Polymorphisms

Polymorphisms are typically defined as a variation in DNA sequence (compared to a reference group) found in greater than 1% of a population. These can occur in any part of the genome, and are readily found in many genes including promoters, coding regions, and 3 prime UTRs. Polymorphisms within the coding region that alter the encoded amino acid are termed nonsynonymous polymorphisms. Shown above is a prototypic G-protein coupled receptor (GPCR) with the 7 transmembrane spanning domains. The approximate position and character of the nonsynonymous coding polymorphisms that we have discovered in the α2_ARs and β_ARs are shown.

We have considered that common polymorphisms could have three general effects:

1. They could be risk factors for developing a disease
2. They could define certain properties of a disease (disease modifiers)
3. They could alter the response to therapy, a field called pharmacogenetics (or pharmacogenomics)

These three potential effects can be interrelated. For example, a polymorphism may promote a more severe form of a disease and thereby result in lower efficacy of a given therapeutic agent. This may be so even when the drug does not act at the polymorphic protein.

Our studies of polymorphisms have been with the α2_AR and β_AR subtypes. The laboratory was the first to define a discreet polymorphism of any GPCR, the first to recombinantly express the two variants in model cells, and the first to transgenically express two human polymorphic variants in mouse hearts and study their physiologic significance. We also were the first to define the specific combinations of polymorphisms (called the haplotype) of a GPCR gene. With our collaborators, we have also performed numerous association studies to ascertain the relevance of GPCR polymorphisms in asthma and heart failure.