Apolipoprotein E and Complement C3 Polymorphism and Their Role in the Response to Gemfibrozil and Low Fat Low Cholesterol Therapy

Németh, Attila; Szakmary, Kati; Kramer, Judith M.; Dinya, Elek; Pados, Gyula; Füst, G.; Huettinger, Manfred

doi:10.1515/cclm.1995.33.11.799

Cited by 8 publications

(6 citation statements)

References 29 publications

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“…For example, studies of cholesterol-lowering drugs, the hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, conducted in fairly large populations with specific clinical endpoints (beyond lipid changes), have focused on genetic polymorphisms in proteins not directly involved in the pharmacologic mechanism of the drug, namely apolipoprotein E (APOE), cholesteryl ester transfer protein (CETP), stromelysin-1 and β-fibrinogen. [64][65][66]68,69,72] These studies and their results have been strikingly consistent. Firstly, they investigated a genetic polymorphism thought or documented to be associated with an adverse clinical outcome (e.g.…”

Section: Associations Between Polymorphisms Of Disease Pathogenesis Psupporting

confidence: 69%

Drug Target Pharmacogenomics

Johnson

2001

American Journal of PharmacoGenomics

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Pharmacogenomics is a field aimed at understanding the genetic contribution to variability in drug efficacy and toxicity. The goal is to be able to select the drugs with the greatest likelihood of benefit and the least likelihood of harm in individual patients, based on their genetic make-up. Pharmacogenetics has historically been a field focused primarily on genetic polymorphisms in drug metabolizing enzymes and their impact on drug efficacy and toxicity. More recently, investigators have begun to study the relationship between drug target polymorphisms and drug efficacy and toxicity. There are now numerous examples in the literature of associations between drug target polymorphisms and drug effect. Drug targets can be broken into three main categories: the direct protein target of the drug, signal transduction cascades or downstream proteins, and disease pathogenesis proteins. While the drug target pharmacogenetics literature provides 'proof of concept' that genetic variability contributes to the variability in drug response, the data are not to the point of being clinically useful in most cases. Specific problems to date include the inability of a single polymorphism to be highly predictive of response, and inconsistencies across studies of the same polymorphism. It seems likely that an important factor in the above limitations is the approach of focusing on a single polymorphism in a single gene. Given that most drug responses involve a large number of proteins, all of whose genes could have several polymorphisms, it seems unlikely that a single polymorphism in a single gene would explain a high degree of drug response variability in a consistent fashion. Thus, it seems that a polygenic, or genomic approach will be more appropriate. Candidate gene and genome scanning approaches to pharmacogenomics have shown promise in relating drug target polymorphisms to response or toxicity, and pharmacogenomic strategies for drug discovery and drug development are now being implemented by most major pharmaceutical companies. Pharmacogenomics has the potential to significantly enhance the ability of clinicians to use medications in a safe and effective manner and, as such, represents an exciting field with tremendous clinical potential.

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Section: Associations Between Polymorphisms Of Disease Pathogenesis Psupporting

confidence: 69%

Drug Target Pharmacogenomics

Johnson

2001

American Journal of PharmacoGenomics

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“…1 Therapeutic interventions related to the common apo E genotype. In addition, Nemeth et al (84) observed that the relationship between apo E genotype and gemfibrozil response depends on the type of hyperlipoproteinemia under scrutiny. Both primary and familial hypercholesterolemia, diabetes, and postmenopausal syndrome have been investigated.…”

Section: Involvement Of Apo E In Drugs and Dietary Responsesmentioning

confidence: 99%

Apolipoprotein E Polymorphisms and Concentration in Chronic Diseases and Drug Responses

Siest

Bertrand²,

Herbeth³

et al. 2000

CCLM

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Apolipoprotein (apo) E is an important circulating and tissue protein involved in cholesterol homeostasis and many other functions. The common polymorphism in the coding region of the gene, four polymorphisms in the promoter region, other additional single nucleotide polymorphisms, as well as several apo E variants have been identified. The common coding polymorphism strongly influences the lipid metabolism and the circulating concentration of apo E itself. This polymorphism is at the origin of the implication of apo E in cardiovascular and neurodegenerative diseases, but also of the relation of apo E with longevity. Probably due to its many metabolic and functional consequences, apo E polymorphism has been shown to influence the responses of patients to several drugs (fibrates, statins, hormone replacement therapy, anti-Alzheimer drugs) or environmental interventions (black tea, alcohol, diet). Apo E genotyping may be clinically helpful in defining the risk of patients and their responses to therapeutics. Finally, circulating apo E concentration appears to be altered in diseases and can be modulated by some of the drugs cited above. This parameter can thus also give interesting clinical information and could be a therapeutic target, providing it is validated. At the present time, we cannot exclude that apo E concentration may be the most prominent apo E parameter to be considered in health and disease, while apo E polymorphisms would represent only secondary parameters influencing apo E concentration.

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“…The outcome literature with HMG CoA-reductase inhibitors (statins) are particularly interesting in this regard. Studies of the statins that were conducted in fairly large populations with induced dyskinesias specific clinical endpoints (beyond lipid changes) have focused on the polymorphic genes coding the following proteins: apolipoprotein E, cholesteryl ester transfer protein (CETP), stromelysin-1, and β-fibrinogen (28,29,49,81,110,114). These studies and their results have been strikingly consistent.…”

Section: Drug Target Pharmacogenetics and Pharmacogenomicsmentioning

confidence: 92%

Pharmacogenomics: The Inherited Basis for Interindividual Differences in Drug Response

Evans

Johnson

2001

Annu. Rev. Genom. Hum. Genet.

375

222

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It is well recognized that most medications exhibit wide interpatient variability in their efficacy and toxicity. For many medications, these interindividual differences are due in part to polymorphisms in genes encoding drug metabolizing enzymes, drug transporters, and/or drug targets (e.g., receptors, enzymes). Pharmacogenomics is a burgeoning field aimed at elucidating the genetic basis for differences in drug efficacy and toxicity, and it uses genome-wide approaches to identify the network of genes that govern an individual's response to drug therapy. For some genetic polymorphisms (e.g., thiopurine S-methyltransferase), monogenic traits have a marked effect on pharmacokinetics (e.g., drug metabolism), such that individuals who inherit an enzyme deficiency must be treated with markedly different doses of the affected medications (e.g., 5%-10% of the standard thiopurine dose). Likewise, polymorphisms in drug targets (e.g., beta adrenergic receptor) can alter the sensitivity of patients to treatment (e.g., beta-agonists), changing the pharmacodynamics of drug response. Recognizing that most drug effects are determined by the interplay of several gene products that govern the pharmacokinetics and pharmacodynamics of medications, pharmacogenomics research aims to elucidate these polygenic determinants of drug effects. The ultimate goal is to provide new strategies for optimizing drug therapy based on each patient's genetic determinants of drug efficacy and toxicity. This chapter provides an overview of the current pharmacogenomics literature and offers insights for the potential impact of this field on the safe and effective use of medications.

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Apolipoprotein E and Complement C3 Polymorphism and Their Role in the Response to Gemfibrozil and Low Fat Low Cholesterol Therapy

Cited by 8 publications

References 29 publications

Drug Target Pharmacogenomics

Drug Target Pharmacogenomics

Apolipoprotein E Polymorphisms and Concentration in Chronic Diseases and Drug Responses

Pharmacogenomics: The Inherited Basis for Interindividual Differences in Drug Response

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