading science-based biopharmaceutical company that discovers, invents, develops, manufactures and commercializes medicines for the treatment of serious medical conditions. All Regeneron commercialized medicines were discovered and developed by our own scientists, including therapies for eye diseases, high LDL cholesterol, atopic dermatitis, rheumatoid arthritis and a rare inflammatory condition. Regeneron also has product candidates in development in other areas of high unmet medical need, including asthma, pain, cancer and infectious diseases. Regeneron invented the leading VelociSuite® technologies, which are a suite of complementary genetics-based technologies that accelerate, improve and disrupt the traditional drug discovery and development process and established the Regeneron Genetics Center, one of the largest genetic sequencing efforts in the world. For additional information about the company, please visit www.regeneron.com or follow @Regeneron on Twitter. Forward-Looking Statements and Use of Digital Media This news release includes forward-looking statements that involve risks and uncertainties relating to future events and the future performance of Regeneron Pharmaceuticals, Inc. ("Regeneron" or the "Company"), and actual events or results may differ materially from these forward-looking statements. Words such as "anticipate," "expect," "intend," "plan," "believe," "seek," "estimate," variations of such words, and similar expressions are intended to identify such forward-looking statements, although not all forward-looking statements contain these identifying words. These statements concern, and these risks and uncertainties include, among others, the nature, timing, and possible success and therapeutic applications of Regeneron's products, product candidates, and research and clinical programs now underway or planned, including without limitation evinacumab (Regeneron's investigational angiopoietin-like 3 (ANGPTL3) antibody); the likelihood and timing of possible regulatory approval and commercial launch of Regeneron's product candidates, such as evinacumab in patients with Homozygous Familial Hypercholesterolemia or other potential indications; the extent to which the results from Regeneron's research programs or preclinical testing may lead to advancement of product candidates to clinical trials or therapeutic applications; unforeseen safety issues resulting from the administration of products and product candidates in patients, including serious complications or side effects in connection with the use of Regeneron's product candidates in clinical trials, such as evinacumab; determinations by regulatory and administrative governmental authorities which may delay or restrict Regeneron's ability to continue to develop or commercialize Regeneron's products and product candidates, such as evinacumab; ongoing regulatory obligations and oversight impacting Regeneron's marketed products, research and clinical programs, and business, including those relating to patient privacy; competing drugs and product candidates that may be superior to Regeneron's products and product candidates; uncertainty of market acceptance and commercial success of Regeneron's products and product candidates and the impact of studies (whether conducted by Regeneron or others and whether mandated or voluntary) on the commercial success of Regeneron's products and product candidates; coverage and reimbursement determinations by third-party payers, including Medicare and Medicaid; the ability of Regeneron to manufacture and manage supply chains for multiple products and product candidates; the ability of Regeneron's collaborators, suppliers, or other third parties to perform filling, finishing, packaging, labelling, distribution, and other steps related to Regeneron's products and product candidates; unanticipated expenses; the costs of developing, producing, and selling products; the ability of Regeneron to meet any of its sales or other financial projections or guidance and changes to the assumptions underlying those projections or guidance; the potential for any license or collaboration agreement, including Regeneron's agreements with Sanofi, Bayer, and Teva Pharmaceutical Industries Ltd. (or their respective affiliated companies, as applicable), to be cancelled or terminated without any further product success; and risks associated with intellectual property of other parties and pending or future litigation relating thereto, including without limitation the patent litigation relating to Praluent® (alirocumab) Injection, the permanent injunction granted by the United States District Court for the District of Delaware that, if upheld on appeal, would prohibit Regeneron and Sanofi from marketing, selling, or commercially manufacturing Praluent in the United States, the outcome of any appeals regarding such injunction, the ultimate outcome of such litigation, and the impact any of the foregoing may have on Regeneron's business, prospects, operating results, and financial condition. A more complete description of these and other material risks can be found in Regeneron's filings with the United States Securities and Exchange Commission, including its Form 10-K for the year ended December 31, 2016 and its Form 10-Q for the quarterly period ended March 31, 2017. Any forward-looking statements are made based on management's current beliefs and judgment, and the reader is cautioned not to rely on any forward-looking statements made by Regeneron. Regeneron does not undertake any obligation to update publicly any forward-looking statement, including without limitation any financial projection or guidance, whether as a result of new information, future events, or otherwise. Regeneron uses its media and investor relations website and social media outlets to publish important information about the Company, including information that may be deemed material to investors. Financial and other information about Regeneron is routinely posted and is accessible on Regeneron's media and investor relations website (http://newsroom.regeneron.com) and its Twitter feed (http://twitter.com/regeneron). To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/regeneron-announces-angptl3evinacumab-publication-in-new-england-journal-of-medicine-and-positive-phase-2-data-in-people-with-hofh-300463393.html


Grant
Agency: GTR | Branch: MRC | Program: | Phase: Intramural | Award Amount: 9.60M | Year: 2013

In UK Biobank, questionnaire data, physical measurements and biological samples have been collected from 500,000 men and women aged 40-69, and their health is now being followed long-term. A prospective cohort like UK Biobank allows reliable assessment of the relevance of many different exposures to the development of many different diseases. However, such studies need to be big because only a relatively small proportion of participants will develop any particular disease. It is now planned to conduct specialised imaging of the brain, heart, large blood vessels, abdomen, bone and joints in 100,000 UK Biobank participants. Although imaging has been done in some other studies, these have involved only small numbers of people (typically less than 5,000) and have focussed on imaging particular parts of the body. By contrast, combination of imaging data from different parts of the body in 100,000 UK Biobank participants with the detailed non-imaging data already collected will provide a unique resource for researchers from around the world to investigate the causes of different diseases. (For example, dementia may be related to imaging measures not only from the brain but also from other parts of the body, as well as to genetic, biochemical or environmental information.)


Grant
Agency: GTR | Branch: MRC | Program: | Phase: Intramural | Award Amount: 10.00M | Year: 2013

During the next 18 months, it is intended to measure about 600,000 genetic markers in the DNA extracted from blood samples that have already been collected from each of the 500,000 participants in UK Biobank. When these “genotype” measurements are combined with whole genome sequence data from a few thousand or tens of thousands of UK individuals, it will be possible to “impute” (i.e. estimate) very many more genetic variants in the region of the DNA adjacent to the variants that have been measured. The combination of these detailed genotyping data with the extensive range of known biochemical risk factors that are currently being measured in blood and urine samples from the UK Biobank participants, along with the detailed information from questionnaires and physical measurements conducted at the initial assessment visits and from linkage to health records about the development of disease during long-term follow-up, will make UK Biobank uniquely rich as a resource for researchers from all areas of health to conduct studies of the relevance of genes to disease rapidly and cost-effectively. Hence, these detailed genotype data will facilitate research that harnesses the full power of UK Biobank to help understand the causes of many different diseases.


Grant
Agency: GTR | Branch: MRC | Program: | Phase: Intramural | Award Amount: 9.37M | Year: 2016

The challenges of understanding the determinants of common life-threatening and disabling diseases are substantial. Such conditions are typically caused by many different exposures that each have moderate effects and interact with each other in complex ways. Prospective cohorts, such as UK Biobank, have advantages for the comprehensive and reliable quantification of the combined effects of different types of risk factor on health outcomes. In particular, exposures can be assessed before they are affected by disease or its management, and diseases can be assessed that are not readily investigated by retrospective studies (e.g. dementia). Moreover, all of the beneficial and adverse effects of a specific factor on the life-time risks of different diseases can be considered. Prospective studies do, however, need to involve large numbers of participants because only a relatively small proportion will develop any particular condition. UK Biobank has involved the collection of extensive baseline questionnaire data, physical measurements and biological samples from 500,000 men and women aged 40-69 at baseline, and their health is now being followed long-term. This proposal is for enhanced phenotyping of 100,000 of the participants with a set of imaging modalities that have been carefully chosen to provide considerable additional information that is likely to be relevant to many different health outcomes.

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