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

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.