The molecular basis of individual differences in phenylthiocarbamide and propylthiouracil bitterness perception.

Objective. Flavor is the primary dimension by which young children determine food acceptance. However, children are not merely miniature adults because sensory systems mature postnatally and their responses to certain tastes differ markedly from adults. Among these differences are heightened preferences for sweet-tasting and greater rejection of bitter-tasting foods. The present study tests the hypothesis that genetic variations in the newly discovered TAS2R38 taste gene as well as cultural differences are associated with differences in sensitivity to the bitter taste of propylthiouracil (PROP) and preferences for sucrose and sweet-tasting foods and beverages in children and adults. Design. Genomic DNA was extracted from cheek cells of a racially and ethnically diverse sample of 143 children and their mothers. Alleles of the gene TAS2R38 were genotyped. Participants were grouped by the first variant site, denoted A49P, because the allele predicts a change from the amino acid alanine (A) to proline (P) at position 49. Henceforth, individuals who were homozygous for the bitter-insensitive allele are referred to as AA, those who were heterozygous for the bitter-insensitive allele are referred to as AP, and those who were homozygous for the bitter-sensitive allele are referred to as PP. Using identical procedures for children and mothers, PROP sensitivity and sucrose preferences were assessed by using forced-choice procedures that were embedded in the context of games that minimized the impact of language development and were sensitive to the cognitive limitations of pediatric populations. Participants were also asked about their preferences in cereals and beverages, and mothers completed a standardized questionnaire that measured various dimensions of their children9s temperament. Results. Genetic variation of the A49P allele influenced bitter perception in children and adults. However, the phenotype-genotype relationship was modified by age such that 64% of heterozygous children, but only 43% of the heterozygous mothers, were sensitive to the lowest concentration (56 micromoles/liter) of PROP. Genotypes at the TAS2R38 locus were significantly related to preferences for sucrose and for sweet-tasting beverages and foods such as cereals in children. AP and PP children preferred significantly higher concentrations of sucrose solutions than did AA children. They were also significantly less likely to include milk or water as 1 of their 2 favorite beverages (18.6% vs 40%) and were more likely to include carbonated beverages as 1 of their most preferred beverages (46.4% vs 28.9%). PP children liked cereals and beverages with a significantly higher sugar content. There were also significant main effects of race/ethnicity on preferences and food habits. As a group, black children liked cereals with a significantly higher sugar content than did white children, and they were also significantly more likely to report that they added sugar to their cereals. Unlike children, there was no correspondence between TAS2R38 genotypes and sweet preference in adults. Here, the effects of race/ethnicity were the strongest determinants, thus suggesting that cultural forces and experience may override this genotype effect on sweet preferences. Differences in taste experiences also affected mother–child interaction, especially when the 2 resided in different sensory worlds. That is, children who had 1 or 2 bitter-sensitive alleles, but whose mothers had none, were perceived by their mothers as being more emotional than children who had no bitter-sensitive alleles. Conclusion. Variations in a taste receptor gene accounted for a major portion of individual differences in PROP bitterness perception in both children and adults, as well as a portion of individual differences in preferences for sweet flavors in children but not in adults. These findings underscore the advantages of studying genotype effects on behavioral outcomes in children, especially as they relate to taste preferences because cultural forces may sometimes override the A49P genotypic effects in adults. New knowledge about the molecular basis of food likes and dislikes in children, a generation that will struggle with obesity and diabetes, may suggest strategies to overcome diet-induced diseases.

https://pediatrics.aappublications.org/content/pediatrics/115/2/e216.full.pdf

Genetic and environmental determinants of bitter perception and sweet preferences

In the past several years, tremendous progress has been achieved with the discovery and characterization of vertebrate taste receptors from the T1R and T2R families, which are involved in recognition of bitter, sweet, and umami taste stimuli. Individual differences in taste, at least in some cases, can be attributed to allelic variants of the T1R and T2R genes. Progress with understanding how T1R and T2R receptors interact with taste stimuli and with identifying their patterns of expression in taste cells sheds light on coding of taste information by the nervous system. Candidate mechanisms for detection of salts, acids, fat, complex carbohydrates, and water have also been proposed, but further studies are needed to prove their identity.

Taste Receptor Genes

Bitter taste markers explain variability in vegetable sweetness, bitterness, and intake.

Psychophysical comparisons seem to show that obese individuals experience normal sweet and fat sensations, they like sweetness the same or less, but like fat more than the non-obese do. These psychophysical comparisons have been made using scales (visual analogue or category) that assume intensity labels (e.g. extremely) which denote the same absolute perceived intensity to all. In reality, the perceived intensities denoted by labels vary because they depend on experiences with the substances to be judged. This variation makes comparisons invalid. Valid comparisons can be made by asking the subjects to rate their sensory/hedonic experiences in contexts that are not related to the specific experiences of interest. Using this methodology, we present the evidence that the sensory and hedonic properties of sweet and fat vary with body mass index. The obese live in different orosensory and orohedonic worlds than do the non-obese; the obese experience reduced sweetness, which probably intensifies fat sensations, and the obese like both sweet and fat more than the non-obese do. Genetic variation as well as taste pathology contribute to these results. These psychophysical advances will impact experimental as well as clinical studies of obesity and other eating disorders.

/pdf/psychophysics-of-sweet-and-fat-perception-in-obesity-4um2wn02qu.pdf

Psychophysics of sweet and fat perception in obesity: problems, solutions and new perspectives

STRONG SUPPORT EXISTS for a familial component in the etiology of alcoholism and alcohol use [see Dick and Foroud (2003) for review]. Twin studies show that the heritability of alcoholism ranges from 50 to 60% (Heath et al., 1997) and that genetic influences can explain a 5-fold difference in alcohol use among adolescents in alcohol-predisposing environments (Dick et al., 2001). Genetic risk for alcoholism is complex; several different genes undoubtedly exert effects on the rewarding influence of drinking alcohol, on the metabolic tolerance of alcohol overconsumption, on brain systems that respond to reward, and on response to alcohol withdrawal (Crabbe, 2002). Specific gene mechanisms have been linked to, for example, the metabolism of alcohol via alcohol dehydrogenase (Mulligan et al., 2003; Osier et al., 1999) and aldehyde dehydrogenase (Oota et al., 2004), as well as dependence via γ-aminobutyric acid receptors (Song et al., 2003). The purpose of this study was to examine the association between genetic variation in taste and alcohol use in a group of reportedly healthy young adults.

Genetic variation in taste influences the sensations from alcoholic beverages and could be one of the genetic factors that interacts with environmental factors to determine the risk of alcohol overconsumption, as suggested by models of gene-environment interaction (Heath and Nelson, 2002). The ability to taste the bitterness of phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP), which share an group, is a well documented phenotypic polymorphism. The distribution of thresholds for PTC or PROP tasting is bimodal: “nontasters” have increased thresholds (low sensitivity), and “tasters” have lower thresholds (higher sensitivity). Family studies have generally supported the model that tasting was a dominant trait and nontasting a recessive trait (Blakeslee, 1932; Snyder, 1931).

An important gene contributing to PTC perception has been identified (Kim et al., 2003). The gene (TAS2R38), located on chromosome 7q36, is a member of the bitter taste receptor family. There are two common molecular forms [proline-alanine-valine (PAV) and alanine-valine-isoleucine (AVI)] of this receptor defined by three nucleotide polymorphisms that result in three amino acid substitutions: Pro49Ala, Ala262Val, and Val296Ile. The ancestral human haplotype at these three amino acids—determined by sequencing DNA from several other ape species, an old world monkey, and a new world monkey—is PAV (Kim et al., 2003; Wooding et al., 2004). This molecular form is common in humans and is associated with tasting; the other common form, the triply derived molecular form, AVI, is associated with nontasting. Three other haplotypes have been observed: AAV, AAI, and PVI. The original report (Kim et al., 2003) studied 200 Europeans and 118 individuals from other regions.

Historically, researchers have used detection thresholds to classify individuals as nontasters or tasters of these bitter compounds (e.g., Fox, 1931; Harris and Kalmus, 1949). Fischer and Griffin (1964) replaced PTC with its chemical relative PROP, which lacks the sulfurous odor of PTC and may be less toxic (Barnicot et al., 1951; Lawless, 1980). Insensitivity to PTC or PROP is estimated at 30% in European populations, although the percentages vary with sex and among ethnic groups globally (Bartoshuk et al., 1994; Guo and Reed, 2001).

The taster group shows significant variability in the perceived bitterness of PROP. Although threshold measures may be used to separate individuals with low thresholds (tasters) from individuals with increased thresholds (nontasters), subsequent work by Bartoshuk et al. (1994) identified two distinct populations within the taster group. By comparing the perceived intensity of concentrated PROP, the taster group is subdivided into those who taste concentrated PROP (3.2 mM) as “strongly” bitter (medium tasters) and those who taste PROP as greater than “very strongly” bitter (supertasters) (Bartoshuk et al., 1994). Supertasters cannot be identified via thresholds, because the distributions between those who are sensitive and extremely sensitive to PROP overlap (Reed et al., 1995). Supertasters differ from medium tasters and nontasters in the number of taste papillae on the anterior tongue (fungiform papilla); PROP supertasters have, on average, the most fungiform papillae and taste buds as assessed with videomicroscopy (Bartoshuk et al., 1994). A positive relationship between PROP bitterness and fungiform papillae number is also observed by using lower magnification for papillae counting (Delwiche et al., 2001; Tepper and Nurse, 1997). Supertasting may result from an anatomical difference related to the density of fungiform papillae on the tongue, as well as an allelic variation of TAS2R38 that results in the presence or absence of a functional receptor, as proposed by Bartoshuk et al. (2001) and as supported by data shown in this article. The genetic control of fungiform papilla density is unknown.

The perceived bitterness of PROP is correlated with unpleasant and pleasant sensations from alcohol. Those who taste PROP as more bitter also report ethanol (Bartoshuk et al., 1993; Duffy et al., 2004; Prescott and Swain-Campbell, 2000), some types of beer (Intranuovo and Powers, 1998), scotch (Lanier et al., 2004), and red wines (Pickering et al., 2004) as more bitter or irritating. Nontasters not only perceive scotch as less bitter but also as more sweet than do supertasters (Lanier et al., 2005). The density of fungiform papillae can explain some of the oral sensory differences associated with PROP tasting, as first suggested by Miller and Reedy (1990). The taste buds are surrounded by fibers of the trigeminal nerve (cranial nerve V), which are believed to mediate oral burn (Finger et al., 1994; Whitehead et al., 1985; Whitehead and Kachele, 1994). It is interesting to note that sucrose and ethanol stimulate similar central brain centers in rats (Lemon et al., 2004) and that ethanol stimulates taste nerve fibers responsive to sucrose in primates (Hellekant et al., 1997).

Supertasters may have an inherent sensory aversion to consuming alcoholic beverages with high levels of ethanol and a pronounced alcohol flavor. Young adults who taste PROP as more bitter have been found to consume less beer (Guinard et al., 1996), including during their first year of drinking (Intranuovo and Powers, 1998). In young adults who were not college undergraduates, we found that PROP supertasters reported consuming alcoholic beverages less frequently than did nontasters (Duffy et al., 2004), a finding that was also seen in preliminary data in adults (primarily men) recruited through an industrial worksite wellness program (Hutchins et al., 2002). Not all studies, however, find associations between PROP bitterness and alcohol intake (e.g., Mattes and DiMeglio, 2001).

The literature is inconsistent with respect to a relationship between PROP tasting and risk of alcoholism. In studies with alcoholics compared with controls, some report an excess of nontasters among alcoholics (DiCarlo and Powers, 1998; Peeples, 1962; Spiegel, 1972), whereas other studies do not (Reid et al., 1968; Smith, 1972; Swinson, 1973). In studies examining family history of alcoholism, Pelchat and Danowski (1992) found significantly more PROP nontasters among children of alcoholics than among children of nonalcoholics, whether or not the children themselves were alcoholic. Kranzler and colleagues, however, were unable to show a significant relationship between PROP threshold and parental history of alcohol dependence in nonalcoholic young adults (Kranzler et al., 1998) or in those with alcohol dependency (Kranzler et al., 1996). One study found comorbidity between depression and alcoholism in college students who reported PROP as very bitter (DiCarlo and Powers, 1998).

Some of the inconsistencies in PROP effects on alcohol consumption behaviors could relate to the measurement of PROP tasting. A number of studies relating alcohol-ingestive behaviors to PROP have relied on a threshold procedure (Kranzler et al., 1996, 1998; Peeples, 1962; Pelchat and Danowski, 1992; Spiegel, 1972), which, because it cannot identify supertasters (Bartoshuk et al., 1994), has the potential to fail to find PROP effects. In fact, we reported positive and significant associations between the frequency of consuming alcoholic beverages and PROP bitterness, but not PROP threshold (Duffy et al., 2004). Distinguishing PROP supertasters from medium tasters and nontasters requires valid scaling methods, as reviewed previously (Bartoshuk et al., 2002b, 2004a,Bartoshuk et al., b).

Discovery of allelic variation in TAS2R38, the gene for the PTC receptor, presented the opportunity for examining its ability to predict the oral sensation from an ethanol probe and the frequency of consuming alcoholic beverages in a sample of healthy adults who were recruited into a study of taste genetics and dietary behaviors and who reported consuming alcoholic beverages. Analysis of these data showed that genotype predicts PROP bitterness and, because of its association with PROP bitterness, predicts alcohol intake. However, genotype fully accounts neither for supertasting nor for some of the oral sensations from alcohol.

Bitter Receptor Gene (TAS2R38), 6-n-Propylthiouracil (PROP) Bitterness and Alcohol Intake

Taste and oral sensations vary in humans. Some of this variation has a genetic basis, and two commonly measured phenotypes are the bitterness of propylthiouracil (PROP) and the number of fungiform papillae on the anterior tongue. While the genetic control of fungiform papilla is unclear, PROP bitterness associates with allelic variation in the taste receptor gene, TAS2R38. The two common alleles are AVI and PAV (proline, alanine, valine, and isoleucine); AVI/AVI homozygotes taste PROP as less bitter than heterozygous or homozygous PAV carriers. In this laboratory-based study, we determined whether taste of a bitter probe (quinine) and vegetable intake varied by taste phenotypes and TAS2R38 genotype in healthy adults (mean age=26 years). Vegetable intake was assessed via two validated, complementary methods: food records (Food Pyramid servings standardized to energy intake) and food frequency questionnaire (general intake question and composite vegetable groups). Quinine bitterness varied with phenotypes but not TAS2R38; quinine was more bitter to those who tasted PROP as more bitter or had more papillae. Nontasters by phenotype or genotype reported greater consumption of vegetables, regardless of type (i.e., the effect generalized to all vegetables and was not restricted to those typically thought of as being bitter). Furthermore, nontasters with more papillae reported greater vegetable consumption than nontasters with fewer papillae, suggesting that when bitterness does not predominate, more papillae enhance vegetable liking. These findings suggest that genetic variation in taste, measured by multiple phenotypes or TAS2R38 genotype, can explain differences in overall consumption of vegetables, and this was not restricted to vegetables that are predominantly bitter.

/pdf/vegetable-intake-in-college-aged-adults-is-explained-by-oral-130ntj7ib0.pdf

Andrew C. Davidson

Papers

Bitter Receptor Gene (TAS2R38), 6-n-Propylthiouracil (PROP) Bitterness and Alcohol Intake

Vegetable Intake in College-Aged Adults Is Explained by Oral Sensory Phenotypes and TAS2R38 Genotype.

Revealing associations between PTC/PROP gene, 6-n-propylthiouracil bitterness and vegetable intake