TY - JOUR
AU - Hayes, John, E
AB - Abstract 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. genetics, hypergeusia, propylthiouracil, supertasting, taste phenotype Introduction The suprathreshold intensity of the bitter chemical propylthiouracil (PROP) correlates with the intensity of sensations evoked by a variety of compounds, including prototypical tastants (Bartoshuk et al. 1992; Drewnowski et al. 1998; Ly and Drewnowski 2001; Hansen et al. 2006; Bajec and Pickering 2008; Hayes et al. 2008), chemesthetic agents (Bartoshuk et al. 1993; Campbell 2000), and real foods and beverages (Prescott et al. 2004; Shen et al. 2016). Generally, individuals who perceive greater bitterness from PROP also perceive increased intensity of sensations from these compounds and foods than do individuals reporting lower or no bitterness from PROP. This relationship is also seen with sampled alcohol or alcoholic beverage (Bartoshuk et al. 1993; Intranuovo and Powers 1998; Duffy et al. 2004) and nonnutritive sweeteners (Bartoshuk 1979; Gent and Bartoshuk 1983; Zhao and Tepper 2007; Allen et al. 2013). Moreover, this association has been reported for other orosensory qualities including astringency (Pickering et al. 2004; Bajec and Pickering 2008), sourness (Bajec and Pickering 2008), and fat (Tepper and Nurse 1997; Drewnowski et al. 1998; Tepper and Nurse 1998). However, greater PROP bitterness does not always associate with heightened sensations for all oral stimuli (e.g., Horne et al. 2002; Lim et al. 2008). Furthermore, this measure of PROP phenotype is associated with reported preference and intake of foods and beverages (Keller et al. 2002; Duffy et al. 2004; Ullrich 2004; Mennella et al. 2005; Dinehart et al. 2006; see Tepper 2008; Keller and Adise 2016 for reviews). For example, individuals who experience greater bitterness from PROP report consuming fewer vegetables compared with PROP nontasters (Keller et al. 2002; Bell and Tepper 2006; Dinehart et al. 2006; Duffy et al. 2010). In summary, measuring PROP response is a relatively quick phenotypic measure, which can serve as a predictor of individual variability food preference and intake, which in turn are partially driven by differences in perception of various sensory properties. However, it is only one taste phenotype, and it may not relate or generalize to other measures of taste function (see Hayes and Keast 2011; Kalva et al. 2014; Webb et al. 2015). A major breakthrough in the mechanistic understanding of individual differences in the perception of thiourea (N–C=S) compounds was made in 2003 by Kim et al. (2003). They showed variable detection thresholds for phenylthiocarbamide (PTC) were due to polymorphisms in the bitter taste receptor gene PTC, which was subsequently renamed TAS2R38 (HGNC: 9584). Soon thereafter, this finding was extended to suprathreshold bitterness of PROP by multiple research groups (Duffy et al. 2004; Bufe et al. 2005). The TAS2R38 gene contains 3 single nucleotide polymorphisms (SNPs) that are typically (but not always) inherited together; these 3 SNPs are named for the resulting amino acid substitutions (A49P, V262A, and I296V), and they form 2 common (PAV and AVI) and 4 uncommon (AAV, AAI, PAI, and PVI) haplotypes (see Bufe et al. 2005; Garneau et al. 2014; Boxer and Garneau 2015). The TAS2R38 genotype has been repeatedly shown to associate with PROP bitterness (e.g., Duffy et al. 2004; Bufe et al. 2005; Hayes et al. 2008; Allen et al. 2013; Boxer and Garneau 2015). There is also evidence of TAS2R38 genotype explaining variability in preference and intake of foods and beverages (Duffy et al. 2004, 2010; Gorovic et al. 2011; Hayes et al. 2011; Beckett et al. 2017). Since discovery of the functional polymorphisms in TAS2R38 in 2003, many of the relationships originally reported between PROP intensity and other sensory properties have been attributed to genetic variation in TAS2R38. Critically however, it would be inaccurate to conclude that all observed relationships between the suprathreshold bitterness of PROP (e.g., Hayes et al. 2008; Hayes and Keast 2011; Webb et al. 2015) and differences in food sensations, affective responses, or food intake (see reviews by Keller and Adise 2016; Diószegi et al. 2019) are due to functional variation in a bitter taste receptor that is narrowly tuned to the N–C=S moiety found on thiourea compounds (Barnicot et al. 1951; Wooding et al. 2010). For example, there is no simple biologically plausible mechanism by which TAS2R38 genotype should influence a sensation like creaminess, yet, the absence of a simple mechanism does not preclude a reproduceable relationship between PROP bitterness (the phenotype) and creaminess (e.g., Tepper and Nurse 1998; Hayes and Duffy 2007). Indeed, prior work demonstrated that elevated responses to various stimuli (i.e., supertasting) cannot be explained by TAS2R38 genotype (Hayes et al. 2008). The goal of the present work was to use a large laboratory cohort to test the predictive utility of PROP bitterness on other oral sensations after controlling for TAS2R38 genotype. Materials and methods Overview The results presented here were drawn from a larger study focused on the genetics of oral sensation. The full protocol involved 4 test sessions on separate days. Data presented here were obtained in the first visit, so the description of the methods will be restricted to session 1. Details on the other visits have been reported elsewhere (Allen et al. 2014; Feeney and Hayes 2014b; Nolden et al. 2016). Briefly, the first test session took roughly 1 h to complete and was conducted one-on-one with research staff. Testing included obtaining consent, completion of a food liking questionnaire, tasting multiple chemical stimuli, measurement of anthropometric data, and collection of a salivary DNA sample. After being oriented to the scaling procedure (details below), participants sampled 6 compounds (both tastants and irritants) for multiple sensory qualities. Lastly, PROP phenotype was collected via a standard protocol, using PROP, salt, and auditory stimuli (e.g., Duffy et al. 2004; Hayes et al. 2008). Other data were also collected in session 1 (e.g., Byrnes and Hayes 2013) but are not described here for brevity. Participants provided written informed consent and were compensated for their time. All procedures were approved by the Pennsylvania State University Institutional Review Board (protocol number #33176), and this study complies with the Helsinki declaration. Participants Interested individuals were screened prior to scheduling the first visit to ensure they eligibility criteria. These included: between 18 and 45 years old, not pregnant or breastfeeding, nonsmoker (had not smoked in the last 30 days), no known defects of smell or taste, no lip, cheek, or tongue piercings, no history of any condition involving chronic pain, not currently taking any prescription pain medication, no reported history of choking or difficulty swallowing, and no history of thyroid disease. Participants also needed to be willing to provide a salivary DNA sample. Additional demographic details on participants are provided below in the results. Psychophysical scaling and rating of stimuli Participants rated stimuli on a general Labeled Magnitude Scale (gLMS) (Snyder et al. 2004). The gLMS ranges from “no sensation” (0) to “the strongest imaginable sensation of any kind” (100), with intermediate descriptors at 1.4 (barely detectable), 6 (weak), 17 (moderate), 35 (strong), and 51 (very strong). Each participant was oriented to the scale, first with a verbal explanation of the gLMS, followed by a practice session where participants made ratings for a list of 15 imagined or remembered sensations that included both food and nonfood items (Hayes et al. 2013). The orientation and practice were meant to encourage participants to make ratings on the scale in a generalized context that not limited to oral sensations. They were also instructed to not let whether or not a stimulus was liked or disliked influence their intensity rating, and that they should click anywhere along the scale, not merely near the verbal labels. Participants were also told, “You may receive stimuli causing more than one quality. Please attend to all sensations on all trials.” Separate ratings for sweetness, bitterness, sourness, burning/stinging, savory/umami, and saltiness were collected for each stimulus. All ratings were collected using Compusense five, version 5.2. Stimuli and tasting procedure Six stimuli were presented to participants in this portion of the experiment (see Allen et al. 2013), but only 3 are analyzed here: 0.41 mM quinine HCl, 0.5 M sucrose, and 25 µM capsaicin. Data for the other tastants (potassium chloride, acesulfame potassium, and a blend of monosodium glutamate and inosine 5’-monophosphate [MSG/IMP]), have been described elsewhere (Allen et al. 2013; Feeney and Hayes 2014a, 2014b). All solutions were made fresh weekly with food grade reagents and stored in a refrigerator; all samples were brought to room temperature before tasting. Participants swished a 10-mL sample for 3 s and then expectorated prior to rating. Presentation order of all 6 stimuli was counterbalanced across participants using a Williams’ design. Prior to sampling the first solution and between each solution, participants rinsed with room temperature reverse osmosis (RO) water. A minimum of break of 30 s was enforced between each; however, participants were encouraged to wait longer if any lingering sensation remained. Determining an individual’s PROP phenotype PROP phenotypes were determined using a standard method described previously (e.g., Duffy et al. 2004; Dinehart et al. 2006; Hayes et al. 2010). Briefly, participants rated the intensity of 5 PROP solutions, 5 salt solutions, and 5 1-kHz tones. The salt and PROP concentrations were presented in duplicate, while the sets of tones were repeated 5 times. The presentation order of stimuli was blocked, so participants received solutions and tones in alternating series: specifically, 5 tones, 5 salt solutions, 5 tones, 5 salt solutions, 5 tones, 5 PROP solutions, 5 tones, 5 PROP solutions, and 5 tones. Within a block, concentrations and tones were presented in counterbalanced orders. The concentrations of PROP solutions were made with USP grade PROP (Sigma) and had a final concentration of 0.032, 0.1, 0.32, 1, and 3.2 mM, while the salt solutions were 0.01, 0.032, 0.1, 0.32, and 1 M sodium chloride. All solutions were prepared with RO water. The 1-kHz tones were generated with a Maico MA39 audiometer, which had been modified to deliver tones binaurally. The auditory stimuli were presented in a wide range, from 50 to 90 dB in 10 dB steps. Participants rinsed with room temperature RO water between each sample, waiting a minimum of 30 s before next sample. Means of the 3.2 mM PROP and 80 dB tones were calculated for each participant, and used in all subsequent analyses. Genetic analysis Each participant provided a salivary DNA sample using an Oragene collection kit according to the manufacturer’s instructions (Genotek Inc). Three SNPs in TAS2R38 were determined using Sequenom MassARRAY technology (Sequenom). The 3 SNPs analyzed here include rs713598 (A49P), rs1726866 (V262A), and rs10246939 (I269V), which are commonly inherited together, forming 3 common haplotypes (PAV/PAV, PAV/AVI, or AVI/AVI). All primers were purchased from Integrated DNA Technologies. Participant’s genotypes were automatically determined using MassARRAY software (Sequenom). Additionally, 2 technicians independently inspected the genotypes. As a measure of reliability, a total of 15% of samples were rerun. Statistical analysis Haplotypes were determined using Bayesian imputation using PHASE, and only those with a probability greater than 0.80 are reported. Data were analyzed using SAS 9.4. Genetic variants were analyzed via analysis of variance (ANOVA) via proc mixed, and pairwise comparisons were adjusted for multiple comparisons using the Tukey–Kramer method. Pearson correlations were conducted via proc corr to determine the association between rated sensations. Multiple regression models were created using proc reg to determine the association between rated sensations and dB tones; information regarding the contributions of individual variables are reported as semipartial correlations (sr). Results TAS2R38 diplotype are associated with PROP bitterness Of the total number of participants in the study, 89% (n = 220) carried common diplotypes: PAV/PAV, PAV/AVI, or AVI/AVI. The majority of these participants were common haplotype heterozygotes (PAV/AVI; n = 121) with roughly balanced frequencies of PAV homozygotes (n = 48) and AVI homozygotes (n = 51), which is generally consistent with convenience samples in the United States (e.g., Kim et al. 2005; Hayes et al. 2008; Duffy et al. 2010; Garneau et al. 2014). As expected, some participants had rare diplotypes, including 8 PAV/AAV and 12 AVI/AAV individuals; the remaining 6 individuals had other rare diplotypes. Due to these low counts, individuals with rare diplotypes were dropped from further analysis to focus on the common diplotypes (i.e., PAV/PAV, PAV/AVI, and AVI/AVI). Of the 220 participants whose data are reported below, 89 were men, and 131 were women, with a mean age of 25.7 (standard deviation 7.2). Using categories provided by the 1997 OMB Directive 15 guidelines, the majority of the participants self-identified as White/Caucasian (n = 152), followed by Asian (n = 34), and African American (n = 5). As expected, TAS2R38 diplotype was significantly associated with PROP bitterness (F(2,217) = 48.54; P < 0.0001). As shown in Figure 1, the PAV homozygotes rated PROP as being more bitter (55.5 ± 2.7 SEM) than heterozygotes (43.6 ± 1.7 SEM), or AVI homozygotes (19.4 ± 2.6 SEM). In pairwise comparisons (Tukey–Kramer), all groups differed from each other (all Ps < 0.001). Figure 1. Open in new tabDownload slide Participants are grouped by TAS2R38 diplotype. PROP bitterness ratings (gLMS) are reported on the y-axis, with labels of barely detectable (BD), weak, moderate, strong, very strong, at 1.4, 6, 17, 35, and 51 on the right y-axis. In pairwise comparisons, all 3 diplotype groups were significantly different from each other (Tukey–Kramer; all Ps < 0.001). Figure 1. Open in new tabDownload slide Participants are grouped by TAS2R38 diplotype. PROP bitterness ratings (gLMS) are reported on the y-axis, with labels of barely detectable (BD), weak, moderate, strong, very strong, at 1.4, 6, 17, 35, and 51 on the right y-axis. In pairwise comparisons, all 3 diplotype groups were significantly different from each other (Tukey–Kramer; all Ps < 0.001). The bitterness of quinine, sweetness of sucrose, and burn of capsaicin are associated with PROP bitterness, but not TAS2R38 diplotype To determine if ratings of sampled stimuli associated with both PROP bitterness and TAS2R38 genotype, correlations and ANOVA models were performed for the common diplotypes. As shown in Figure 2 (left), quinine bitterness was significantly correlated with PROP bitterness (r = +0.39; P < 0.0001). Conversely, quinine bitterness did not differ by TAS2R38 genotype (F(2,217) = 1.86; P = 0.16). As shown in Figure 2 (right), as expected, the bitterness of quinine showed no differences between PAV homozygotes (30.0±2.78), heterozygotes (24.4 ± 1.75), or AVI homozygotes (28.8±2.70). Figure 2. Open in new tabDownload slide Bitterness of quinine, as a function of bitterness of PROP bitterness (left) and TAS2R38 diplotype (right). Figure 2. Open in new tabDownload slide Bitterness of quinine, as a function of bitterness of PROP bitterness (left) and TAS2R38 diplotype (right). The same analysis was then carried out for the sweetness of sucrose, where sweetness intensity was predicted separately from the bitterness of PROP and TAS2R38 genotype. As above, the sweetness of sucrose was significantly correlated with PROP bitterness (r = +0.23; P = 0.0008), as shown in Figure 3 (left). Somewhat surprisingly, TAS2R38 genotype was marginally associated with the sweetness of sucrose (F(2,217) = 3.25; P = 0.04). However, as Figure 3 (right) shows, pairwise comparisons (Tukey–Kramer) revealed no significant differences (all Ps > 0.077) between PAV homozygotes, heterozygotes, or AVI homozygotes for sweetness (mean ratings of 31.5 ± 2.45, 26.0 ± 1.54, and 32.2 ± 2.38, respectively). Figure 3. Open in new tabDownload slide Sweetness of sucrose, as a function of bitterness of PROP bitterness (left) and TAS2R38 diplotype (right). In the right panel, there was weak evidence of a main effect of genotype, but in pairwise comparisons (Tukey–Kramer), none of the groups differed from each other (all Ps > 0.077). Figure 3. Open in new tabDownload slide Sweetness of sucrose, as a function of bitterness of PROP bitterness (left) and TAS2R38 diplotype (right). In the right panel, there was weak evidence of a main effect of genotype, but in pairwise comparisons (Tukey–Kramer), none of the groups differed from each other (all Ps > 0.077). Finally, the same analysis was performed for the burn of capsaicin. Again, there was a positive correlation between the burn of capsaicin and PROP bitterness (r = +0.26; P < 0.0001), as shown in Figure 4 (left). However, there was no relationship between the burn of capsaicin and TAS2R38 genotype (F(2,217) = 1.27; P = 0.28), as shown in Figure 4 (right). Mean ratings of capsaicin burn for PAV homozygotes, heterozygotes, or AVI homozygotes were 37.2 ± 2.99, 32.5 ± 1.88, and 37.7 ± 2.90, respectively. Figure 4. Open in new tabDownload slide Burn of capsaicin, as a function of bitterness of PROP bitterness (left) and TAS2R38 diplotype (right). Figure 4. Open in new tabDownload slide Burn of capsaicin, as a function of bitterness of PROP bitterness (left) and TAS2R38 diplotype (right). Controlling for tone intensity ratings does not alter relationships between PROP bitterness and the prototypical quality of each stimulus Because scale usage can vary across individuals (e.g., Webb et al. 2015), multiple regression models were used to partition out potential differences in scale usage that would otherwise inflate apparent relationships between PROP bitterness and the prototypical stimuli (i.e., the bitterness of quinine, the sweetness of sucrose, and the burning of capsaicin). That is, if some individuals tended to rate all stimuli as more intense, while other individuals rated all stimuli as less intense, this scaling bias would make the bitterness of PROP appear to be correlated with the intensity of quinine, sucrose, and capsaicin. By including a cross-modal standard like tone intensities in the model, we can test if the elevated ratings are specific to chemosensation rather than merely being an artifact of how participants differ in their usage of the scale. In a multiple regression model predicting the bitterness intensity of quinine, mean ratings of the 80 dB tones, and PROP bitterness explained 18.9% of the variability (P < 0.0001); both 80 dB tones (sr = 0.21; P = 0.0007) and PROP bitterness (sr = 0.30; P < 0.0001) were significant predictors. A similar result was obtained for a multiple regression model predicting the sweetness of sucrose: the overall model explained 11.4% of the variation in sucrose intensity, with both 80 dB tone ratings (sr = 0.25, P = 0.0001) and PROP bitterness (sr = 0.14; P = 0.031) as significant predictors. Finally, the multiple regression model for capsaicin burn explained 10.1% of the variation in burn ratings, and again, both mean 80 dB tone ratings (sr = 0.18; P = 0.005) and PROP bitterness (sr = 0.19; P = 0.003) contributed significantly to the model. In summary, mean ratings for 80 dB tones were significant predictors of quinine bitterness, sucrose sweetness, and capsaicin burn in simple regression models (not shown), but when PROP bitterness was added to each model, additional variance was explained above and beyond what was explained by ratings of the 1-kHz tones. Collectively, this suggests that the ability of PROP bitterness to predict the burn of capsaicin, the sweetness of sucrose, and the bitterness of quinine is not merely an artifact due to differential scale usage. Capsaicin burn is a better predictor of sucrose sweetness and quinine bitterness than PROP bitterness, but partitioning participants by genotype improves correlations between PROP bitterness and ratings for the other stimuli As shown in Table 1, the ratings for the predominant qualities for all of the stimuli were significantly correlated with each other. In general, the ability of PROP bitterness to predict the intensity of other stimuli increased when effects of genotype were partitioned out (Table 2). Table 1. Matrix of Pearson correlations for ratings of prototypical qualities across all 220 participants . Capsaicin . Quinine . Sucrose . Quinine +0.48 — — <0.0001 Sucrose +0.48 +0.51 — <0.0001 <0.0001 PROP +0.26 +0.38 +0.23 <0.0001 <0.0001 0.0008 . Capsaicin . Quinine . Sucrose . Quinine +0.48 — — <0.0001 Sucrose +0.48 +0.51 — <0.0001 <0.0001 PROP +0.26 +0.38 +0.23 <0.0001 <0.0001 0.0008 Bold indicates significant correlations. Open in new tab Table 1. Matrix of Pearson correlations for ratings of prototypical qualities across all 220 participants . Capsaicin . Quinine . Sucrose . Quinine +0.48 — — <0.0001 Sucrose +0.48 +0.51 — <0.0001 <0.0001 PROP +0.26 +0.38 +0.23 <0.0001 <0.0001 0.0008 . Capsaicin . Quinine . Sucrose . Quinine +0.48 — — <0.0001 Sucrose +0.48 +0.51 — <0.0001 <0.0001 PROP +0.26 +0.38 +0.23 <0.0001 <0.0001 0.0008 Bold indicates significant correlations. Open in new tab Table 2. Matrix of Pearson correlations for ratings of prototypical qualities, broken down by TAS2R38 genotype group . Capsaicin . Quinine . Sucrose . AVI/AVI homozygotes (n = 51)  Quinine +0.60 — — <0.0001  Sucrose +0.71 +0.58 — <0.0001 <0.0001  PROP +0.36 +0.40 +0.29 0.0094 0.0033 0.0365 PAV/AVI heterozygotes (n = 121)  Quinine +0.38 — — <0.0001  Sucrose +0.33 +0.47 — 0.0002 <0.0001  PROP +0.30 +0.55 +0.27 0.0008 <0.0001 0.0026 PAV/PAV homozygotes (n = 48)  Quinine +0.45 — — 0.0013  Sucrose +0.36 +0.44 — 0.0125 0.0020  PROP +0.39 +0.44 +0.46 0.0058 0.0017 0.0010 . Capsaicin . Quinine . Sucrose . AVI/AVI homozygotes (n = 51)  Quinine +0.60 — — <0.0001  Sucrose +0.71 +0.58 — <0.0001 <0.0001  PROP +0.36 +0.40 +0.29 0.0094 0.0033 0.0365 PAV/AVI heterozygotes (n = 121)  Quinine +0.38 — — <0.0001  Sucrose +0.33 +0.47 — 0.0002 <0.0001  PROP +0.30 +0.55 +0.27 0.0008 <0.0001 0.0026 PAV/PAV homozygotes (n = 48)  Quinine +0.45 — — 0.0013  Sucrose +0.36 +0.44 — 0.0125 0.0020  PROP +0.39 +0.44 +0.46 0.0058 0.0017 0.0010 Bold indicates significant correlations. Open in new tab Table 2. Matrix of Pearson correlations for ratings of prototypical qualities, broken down by TAS2R38 genotype group . Capsaicin . Quinine . Sucrose . AVI/AVI homozygotes (n = 51)  Quinine +0.60 — — <0.0001  Sucrose +0.71 +0.58 — <0.0001 <0.0001  PROP +0.36 +0.40 +0.29 0.0094 0.0033 0.0365 PAV/AVI heterozygotes (n = 121)  Quinine +0.38 — — <0.0001  Sucrose +0.33 +0.47 — 0.0002 <0.0001  PROP +0.30 +0.55 +0.27 0.0008 <0.0001 0.0026 PAV/PAV homozygotes (n = 48)  Quinine +0.45 — — 0.0013  Sucrose +0.36 +0.44 — 0.0125 0.0020  PROP +0.39 +0.44 +0.46 0.0058 0.0017 0.0010 . Capsaicin . Quinine . Sucrose . AVI/AVI homozygotes (n = 51)  Quinine +0.60 — — <0.0001  Sucrose +0.71 +0.58 — <0.0001 <0.0001  PROP +0.36 +0.40 +0.29 0.0094 0.0033 0.0365 PAV/AVI heterozygotes (n = 121)  Quinine +0.38 — — <0.0001  Sucrose +0.33 +0.47 — 0.0002 <0.0001  PROP +0.30 +0.55 +0.27 0.0008 <0.0001 0.0026 PAV/PAV homozygotes (n = 48)  Quinine +0.45 — — 0.0013  Sucrose +0.36 +0.44 — 0.0125 0.0020  PROP +0.39 +0.44 +0.46 0.0058 0.0017 0.0010 Bold indicates significant correlations. Open in new tab Discussion In the data described here, variability in suprathreshold ratings of sampled quinine, sucrose, and capsaicin were associated with the bitterness of PROP but not TAS2R38 genotype. Further, as expected, we confirm numerous prior reports that show variability in PROP bitterness associates with TAS2R38, with greater PROP ratings observed within PAV heterozygotes, compared with heterozygotes and AVI homozygotes (e.g., Kim et al. 2003; Bufe et al. 2005; Hayes et al. 2008; Duffy et al. 2010; Mennella et al. 2010; Garneau et al. 2014). Prior work indicates bitterness, sourness, saltiness, sweetness, metallic, and astringent ratings for prototypical chemosensory stimuli are positively correlated with PROP bitterness (e.g., Pickering et al. 2004; Bajec and Pickering 2008; Hayes et al. 2008). Similarly, the creaminess of dairy products has been positively associated with PROP bitterness (Tepper and Nurse 1997; Kirkmeyer and Tepper 2005), although not all studies agree (cf. Hayes and Duffy 2007; Lim et al. 2008). Likewise, the sweetness of acesulfame potassium (AceK) (but not the bitterness) associates with the bitterness of PROP (Allen et al. 2013). Here, we find similar effects, with significant positive relationships between quinine bitterness, sucrose sweetness, and capsaicin burn with PROP bitterness. Notably, Lim et al. (2008) reported the sweetness of sucrose was more highly correlated with ratings for other tastants, including salt, citric acid, and quinine than with PROP. Using a similar analysis here, we found evidence that the relationship between a chemesthetic agent (capsaicin) and various prototypical tastants was greater than with PROP (see Table 1), at least before controlling for genetic variation. The correlation between burn of capsaicin and the tastants (sucrose and quinine) was greater than with the bitterness of PROP, suggesting the burn of capsaicin is a better predictor of the intensity of tastants in water than PROP bitterness. Here, we also show that correlations between PROP bitterness and the intensity of sucrose, quinine, and capsaicin appear to be due to real differences in psychophysical responses, and are not merely an artifact of scale usage. Individuals may use the scale differently (e.g., Webb et al. 2015), with some individuals rating all stimuli as more intense, while other individuals rating all stimuli as less intense. Here, we confirm that PROP bitterness is associated with intensity ratings of sucrose, quinine, and capsaicin, even after controlling for intensity ratings of a cross-modal standard (i.e., 80 dB tone). In other words, we can conclude that elevated ratings are specific to chemosensory responses and are not merely driven by differential usage of the scale. While diverse oral sensations correlate with greater bitterness from PROP, mechanistically, it would be inaccurate to conclude these findings are driven by the TAS2R38 genotype. Here, we illustrate that suprathreshold ratings of stimuli other than PROP were not associated with TAS2R38 genotype, which is wholly consistent with the narrow tuning of this receptor (Meyerhof et al. 2010). However, these data do contradict 1 prior report (Laaksonen et al. 2013) which found a significant relationship between TAS2R38 and astringency and sourness of berry juices in a relatively small group of participants (n = 41). Specifically, PAV homozygotes (n = 12) reported less astringency and sourness than AVI homozygotes (n = 14) (Laaksonen et al. 2013). Accordingly, this may represent sampling error due to low numbers of participants. Further, while the differences were statistically significant between PAV homozygotes and AVI homozygotes, they were relatively small (~2 points on a gLMS) (Laaksonen et al. 2013). On balance, current and prior data suggest TAS2R38 genotype is not a strong predictor of intensity of suprathreshold tastants and chemesthetic compounds other than PROP. The present data recapitulate prior reports which find no relationship between TAS2R38 and suprathreshold ratings of other chemosensory stimuli (e.g., Hayes et al. 2008). The present study emphasizes that the genotype is not the phenotype. Frequently, PROP phenotype is evaluated as a proxy for TAS2R38 genotype; yet, it has been demonstrated that PROP “taster status” does not always conform to genotype (Bufe et al. 2005; Green 2013). In other words, the TAS2R38 haplotype does not explain all the variability observed with the PROP phenotype, suggesting additional factors influence PROP perception. Some of these factors may include anatomical differences, such as fungiform papillae density (although data conflict, contrast Feeney and Hayes, 2014a; Garneau et al. 2014, with Duffy et al. 2004; Hayes et al. 2008), differences in relative protein expression in heterozygotes (e.g., Lipchock et al. 2013), salivary proteins (e.g., Melis et al. 2013), or polymorphisms in the gustin (CA6) gene (although again, data conflict, cf. Feeney and Hayes, 2014a, with Padiglia et al. 2010; Calo et al. 2011).Previously, Hayes and colleagues speculated the existence of second PROP receptor (i.e., another TAS2R also activated by PROP) could explain the apparent recovery of function observed in some AVI homozygotes who should not otherwise respond to PROP (Hayes et al. 2008). Here, in Figure 1, we see a handful of AVI homozygotes who still report strong bitterness from PROP, even though the AVI variant of TAS2R38 is thought to be nonfunctional. Additional work is needed to determine if another TAS2R receptor responds to PROP, and whether polymorphisms in the corresponding TAS2R gene can explain additional variation in PROP phenotype. Multiple factors have been suggested or identified as having a relationship with heightened taste responsiveness. It has been proposed that PROP response alone is not a strong predictor of heightened overall chemosensation (Webb et al. 2015); indeed, other recent studies (e.g., Kalva et al. 2014) have defined supertasting using intensity ratings of multiple chemical stimuli (i.e., NaCl, sucrose, citric acid, and quinine) presented at suprathrehold concentrations. An increased chemosensory response across diverse taste qualities aligns with the central gain theory proposed previously by Green and George (2004). Further, elevated psychophysical responses are not unique to taste and have been observed in other modalities (e.g., auditory sensations; Schneider et al. 2011). The central gain theory suggests that suprathreshold responses for all chemosensory stimuli may be partly determined by differences in taste transduction mechanism in the periphery, such as nerve stimulation, but also cognitive processes (Green 2013). This view fits with other findings by Webb et al. (2015), who concluded that no single measure of taste—be it detection thresholds, recognition thresholds, suprathreshold intensity ratings for PROP, or for other taste stimuli—is able to fully characterize overall taste function. Conclusions Present data support that PROP bitterness is a significant predictor of both taste and chemesthetic responses to diverse chemical stimuli. Participants who rated the bitterness of PROP more intensely also gave higher ratings for sucrose, quinine, and capsaicin, and this was not due merely to differences in scale usage. As expected, PROP bitterness was significantly associated with the TAS2R38 genotype. Critically however, TAS2R38 genotype was unable to explain differences in the sweetness of sucrose, bitterness of quinine, and burn of capsaicin. Also, ratings for sucrose, quinine, and capsaicin had higher correlations with each other than with PROP bitterness. Notably, correlations between PROP bitterness and both sucrose and quinine increased when participants were grouped by TAS2R38 genotype. Additional work is needed to determine why the predictive value of PROP bitterness is greater when stratified by diplotype, versus looking across all participants. Present data also reinforce the view that nominal relationships between measures of PROP bitterness and other orosensory qualities cannot be attributed to TAS2R38 genotype despite clear and robust relationships between TAS2R38 and PROP bitterness. Acknowledgments The authors wish to thank Emma L. Feeney, PhD, Nadia K. Byrnes, PhD, and Meghan Kane, BS for their assistance in collecting the psychophysical data. We also thank Samantha M. Bennett, MS for help with development of the protocol, and Kayla (Beaucage) Dwyer, BS for genotyping DNA samples. We also thank our study participants for their time, saliva, and participation. Funding This work was supported by National Institutes of Health grants from the National Institute of Deafness and Communication Disorders to JEH (DC010904), the National Center for Research Resources to JEM (RR023457), an institutional Clinical and Translational Sciences TL1 Predoctoral Fellowship from the National Center for Advancing Translational Sciences (TR000125) to AAN, and a Ruth L. Kirschstein National Research Service Award F31 Predoctoral Fellowship from the National Institute of Deafness and Communication Disorders (DC014651) to AAN. Additional support was provided by Shared Equipment grants (ShEEP) from the Medical Research Service of the Department of Veterans Affairs, United States Department of Agriculture (USDA) National Institute of Food and Agriculture (NIFA) and Hatch Act Appropriations (project PEN04708 and accession #1019852), and discretionary funds from the Pennsylvania State University. None of these organizations had any role in study conception, design, or interpretation, or the decision to publish these data. The findings and conclusions in this publication are those of the authors, and do not represent the views of the U.S. Department of Veterans Affairs, the U.S. Department of Agriculture, and do not represent any US Government determination, position, or policy. Conflict of interest AAN and JEM have no potential conflicts to report. JEH has received speaking, travel, and consulting fees from nonprofit organizations, federal agencies, commodity boards, and corporate clients in the food industry. 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TI - Predominant Qualities Evoked by Quinine, Sucrose, and Capsaicin Associate With PROP Bitterness, but not TAS2R38 Genotype
JF - Chemical Senses
DO - 10.1093/chemse/bjaa028
DA - 2020-05-29
UR - https://www.deepdyve.com/lp/oxford-university-press/predominant-qualities-evoked-by-quinine-sucrose-and-capsaicin-Es6RYrE2PI
SP - 383
VL - 45
IS - 5
DP - DeepDyve
ER -