Archive for the ‘PCSK9 Inhibitor Therapy’ Category

Triglycerides: Is it a Risk Factor or a Risk Marker for Atherosclerosis and Cardiovascular Disease? – The Impact of Genetic Mutations on (ANGPTL4) Gene, encoder of (angiopoietin-like 4) Protein, inhibitor of Lipoprotein Lipase

Posted in Atherogenic Processes & Pathology, Epigenetics and Cardiovascular Risks, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Endocrinology, Glycobiology: Biopharmaceutical Production, HTN, Lipid metabolism, Metabolomics, Molecular Genetics & Pharmaceutical, Origins of Cardiovascular Disease, PCSK9 Inhibitor Therapy, Pharmacotherapy of Cardiovascular Disease on March 13, 2016| Leave a Comment »

Triglycerides: Is it a Risk Factor or a Risk Marker for Atherosclerosis and Cardiovascular Disease ? The Impact of Genetic Mutations on (ANGPTL4) Gene, encoder of (angiopoietin-like 4) Protein, inhibitor of Lipoprotein Lipase

 

Reporters, Curators and Authors: Aviva Lev-Ari, PhD, RN and Larry H. Bernstein, MD, FCAP

Introduction

The role for triglycerides as a risk factor for cardiovascular disease is not new, going back to Donald Frederickson’s classification of hyperlipidemias, at least with respect to Type I and Type IIb. Whether there was a mechanism beyond the observations was yet an open question.  The paper that follows addresses such a question.

 

Large Genetic Studies Support Role For Triglycerides In Cardiovascular Disease

SOURCE

http://cardiobrief.org/2016/03/03/large-genetic-studies-support-role-for-triglycerides-in-cardiovascular-disease/#comments

March 3, 2016 by Larry Husten

 

Two  papers published in the New England Journal of Medicine offer new genetic evidence to support the increasingly accepted though still controversial view that triglycerides play an important causal role in cardiovascular disease. If fully validated the new findings could lead to new drugs to prevent and treat cardiovascular disease, though others caution that there is still a long way to go before this could happen.

Both studies describe the impact of genetic mutations on a gene (ANGPTL4) which encodes for a protein (angiopoietin-like 4) that inhibits lipoprotein lipase, an enzyme that plays a key role in breaking down and removing triglycerides from the blood. The large studies found that people with  mutations that inactivate ANGPTL4 have lower levels of triglycerides, higher levels of HDL cholesterol, and decreased risk for cardiovascular disease.

The findings, writes Sander Kersten (Wageningen University, the Netherlands) in an accompanying editorial, “suggest that lowering plasma triglyceride levels is a viable approach to reducing the risk of coronary artery disease.”

The Genetics of Dyslipidemia — When Less Is More

Sander Kersten, Ph.D.   Mar 2, 2016;   http://dx.doi.org:/10.1056/NEJMe1601117

Two groups of investigators now describe in the Journal important genetic evidence showing a causal role of plasma triglycerides in coronary heart disease. Stitziel and colleagues2 tested 54,003 coding-sequence variants covering 13,715 human genes in more than 72,000 patients with coronary artery disease and 120,000 controls. Dewey and colleagues3 sequenced the exons of the gene encoding angiopoietin-like 4 (ANGPTL4) in samples obtained from nearly 43,000 participants in the DiscovEHR human genetics study. The two groups found a significant association between an inactivating mutation (E40K) in ANGPTL4 and both low plasma triglyceride levels and high levels of HDL cholesterol. ANGPTL4 is an inhibitor of lipoprotein lipase, the enzyme that breaks down plasma triglycerides along the capillaries in heart, muscle, and fat.4 Extensive research has shown that ANGPTL4 orchestrates the processing of triglyceride-rich lipoproteins during physiologic conditions such as fasting, exercise, and cold exposure.4 The E40K mutation in ANGPTL4 was previously shown to nearly eliminate the ability of ANGPTL4 to inhibit lipoprotein lipase, a mechanism that may result in part from the destabilization of ANGPTL4.5

The key finding in each study was that carriers of the E40K mutation and other rare mutations in ANGPTL4 had a lower risk of coronary artery disease than did noncarriers, a result that is consistent with the lower triglyceride levels and higher HDL cholesterol levels among mutation carriers. These findings confirm previous data6 and provide convincing genetic evidence that an elevated plasma triglyceride level increases the risk of coronary heart disease. In combination with extensive recent data on other genetic variants that modulate plasma triglyceride levels, the studies suggest that lowering plasma triglyceride levels is a viable approach to reducing the risk of coronary artery disease.

However, as a cautionary note, Talmud and colleagues7 previously found that the presence of the E40K variant was associated with an increased risk of coronary heart disease after adjustment for the altered plasma lipids. Consistent with this hypothesis, the overexpression of Angptl4 in mice was found to protect against atherosclerosis independent of plasma lipids.8

The studies also “implicate targeted inactivation of ANGPTL4 as a potential weapon in the war on heart disease,” though he also points to a previous study that did not support this hypothesis. Sekar Kathiresan (Broad Institute), senior author of one of the NEJM studies, told me that the previous study was small and “basically got the result wrong. Between, the two papers in this NEJM issue, we are looking at 10X more data.”

Recent large genetic studies have resulted in an important change in the field. Many researchers now believe that HDL, which was once thought to play an important protective role in atherosclerosis, is only a marker of disease. In contrast, triglycerides are now thought by many to play an important functional role.

One of the NEJM papers showed that a human monoclonal antibody to ANGPTL4 lowered triglyceride levels in animals. The study was funded by Regeneron and was performed by researchers at Regeneron and Geisinger, as part of an ongoing collaboration using deidentified genetic data from Geisinger patients. In their NEJM paper the researchers reported inflammation and other side effects in the animals treated with the antibody, but they said that no such problem has been observed in humans who have mutations that have the same functional effect as the antibody.

Coding Variation in ANGPTL4, LPL, and SVEP1and the Risk of Coronary Disease Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators

March 2, 2016     http://dx.doi.org:/10.1056/NEJMoa1507652

Although genomewide association studies have identified more than 56 loci associated with the risk of coronary artery disease,1-3 the disease-associated variants are typically common (minor-allele frequency >5%) and located in noncoding sequences; this has made it difficult to pinpoint causal genes and affected pathways. This lack of a causal mechanism has in part hindered the immediate translation of the findings of genomewide association studies into new therapeutic targets. However, the discovery of rare or low-frequency coding-sequence variants that affect the risk of coronary artery disease has facilitated advances in the prevention and treatment of disease. The most recent example of such advances is the development of a new class of therapeutic agents that is based on the discovery of the gene encoding proprotein convertase subtilisin/kexin type 9 (PCSK9) as a regulator of low-density lipoprotein (LDL) cholesterol4 and the discovery that low-frequency and loss-of-function variants in this gene protect against coronary artery disease.5,6

Recently, low-frequency coding variation across the genome was systematically tabulated with the use of next-generation exome and whole-genome sequencing data from more than 12,000 persons of various ancestries (including a major contribution from the National Heart, Lung, and Blood Institute Exome Sequencing Project). Protein-altering variants (i.e., nonsynonymous, splice-site, and nonsense single-nucleotide substitutions) that were observed at least twice among these 12,000 persons were included in a genotyping array (hereafter referred to as the exome array). In addition, the exome array contains previously described variants from genomewide association studies, a sparse genomewide grid of common markers, markers that are informative with regard to ancestry (i.e., African American, Native American, and European), and some additional content. Additional information on the design of the exome array is provided at http://genome.sph.umich.edu/wiki/Exome_Chip_Design. In this study, we focused on the 220,231 autosomal variants that were present on the array and were expected to alter protein sequence (i.e., missense, nonsense, splice-site, and frameshift variants) and used these to test the contribution of low-frequency coding variation to the risk of coronary artery disease.

Low-Frequency Coding Variants Associated with Coronary Artery Disease

The discovery cohort comprised 120,575 persons (42,335 patients and 78,240 controls) (Table S1 in the Supplementary Appendix). In the discovery cohort, we found significant associations between low-frequency coding variants in theLPA and PCSK9 genes and coronary artery disease (Table 1

TABLE 1

Low-Frequency Coding Variations Previously Associated with Coronary Artery Disease.). Both gene loci also harbor common noncoding variants associated with coronary artery disease that had previously been discovered through genomewide association studies. These variants were also present on the exome array and had significant associations with coronary artery disease in our study (Table 1). In a conditional analysis, the associations between coronary artery disease and the low-frequency coding variants in both LPA and PCSK9 were found to be independent of the associations between coronary artery disease and the more common variants (Table 1). ….

We found a significant association between SVEP1 p.D2702G and blood pressure (Table 3TABLE 3   Association between Low-Frequency Variants and Traditional Risk Factors., and Table S7 in the Supplementary Appendix). The allele associated with an increased risk of coronary artery disease was also associated with higher systolic blood pressure (0.94 mm Hg higher for each copy of the allele among allele carriers, P=3.0×10⁻⁷) and higher diastolic blood pressure (0.57 mm Hg higher for each copy of the allele among allele carriers, P=4.4×10⁻⁷). We did not find an association between SVEP1 p.D2702G and any plasma lipid trait. In contrast, ANGPTL4 p.E40K was not associated with blood pressure but instead was found to be associated with significantly lower levels of triglycerides (approximately 0.3 standard deviation units lower for each copy of the allele among allele carriers, P=1.6×10⁻¹³) (Table 3) and with higher levels of high-density lipoprotein (HDL) cholesterol (approximately 0.3 standard deviation units higher for each copy of the allele among allele carriers, P=8.2×10⁻¹¹) (Table 3). In a conditional analysis, these effects appeared to be at least partially independent of each other (Table S8 in the Supplementary Appendix). We did not observe any significant association between ANGPTL4 p.E40K and LDL cholesterol level (Table 3). Both SVEP1 p.D2702G and ANGPTL4 p.E40K were nominally associated with type 2 diabetes in a direction concordant with the associated risk of coronary artery disease.

ANGPTL4 Loss-of-Function Mutations, Plasma Lipid Levels, and Coronary Artery Disease

The finding that a missense allele in ANGPTL4 reduced the risk of coronary artery disease, potentially by reducing triglyceride levels, raised the possibility that complete loss-of-function variants in ANGPTL4 may have an even more dramatic effect on triglyceride concentrations and the risk of coronary artery disease. We therefore examined sequence data for the seven protein-coding exons of ANGPTL4 in 6924 patients with early-onset myocardial infarction and 6834 controls free from coronary artery disease (details of the patients and controls are provided in Table S3 in the Supplementary Appendix). We discovered a total of 10 variants that were predicted to lead to loss of gene function (Figure 1A FIGURE 1    

Loss-of-Function Alleles in ANGPTL4 and Plasma Lipid Levels., and Table S9 in the Supplementary Appendix), carried by 28 heterozygous persons; no homozygous or compound heterozygous persons were discovered. Carriers of loss-of-function alleles had significantly lower levels of triglycerides than did noncarriers (a mean of 35% lower among carriers, P=0.003) (Figure 1B, and Table S10 in the Supplementary Appendix), with no significant difference in LDL or HDL cholesterol levels. Moreover, we found a lower risk of coronary artery disease among carriers of loss-of-function alleles (9 carriers among 6924 patients vs. 19 carriers among 6834 controls; odds ratio for disease, 0.47; P=0.04) (Table S11 in the Supplementary Appendix). A similar investigation was performed for the 48 protein-coding exons of SVEP1; however, only 3 loss-of-function allele carriers were discovered (2 carriers among 6924 patients vs. 1 carrier among 6834 controls).

Coding Variation in LPL and the Risk of Coronary Artery Disease

On the basis of the fact that a loss of ANGPTL4 function was associated with reduced risk of coronary artery disease and that ANGPTL4 inhibits lipoprotein lipase (LPL), one would expect a gain of LPL function to also be associated with a lower risk of coronary artery disease, whereas a loss of LPL function would be expected to be associated with a higher risk. In observations consistent with these expectations, we found a low-frequency missense variant in LPL on the exome array that was associated with an increased risk of coronary artery disease (p.D36N; minor-allele frequency, 1.9%; odds ratio for disease, 1.13; P=2.0×10⁻⁴) (Table S12 in the Supplementary Appendix); previous studies have shown that this allele (also known as p.D9N) is associated with LPL activity that is 20% lower in allele carriers than in noncarriers.8 We also identified a nonsense mutation in LPL on the exome array that was significantly associated with a reduced risk of coronary artery disease (p.S447*; minor-allele frequency, 9.9%; odds ratio, 0.94; P=2.5×10⁻⁷) (Table S12 in the Supplementary Appendix). Contrary to most instances in which the premature introduction of a stop codon leads to loss of gene function, this nonsense mutation, which occurs in the penultimate codon of the gene, paradoxically induces a gain of LPL function.9 …..

Through large-scale exomewide screening, we identified a low-frequency coding variant in ANGPTL4 that was associated with protection against coronary artery disease and a low-frequency coding variant in SVEP1 that was associated with an increased risk of the disease. Moreover, our results highlight LPL as a significant contributor to the risk of coronary artery disease and support the hypothesis that a gain of LPL function or loss of ANGPTL4 inhibition protects against the disease.

ANGPTL4 has previously been found to be involved in cancer pathogenesis and wound healing.10 Previous functional studies also revealed that ANGPTL4 regulates plasma triglyceride concentration by inhibiting LPL.11 The minor allele at p.E40K has previously been associated with lower levels of triglycerides and higher levels of HDL cholesterol.12 We now provide independent confirmation of these lipid effects. In vitro and in vivo experimental evidence suggests that the lysine allele at p.E40K results in destabilization of ANGPTL4 after its secretion from the cell in which it was synthesized. It may be that the p.E40K variant leads to increases in the enzymatic activity of LPL because of this destabilization.13 Previous, smaller studies produced conflicting results regarding p.E40K and the risk of coronary artery disease14,15; we now provide robust support for an association between p.E40K and a reduced risk of coronary artery disease.

An important caveat  to this research is that it is still very early. Most promising therapeutic targets do not work out. James Stein (University of Wisconsin) praised the papers but also offered a word of caution. “This is great science and important research that sheds light on the genetic regulation of TG-rich lipoproteins, serum TG levels, and CVD risk,” he said. “Since it is hard, if not impossible, to disconnect TG-rich lipoproteins from LDL, we should be humble in extrapolating these findings to clinical medicine in an era of low LDL due to statins and PCSK9 inhibitors. I hope this research identifies new targets for drug therapy and better understanding of CVD risk prediction– only time will tell.”

Previous studies with fibrates and other drugs have failed to convincingly show that lowering triglycerides is beneficial. Kathiresan said that what really seems to matter is “how you alter the plasma triglyceride-rich lipoproteins (TRLs).” Some genes that alter TRLs have other metabolic effects. As an example he cited a gene that lowers TRLs but increases the risk for type 2 diabetes. The NEJM papers, by observing the effect of specific mutations, therefore point the way to targets that may be clinically significant.

Conclusions:  The work that has been presented puts a new light on the possible role of triglycerides in the development of congenitally predetermined cardiovascular disease. It does not necessarily establish a general link to mechanism of cardiovascular disease, but it opens up new pathways to our understanding.

SOURCE

http://cardiobrief.org/2016/03/03/large-genetic-studies-support-role-for-triglycerides-in-cardiovascular-disease/#comments

John Contois commented on your update “Are triglycerides a CHD risk factor? The answer is still maybe. Triglyceride-rich lipoproteins are inextricably linked to LDL metabolism and LDL particle number (and apo B). Still these are important new data and targets for novel therapeutics.”

 

 

Risk of Dis-lipids Syndrome in Modern Society

Aurelian Udristioiuᶪ, Manole Cojocaru²
¹Department of Biochemistry, Clinical Laboratory, Emergency County Hospital Targu Jiu & Titu Maiorescu University, Bucharest, Romania,
Department of Physiology, Faculty of Medicine, Titu Maiorescu University, Bucharest, Romania

Abstract
Aim of this work was to emphasis the preclinical evaluation of dis-lipids syndromes types at the patients which were presented to a routine control for checking health status, in the hospital ambulatory.
Material and Method:
Were analyzed 60 patients, registered in Clinical Laboratory, assessing by running on the Hitachi 912 Analyzer, the principal biochemical parameters of lipid metabolism: Cholesterol, Triglycerides and fractions of Cholesterol, HDL and LDL. From the total of 60 patients 35 were females and 25 males.
Results
The persons with an alarm signal of atherosclerotic process were in 28 % and persons with low HDL was in 17%. The cases with atherosclerotic index, report-LDL/HDL>3.5 for men and 2.5 for women were in 14 % , the cases with predictive value with coronary risk, report-CO/HDL>5 were presented in 5 % and the cases with dis-lipid syndrome type 2- 4, with high Cholesterol and Triglycerides, were presented in 30% percent.
Conclusions
Lipids controls, and its fractions, are necessary to be prevented atherosclerotic process in the incipient status of ill.

 

http://video.epccs.eu/video_1466.html

 

 

REFERENCES

http://www.nejm.org/doi/full/10.1056/NEJMe1601117

http://www.nejm.org/doi/full/10.1056/NEJMoa1507652

March 2, 2016 Regeneron Genetics Center Publication in New England Journal of Medicine Links ANGPTL4 Inhibition and Risk of Coronary Artery Disease Demonstrates power of large-scale Precision Medicine initiatives

http://files.shareholder.com/downloads/REGN/1634352863x0x879015/042D3D02-04CB-4DD1-89FE-53927F422025/REGN_News_2016_3_2_General_Releases.pdf

e-Books by Leaders in Pharmaceutical Business Intelligence (LPBI) Group

• Perspectives on Nitric Oxide in Disease Mechanisms, on Amazon since 6/2/12013

http://www.amazon.com/dp/B00DINFFYC

• Metabolic Genomics and Pharmaceutics, on Amazon since 7/21/2015

http://www.amazon.com/dp/B012BB0ZF0

• Genomics Orientations for Personalized Medicine, on Amazon since 11/23/2015

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• Milestones in Physiology: Discoveries in Medicine, Genomics and Therapeutics, on Amazon.com since 12/27/2015

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• Cardiovascular, Volume Two: Cardiovascular Original Research: Cases in Methodology Design for Content Co-Curation, on Amazon since 11/30/2015

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• Cardiovascular Diseases, Volume Three: Etiologies of Cardiovascular Diseases: Epigenetics, Genetics and Genomics, on Amazon since 11/29/2015

http://www.amazon.com/dp/B018PNHJ84

• Cardiovascular Diseases, Volume Four: Regenerative and Translational Medicine: The Therapeutics Promise for Cardiovascular Diseases, on Amazon since 12/26/2015

http://www.amazon.com/dp/B019UM909A

Other related articles on this topic published in this Open Access Online Scientific Journal include the following:

Editorial & Publication of Articles in e-Books by  Leaders in Pharmaceutical Business Intelligence:  Contributions of Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/10/16/editorial-publication-of-articles-in-e-books-by-leaders-in-pharmaceutical-business-intelligence-contributions-of-larry-h-bernstein-md-fcap/

Editorial & Publication of Articles in e-Books by Leaders in Pharmaceutical Business Intelligence: Contributions of Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2014/10/16/editorial-publication-of-articles-in-e-books-by-leaders-in-pharmaceutical-business-intelligence-contributions-of-aviva-lev-ari-phd-rn/

TRIGLYCERIDES

http://pharmaceuticalintelligence.com/?s=Triglycerides

HDL

http://pharmaceuticalintelligence.com/?s=HDL

PCSK9

http://pharmaceuticalintelligence.com/?s=PCSK9

STATINS

http://pharmaceuticalintelligence.com/?s=Statins

STATIN

http://pharmaceuticalintelligence.com/?s=STATIN

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PCSK9: A Recent Discovery in Understanding Cholesterol Regulation @ AMGEN Cardiovascular

Posted in Atherogenic Processes & Pathology, Cardiovascular Research, Epigenetics and Cardiovascular Risks, Frontiers in Cardiology and Cardiovascular Disorders, Origins of Cardiovascular Disease, PCSK9 Inhibitor Therapy on August 4, 2015| Leave a Comment »

UPDATED on 3/16/2019

https://www.medpagetoday.com/cardiology/prevention/78202?xid=nl_mpt_SRCardiology_2019-02-25&eun=g99985d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=CardioUpdate_022519&utm_term=NL_Spec_Cardiology_Update_Active

Patients with necrotizing autoimmune myopathy from statins may benefit from a PCSK9 inhibitor, a case report from Spain noted in the Annals of Internal Medicine.

PCSK9: A Recent Discovery in Understanding Cholesterol Regulation @ AMGEN Cardiovascular

Reporter: Aviva Lev-Ari, PhD, RN

 

UPDATED on 3/28/2016

·       by Crystal Phend 
Senior Associate Editor, MedPage Today

Alirocumab (Praluent) reduced the frequency of apheresis by 75% compared with placebo and eliminated the need for apheresis for 63%, according to top-line results from the 62-patient phase III ODYSSEY ESCAPE trial in heterozygous familial hypercholesterolemia getting the treatments.

SOURCE

http://www.medpagetoday.com/Cardiology/Prevention/56973?isalert=1&uun=g99985d4930R5099207u&xid=NL_breakingnews_2016-03-28

UPDATED on 3/21/2016

The PPAR-delta agonist MBX-8025 was associated with a drop in LDL cholesterol by at least 15% for the majority of genetically-confirmed homozygous familial hypercholesterolemia patients when added to ezetimibe (Zetia) and maximal statin therapy in a small open-label, dose-escalation phase II trial. The company plans a pilot study combining the agent with a PCSK9 inhibitor too.

SOURCE

http://www.medpagetoday.com/Cardiology/Prevention/56832?isalert=1&uun=g99985d4908R5099207u&xid=NL_breakingnews_2016-03-21

 

CVD = cardiovascular disease;

HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A;

LDL = low-density lipoprotein;

LDL-C = low-density lipoprotein cholesterol;

LDLR = low-density lipoprotein receptor;

PCSK9 = proprotein convertase subtilisin/kexin type 9.

 

 

References

1. Brown MS, Goldstein JL. Proc Natl Acad Sci USA. 1979;76:3330-3337.
2. Goldstein JL, Brown MS. Arterioscler Thromb Vasc Biol. 2009;29:431-438.
3. Qian Y-W, Schmidt RJ, Zhang Y, et al. J Lipid Res. 2007;48:1488-1498.
4. Brown MS, Goldstein JL. Science. 1986;232:34-47.
5. Horton JD, Cohen JC, Hobbs HH. J Lipid Res. 2009;50(suppl):S172-S177.

VIEW VIDEO

http://www.cholesterolneversleeps.com/what-is-pcsk9.html?WT.z_co=A&WT.z_in=DSY&WT.z_ch=DSPWT.z_ag=AG705&WT.tsrc=DSP&WT.mc_id=DSY_DSP_AG705_DSP

 

PCSK9 gene mutations can have profound effects on plasmaLDL-C levels¹

PCSK9 Loss of Function Mutations

Increase LDLR levels on the surface of the hepatocyte, which leads to an increase in LDL clearance, resulting in low plasma LDL-C levels^2,3

PCSK9 Gain of Function Mutations

Decrease LDLR levels on the surface of the hepatocyte, which leads to a reduction in LDL clearance, resulting in high plasma LDL-C levels^2,3

PCSK9 and Cholesterol Homeostasis

• The Biology of Cholesterol Synthesis and Metabolism

HMG-COA REDUCTASE IS THE RATE-CONTROLLING ENZYME IN CHOLESTEROL BIOSYNTHESIS.¹

Both HMG-CoA reductase and LDLRs are tightly regulated and can be increased or decreased, affecting cholesterol synthesis and homeostasis.²

HMG-CoA
Reductase

Incoming hepatic cholesterol suppresses HMG-CoA reductase, turning off cholesterol synthesis in the cell.¹

LDLR

In addition, LDLR synthesis is turned off, preventing further entry of LDL and protecting cells against an overaccumulation of cholesterol.¹

Recycling of LDLRs enables efficient clearance of plasma LDL particles.²

LDLRs bind to LDL particles and transport them into the hepatocyte. The LDL particles then dissociate from the LDLRs and are broken down. The LDLRs are then free to recycle back to the cell surface and bind to additional LDL particles, clearing them from the blood.² The ability of LDLRs to be recycled is key to the liver’s ability to lower plasma LDL-C levels.

PCSK9 regulates the recycling of LDLRs by targeting the LDLR for degradation³

While HMG-CoA reductase plays a critical role in cholesterol biosynthesis, PCSK9 plays a critical role in cholesterol metabolism.^4,5 By promoting LDLR degradation within hepatocytes, PCSK9 reduces the concentration of LDLRs on the hepatocyte surface, resulting in increased plasma LDL-C levels.³

SOURCE

AMGEN Cardiovascular

http://www.cholesterolneversleeps.com/what-is-pcsk9.html

Over 20 related articles published on PCSK9 in Cholesterol Regulation on this Open Access Scientific Journal, include the following:

http://pharmaceuticalintelligence.com/?s=PCSK9

and

Series A: e-Books on Cardiovascular Diseases

Series A Content Consultant: Justin D Pearlman, MD, PhD, FACC

• Volume One: Perspectives on Nitric Oxide in Disease Mechanisms
• Cover Page to CVD e-Volumes II, III, IV
• Volume Two: Cardiovascular Original Research: Cases in Methodology Design for Content Co-Curation
• Volume Three: Etiologies of Cardiovascular Diseases – Epigenetics, Genetics and Genomics
• Volume Four: Therapeutic Promise: Cardiovascular Diseases, Regenerative & Translational Medicine
• Volume Five: Pharmacological Agents in Treatment of Cardiovascular Diseases
• Volume Six: Interventional Cardiology, Cardiac Surgery and Cardiovascular Imaging for Disease Diagnosis and Guidance of Treatment

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Two Mutations, in the PCSK9 Gene: Eliminates a Protein involved in Controlling LDL Cholesterol

Posted in Biomarkers & Medical Diagnostics, Chemical Biology and its relations to Metabolic Disease, Genome Biology, Genomic Testing: Methodology for Diagnosis, PCSK9 Inhibitor Therapy, Personalized and Precision Medicine & Genomic Research, tagged African American, Cardiovascular disease, Elias Zerhouni, Food and Drug Administration, LDL, Low-density lipoprotein, National Institutes of Health, Sanofi, Texas Medical Center, World Health Organization on April 15, 2013| 2 Comments »

Two Mutations, in the PCSK9 Gene: Eliminates a Protein involved in Controlling LDL Cholesterol

Reporter: Aviva Lev-Ari, PhD, RN

UPDATED on 11/15/2013

Relax, PCSK9ers: FDA won’t roadblock blockbusters from Sanofi, Amgen

By Damian Garde

On the heels of new guidelines casting doubts on a much-hyped new class of cholesterol drugs, the FDA said it would not demand long and costly outcomes trials before approving PCSK9 treatments from the likes of Amgen ($AMGN), Sanofi ($SNY) and Regeneron ($REGN), clearing the way for treatments expected to rake in up to $3 billion a year.

As Bloomberg reports, the FDA plans to stick to its guns in vetting cardiovascular drugs, looking at reductions in LDL cholesterol and blood pressure as surrogate endpoints for long-term health benefits. That’s a relief for the developers of PCSK9-targeting drugs, who have faced mounting uncertainty about what they’ll need to do to get their would-be blockbusters to market. Partners Sanofi and Regeneron lead the pack with the promising alirocumab, followed by Amgen, Pfizer ($PFE) and numerous others.

Earlier this week, the American College of Cardiology and the American Heart Association put out new guidelines for prescribing cholesterol treatments, recommending tried-and-true statins over more novel therapies because the old drugs’ down-the-line cardiovascular benefits are well-told. That stirred up long-running concerns that the FDA would toughen up its requirements for the coming crop of PCSK9 treatments, asking drug developers to dump millions into long-term studies that demonstrate hard outcomes

But while PCSK9 developers may not have to worry about new regulatory hurdles, what’s good enough for the FDA won’t necessarily sway payers, and the billion-dollar sales estimates tied to PCSK9 drugs are contingent on widespread adoption. With that in mind, Pfizer is plotting a massive, 22,000-patient outcomes trial, looking to demonstrate the PCSK9-targeting RN-316’s ability to improve cardiovascular health in the long run, a move that may spur its competitors to follow suit.

And the FDA’s conventional wisdom on cardiovascular endpoints may not stand pat. Eric Colman, a deputy director at CDER, told Bloomberg the agency is keeping a close eye on a post-market study of Merck’s ($MRK) Vytorin, and if the drug’s LDL-lowering ability doesn’t translate to lower rates of cardiovascular events, it may well rethink its requirements.

Related Articles:

AstraZeneca wins, Merck and AbbVie lose with new statin-use guidelines

Sanofi, Regeneron take the lead in blockbuster PhIII race of PCSK9 drugs

Pfizer bets big on PCSK9 with ‘massive’ Phase III outcomes study

 SOURCE

From: FierceBiotech <editors@fiercebiotech.com>
Reply-To: <editors@fiercebiotech.com>
Date: Fri, 15 Nov 2013 17:56:42 +0000 (GMT)
To: <avivalev-ari@alum.berkeley.edu>
Subject: | 11.15.13 | Sanofi, Amgen dodge PCSK9 hurdles

 

http://www.nature.com/news/genetics-a-gene-of-rare-effect-1.12773?goback=%2Egde_96118_member_230797138

Genetics: A Gene of Rare Effect

A mutation that gives people rock-bottom cholesterol levels has led geneticists to what could be the next blockbuster heart drug.

Stephen S. Hall

09 April 2013

ADAPTED FROM: PETER DAZELEY/GETTY

Indeed, Tracy’s well-being has been inspiring to doctors, geneticists and now pharmaceutical companies precisely because she is so normal. Using every tool in the modern diagnostic arsenal — from brain scans and kidney sonograms to 24-hour blood-pressure monitors and cognitive tests — researchers at the Texas medical centre have diagnostically sliced and diced Tracy to make sure that the two highly unusual genetic mutations she has carried for her entire life have produced nothing more startling than an incredibly low level of cholesterol in her blood. At a time when the target for low-density lipoprotein (LDL) cholesterol, more commonly called ‘bad cholesterol’, in Americans’ blood is less than 100 milligrams per decilitre (a level many people fail to achieve), Tracy’s level is just 14.

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• Cholesterol limits lose their lustre
• ENCODE: The human encyclopaedia
• Humans riddled with rare genetic variants

More related stories

A compact woman with wide-eyed energy, Tracy (not her real name) is one of a handful of African Americans whose genetics have enabled scientists to uncover one of the most promising compounds for controlling cholesterol since the first statin drug was approved by the US Food and Drug Administration in 1987. Seven years ago, researchers Helen Hobbs and Jonathan Cohen at UT-Southwestern reported¹ that Tracy had inherited two mutations, one from her father and the other from her mother, in a gene called PCSK9, effectively eliminating a protein in the blood that has a fundamental role in controlling the levels of LDL cholesterol. African Americans with similar mutations have a nearly 90% reduced risk of heart disease. “She’s our girl, our main girl,” says Barbara Gilbert, a nurse who has drawn some 8,000 blood samples as part of Cohen and Hobbs’ project to find genes important to cholesterol metabolism.

Of all the intriguing DNA sequences spat out by the Human Genome Project and its ancillary studies, perhaps none is a more promising candidate to have a rapid, large-scale impact on human health than PCSK9. Elias Zerhouni, former director of the US National Institutes of Health (NIH) in Bethesda, Maryland, calls PCSK9 an “iconic example” of translational medicine in the genomics era. Preliminary clinical trials have already shown that drugs that inhibit the PCSK9 protein — used with or without statins — produce dramatic reductions in LDL cholesterol (more than 70% in some patients). Half-a-dozen pharmaceutical companies — all aiming for a share of the global market for cholesterol-reducing drugs that could reach US$25 billion in the next five years according to some estimates — are racing to the market with drugs that mimic the effect of Tracy’s paired mutations.

Free interview

Stephen Hall talks about Sharlayne’s unusual condition and whether similar cases might lead to a new line of drugs.

Zerhouni, now an in-house champion of this class of drug as an executive at drug firm Sanofi, headquartered in Paris, calls the discovery and development of PCSK9 a “beautiful story” in which researchers combined detailed physical information about patients with shrewd genetics to identify a medically important gene that has made “super-fast” progress to the clinic. “Once you have it, boy, everything just lines up,” he says. And although the end of the PCSK9 story has yet to be written — the advanced clinical trials now under way could still be derailed by unexpected side effects — it holds a valuable lesson for genomic research. The key discovery about PCSK9‘s medical potential was made by researchers working not only apart from the prevailing scientific strategy of genome research over the past decade, but with an almost entirely different approach.

As for Tracy, who lives in the southern part of Dallas County, the implications of her special genetic status have become clear. “I really didn’t understand at first,” she admits. “But now I’m watching ads on TV [for cholesterol-lowering drugs], and it’s like, ‘Wow, I don’t have that problem’.”

A heart problem

Cardiovascular disease is — and will be for the foreseeable future, according to the World Health Organization — the leading cause of death in the world, and its development is intimately linked to elevated levels of cholesterol in the blood. Since their introduction, statin drugs have been widely used to lower cholesterol levels. But Jan Breslow, a physician and geneticist at Rockefeller University in New York, points out that up to 20% of patients cannot tolerate statins’ side effects, which include muscle pain and even forgetfulness. And in many others, the drugs simply don’t control cholesterol levels well enough.

The search for better treatments for heart disease gained fresh impetus after scientists published the draft sequence of the human genome in 2001. In an effort to identify the genetic basis of common ailments such as heart disease and diabetes, geneticists settled on a strategy based on the ‘common variant hypothesis’. The idea was that a handful of disease-related versions (or variants) of genes for each disease would be common enough — at a frequency of roughly 5% or so — to be detected by powerful analyses of the whole genome. Massive surveys known as genome-wide association studies compared the genomes of thousands of people with heart disease, for example, with those of healthy controls. By 2009, however, many scientists were lamenting the fact that although the strategy had identified many common variants, each made only a small contribution to the disease. The results for cardiovascular disease have been “pretty disappointing”, says Daniel Steinberg, a lipoprotein expert at the University of California, San Diego.

Single-minded: Helen Hobbs and Jonathan Cohen’s approach to heart-disease genetics yielded a target for drugs that could compete with statins.MISTY KEASLER/REDUX/EYEVINE

More than a decade earlier, in Texas, Hobbs and Cohen had taken the opposite tack. They had backgrounds in Mendelian, or single-gene, disorders, in which an extremely rare variant can have a big — often fatal — effect. They also knew that people with a particular Mendelian disorder didn’t share a single common mutation in the affected gene, but rather had a lot of different, rare mutations. They hypothesized that in complex disorders, many different rare variants were also likely to have a big effect, whereas common variants would have relatively minor effects (otherwise natural selection would have weeded them out). “Jonathan and I did not see any reason why it couldn’t be that rare variants cumulatively contribute to disease,” Hobbs says. To find these rare variants, the pair needed to compile detailed physiological profiles, or phenotypes, of a large general population. Cohen spoke of the need to “Mendelize” people — to compartmentalize them by physiological traits, such as extremely high or low cholesterol levels, and then look in the extreme groups for variations in candidate genes known to be related to the trait.

The pair make a scientific odd couple. Hobbs, who trained as an MD, is gregarious, voluble and driven. Cohen, a soft-spoken geneticist from South Africa, has a laid-back, droll manner and a knack for quantitative thinking. In 1999, they set out to design a population-based study that focused on physical measurements related to heart disease. Organized with Ronald Victor, an expert on high blood pressure also at UT Southwestern, and funded by the Donald W. Reynolds Foundation in Las Vegas, Nevada, the Dallas Heart Study assembled exquisitely detailed physiological profiles on a population of roughly 3,500 Dallas residents². Crucially, around half of the participants in the study were African Americans, because the researchers wanted to probe racial differences in heart disease and high blood pressure. The team measured blood pressure, body mass index, heart physiology and body-fat distribution, along with a battery of blood factors related to cholesterol metabolism — triglycerides, high-density lipoprotein (HDL) cholesterol and LDL cholesterol. In the samples of blood, of course, they also had DNA from each and every participant.

As soon as the database was completed in 2002, Hobbs and Cohen tested their rare-variant theory by looking at levels of HDL cholesterol. They identified the people with the highest (95th percentile) and lowest (5th percentile) levels, and then sequenced the DNA of three genes known to be key to metabolism of HDL cholesterol. What they found, both in Dallas and in an independent population of Canadians, was that the number of mutations was five times higher in the low HDL group than in the high group³. This made sense, Cohen says, because most human mutations interfere with the function of genes, which would lead to the low HDL numbers. Published in 2004, the results confirmed that rare, medically important mutations could be found in a population subdivided into extreme phenotypes.

Armed with their extensive database of cardiovascular traits, Hobbs and Cohen could now dive back into the Dallas Heart Study whenever they had a new hypothesis about heart disease and, as Cohen put it, “interrogate the DNA”. It wasn’t long before they had an especially intriguing piece of DNA at which to look.

The missing link

In February 2003, Nabil Seidah, a biochemist at the Clinical Research Institute of Montreal in Canada, and his colleagues reported the discovery of an enigmatic protein⁴. Seidah had been working on a class of enzymes known collectively as proprotein convertases, and the researchers had identified what looked like a new member of the family, called NARC-1: neural apoptosis-regulated convertase 1.

“We didn’t know what it was doing, of course,” Seidah says. But the group established that the gene coding the enzyme showed activity in the liver, kidney and intestines as well as in the developing brain. The team also knew that in humans the gene mapped to a precise genetic neighbourhood on the short arm of chromosome 1.

That last bit of geographical information pointed Seidah to a group led by Catherine Boileau at the Necker Hospital in Paris. Her team had been following families with a genetic form of extremely high levels of LDL cholesterol known as familial hypercholesterolaemia, which leads to severe coronary artery disease and, often, premature death. Group member Marianne Abifadel had spent five fruitless years searching a region on the short arm of chromosome 1 for a gene linked to the condition. When Seidah contacted Boileau and told her that he thought NARC-1 might be the gene she was looking for, she told him, “You’re crazy”, Seidah recalls. Seidah bet her a bottle of champagne that he was correct; within two weeks, Boileau called back, saying: “I owe you three bottles.”

“The PCSK9 story is a terrific example of an up-and-coming pattern of translational research.”

In 2003, the Paris and Montreal groups reported that the French families with hypercholesterolaemia had one of two mutations in this newly discovered gene, and speculated that this might cause increased production of the enzyme⁵. Despite Seidah’s protests, the journal editors gave both the gene and its protein product a new name that fit with standard nomenclature: proprotein convertase subtilisin/kexin type 9, or PCSK9. At around the same time, Kara Maxwell in Breslow’s group at Rockefeller University⁶ and Jay Horton, a gastroenterologist at UT-Southwestern⁷ also independently identified the PCSK9 gene in mice and revealed its role in a previously unknown pathway regulating cholesterol⁸.

The dramatic phenotype of the French families told Hobbs that “this is an important gene”. She also realized that in genetics, mutations that knock out a function are much more common than ones that amplify function, as seemed to be the case with the French families. “So immediately I’m thinking, a loss-of-function mutation should manifest as a low LDL level,” she says. “Let’s go and see if that’s true.”

Going to extremes

Hobbs and Cohen had no further to look than in the extreme margins of people in the Dallas Heart Study. In quick order, they identified the highest and lowest LDL readings in four groups: black women, black men, white women and white men. They then resequenced the PCSK9 gene in the low-cholesterol groups, looking for mutations that changed the make-up of the protein.

They found seven African Americans with one of two distinct ‘nonsense’ mutations in PCSK9 — mutations that essentially aborted production of the protein. Then they went back and looked for the same mutations in the entire population. Just 2% of all black people in the Dallas study had either of the two PCSK9 mutations — and those mutations were each associated with a 40% reduction of LDL cholesterol in the blood⁹. (The team later detected a ‘missense mutation’ in 3% of white people, which impaired but did not entirely block production of the protein.) The frequency of the mutations was so low, Hobbs says, that they would never have shown up in a search for common variants.

When Hobbs and Cohen published their findings in 2005, they suggested that PCSK9 played a crucial part in regulating bad cholesterol, but said nothing about whether the mutations had any effect on heart disease. That evidence came later that year, when they teamed up with Eric Boerwinkle, a geneticist at the University of Texas Health Science Center in Houston, to look forPCSK9 mutations in the Atherosclerosis Risk in Communities (ARIC) study, a large prospective study of heart disease that had been running since 1987. To experts such as Steinberg, the results¹⁰ — published in early 2006 — were “mind-blowing”. African Americans in ARIC who had mutations in PCSK9 had 28% less LDL cholesterol and an 88% lower risk of developing heart disease than people without the mutations. White people with the less severe mutation in the gene had a 15% reduction in LDL and a 47% reduced risk of heart disease.

How did the gene exert such profound effects on LDL cholesterol levels? As researchers went on to determine¹¹, the PCSK9 protein normally circulates in the bloodstream and binds to the LDL receptor, a protein on the surface of liver cells that captures LDL cholesterol and removes it from the blood. After binding with the receptor, PCSK9 escorts it into the interior of the cell, where it is eventually degraded. When there is a lot of PCSK9 (as in the French families), there are fewer LDL receptors remaining to trap and remove bad cholesterol from the blood. When there is little or no PCSK9 (as in the black people with mutations), there are more free LDL receptors, which in turn remove more LDL cholesterol.

“We didn’t understand why everybody wasn’t doing what we were doing.”

The UT-Southwestern group, meanwhile, went back into the community looking for family members who might carry additional PCSK9 mutations. In September 2004, Gilbert, the nurse known as ‘the cholesterol lady’ in south Dallas because of her frequent visits, knocked on the door of Sharlayne Tracy’s mother, an original member of the Dallas Heart Study. Gilbert tested Tracy, as well as her sister, brother and father. “They tested all of us, and I was the lowest,” Tracy says. Zahid Ahmad, a doctor working with Hobbs at UT-Southwestern, was one of the first to look at Tracy’s lab results. “Dr Zahid was in awe,” Tracy recalled. “He said, ‘You’re not supposed to be so healthy!’.”

It wasn’t just that her LDL cholesterol measured 14. As a person with two dysfunctional copies of the gene — including a new type of mutation — Tracy was effectively a human version of a knockout mouse. The gene had been functionally erased from her genome, and PCSK9 was undetectable in her blood without any obvious untoward effects. The genomics community might have been a little slow to understand the significance, Hobbs says, “but the pharmaceutical companies got it right away”.

The next statin?

This being biology, however, the road to the clinic was not completely smooth. The particular biology of PCSK9 has so far thwarted efforts to find a small molecule that would interrupt its interaction with the LDL receptor and that could be packaged in a pill. But the fact that the molecule operates outside cells means that it is vulnerable to attack by monoclonal antibodies — one of the most successful (albeit most expensive) forms of biological medicine.

The results of early clinical trials have caused a stir. Regeneron Pharmaceuticals of Tarrytown, New York, collaborating with Sanofi, published phase II clinical-trial results¹² last October showing that patients with high LDL cholesterol levels who had injections every two weeks of an anti-PCSK9 monoclonal antibody paired with a high-dose statin saw their LDL cholesterol levels fall by 73%; by comparison, patients taking high-dose statins alone had a decrease of just 17%. Last November, Regeneron and Sanofi began to recruit 18,000 patients for phase III trials that will test the ability of their therapy to cut cardiovascular events, including heart attacks and stroke. Amgen of Thousand Oaks, California, has also launched several phase III trials of its own monoclonal antibody after it reported similarly promising results¹³. Among other companies working on PCSK9-based therapies are Pfizer headquartered in New York, Roche based in Basel, Switzerland, and Alnylam Pharmaceuticals of Cambridge, Massachusetts. (Hobbs previously consulted for Regeneron and Pfizer, and now sits on the corporate board of Pfizer.)

Not everyone is convinced that a huge market awaits this class of cholesterol-lowering drugs. Tony Butler, a financial analyst at Barclays Capital in New York, acknowledges the “beautiful biology” of the PCSK9 story, but wonders if the expense of monoclonal drugs — and a natural reluctance of both patients and doctors to use injectable medicines — will constrain potential sales. “I have no idea what the size of the market may be,” he says.

“Everything hinges on the phase III side effects,” says Steinberg. So far, the main side effects reported have been minor, such as reactions at the injection site, diarrhoea and headaches. But animal experiments have raised potential red flags: the Montreal lab reported in 2006 that knocking out the gene in zebrafish is lethal to embryos¹⁴. That is why the case of Tracy was “very, very helpful” to drug companies, says Hobbs. Although her twin mutations have essentially deprived her of PCSK9 throughout her life, doctors have found nothing abnormal about her.

That last point may revive a debate in the cardiology community: should drug therapy to lower cholesterol levels, including statins and the anti-PCSK9 medicines, if they pan out, be started much earlier in patients than their 40s or 50s? That was the message Steinberg took from the people withPCSK9 mutations in the ARIC study — once he got over his shock at the remarkable health effects. “My first reaction was, ‘This must be wrong. How could that be?’And then it hit me — these people had low LDL from the day they were born, and that makes all the difference.” Steinberg argues that cardiologists “should get off our bums” and reach a consensus about beginning people on cholesterol-lowering therapy in their early thirties. But Breslow, a former president of the American Heart Association, cautions against being too aggressive too soon. “Let’s start out with the high-risk individuals and see how they do,” he says.

Not long after Hobbs and Cohen published their paper in 2006, they began to get invited to give keynote talks at major cardiology meetings. Soon after, the genetics community began to acknowledge the strength of their approach. In autumn 2007, then-NIH director Zerhouni organized a discussion at the annual meeting of the institutes’ directors to raise the profile of the rare-variant approach and contrast it with genome-wide studies. “Obviously, the two approaches are opposed to each other, and the question was, what was the relative value of each?” says Zerhouni. “I thought the PCSK9 story was a terrific example of an up-and-coming pattern of translational research” — indeed, he adds, “a harbinger of things to come”.

Hobbs and Cohen might not have found their gene if they had not had a hunch about where to look, but improved sequencing technology and decreasing costs now allow genomicists to incorporate the rare variant approach and to mount large-scale sweeps in search of such variants. “Gene sequencing is getting cheap enough that if there’s another gene like PCSK9 out there, you could probably find it genome-wide,” says Jonathan Pritchard, a population biologist at the University of Chicago, Illinois.

“What was amazing to us,” says Hobbs, “was that the genome project was spending all this time, energy, effort sequencing people, and they weren’t phenotyped, so there was no potential for discovery. We didn’t understand, and couldn’t understand, why everybody wasn’t doing what we were doing. Particularly when we started making discoveries.”

SOURCE:

Nature 496, 152–155 (11 April 2013) doi:10.1038/496152a

References

1. Zhao, Z. et al. Am. J. Hum. Genet. 79, 514–523 (2006).
   • Article
   • PubMed
   • ISI
   • ChemPort

   Show context

2. Victor, R. G. et al. Am. J. Cardiol. 93, 1473–1480 (2004).
   • Article
   • PubMed
   • ISI

   Show context

3. Cohen, J. C. et al. Science 305, 869–872 (2004).
   • Article
   • PubMed
   • ISI
   • ChemPort

   Show context

4. Seidah, N. G. et al. Proc. Natl Acad. Sci. USA 100, 928–933 (2003).
   • Article
   • PubMed
   • ChemPort

   Show context

5. Abifadel, M. et al. Nature Genet. 34, 154–156 (2003).
   • Article
   • PubMed
   • ISI
   • ChemPort

   Show context

6. Maxwell, K. N., Soccio, R. E., Duncan, E. M., Sehayek, E. & Breslow, J. L. J. Lipid Res. 44,2109–2119 (2003).
   • Article
   • PubMed
   • ISI
   • ChemPort

   Show context

7. Horton, J. D. et al. Proc. Natl Acad. Sci. USA 100, 12027–12032 (2003).
   • Article
   • PubMed
   • ChemPort

   Show context

8. Maxwell, K. N. & Breslow, J. L. Proc. Natl Acad. Sci. USA 101, 7100–7105 (2004).
   • Article
   • PubMed
   • ChemPort

   Show context

9. Cohen, J. et al. Nature Genet. 37, 161–165 (2005).
   • Article
   • PubMed
   • ChemPort

   Show context

10. Cohen, J. C., Boerwinkle, E., Mosley, T. H. Jr & Hobbs, H. H. N. Engl. J. Med. 354, 1264–1272(2006).
    • Article
    • PubMed
    • ISI
    • ChemPort

    Show context

11. Horton, J. D., Cohen, J. C. & Hobbs, H. H. J. Lipid Res. 50, S172–S177 (2009).
    • Article
    • PubMed
    • ISI
    • ChemPort

    Show context

12. Roth, E. M., McKenney, J. M., Hanotin, C., Asset, G. & Stein, E. A. N. Engl. J. Med. 367,1891–1900 (2012).
    • Article
    • PubMed
    • ISI
    • ChemPort

    Show context

13. Koren, M. J. et al. Lancet 380, 1995–2006 (2012).
    • Article
    • PubMed
    • ISI
    • ChemPort

    Show context

14. Poirier, S. et al. J. Neurochem. 98, 838–850 (2006).
    • Article
    • PubMed
    • ISI
    • ChemPort

    Show context

Related stories and links

From nature.com

• Cholesterol limits lose their lustre

  26 February 2013

• ENCODE: The human encyclopaedia

  05 September 2012

• Humans riddled with rare genetic variants

  17 May 2012

• Human genome at ten: Life is complicated

  31 March 2010

• Hiding place for missing heritability uncovered

  25 January 2010

• Personal genomes: The case of the missing heritability

  05 November 2008

• Nature speical: ENCODE

• Nature special: Human genome at 10

• Nature human genome issue, 2001

From elsewhere

• Hobbs-Cohen lab

Author information

Affiliations

1. Stephen S. Hall is a science writer in New York who also teaches public communication to graduate students in science at New York University.

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