The role of ezetimibe in lowering plasma cholesterol has been established; however, controversy remains about its clinical benefit. A recent study utilizes naturally occurring genetic variation within the NPC1-like 1 gene (NPC1L1) to demonstrate the potential for pharmacologic inhibition of the protein to reduce the risk of coronary heart disease. This research demonstrates the application of the concept of genocopy to a population-based validation of NPC1L1 as a therapeutic target

Corbin, Laura J

Timpson, Nicholas John

Genome Medicine

PubMed

Explore Bristol Research

                          Corbin, L. J., & Timpson, N. J. (2015). Using inactivating mutations toprovide insight into drug action. Genome Medicine, 7(1), [7].10.1186/s13073-015-0130-xPublisher's PDF, also known as Final Published VersionLink to published version (if available):10.1186/s13073-015-0130-xLink to publication record in Explore Bristol ResearchPDF-documentUniversity of Bristol - Explore Bristol ResearchGeneral rightsThis document is made available in accordance with publisher policies. Please cite only the publishedversion using the reference above. Full terms of use are available:http://www.bristol.ac.uk/pure/about/ebr-terms.htmlTake down policyExplore Bristol Research is a digital archive and the intention is that deposited content should not beremoved. However, if you believe that this version of the work breaches copyright law please contactopen-access@bristol.ac.uk and include the following information in your message:• Your contact details• Bibliographic details for the item, including a URL• An outline of the nature of the complaintOn receipt of your message the Open Access Team will immediately investigate your claim, make aninitial judgement of the validity of the claim and, where appropriate, withdraw the item in questionfrom public view.RESEARCH HIGHLIGHTUsing inactivating mutations to provide insightinto drug actionLaura J Corbin* and Nicholas J TimpsonAbstractThe role of ezetimibe in lowering plasma cholesterol hasbeen established; however, controversy remains about itsclinical benefit. A recent study utilizes naturally occurringgenetic variation within the NPC1-like 1 gene (NPC1L1) todemonstrate the potential for pharmacologic inhibitionof the protein to reduce the risk of coronary heartdisease. This research demonstrates the applicationof the concept of genocopy to a population-basedvalidation of NPC1L1 as a therapeutic target.Ezetimibe as an adjunct to statin therapy incardiovascular diseaseCardiovascular diseases (CVDs) are the primary cause ofdeath globally [1]. In 2008, 30% of all global deaths wereattributed to CVDs, including an estimated 7.3 milliondeaths caused by coronary heart disease (CHD) [1]. Asa major risk factor for CHD, increased circulating chol-esterol - particularly low-density lipoprotein choles-terol (LDL-C) - is a well-established target for clinicalintervention. Although treatment with 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) inhibitors(statins) has been shown both to lower LDL-C levels andto reduce major cardiovascular events, in some cases sta-tin therapy alone is insufficient to achieve optimal LDL-Clevels [2]. Currently, ezetimibe, which inhibits the functionof the NPC1L1 protein, can be prescribed alongside sta-tins in order to achieve further reductions in LDL-C or asan alternative in instances where statins are contraindi-cated. Whilst the ability of ezetimibe to independently andadditively lower LDL-C beyond the levels achieved bystatins alone does not appear to be in question, the degreeto which the drug contributes to a reduction in the risk ofclinically relevant cardiovascular outcomes such as CHDis unclear.* Correspondence: laura.corbin@bristol.ac.ukMRC Integrative Epidemiology Unit (IEU), University of Bristol, Oakfield House,Oakfield Grove, Bristol BS8 2BN, UKNumerous trials have been conducted to assess theclinical utility of LDL-C-lowering therapies in reducingthe incidence of CVD. The Pravastatin or AtorvastatinEvaluation and Infection Therapy Trial (PROVE-IT)demonstrated that more intensive lipid lowering achievedthrough an increased statin dose clinically benefited pa-tients who had previously suffered an acute coronary syn-drome [3]. However, whether the same benefits can beachieved by prescribing ezetimibe alongside statins toachieve similar reductions in LDL-C remains uncertainowing to inconsistent trial outcomes, particularly whereendpoints such as carotid intimal thickening and vascularreactivity have been used as surrogates for CVD risk [2].Two of the largest randomized control trials (RCTs)designed to determine whether adding ezetimibe to statinsprovides clinical benefit (over and above statin monother-apy) carried out to date are the Ezetimibe and Simvastatinin Hypercholesterolemia Enhances Atherosclerosis Regres-sion (ENHANCE) trial and IMProved Reduction of Out-comes: Vytorin Efficacy International Trial (IMPROVE-IT).The ENHANCE trial (in which patients with heterozygousfamilial hypercholesterolemia received simvastatin with orwithout ezetimibe) was designed to study the effect of ezeti-mibe on the progression of atherosclerosis, using carotidintima-media thickness (IMT) as a target endpoint. In thistrial, the addition of ezetimibe to simvastatin therapy in thetreatment of familial hypercholesterolemia did not producea reduction in carotid IMT, despite achieving a differentialreduction in LDL-C [4]. This result was contrary to findingsof similar trials conducted around the same time [2]. InNovember 2014, preliminary results of the landmarkIMPROVE-IT, designed to determine whether adding eze-timibe to simvastatin in patients presenting with acutecoronary syndromes adds clinical benefit by further redu-cing major cardiovascular events compared with simva-statin monotherapy [5], were presented at the AmericanHeart Association Annual Meeting (Chicago, IL, Nov.15-19, 2014). Although a full description of the findingsis yet to be published, preliminary results apparentlysuggest a modest benefit in reducing cardiovascular events© 2015 Corbin and Timpson; licensee BioMed Central. This is an Open Access article distributed under the terms of theCreative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use,distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons PublicDomain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in thisarticle, unless otherwise stated.Corbin and Timpson Genome Medicine  (2015) 7:7 DOI 10.1186/s13073-015-0130-xwith the addition of ezetimibe to simvastatin in thispopulation of around 18,000 patients from 39 countries.However, overall, the discordant results of studies carriedout to date has generated a degree of scepticism aboutwhether ezetimibe offers any health benefits above and be-yond those afforded by statin therapy.Using a population-based approach theoretically derivedfrom the concept of genocopy, Stitziel et al. [6] offer evi-dence to strengthen inference from existing observationaland RCT studies and to inform future research. The term‘genocopy’ refers to genetic variation that generates anoutcome similar to that produced by an environmentalexposure [7]. An illustrative example of this phenomenonis the autosomal recessive condition of Hartnup disease.This disease is caused by a mutation in solute carrier fam-ily 6 member 19 (SLC6A19; the ‘genocopy’) but a verysimilar clinical manifestation occurs in cases of dietaryniacin deficiency, a condition known as pellagra (the‘phenocopy’). Using a Mendelian randomization approachthat takes advantage of the properties of genetic variationand follows similar logic (such that mutations in NCP1L1act as genocopies mimicking the action of ezetimibe),Stitziel et al. [6] attempt to separate causation from asso-ciation, providing validation of NCP1L1 as a therapeutictarget.Using human genetics to validate the role ofNCP1L1 in coronary heart diseaseUsing sequence data from over 22,000 individuals ofvarying ancestry, Stitziel and colleagues [6] identify 15mutations that are predicted to inactivate NCP1L1. Themutations lie within one of the gene’s 20 protein-codingexons and, for the researchers to consider them as inacti-vating, they had to be classified as nonsense, splice-site orframeshift mutations. The variants identified are rare, be-ing found in only around 1 in 650 participants, and exist-ing only in a heterozygous state. The most frequentlyobserved mutation was p.Arg406X, which had a minor al-lele frequency of 0.02% among participants of Europeanancestry. Stitziel and co-workers [6] went on to genotypethis variant in a further nine independent sample sets,totalling 91,002 participants. This targeted genotypingafforded the study a considerable gain in statistical power,increasing the number of participants carrying an inacti-vating variant from 34 in 22,092 to 82 in 113,094.Data obtained for all the participants in the study in-cluded medical history and laboratory assessments for car-diovascular risk factors. These data were combined withthe genetic data, firstly to test the association betweenNCP1L1 protein-activating mutations and plasma lipidlevels, and subsequently to test for an association betweenthese same mutations and risk of CHD. Associationanalyses revealed that carriers of any of the NCP1L1inactivating mutations identified had lower levels oftotal cholesterol, LDL-C and triglycerides. In an analysisthat was restricted to participants characterized as beingfree from CHD, the mean LDL-C level was 12 mg perdecilitre lower in carriers of an inactivating mutation thanin non-carriers, while no difference was observed in high-density lipoprotein cholesterol.Having used the clinical data available for each studyto define CHD status, Stitziel et al. [6] went on to dem-onstrate an odds ratio for the disease among carriers ofinactivating mutations of 0.47 (95% confidence interval,0.25 to 0.87). The odds ratio was calculated based oncarrier frequencies of 0.04% in 29,954 patients with CHDcompared with frequencies of 0.09% in 83,140 unaffectedparticipants. The apparent protective effect of NCP1L1protein-inactivating mutations against high plasma lipidlevels and CHD observed in the entire cohort was alsoevident when the analysis was conducted separately inEuropean and African subgroups.Clinical interpretationBy using naturally occurring genetic variants, Stitziel andcolleagues [6] exploit a natural experiment that simulatesthe effect of exposure to ezetimibe and avoids many of thepitfalls associated with traditional observational studies.Of course, when interpreting the results of such studies itis important to take into consideration (as Stitziel and co-workers [6] do) that genetic models, such as this one forNCP1L1 inactivation, are not a perfect proxy for pharma-cologic therapy. For example, one important caveat is thatthe drug could have off-target effects that may not bemodelled in the case of a single-gene framework. How-ever, when it comes to modelling the long-term effectsof treatment, such Mendelian randomization-style ap-proaches are well placed to detect life course effects.Genetic variation can provide a natural life coursemodel because it represents lifetime exposure to theeffects of mutation, which in this case mirrors the ac-tion of ezetimibe [8,9].The use of genetic variation to assess drug effects is anestablished approach and the identification of novel rarevariants of large effect adds to its potential. Whether theuse of such variants provides benefits over and abovethose seen using common variants is unclear, but it ispossible that the resultant genetic model is one thatmore closely resembles the drug effect being simulatedand has greater power to detect differences in diseaserisk because of the relatively large effect sizes observed.Whether or not this is the case will likely become cleareras more studies are published, with some insight alreadyhaving been provided in a similar study in which multiplemutations in NCP1L1 and HMGCR were considered inconcert using a genetic score approach to explore the im-pact of combination therapy with statins and ezetimibe onCHD risk [10]. There are many situations in which theCorbin and Timpson Genome Medicine  (2015) 7:7 Page 2 of 3approach taken by Stitziel et al. [6] could be utilized,but one particularly important application might be inproviding validation of proposed therapeutic targetsbefore the clinical trial stage.AbbreviationsCHD: Coronary heart disease; CVD: Cardiovascular disease; IMPROVE-IT: IMProvedReduction of Outcomes: Vytorin Efficacy International Trial; IMT: Intima-mediathickness; LDL-C: Low-density lipoprotein cholesterol; PROVE-IT: Pravastatin orAtorvastatin Evaluation and Infection Therapy Trial; RCT: Randomized control trial.Competing interestsThe authors declare that they have no competing interests.AcknowledgmentsLJC and NJT work within the MRC Integrative Epidemiology Unit at theUniversity of Bristol (MC_UU_12013/3).References1. World Health Organization: Cardiovascular Diseases (CVDs): Fact sheet N°317. 2013. http://www.who.int/mediacentre/factsheets/fs317/en/2. Phan BAP, Dayspring TD, Toth PP. Ezetimibe therapy: mechanism of actionand clinical update. Vasc Health Risk Manag. 2012;8:415–27.3. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, et al.Intensive versus moderate lipid lowering with statins after acute coronarysyndromes. N Engl J Med. 2004;350:1495–504.4. Kastelein JJP, Akdim F, Stroes ESG, Zwinderman AH, Bots ML, StalenhoefAFH, et al. Simvastatin with or without ezetimibe in familialhypercholesterolemia. N Engl J Med. 2008;358:1431–43.5. Blazing MA, Giugliano RP, Cannon CP, Musliner TA, Tershakovec AM, WhiteJA, et al. Evaluating cardiovascular event reduction with ezetimibe as anadjunct to simvastatin in 18,144 patients after acute coronary syndromes:final baseline characteristics of the IMPROVE-IT study population. Am HeartJ. 2014;168:205–12.6. The Myocardial Infarction Genetics Consortium Investigators. Inactivatingmutations in NPC1L1 and protection from coronary heart disease. N Engl JMed. 2014;371:2072–82.7. Khoury M, Bedrosian S, Gwinn M, Higgins J, Ioannidis J, Little J. Humangenome epidemiology. 2nd ed. Oxford University Press; 2010.8. The Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR)Consortium. The interleukin-6 receptor as a target for prevention ofcoronary heart disease: a mendelian randomisation analysis. Lancet.2012;379:1214–24.9. Swerdlow DI, Preiss D, Kuchenbaecker KB, Holmes MV, Engmann JEL, ShahT, et al. HMG-coenzyme A reductase inhibition, type 2 diabetes, andbodyweight: evidence from genetic analysis and randomised trials. Lancet2014. doi: 10.1016/S0140-6736(14)61183-1.10. Ference BA, Majeed F, Brook RD, Hedquist L, Penumetcha R, Flack JM. Effectof naturally random allocation to lower LDL-C mediated by polymorphismsin NPC1L1, HMGCR or both on the risk of coronary heart disease: a 2x2factorial Mendelian randomization study [abstract]. Circulation. 2014;130:A19754.Corbin and Timpson Genome Medicine  (2015) 7:7 Page 3 of 3

Using inactivating mutations to provide insight into drug action

Laura J Corbin

Nicholas J Timpson

Crossref

Corbin and Timpson Genome Medicine  (2015) 7:7 DOI 10.1186/s13073-015-0130-xRESEARCH HIGHLIGHTUsing inactivating mutations to provide insightinto drug actionLaura J Corbin* and Nicholas J TimpsonAbstractThe role of ezetimibe in lowering plasma cholesterol hasbeen established; however, controversy remains about itsclinical benefit. A recent study utilizes naturally occurringgenetic variation within the NPC1-like 1 gene (NPC1L1) todemonstrate the potential for pharmacologic inhibitionof the protein to reduce the risk of coronary heartdisease. This research demonstrates the applicationof the concept of genocopy to a population-basedvalidation of NPC1L1 as a therapeutic target.endpoints such as carotid intimal thickening and vascularEzetimibe as an adjunct to statin therapy incardiovascular diseaseCardiovascular diseases (CVDs) are the primary cause ofdeath globally [1]. In 2008, 30% of all global deaths wereattributed to CVDs, including an estimated 7.3 milliondeaths caused by coronary heart disease (CHD) [1]. Asa major risk factor for CHD, increased circulating chol-esterol - particularly low-density lipoprotein choles-terol (LDL-C) - is a well-established target for clinicalintervention. Although treatment with 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) inhibitors(statins) has been shown both to lower LDL-C levels andto reduce major cardiovascular events, in some cases sta-tin therapy alone is insufficient to achieve optimal LDL-Clevels [2]. Currently, ezetimibe, which inhibits the functionof the NPC1L1 protein, can be prescribed alongside sta-tins in order to achieve further reductions in LDL-C or asan alternative in instances where statins are contraindi-cated. Whilst the ability of ezetimibe to independently andadditively lower LDL-C beyond the levels achieved bystatins alone does not appear to be in question, the degreeto which the drug contributes to a reduction in the risk ofclinically relevant cardiovascular outcomes such as CHDis unclear.* Correspondence: laura.corbin@bristol.ac.ukMRC Integrative Epidemiology Unit (IEU), University of Bristol, Oakfield House,Oakfield Grove, Bristol BS8 2BN, UK© 2015 Corbin and Timpson; licensee BioMedCreative Commons Attribution License (http:/distribution, and reproduction in any mediumDomain Dedication waiver (http://creativecomarticle, unless otherwise stated.Numerous trials have been conducted to assess theclinical utility of LDL-C-lowering therapies in reducingthe incidence of CVD. The Pravastatin or AtorvastatinEvaluation and Infection Therapy Trial (PROVE-IT)demonstrated that more intensive lipid lowering achievedthrough an increased statin dose clinically benefited pa-tients who had previously suffered an acute coronary syn-drome [3]. However, whether the same benefits can beachieved by prescribing ezetimibe alongside statins toachieve similar reductions in LDL-C remains uncertainowing to inconsistent trial outcomes, particularly wherereactivity have been used as surrogates for CVD risk [2].Two of the largest randomized control trials (RCTs)designed to determine whether adding ezetimibe to statinsprovides clinical benefit (over and above statin monother-apy) carried out to date are the Ezetimibe and Simvastatinin Hypercholesterolemia Enhances Atherosclerosis Regres-sion (ENHANCE) trial and IMProved Reduction of Out-comes: Vytorin Efficacy International Trial (IMPROVE-IT).The ENHANCE trial (in which patients with heterozygousfamilial hypercholesterolemia received simvastatin with orwithout ezetimibe) was designed to study the effect of ezeti-mibe on the progression of atherosclerosis, using carotidintima-media thickness (IMT) as a target endpoint. In thistrial, the addition of ezetimibe to simvastatin therapy in thetreatment of familial hypercholesterolemia did not producea reduction in carotid IMT, despite achieving a differentialreduction in LDL-C [4]. This result was contrary to findingsof similar trials conducted around the same time [2]. InNovember 2014, preliminary results of the landmarkIMPROVE-IT, designed to determine whether adding eze-timibe to simvastatin in patients presenting with acutecoronary syndromes adds clinical benefit by further redu-cing major cardiovascular events compared with simva-statin monotherapy [5], were presented at the AmericanHeart Association Annual Meeting (Chicago, IL, Nov.15-19, 2014). Although a full description of the findingsis yet to be published, preliminary results apparentlysuggest a modest benefit in reducing cardiovascular eventsCentral. This is an Open Access article distributed under the terms of the/creativecommons.org/licenses/by/4.0), which permits unrestricted use,, provided the original work is properly credited. The Creative Commons Publicmons.org/publicdomain/zero/1.0/) applies to the data made available in thisCorbin and Timpson Genome Medicine  (2015) 7:7 Page 2 of 3with the addition of ezetimibe to simvastatin in thispopulation of around 18,000 patients from 39 countries.However, overall, the discordant results of studies carriedout to date has generated a degree of scepticism aboutwhether ezetimibe offers any health benefits above and be-yond those afforded by statin therapy.Using a population-based approach theoretically derivedfrom the concept of genocopy, Stitziel et al. [6] offer evi-dence to strengthen inference from existing observationaland RCT studies and to inform future research. The term‘genocopy’ refers to genetic variation that generates anoutcome similar to that produced by an environmentalexposure [7]. An illustrative example of this phenomenonis the autosomal recessive condition of Hartnup disease.This disease is caused by a mutation in solute carrier fam-ily 6 member 19 (SLC6A19; the ‘genocopy’) but a verysimilar clinical manifestation occurs in cases of dietaryniacin deficiency, a condition known as pellagra (the‘phenocopy’). Using a Mendelian randomization approachthat takes advantage of the properties of genetic variationand follows similar logic (such that mutations in NCP1L1act as genocopies mimicking the action of ezetimibe),Stitziel et al. [6] attempt to separate causation from asso-ciation, providing validation of NCP1L1 as a therapeutictarget.Using human genetics to validate the role ofNCP1L1 in coronary heart diseaseUsing sequence data from over 22,000 individuals ofvarying ancestry, Stitziel and colleagues [6] identify 15mutations that are predicted to inactivate NCP1L1. Themutations lie within one of the gene’s 20 protein-codingexons and, for the researchers to consider them as inacti-vating, they had to be classified as nonsense, splice-site orframeshift mutations. The variants identified are rare, be-ing found in only around 1 in 650 participants, and exist-ing only in a heterozygous state. The most frequentlyobserved mutation was p.Arg406X, which had a minor al-lele frequency of 0.02% among participants of Europeanancestry. Stitziel and co-workers [6] went on to genotypethis variant in a further nine independent sample sets,totalling 91,002 participants. This targeted genotypingafforded the study a considerable gain in statistical power,increasing the number of participants carrying an inacti-vating variant from 34 in 22,092 to 82 in 113,094.Data obtained for all the participants in the study in-cluded medical history and laboratory assessments for car-diovascular risk factors. These data were combined withthe genetic data, firstly to test the association betweenNCP1L1 protein-activating mutations and plasma lipidlevels, and subsequently to test for an association betweenthese same mutations and risk of CHD. Associationanalyses revealed that carriers of any of the NCP1L1inactivating mutations identified had lower levels oftotal cholesterol, LDL-C and triglycerides. In an analysisthat was restricted to participants characterized as beingfree from CHD, the mean LDL-C level was 12 mg perdecilitre lower in carriers of an inactivating mutation thanin non-carriers, while no difference was observed in high-density lipoprotein cholesterol.Having used the clinical data available for each studyto define CHD status, Stitziel et al. [6] went on to dem-onstrate an odds ratio for the disease among carriers ofinactivating mutations of 0.47 (95% confidence interval,0.25 to 0.87). The odds ratio was calculated based oncarrier frequencies of 0.04% in 29,954 patients with CHDcompared with frequencies of 0.09% in 83,140 unaffectedparticipants. The apparent protective effect of NCP1L1protein-inactivating mutations against high plasma lipidlevels and CHD observed in the entire cohort was alsoevident when the analysis was conducted separately inEuropean and African subgroups.Clinical interpretationBy using naturally occurring genetic variants, Stitziel andcolleagues [6] exploit a natural experiment that simulatesthe effect of exposure to ezetimibe and avoids many of thepitfalls associated with traditional observational studies.Of course, when interpreting the results of such studies itis important to take into consideration (as Stitziel and co-workers [6] do) that genetic models, such as this one forNCP1L1 inactivation, are not a perfect proxy for pharma-cologic therapy. For example, one important caveat is thatthe drug could have off-target effects that may not bemodelled in the case of a single-gene framework. How-ever, when it comes to modelling the long-term effectsof treatment, such Mendelian randomization-style ap-proaches are well placed to detect life course effects.Genetic variation can provide a natural life coursemodel because it represents lifetime exposure to theeffects of mutation, which in this case mirrors the ac-tion of ezetimibe [8,9].The use of genetic variation to assess drug effects is anestablished approach and the identification of novel rarevariants of large effect adds to its potential. Whether theuse of such variants provides benefits over and abovethose seen using common variants is unclear, but it ispossible that the resultant genetic model is one thatmore closely resembles the drug effect being simulatedand has greater power to detect differences in diseaserisk because of the relatively large effect sizes observed.Whether or not this is the case will likely become cleareras more studies are published, with some insight alreadyhaving been provided in a similar study in which multiplemutations in NCP1L1 and HMGCR were considered inconcert using a genetic score approach to explore the im-pact of combination therapy with statins and ezetimibe onCHD risk [10]. There are many situations in which theCorbin and Timpson Genome Medicine  (2015) 7:7 Page 3 of 3approach taken by Stitziel et al. [6] could be utilized,but one particularly important application might be inproviding validation of proposed therapeutic targetsbefore the clinical trial stage.AbbreviationsCHD: Coronary heart disease; CVD: Cardiovascular disease; IMPROVE-IT: IMProvedReduction of Outcomes: Vytorin Efficacy International Trial; IMT: Intima-mediathickness; LDL-C: Low-density lipoprotein cholesterol; PROVE-IT: Pravastatin orAtorvastatin Evaluation and Infection Therapy Trial; RCT: Randomized control trial.Competing interestsThe authors declare that they have no competing interests.AcknowledgmentsLJC and NJT work within the MRC Integrative Epidemiology Unit at theUniversity of Bristol (MC_UU_12013/3).References1. World Health Organization: Cardiovascular Diseases (CVDs): Fact sheet N°317. 2013. http://www.who.int/mediacentre/factsheets/fs317/en/2. Phan BAP, Dayspring TD, Toth PP. Ezetimibe therapy: mechanism of actionand clinical update. Vasc Health Risk Manag. 2012;8:415–27.3. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, et al.Intensive versus moderate lipid lowering with statins after acute coronarysyndromes. N Engl J Med. 2004;350:1495–504.4. Kastelein JJP, Akdim F, Stroes ESG, Zwinderman AH, Bots ML, StalenhoefAFH, et al. Simvastatin with or without ezetimibe in familialhypercholesterolemia. N Engl J Med. 2008;358:1431–43.5. Blazing MA, Giugliano RP, Cannon CP, Musliner TA, Tershakovec AM, WhiteJA, et al. Evaluating cardiovascular event reduction with ezetimibe as anadjunct to simvastatin in 18,144 patients after acute coronary syndromes:final baseline characteristics of the IMPROVE-IT study population. Am HeartJ. 2014;168:205–12.6. The Myocardial Infarction Genetics Consortium Investigators. Inactivatingmutations in NPC1L1 and protection from coronary heart disease. N Engl JMed. 2014;371:2072–82.7. Khoury M, Bedrosian S, Gwinn M, Higgins J, Ioannidis J, Little J. Humangenome epidemiology. 2nd ed. Oxford University Press; 2010.8. The Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR)Consortium. The interleukin-6 receptor as a target for prevention ofcoronary heart disease: a mendelian randomisation analysis. Lancet.2012;379:1214–24.9. Swerdlow DI, Preiss D, Kuchenbaecker KB, Holmes MV, Engmann JEL, ShahT, et al. HMG-coenzyme A reductase inhibition, type 2 diabetes, andbodyweight: evidence from genetic analysis and randomised trials. Lancet2014. doi: 10.1016/S0140-6736(14)61183-1.10. Ference BA, Majeed F, Brook RD, Hedquist L, Penumetcha R, Flack JM. Effectof naturally random allocation to lower LDL-C mediated by polymorphismsin NPC1L1, HMGCR or both on the risk of coronary heart disease: a 2x2factorial Mendelian randomization study [abstract]. Circulation. 2014;130:A19754.

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Using inactivating mutations to provide insight into drug action

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