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.

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)

Our 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 targeted to mouse hearts and to 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.

  • Parsa A, Chang YP, Kelly RJ, Corretti MC, Ryan KA, Robinson SW, Gottlieb SS, Kardia SL, Shuldiner AR, and Liggett SB. Hypertrophy-associated polymorphisms ascertained in a founder cohort applied to heart failure risk and mortality. Clin Transl Sci 4: 17-23, 2011.
  • Duan QL, Gaume BR, Hawkins GA, Himes BE, Bleecker ER, Klanderman B, Irvin CG, Peters SP, Meyers DA, Hanrahan JP, Lima JJ, Litonjua AA, Tantisira KG, and Liggett SB. Regulatory haplotypes in ARG1 are associated with altered bronchodilator response. Am J Respir Crit Care Med 183: 449-454, 2011.
  • Liggett SB. alpha2A-adrenergic receptors in the genetics, pathogenesis, and treatment of type 2 diabetes. Sci Transl Med 1: 12ps15, 2009.
  • Bristow MR, Murphy GA, Krause-Steinrauf H, Anderson JL, Carlquist JF, Thaneemit-Chen S, Krishnan V, Abraham WT, Lowes BD, Port JD, Davis GW, Lazzeroni LC, Robertson AD, Lavori PW, and Liggett SB. An alpha2C-adrenergic receptor polymorphism alters the norepinephrine-lowering effects and therapeutic response of the beta-blocker bucindolol in chronic heart failure. Circ Heart Fail 3: 21-28, 2010.
  • Kardia SL, Kelly RJ, Keddache MA, Aronow BJ, Grabowski GA, Hahn HS, Case KL, Wagoner LE, Dorn GW, 2nd, and Liggett SB. Multiple interactions between the alpha 2C- and beta1-adrenergic receptors influence heart failure survival. BMC Med Genet 9: 93, 2008.
  • Swift SM, Gaume BR, Small KM, Aronow BJ, and Liggett SB. Differential coupling of Arg- and Gly389 polymorphic forms of the beta1-adrenergic receptor leads to pathogenic cardiac gene regulatory programs. Physiol Genomics 35: 123-131, 2008.
  • Wang WC, Mihlbachler KA, Bleecker ER, Weiss ST, and Liggett SB. A polymorphism of G-protein coupled receptor kinase5 alters agonist-promoted desensitization of beta2-adrenergic receptors. Pharmacogenet Genomics 18: 729-732, 2008.
  • Liggett SB, Cresci S, Kelly RJ, Syed FM, Matkovich SJ, Hahn HS, Diwan A, Martini JS, Sparks L, Parekh RR, Spertus JA, Koch WJ, Kardia SL, and Dorn GW, 2nd. A GRK5 polymorphism that inhibits beta-adrenergic receptor signaling is protective in heart failure. Nature Medicine 14: 510-517, 2008.
  • Einstein R, Jordan H, Zhou W, Brenner M, Moses EG, and Liggett SB. Alternative splicing of the G protein-coupled receptor superfamily in human airway smooth muscle diversifies the complement of receptors. Proc Natl Acad Sci U S A 105: 5230-5235, 2008.
  • Liggett SB, Kelly RJ, Parekh RR, Matkovich SJ, Benner BJ, Hahn HS, Syed FM, Galvez AS, Case KL, McGuire N, Odley AM, Sparks L, Kardia SL, and Dorn GW, 2nd. A functional polymorphism of the Galphaq (GNAQ) gene is associated with accelerated mortality in African-American heart failure. Hum Mol Genet 16: 2740-2750, 2007.
  • Tantisira KG, Small KM, Litonjua AA, Weiss ST, and Liggett SB. Molecular properties and pharmacogenetics of a polymorphism of adenylyl cyclase type 9 in asthma: interaction between beta-agonist and corticosteroid pathways. Hum Mol Genet 14: 1671-1677, 2005.
  • Mialet Perez J, Rathz DA, Petrashevskaya NN, Hahn HS, Wagoner LE, Schwartz A, Dorn GW, and Liggett SB. Beta 1-adrenergic receptor polymorphisms confer differential function and predisposition to heart failure. Nature Medicine 9: 1300-1305, 2003.
  • Liggett SB. Genetically modified mouse models for pharmacogenomic research. Nat Rev Genet 5: 657-663, 2004.
  • Small KM, Brown KM, Seman CA, Theiss CT, and Liggett SB. Complex haplotypes derived from noncoding polymorphisms of the intronless alpha2A-adrenergic gene diversify receptor expression. Proc Natl Acad Sci U S A103: 5472-5477, 2006.
  • Liggett SB, Mialet-Perez J, Thaneemit-Chen S, Weber SA, Greene SM, Hodne D, Nelson B, Morrison J, Domanski MJ, Wagoner LE, Abraham WT, Anderson JL, Carlquist JF, Krause-Steinrauf HJ, Lazzeroni LC, Port JD, Lavori PW, and Bristow MR. A polymorphism within a conserved beta(1)-adrenergic receptor motif alters cardiac function and beta-blocker response in human heart failure. Proc Natl Acad Sci U S A 103:11288-11293, 2006.