Polymorphic variants

Ethnic differences have been shown to influence response to psychotropic medications. Much of the focus on the explanation for such differences has been on drug-metabolizing (CYP) enzymes of the liver and their sway over pharmacokinetic factors. It is now well recognized that differences in the distribution of polymorphic variants of CYP enzymes exist between different ethnic groups. However, within ethnic groups there are considerable inter-individual variations in drug kinetics, which may not be accounted for solely by genetic variation. Responses to pharmacotherapy are multifaceted and involve the interaction of environmental and... 

Hereditary deficiency of phosphoglycerate kinase (PGK) is associated with hereditary hemolytic anemia and often with central nervous system dysfunction and/or myopathy. The first case, reported by Kraus et al. (K24), is a heterozygous female, and the results are not so clear. The second family, reported by Valentine et al. (V3), is a large Chinese family, whose pedigree study indicates that PGK deficiency is compatible with X-linked inheritance. To date, 22 families have been reported (04, T25, Y3). Nine of these have manifested both symptoms five have shown only hemolysis seven have shown the central nervous system dysfunction and/or myopathy but without hemolysis and one case, PGK Munchen, is without clinical symptoms (F5). PGK II is an electrophoretic variant found in New Guinea populations (Y2). Red blood cell enzyme activity, specific activity, and the kinetic properties of this polymorphic variant are normal. 

J. M Britt, R. P Vulliamy, T. J., Luzzatto, L and Mason, P. J., A new glucose-6-phosphate dehydrogenase variant, G6PD Orissa (44 Ala-Kjly), is the major polymorphic variant in tribal populations in India. Am. J. Hum. Genet. 57, 1335-1341 (1995). 

Tab. 21.2 Characteristics of the human class I isozymes and their polymorphic variants...

Gene Subunit Amino acid substitution in polymorphic variants K, [Ethanol] [mM] Turnover rate [min-1] Three- dimensional structure... 

Fig. 21.1 The interactions between the bound coenzyme molecule and the amino acids at positions 47 and 369 in the / , / 2, and / 3 polymorphic variants as observed in their respective structures determined by X-ray crystallography. The dashed lines indicate possible hydrogen-bonds between the amino acids and the phosphate oxygens of the bound coenzyme molecule, NAD(H). Arg47 is substituted by a His residue in the f 2 isozyme and Arg369 is substituted by a Cys residue in the / 3 isozyme. In each case, the substitution results in a net loss of hydrogen-bonding interactions and weaker affinity for the coenzyme.

Polymorphic variant A gene, mRNA, cDNA, polypeptide or peptide whose nucleotide or amino acid sequence varies from a reference sequence due to the presence of a polymorphism in the gene. 

Aldurazyme (tradename, also known as laronidase) is a recombinant version of one polymorphic variant of the human enzyme a-L-iduronidase. It was approved for general medical use in the USA in 2003 and is indicated for the treatment of patients with certain forms of the rare inherited disease MPS I. MPS I is caused by a deficiency of a lysosomal a-L-iduronidase, which normally catalyses the hydrolysis of terminal a-L-iduronic acid residues from the glycosaminoglycans dermatan sulfate and heparin sulfate. The deficiency results in accumulation of the glycosaminoglycans throughout the body, causing widespread cell and tissue dysfunction. 

Ioannidis et al. recently showed that after initial reports of associations between polymorphic variants and disease, subsequent studies had lower odds ratios, which were often insignificant, even when meta-analysis... 

The low predictive values of pharmacogenetic tests for most polymorphic variants means there will be false positive (when PPV is low) and false negative (when NPV is low) test results. Both reduce the clinical utility of the tests. There are a number of reasons for the reduced predictive values. 

Keywords Activation agonist antagonist desensitization efficacy G protein-coupled receptor pharmacogenetics potency single nucleotide polymorphism variant. 

Gene Polymorphic variant Extensive metabohzers (%) Intermediate metabohzers (%) Poor metabohzers (%) Ultrarapid metabohzers (%)... 

PMs. Likewise, the PRNP-M129M variant was present in 100% of PMs and UMs (42) (see Table 10.5). These association studies clearly show that in PMs and UMs there is an accumulation of AD-related polymorphic variants of risk that might be responsible for the defective therapeutic responses currently seen in these AD clusters (42). 

The ACE gene encodes two isozymes (somatic ACE isozyme and germinal ACE isozyme). ACE is a membrane-bound enzyme on the surface of vascular endothelial cells that also circulates in plasma and shows great individual variability determined by an I/D polymorphism in intron 16 of the ACE gene (ACE-I/D polymorphism). More than 160 ACE polymorphisms have been reported, 34 of which are located in coding regions, and 18 are missense mutations (606). ACE-related polymorphic variants have been associated with hypertension, atherosclerosis, stroke, left ventricular hypertrophy, chronic renal failure in IgA nephropathy, Henoch-Schonlein purpura nephritis, mechanical efficiency of skeletal muscle, intracranial aneurysms, susceptibility to myocardial infarction, diabetic nephropathy, AD, and longevity (12,606,607). 

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