Causal Relevance of Blood Lipid Fractions in the Development of Carotid Atherosclerosis

Shah, Sonia; Casas, Juan P.; Drenos, Fotios; Whittaker, John C.; Deanfield, John; Swerdlow, Daniel I.; Holmes, Michael V.; Kivimäki, Mika; Langenberg, Claudia; Wareham, Nick; Gertow, Karl; Sennblad, Bengt; Strawbridge, Rona J.; Baldassarre, Damiano; Veglia, Fabrizio; Tremoli, Elena; Gigante, Bruna; Fairé, Ulf dé; Talmud, Philippa J.; Hamsten, Anders; Humphries, Steve E.; Hingorani, Aroon D.

doi:10.1161/circgenetics.112.963140

Cited by 41 publications

(26 citation statements)

References 47 publications

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“…Additional evidence against the role of HDL in CVD risk has come from genetic studies, designed to examine the associations of LDL, HDL and TG with CVD risk [29,30]. Early studies showed that rare mutations that encode LCAT (lecithin cholesterol acyl transferase) and ABCA1 (ATP-binding cassette transporter, also known as cholesterol efflux regulatory protein (CERP)), which profoundly reduce HDL levels, were inconsistently associated with CVD risk [29].…”

Section: Discussionmentioning

confidence: 99%

The effect of a low-fat, plant-based lifestyle intervention (CHIP) on serum HDL levels and the implications for metabolic syndrome status – a cohort study

et al. 2013

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BackgroundLow levels of high-density lipoproteins (HDL) are considered an important risk factor for cardiovascular disease and constitute one of the criteria for the Metabolic Syndrome (MetS). Lifestyle interventions promoting a low-fat, plant-based eating pattern appear to paradoxically reduce cardiovascular risk but also HDL levels. This study examined the changes in MetS risk factors, in particular HDL, in a large cohort participating in a 30-day lifestyle intervention that promoted a low-fat, plant-based eating pattern.MethodsIndividuals (n = 5,046; mean age = 57.3 ± 12.9 years; 33.5% men, 66.5% women) participating in a in a Complete Health Improvement Program (CHIP) lifestyle intervention within the United States were assessed at baseline and 30 days for changes in body mass index (BMI), blood pressure (BP), lipid profile and fasting plasma glucose (FPG).ResultsHDL levels decreased by 8.7% (p<0.001) despite significant reductions (p<0.001) in BMI (-3.2%), systolic BP (-5.2%), diastolic BP (-5.2%), triglycerides (TG; -7.7%), FPG (-6.3%), LDL (-13.0%), total cholesterol (TC, -11.1%), TC: HDL ratio (-3.2%), and LDL: HDL ratio (-5.3%). While 323 participants classified as having MetS at program entry no longer had this status after the 30 days, 112 participants acquired the MetS classification as a result of reduction in their HDL levels.ConclusionsWhen people move towards a low-fat, plant-based diet, HDL levels decrease while other indicators of cardiovascular risk improve. This observation raises questions regarding the value of using HDL levels as a predictor of cardiovascular risk in populations who do not consume a typical western diet. As HDL is part of the assemblage of risk factors that constitute MetS, classifying individuals with MetS may not be appropriate in clinical practice or research when applying lifestyle interventions that promote a plant-based eating pattern.

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Section: Discussionmentioning

confidence: 99%

The effect of a low-fat, plant-based lifestyle intervention (CHIP) on serum HDL levels and the implications for metabolic syndrome status – a cohort study

et al. 2013

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“…One study investigated the LDLR locus and found that individuals carrying protective alleles in the LDLR gene have a reduced lifelong exposure to LDL-C of 0.19 mmol/L per T allele compared with C allele homozygotes, translating into a 21–23% lower risk of MI 20. By using weighted genetic scores, subsequent MR studies have expanded the investigation to include multiple LDL-C associated single nucleotide polymorphisms (SNPs) and all have confirmed this association, concluding that LDL-C is causal in the CHD pathway 10 21 22. The conclusions of these MR studies further support the notion that lowering LDL-C results in successful prevention of CHD.…”

Section: Mendelian Randomisation: An Emerging Methodologymentioning

confidence: 99%

“…They concluded that HDL-C plasma levels were not causal for MI risk. Two other studies using an HDL-C genetic score also found that HDL-C levels were not causal in the onset of CHD 21 22. A study by Holmes et al included two genetic scores in their analysis of HDL-C, one which included SNPs with pleiotropic effects on LDL-C and TGs and another which limited its genetic score to SNPs that associated exclusively with HDL-C.…”

Section: Mendelian Randomisation: An Emerging Methodologymentioning

confidence: 99%

Mendelian randomisation applied to drug development in cardiovascular disease: a review

et al. 2014

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Despite increased expenditure, productivity of the pharmaceutical industry has decreased and currently 90% of developed molecules entering phase II and phase III clinical trials fail to gain regulatory approval. Most of these failures are due to lack of therapeutic efficacy rather than lack of safety, suggesting that drug development failures may often be due to poor drug target validation. Currently, drug targets are largely validated using in vitro assays and animal models which may not translate well to human disease. Emerging methods from human genetics, such as Mendelian randomisation (MR), can enable the validation of putative biomarker drug targets in humans prior to the initiation of clinical trials. MR studies can provide evidence as to whether genetically determined levels of a biomarker influence disease aetiology, enabling investigators to infer whether the biomarker is causal. We review the extent to which MR techniques may be helpful in biomarker validation by assessing the concordance between the results from MR studies and phase III clinical trials for lipid therapy in cardiovascular disease. Our findings show that concordance is highest when MR provides evidence suggesting that a biomarker is not causal. In contrast, there are many examples of clinical trials that still failed despite targeting confirmed causal biomarkers. We discuss why such trials may not succeed, despite evidence for causality in MR studies, and outline important limitations when using MR for biomarker validation in drug development. Nonetheless, given the current inefficiencies in drug development, MR methods have potential to improve the success rate of drug development and ultimately the delivery of new molecules to clinical care. THE COSTS OF AN INEFFICIENT DRUG PIPELINEMany common diseases require better therapies and many rare diseases have no therapies at all. This has stimulated a substantial public and private investment in basic science and drug development research. However, impact on patient care has been uneven, with 85-90% of all drugs developed since the mid-90s having little clinical advantage.1-4 This is a consequence of an R&D agenda largely aimed at reducing the high failure rate of phase II and phase III trials by choosing to focus on developing 'Me-Too' drugs which mimic the effects of other already available therapies. For example, of the 27 new drugs that were approved by the Food and Drug Administration in 2013, only one-third were considered to be 'First-in-Class' utilising a novel mechanism in the treatment of a disease, and the remaining were reincarnations of existing therapies.1 5 6 Clearly, more innovative therapies are required to address unmet medical needs. 1A potential solution to the 'Me-Too' strategy would be to increase innovation by improving the efficiency of phase II and phase III trials, which exhibit high failure rates (at 82% and 50%, respectively), 7 8 and also consume 63% of the total R&D budget.1 7 8 Despite good safety and target engagement evidence, most drug targets fai...

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“…In an analysis performed in 2 prospective cohorts, Whitehall II (WHII; n=5059) and the British Women's Heart and Health Study (BWHHS; n=3414), individuals in the top versus bottom quintile of an LDL-C GRS consisting of 23 SNPs had a higher risk of CAD (WHII: OR=1.43; BWHHS: OR=1.31). 87 After adjusting for LDL-C levels, this association was completely attenuated in WHII but not in BWHHS. The value of a GRS for CAD risk prediction beyond conventional risk factors has improved beyond previous studies considering a small number of risk variants 88,89 beyond those related to plasma lipid traits to more recent analyses incorporating a more comprehensive list of recently identified CAD loci.…”

Section: Utility Of a Genetic Risk Score For Risk Assessment And Treamentioning

confidence: 98%

Genetics of Coronary Artery Disease

McPherson

Tybjærg‐Hansen

2016

Circulation Research

327

203

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Genetic factors contribute importantly to the risk of coronary artery disease (CAD), and in the past decade, there has been major progress in this area. The tools applied include genome-wide association studies encompassing >200 000 individuals complemented by bioinformatic approaches, including 1000 Genomes imputation, expression quantitative trait locus analyses, and interrogation of Encyclopedia of DNA Elements, Roadmap, and other data sets. close to 60 common SNPs (minor allele frequency>0.05) associated with CAD risk and reaching genomewide significance (P<5×10 −8 ) have been identified. Furthermore, a total of 202 independent signals in 109 loci have achieved a false discovery rate (q<0.05) and together explain 28% of the estimated heritability of CAD. These data have been used successfully to create genetic risk scores that can improve risk prediction beyond conventional risk factors and identify those individuals who will benefit most from statin therapy. Such information also has important applications in clinical medicine and drug discovery by using a Mendelian randomization approach to interrogate the causal nature of many factors found to associate with CAD risk in epidemiological studies. In contrast to genome-wide association studies, whole-exome sequencing has provided valuable information directly relevant to genes with known roles in plasma lipoprotein metabolism but has, thus far, failed to identify other rare coding variants linked to CAD. Overall, recent studies have led to a broader understanding of the genetic architecture of CAD and demonstrate that it largely derives from the cumulative effect of multiple common risk alleles individually of small effect size rather than rare variants with large effects on CAD risk. Despite this success, there has been limited progress in understanding the function of the novel loci; the majority of which are in noncoding regions of the genome. (Circ Res. 2016;118:564-578.

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Causal Relevance of Blood Lipid Fractions in the Development of Carotid Atherosclerosis

Cited by 41 publications

References 47 publications

The effect of a low-fat, plant-based lifestyle intervention (CHIP) on serum HDL levels and the implications for metabolic syndrome status – a cohort study

The effect of a low-fat, plant-based lifestyle intervention (CHIP) on serum HDL levels and the implications for metabolic syndrome status – a cohort study

Mendelian randomisation applied to drug development in cardiovascular disease: a review

Genetics of Coronary Artery Disease

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