Predominant Qualities Evoked by Quinine, Sucrose, and Capsaicin Associate With PROP Bitterness, but not TAS2R38 Genotype.

Genetic variability in the ability to taste thiourea compounds has been studied for 80+ years. Over the last 3 decades, many studies have reported perceived intensity of concentrated propylthiouracil (PROP) associates with greater intensity from a broad range of stimuli, including nonbitter tastants, irritants, and retronasally delivered odorants. Thus, PROP phenotype has become a common measure of individual differences in orosensation. Much, but not all, of the phenotypic variation in PROP bitterness is explained by TAS2R38 polymorphisms. While differences in PROP bitterness are clearly due to genetic variation, mechanistically it is challenging to envision how this receptor (narrowly tuned to the N-C=S moiety) relates to overall orosensory response. Here, we report data for 200+ individuals who had been genotyped for TAS2R38 and phenotyped for PROP in a laboratory setting. Participants also reported the intensity of quinine, capsaicin, and sucrose on a general Labeled Magnitude Scale. Our data recapitulate earlier reports associating PROP bitterness with the intensity of the predominant qualities of sucrose, quinine, and capsaicin; however, we also find correlations between the intensities of sucrose, quinine, and capsaicin were much stronger with each other than with PROP. As expected, TAS2R38 diplotype did not associate with the intensity of sucrose, quinine, or capsaicin. The strength of PROP-capsaicin and PROP-sucrose relationships increased after grouping participants by TAS2R38 diplotype, with the greatest increases in association observed within homozygotes. Collectively, this suggests the suprathreshold intensity of PROP is a confounded phenotype that captures both genetic variation specific to N-C=S compounds and overall orosensation.

Differential Activation of TAS2R4 May Recover Ability to Taste Propylthiouracil for Some TAS2R38 AVI Homozygotes.

Bitterness from phenylthiocarbamide and 6-n-propylthiouracil (PROP) varies with polymorphisms in the TAS2R38 gene. Three SNPs form two common (AVI, PAV) and four rare haplotypes (AAI, AAV, PVI, and PAI). AVI homozygotes exhibit higher detection thresholds and lower suprathreshold bitterness for PROP compared to PAV homozygotes and heterozygotes, and these differences may influence alcohol and vegetable intake. Within a diplotype, substantial variation in suprathreshold bitterness persists, and some AVI homozygotes report moderate bitterness at high concentrations. A second receptor encoded by a gene containing a functional polymorphism may explain this. Early work has suggested that PROP might activate TAS2R4 in vitro, but later work did not replicate this. Here, we identify three TAS2R4 SNPs that result in three diplotypes-SLN/SLN, FVS/SLN, and FVS/FVS-which make up 25.1%, 44.9%, and 23.9% of our sample. These TAS2R4 haplotypes show minimal linkage disequilibrium with TAS2R38, so we examined the suprathreshold bitterness as a function of both. The participants (n = 243) rated five PROP concentrations in duplicate, interleaved with other stimuli. As expected, the TAS2R38 haplotypes explained ~29% (p < 0.0001) of the variation in the bitterness ratings, with substantial variation within the haplotypes (AVI/AVI, PAV/AVI, and PAV/PAV). Notably, the TAS2R4 diplotypes (independent of the TAS2R38 haplotypes) explained ~7-8% of the variation in the bitterness ratings (p = 0.0001). Given this, we revisited if PROP could activate heterologously expressed TAS2R4 in HEK293T cells, and calcium imaging indicated 3 mM PROP is a weak TAS2R4 agonist. In sum, our data are consistent with the second receptor hypothesis and may explain the recovery of the PROP tasting phenotype in some AVI homozygotes; further, this finding may potentially help explain the conflicting results on the TAS2R38 diplotype and food intake.

Do polymorphisms in the TAS1R1 gene contribute to broader differences in human taste intensity?

The TAS1R genes encode heterodimeric receptors that mediate umami (hTAS1R1 + hTAS1R3) and sweet (hTAS1R2 + hTAS1R3) sensations. The question of interest for this study is if TAS1R1 variation associates with differences in overall taste intensity. We leveraged an existing database of adults (n = 92, primarily European American) to test associations between 2 TAS1R1 single nucleotide polymorphisms (SNPs) (intronic rs17492553, C/T and exonic rs34160967, G/A) and intensity of 4 prototypical tastants (NaCl, sucrose, citric acid, and quinine), applied regionally to fungiform and circumvallate loci, and sampled with the whole mouth. Both SNPs were associated with modest shifts in perceived intensities across all taste qualities. Three genotype groups were represented for the intronic SNP-minor allele homozygotes (TT) averaged 40% lower intensities than did CC homozygotes for all regionally applied tastants, as well as whole-mouth NaCl and citric acid. Similar, but less pronounced, intensity differences were seen for the exonic SNP (GG homozygotes reported greater intensities than did the AA/AG group). Our predominantly European American cohort had a low frequency of AA homozygotes, which may have attenuated the SNP-related differences in perceived intensity. These preliminary findings, if replicated, could add TAS1R1 polymorphisms to the repertoire of genotypic and phenotypic markers of heightened taste sensation.