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Allelic Polymorphism within the TAS1R3 Promoter Is Associated with Human Taste Sensitivity to Sucrose

2009; Elsevier BV; Volume: 19; Issue: 15 Linguagem: Inglês

10.1016/j.cub.2009.06.015

1879-0445

Alexey A. Fushan, Christopher T. Simons, Jay P. Slack, Ani Manichaikul, Dennis Drayna,

Olfactory and Sensory Function Studies

Human sweet taste perception is mediated by the heterodimeric G protein-coupled receptor encoded by the TAS1R2 and TAS1R3 genes [1Li X. Staszewski L. Xu H. Durick K. Zoller M. Adler E. Human receptors for sweet and umami taste.Proc. Natl. Acad. Sci. USA. 2002; 99: 4692-4696Crossref PubMed Scopus (1033) Google Scholar, 2Sainz E. Cavenagh M.M. LopezJimenez N.D. Gutierrez J.C. Battey J.F. Northup J.K. Sullivan S.L. The G-protein coupling properties of the human sweet and amino acid taste receptors.Dev. Neurobiol. 2007; 67: 948-959Crossref PubMed Scopus (27) Google Scholar, 3Zhao G.Q. Zhang Y. Hoon M.A. Chandrashekar J. Erlenbach I. Ryba N.J. Zuker C.S. The receptors for mammalian sweet and umami taste.Cell. 2003; 115: 255-266Abstract Full Text Full Text PDF PubMed Scopus (887) Google Scholar, 4Bachmanov A.A. Li X. Reed D.R. Ohmen J.D. Li S. Chen Z. Tordoff M.G. de Jong P.J. Wu C. West D.B. et al.Positional cloning of the mouse saccharin preference (Sac) locus.Chem. Senses. 2001; 26: 925-933Crossref PubMed Scopus (220) Google Scholar, 5Max M. Shanker Y.G. Huang L. Rong M. Liu Z. Campagne F. Weinstein H. Damak S. Margolskee R.F. Tas1r3, encoding a new candidate taste receptor, is allelic to the sweet responsiveness locus Sac.Nat. Genet. 2001; 28: 58-63Crossref PubMed Scopus (440) Google Scholar, 6Montmayeur J.P. Liberles S.D. Matsunami H. Buck L.B. A candidate taste receptor gene near a sweet taste locus.Nat. Neurosci. 2001; 4: 492-498Crossref PubMed Scopus (380) Google Scholar, 7Kitagawa M. Kusakabe Y. Miura H. Ninomiya Y. Hino A. Molecular genetic identification of a candidate receptor gene for sweet taste.Biochem. Biophys. Res. Commun. 2001; 283: 236-242Crossref PubMed Scopus (282) Google Scholar]. Variation in these genes has been characterized [8Kim U.K. Wooding S. Riaz N. Jorde L.B. Drayna D. Variation in the human TAS1R taste receptor genes.Chem. Senses. 2006; 31: 599-611Crossref PubMed Scopus (89) Google Scholar], but the functional consequences of such variation for sweet perception are unknown. We found that two C/T single-nucleotide polymorphisms (SNPs) located at positions −1572 (rs307355) and −1266 (rs35744813) upstream of the TAS1R3 coding sequence strongly correlate with human taste sensitivity to sucrose and explain 16% of population variability in perception. By using a luciferase reporter assay, we demonstrated that the T allele of each SNP results in reduced promoter activity in comparison to the C alleles, consistent with the phenotype observed in humans carrying T alleles. We also found that the distal region of the TAS1R3 promoter harbors a composite cis-acting element that has a strong silencing effect on promoter activity. We conclude that the rs307355 and rs35744813 SNPs affect gene transcription by altering the function of this regulatory element. A worldwide population survey reveals that the T alleles of rs307355 and rs35744813 occur at lowest frequencies in European populations. We propose that inherited differences in TAS1R3 transcription account for a substantial fraction of worldwide differences in human sweet taste perception.