KOICHI SAMESHIMA
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Radiologia, Faculdade de Medicina - Docente
LIM/43 - Laboratório de Medicina Nuclear, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/43 - Laboratório de Medicina Nuclear, Hospital das Clínicas, Faculdade de Medicina - Líder
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- GWAS of human bitter taste perception identifies new loci and reveals additional complexity of bitter taste genetics(2014) LEDDA, Mirko; KUTALIK, Zoltan; DESTITO, Maria C. Souza; SOUZA, Milena M.; CIRILLO, Cintia A.; ZAMBONI, Amabilene; MARTIN, Nathalie; MORYA, Edgard; SAMESHIMA, Koichi; BECKMANN, Jacques S.; COUTRE, Johannes le; BERGMANN, Sven; GENICK, Ulrich K.Human perception of bitterness displays pronounced interindividual variation. This phenotypic variation is mirrored by equally pronounced genetic variation in the family of bitter taste receptor genes. To better understand the effects of common genetic variations on human bitter taste perception, we conducted a genome-wide association study on a discovery panel of 504 subjects and a validation panel of 104 subjects from the general population of Sao Paulo in Brazil. Correction for general taste-sensitivity allowed us to identify a SNP in the cluster of bitter taste receptors on chr12 (10.88- 11.24 Mb, build 36.1) significantly associated (best SNP: rs2708377, P = 5.31 x 10(-13), r(2) = 8.9%, beta = -0.12, s.e. = 0.016) with the perceived bitterness of caffeine. This association overlaps with-but is statistically distinct from-the previously identified SNP rs10772420 influencing the perception of quinine bitterness that falls in the same bitter taste cluster. We replicated this association to quinine perception (P = 4.97 x 10(-37), r(2) = 23.2%, beta = 0.25, s.e. = 0.020) and additionally found the effect of this genetic locus to be concentration specific with a strong impact on the perception of low, but no impact on the perception of high concentrations of quinine. Our study, thus, furthers our understanding of the complex genetic architecture of bitter taste perception.
- Genome-Wide Association Study of Metabolic Traits Reveals Novel Gene-Metabolite-Disease Links(2014) RUEEDI, Rico; LEDDA, Mirko; NICHOLLS, Andrew W.; SALEK, Reza M.; MARQUES-VIDAL, Pedro; MORYA, Edgard; SAMESHIMA, Koichi; MONTOLIU, Ivan; SILVA, Laeticia Da; COLLINO, Sebastiano; MARTIN, Francois-Pierre; REZZI, Serge; STEINBECK, Christoph; WATERWORTH, Dawn M.; WAEBER, Gerard; VOLLENWEIDER, Peter; BECKMANN, Jacques S.; COUTRE, Johannes Le; MOOSER, Vincent; BERGMANN, Sven; GENICK, Ulrich K.; KUTALIK, ZoltanAuthor Summary The concentrations of small molecules known as metabolites, are subject to tight regulation in all organisms. Collectively, the metabolite concentrations make up the metabolome, which differs amongst individuals as a function of their environment and genetic makeup. In our study, we have further developed an untargeted approach to identify genetic factors affecting human metabolism. In this approach, we first identify all genetic variants that correlate with any of the measured metabolome features in a large set of individuals. For these variants, we then compute a profile of significance for association with all features, generating a signature that facilitates the expert or computational identification of the metabolite whose concentration is most likely affected by the genetic variant at hand. Our study replicated many of the previously reported genetically driven variations in human metabolism and revealed two new striking examples of genetic variations with a sizeable effect on the urine metabolome. Interestingly, in these two gene-metabolite pairs both the gene and the affected metabolite are related to human diseases - Crohn's disease in the first case, and kidney disease in the second. This highlights the connection between genetic predispositions, affected metabolites, and human health. Metabolic traits are molecular phenotypes that can drive clinical phenotypes and may predict disease progression. Here, we report results from a metabolome- and genome-wide association study on H-1-NMR urine metabolic profiles. The study was conducted within an untargeted approach, employing a novel method for compound identification. From our discovery cohort of 835 Caucasian individuals who participated in the CoLaus study, we identified 139 suggestively significant (P<5x10(-8)) and independent associations between single nucleotide polymorphisms (SNP) and metabolome features. Fifty-six of these associations replicated in the TasteSensomics cohort, comprising 601 individuals from Sao Paulo of vastly diverse ethnic background. They correspond to eleven gene-metabolite associations, six of which had been previously identified in the urine metabolome and three in the serum metabolome. Our key novel findings are the associations of two SNPs with NMR spectral signatures pointing to fucose (rs492602, P = 6.9x10(-44)) and lysine (rs8101881, P = 1.2x10(-33)), respectively. Fine-mapping of the first locus pinpointed the FUT2 gene, which encodes a fucosyltransferase enzyme and has previously been associated with Crohn's disease. This implicates fucose as a potential prognostic disease marker, for which there is already published evidence from a mouse model. The second SNP lies within the SLC7A9 gene, rare mutations of which have been linked to severe kidney damage. The replication of previous associations and our new discoveries demonstrate the potential of untargeted metabolomics GWAS to robustly identify molecular disease markers.
- Sensitivity of Genome-Wide-Association Signals to Phenotyping Strategy: The PROP-TAS2R38 Taste Association as a Benchmark(2011) GENICK, Ulrich K.; KUTALIK, Zoltan; LEDDA, Mirko; DESTITO, Maria C. Souza; SOUZA, Milena M.; CIRILLO, Cintia A.; GODINOT, Nicolas; MARTIN, Nathalie; MORYA, Edgard; SAMESHIMA, Koichi; BERGMANN, Sven; COUTRE, Johannes leNatural genetic variation can have a pronounced influence on human taste perception, which in turn may influence food preference and dietary choice. Genome-wide association studies represent a powerful tool to understand this influence. To help optimize the design of future genome-wide-association studies on human taste perception we have used the well-known TAS2R38-PROP association as a tool to determine the relative power and efficiency of different phenotyping and data-analysis strategies. The results show that the choice of both data collection and data processing schemes can have a very substantial impact on the power to detect genotypic variation that affects chemosensory perception. Based on these results we provide practical guidelines for the design of future GWAS studies on chemosensory phenotypes. Moreover, in addition to the TAS2R38 gene past studies have implicated a number of other genetic loci to affect taste sensitivity to PROP and the related bitter compound PTC. None of these other locations showed genome-wide significant associations in our study. To facilitate further, target-gene driven, studies on PROP taste perception we provide the genome-wide list of p-values for all SNPs genotyped in the current study.