title: Gene and protein domain-specific patterns of genetic variability within the G-protein coupled receptor superfamily.
abstract: BACKGROUND
  Guanine nucleotide binding proteins (G-proteins) represent the targets for >50% of all therapeutics. There is substantial interindividual variation in response to agonists and antagonists directed to these receptors, which may, in part, be due to genetic polymorphisms. As a class, the sequence variability of G-protein-coupled receptor (GPCR) genes has not been characterized.
  
  
  METHODS
  This variability was investigated by sequencing promoter, 5'- and 3'-UTR, coding blocks, and intron-exon boundaries, of 64 GPCR genes in an ethnically diverse group of 82 individuals.
  
  
  RESULTS
  Of the 675 single-nucleotide variations found, 61% occurred in > or =1% of the population sample and the nature of these 412 single nucleotide polymorphisms (SNPs) was assessed. 5'-UTR (p = 0.002) and coding (p = 0.006) SNPs were observed more often in GPCR genes, compared with 309 non-GPCR genes similarly interrogated. The prevalence of non-synonymous coding SNPs was unexpectedly high, with 65% of GPCR genes having at least one. Intron-containing genes had half as many non-synonymous coding SNPs compared with intronless genes (p = 0.0009), suggesting that when introns are not available coding regions provide sites for variation. A distinct relationship between the prevalence of non-synonymous SNPs and receptor structural domains was evident (p = 0.0006 by ANOVA), with variability being most prominent in the transmembrane spanning domains (38%) and the intracellular loops (24%). Phosphoregulatory domains, particularly the carboxy terminus, often the site for agonist-promoted phosphorylation by G-protein coupled receptor kinases, were the least polymorphic (8%).
  
  
  CONCLUSIONS
  There is substantial genetic variability in potentially pharmacologically relevant coding and noncoding regions of GPCRs. Such variability should be considered in the development of new agents, or optimization of existing agents, targeted to these receptors.
authors.affiliation: Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0564, USA.
authors.forename: Kersten M
authors.initials: KM
authors.lastname: Small
authors.forename: Debra A
authors.initials: DA
authors.lastname: Tanguay
authors.forename: Krishnan
authors.initials: K
authors.lastname: Nandabalan
authors.forename: Ping
authors.initials: P
authors.lastname: Zhan
authors.forename: J Claiborne
authors.initials: JC
authors.lastname: Stephens
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Liggett
mesh_terms: D000704:Analysis of Variance; D019204:GTP-Binding Proteins / Q000737:chemistry* / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D011956:Receptors, Cell Surface; D019204:GTP-Binding Proteins