Receptor Gene Polymorphisms

Most human GPCR genes appear to be polymorphic, and the significance of receptor mutations for cardiovascular disease risk and as determinants of therapeutic responses constitutes another rapidly expanding area of research. Genetic polymorphism is defined as the occurrence within a population of two or more allelic variants of a given gene sequence, in such proportions that the rarest cannot be maintained merely by recurrent mutations. Genetic variation may influence one or more aspects of the function of a given GPCR, which may provide the basis for individual variability in clinical phenotypes and pharmacological responses.32 Several databases have been established to catalogue human gene polymorphisms and make this information available to researchers. One example in cardiovascular medicine is the Gene Canvass (cardiovascular candidate gene polymorphisms) web site: The site was set up to facilitate association analysis and research on how single nucleotide polymorphisms (SNPs) and other sequence variations may influence common cardiovascular disorders. It is currently acknowledged33 that individual SNPs may have poor predictive capacity for disease risk and that more emphasis must be put on interactions of SNPs within haplotypes in determining clinical phenotypes of disease and responses to drug treatment.

Most human GPCR polymorphisms appear as functionally neutral; however, several affect either gene expression (and thus protein abundance) or the structural and functional properties of the encoded protein. Altered abundance or function may be associated with a clinical phenotype. Cardiovascular diseases typically have multifactorial etiologies and result from the synergism of several genes interacting in a complex way with environmental and life style factors. Epidemiological studies have investigated several candidate genes encoding proteins contributing to the control of blood pressure, lipid and energy metabolism, and cardiovascular function, and thus possibly associated with human atherosclerosis, hyperlipidemia, hypertension, and myocardial infarction.

The clinical significance of variant alleles in the LDL receptor gene has already been established. Polymorphisms in the adrenoceptor genes are among the most extensively investigated in the GPCR family. Some of them have already been linked with clinical phenotypes, either involving altered disease risk or outcome or altered drug responses.34 In principle, any gene known or suspected to be involved in normal or pathological physiological regulation of the cardiovascular system may be considered to represent a candidate gene for cardiovascular diseases.

In drug discovery and development of therapeutics, one outcome of pharmaco-genetic and pharmacogenomic research efforts might be a more efficacious use of available drugs. For example, although p-blockers are well recognized as effective therapeutics for patients with congestive heart failure, they are difficult to use and carry relatively high risks for adverse effects. The information that their benefit is largely confined to patients with the angiotensin-converting enzyme DD genotype was obtained retrospectively in a relatively small number of patients.35 Validation of this finding implies that genotyping could be used to identify patients who are especially likely to benefit from therapy with p-blockers.

A second outcome might be validation or rejection of new drug targets at an early stage of development. A drug target with a functionally significant polymorphism might be rejected in favor of one that does not have such genetic variability. Similarly, as the molecular bases for rarely occurring adverse drug effects such as drug-induced arrhythmias or drug-associated hepatotoxicity become better defined in pharmaco-genetic studies, new screening algorithms could be developed to eliminate drugs likely to be associated with these adverse effects at an early stage of development.36

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