Uses and misuses of definitions of genetic polymorphism. A perspective from population pharmacogenetics [letter]

Arias, Teresa Fallas; Jorge, L F; Barrantes, Ramiro

doi:10.1111/j.1365-2125.1991.tb03870.x

Cited by 14 publications

(7 citation statements)

References 15 publications

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“…They pose a more complex problem than pathological mutations, since no substantial set of validated polymorphisms is available for GLA. None is cited for this gene in the UniProt (20‐01‐14) database, and only seven variants are listed in the 1000 Genomes website (http://browser.1000genomes.org/Homo_sapiens/Gene/Variation_Gene/Table?db=core;g=ENSG00000102393;r=X:100652791-100662913#_20-01-14), and all have frequencies below 1%, the threshold for polymorphism . In fact, one of them, D313Y, induces a 40% drop in GLA's activity .…”

Section: Methodsmentioning

confidence: 99%

“…None is cited for this gene in the UniProt 33 (20-01-14) database, and only seven variants are listed in the 1000 Genomes website (http://browser.1000genomes.org/Homo_sapiens/ Gene/Variation_Gene/Table?db5core;g5ENSG00000102393; r5X:100652791-100662913#_20-01-14), and all have frequencies below 1%, the threshold for polymorphism. 34 In fact, one of them, D313Y, induces a 40% drop in GLA's activity. 35 As no prediction method can be obtained using so few observations, we use as an alternative the sequence variation between human and close species for this protein family (Fig.…”

Section: The Mutation Datasetmentioning

confidence: 99%

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Molecular damage inFabry disease: Characterization and prediction of alpha‐galactosidaseApathological mutations

et al. 2014

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Loss-of-function mutations of the enzyme alpha-galactosidase A (GLA) causes Fabry disease (FD), that is a rare and potentially fatal disease. Identification of these pathological mutations by sequencing is important because it allows an early treatment of the disease. However, before taking any treatment decision, if the mutation identified is unknown, we first need to establish if it is pathological or not. General bioinformatic tools (PolyPhen-2, SIFT, Condel, etc.) can be used for this purpose, but their performance is still limited. Here we present a new tool, specifically derived for the assessment of GLA mutations. We first compared mutations of this enzyme known to cause FD with neutral sequence variants, using several structure and sequence properties. Then, we used these properties to develop a family of prediction methods adapted to different quality requirements. Trained and tested on a set of known Fabry mutations, our methods have a performance (Matthews correlation: 0.56-0.72) comparable or better than that of the more complex method, Polyphen-2 (Matthews correlation: 0.61), and better than those of SIFT (Matthews correl.: 0.54) and Condel (Matthews correl.: 0.51). This result is validated in an independent set of 65 pathological mutations, for which our method displayed the best success rate (91.0%, 87.7%, and 73.8%, for our method, PolyPhen-2 and SIFT, respectively). These data confirmed that our specific approach can effectively contribute to the identification of pathological mutations in GLA, and therefore enhance the use of sequence information in the identification of undiagnosed Fabry patients.

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Section: Methodsmentioning

confidence: 99%

Section: The Mutation Datasetmentioning

confidence: 99%

Molecular damage inFabry disease: Characterization and prediction of alpha‐galactosidaseApathological mutations

et al. 2014

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“…Their recognition enables one to discriminate different phenotypes in a population and therefore the existence of genetic polymorphism (i.e. a monogenic trait that exists in at least two phenotypes and two genotypes with frequency of at least 1% in the population) ( 14, 27). Such genes generally affect drug biotransformation by altering the amount of particular enzymes such as glucuronyl transferase, N‐acetyltransferase, alcohol dehydrogenase, debrisoquine/sparteine hydroxylase (CYP2D6) and mephenytoin hydroxylase (CYP2C19).…”

Section: Polymorphic Drug Metabolism and Cytochrome P450 Monooxygenasementioning

confidence: 99%

Pharmacogenetics and psychopharmacotherapy

2000

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Response to drugs can vary between individuals and between different ethnic populations. The biological (age, gender, disease and genetics), cultural and environmental factors which contribute to these variations are considered in this review. The most important aspect is the genetic variability between individuals in their ability to metabolize drugs due to expression of 'polymorphic' enzymes. Polymorphism enables division of individuals within a given population into at least two groups, poor metabolisers (PMs) and extensive metabolisers (EMs) of certain drugs. The two most extensively studied genetic polymorphisms are those involving cytochrome P450 2D6 (CYP2D6) and CYP2C19. CYP2D6 metabolizes a number of antidepressants, antipsychotics, beta-adrenoceptor blockers, and antiarrhythmic drugs. About 7% of Caucasians and 1% of Asians are PMs of CYP2D6 substrates. CYP2C19 enzyme participates in the metabolism of omeprazole, propranolol and psychotropic drugs such as hexobarbital, diazepam, citalopram, imipramine, clomipramine and amitriptyline. The incidence of PMs of CYP2C19 substrates is much higher in Asians (15-30%) than in Caucasians (3-6%). Variations in metabolism of psychotropic drugs result in variations in their pharmacokinetic parameters. This may lead to clinically significant intra- and inter-ethnic differences in pharmacological responses. Such variations are discussed in this review. Differential receptor-mediated response may play a role in ethnic differences in responses to antipsychotics and tricyclic antidepressants, but such pharmacodynamic factors remain to be systematically investigated. The results of studies of ethnic differences in response to psychopharmacotherapy appear to be discrepant, most probably due to limitations of study design, small sample size, inadequately defined study sample, and lack of control of confounding factors. The clinical value of understanding pharmacogenetics is in its use to optimize therapeutic efficacy, to prevent toxicity of those drugs whose metabolism is catalysed by polymorphic isoenzymes, and to contribute to the rational design of new drugs. Finally, applications and impact of pharmacogenetics in the field of psychopharmacotherapy are discussed.

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“…variants that exist in at least 1% of the population). 1 Such genes generally affect drug biotransformation by altering the amount or function of an enzyme. The existence of such polymorphisms explains why drug metabolism shows a polymodal distribution.…”

Section: Linkage Studiesmentioning

confidence: 99%