False positive non-synonymous polymorphisms G-protein coupled receptor genes

Polymorphisms of G-protein coupled receptor (GPCR) genes re associated with disease risk and modification, and the response to receptor-directed therapy. Genomic sequencing (similar to 1700 automated runs) from as many as 120 chromosomes from 60 multiethnic individuals was performed to confirm non-synonymous coding polymorphisms reported in the dbSNP database from 25 randomly selected GPCR genes. These polymorphisms were in regions of the receptors responsible for structural integrity, ligand binding, G-protein coupling and phosphoregulation. However, most of these putative polymorphisms could not be confirmed (false positive rate of 68%). Based on these results, we suggest that the variability of the superfamily is not well defined, and we caution against exclusive reliance on databases for selection of candidate GPCR polymorphisms for disease association and pharmacogenetic studies. (C) 2002 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.