Allelic Variation in TAS2R Bitter Receptor Genes Associates with Variation in Sensations from and Ingestive Behaviors toward Common Bitter Beverages in Adults

Bitter taste receptors in the treatment of asthma: Opportunities and challenges

Specific Alleles of Bitter Receptor Genes Influence Human Sensitivity to the Bitterness of Aloin and Saccharin

Explaining variability in sodium intake through oral sensory phenotype, salt sensation and liking

BackgroundHuman perception of bitter substances is partially genetically determined. Previously we discovered a single nucleotide polymorphism (SNP) within the cluster of bitter taste receptor genes on chromosome 12 that accounts for 5.8% of the variance in the perceived intensity rating of quinine, and we strengthened the classic association between TAS2R38 genotype and the bitterness of propylthiouracil (PROP). Here we performed a genome-wide association study (GWAS) using a 40% larger sample (n = 1999) together with a bivariate approach to detect previously unidentified common variants with small effects on bitter perception.ResultsWe identified two signals, both with small effects (< 2%), within the bitter taste receptor clusters on chromosomes 7 and 12, which influence the perceived bitterness of denatonium benzoate and sucrose octaacetate respectively. We also provided the first independent replication for an association of caffeine bitterness on chromosome 12. Furthermore, we provided evidence for pleiotropic effects on quinine, caffeine, sucrose octaacetate and denatonium benzoate for the three SNPs on chromosome 12 and the functional importance of the SNPs for denatonium benzoate bitterness.ConclusionsThese findings provide new insights into the genetic architecture of bitter taste and offer a useful starting point for determining the biological pathways linking perception of bitter substances.

단맛은 우리 몸에 열량을 공급하는 역할을 담당하는 중요함 감각으로 인지도가 개인마다 조금씩 다르다고 알려져 있으나, 이에 대한 분자수준의 연구는 아직 부족한 실정이다. 본 연구에서는 미각 장애에 미치는 유전적 요인에 대해 알아보고자 50명의 미각 환자 및 100명의 정상인을 대상으로 단맛 민감도 차이와 연관이 있는 TAS1R3 및 GNAT3 유전자의 다형성 간의 관련성을 알아보았다. TAS1R3 유전자 rs307355 및 rs35744813의 유전자형과 대립유전자의 빈도는 미각 장애 환자군과 대조군 간에 통계적으로 유의한 차이가 있었으며, 두 다형성에 대한 일배체형을 분석한 결과, C-C 및 T-T의 두 종류만이 검출되었으며 환자군과 대조군 간의 일배체형 빈도 간에도 통계적으로 유의한 차이를 보였다. GNAT3 유전자에서는 rs7792845의 유전자형 빈도가 환자군과 대조군간에 유의적인 차이를 나타냈었으나, 대립유전자 빈도에서는 차이가 없었다. 이러한 연구결과는 단맛의 민감도 차이에 영향을 미치는 것으로 보고된 TAS1R3 및 GNAT3 유전자의 다형성에 대한 한국인 집단에서의 유전자형 빈도를 조사함으로써 집단유전학적 연구를 위한 기초자료를 제공하고 미각장애환자군과의 비교분석을 통해 TAS1R3 및 GNAT3 유전자의 다형성이 연관성이 있을 가능성이 있음을 제시해 줌으로써 향후 미각장애를 진단하기 위한 검사시 지표로 활용될 수 있으리라 생각된다. 위에 제시한 연구결과는 향후 추가적인 샘플링을 통해 보다 많은 환자군과 대조군에 대한 추가적인 연구가 수행되어야 할 것이다. Taste sensation plays a crucial role in selecting and ingesting foods with different qualities which convey information about their nutrient content and/or safety. Sweetness is one of the five modalities in humans and serves as an energy resource for metabolism. There are reports on allelic polymorphisms which influence perception of sweetness in mice and humans. Since the influence of genetic factors on taste disorder has not been studied, we investigated the association of genetic polymorphisms in TAS1R3 and guanine nucleotide binding protein, alpha transducing 3 (GNAT3) genes and taste disorder. A total of 150 individuals composed of 50 patients with taste disorder and 100 healthy controls were recruited for the study and PCR-mediated directing sequencing method was used to genotype for two different single nucleotide polymorphisms (SNPs) - rs307355 (T>C) and rs35744813 (T>C) in the TAS1R3 gene, and rs7792845 (T>C) and rs1524600 (C>T) in the the GNAT3 gene. The allele and genotype frequencies of rs307355 and rs35744813 in the TAS1R3 gene showed a significant association between patients with taste disorder (p=0.022 and p=0.013 in both of SNPs, respectively). In addition, the frequency of T-T haplotype in the TAS1R3 gene was higher in taste disorder cases than in the controls (OR, 1.93: 95%. CI, 1.09-3.39, p=0.022). In the GNAT3, the genotype frequency of rs7792845 in the patients was also different from the controls (p=0.048), but allele frequency was not significantly associated in either group. Our result provides the frequencies of SNPs and haplotypes of the TAS1R3 and GNAT3 genes for the fundamental information of nutrigenetics in perception of the taste of sweetness in the Korean population. Also, the study suggests that the allelic polymorphisms of TAS1R3 and GNAT3 genes may be useful as a molecular marker for evaluating patients with taste disorder. Further studies with large samples are required to clarify our observation.

Searching for the bitter truth: Insights into receptors for taste

BackgroundTaste receptor genes are expressed in sensory cells located in the tongue and influence food preferences, voluntary feed intake, and other relevant traits. Taste perception may differ between livestock breeds that show differences in eating behaviour and between animals that receive different diets or show phenotypic variation in feed intake or related-traits. The objectives of this work were to deepen the understanding of the regulation of the function of taste receptor genes in the circumvallate papillae of obese Iberian pigs in comparison to Duroc pigs, and to characterize their genetic variation and associations with relevant production traits.ResultsWe performed a gene expression and structural analysis of ten taste receptor genes in Iberian and Duroc pigs. Gene expression was quantified in the circumvallate papillae of 48 growing Iberian and Duroc pigs maintained under identical management conditions but fed isocaloric diets differing in energy source: either high concentration of fat rich in oleic acid (HO) or carbohydrates (CH); and sacrificed after 47 days of treatment (50.5 kg live weight). Gene expression differed between the two breeds for most of the analyzed genes, with the TAS1R1, TAS1R2, TAS1R3, TAS2R4, TAS2R38, TAS2R39, GPR84, and CD36 genes being overexpressed in Duroc pigs. The diet effect was modulated by breed, with TAS1R1, TAS1R3, and TAS2R4 genes being overexpressed only in Duroc pigs fed the HO diet. Detection of genetic variants (single nucleotide polymorphisms, SNPs) for this panel of genes was performed on muscle RNA-seq data, and three SNPs in the TAS1R1, TAS1R3, and CD36 genes were selected for association studies. All three SNPs were associated with various growth, fattening, tissue fat content, and composition traits. Moreover, the CD36:c.910G/T SNP was associated with oral CD36 gene expression and with differences in the predicted mRNA secondary structure.ConclusionsMost taste receptor genes are expressed at lower level in circumvallate papillae from Iberian than Duroc pigs. This aligns with lower overall taste sensitivity, higher feed intake, and obese nature of Iberian pigs. Significant association results were observed for SNPs in the TAS1R1 and TAS1R3 genes with meat quality traits and liver composition, which showed segregation in world-wide distributed breeds, but particularly for a potential causal SNP in the CD36 gene, associated with growth and tissue composition, which segregates in Iberian populations.

Environmental factors as disease accelerators during chronic hepatitis C

Bats represent the largest dietary radiation in a single mammalian order, and have become an emerging model group for studying dietary evolution. Taste receptor genes have proven to be molecular signatures of dietary diversification in bats. For example, all 3 extant species of vampire bats have lost many bitter taste receptor genes (Tas2rs) in association with their dietary shift from insectivory to sanguivory. Indeed, only 8 full-length Tas2rs were identified from the high-quality genome of the common vampire bat (Desmodus rotundus). However, it is presently unknown whether these bitter receptors are functional, since the sense of taste is less important in vampire bats, which have an extremely narrow diet and rely on other senses for acquiring food. Here, we applied a molecular evolutionary analysis of Tas2rs in the common vampire bat compared with non-vampire bats. Furthermore, we provided the first attempt to deorphanize all bitter receptors of the vampire bat using a cell-based assay. We found that all Tas2r genes in the vampire bat have a level of selective pressure similar to that in non-vampire bats, suggesting that this species must have retained some bitter taste functions. We demonstrated that 5 of the 8 bitter receptors in the vampire bat can be activated by some bitter compounds, and observed that the vampire bat generally can not detect naturally occurring bitter compounds examined in this study. Our study demonstrates functional retention of bitter taste in vampire bats as suggested by cell-based functional assays, calling for an in-depth study of extra-oral functions of bitter taste receptors.

Variation in the gene TAS2R38 is associated with the eating behavior disinhibition in Old Order Amish women

Bitter taste receptors play crucial roles in detecting bitter compounds not only in the oral cavity, but also in extraoral tissues where they are involved in a variety of non‒tasting physiological processes. On the other hand, disorders or modifications in the sensitivity or expression of these extraoral receptors can affect physiological functions. Here we evaluated the role of the bitter receptor TAS2R38 in attainment of longevity, since it has been widely associated with individual differences in taste perception, food preferences, diet, nutrition, immune responses and pathophysiological mechanisms. Differences in genotype distribution and haplotype frequency at the TAS2R38 gene between a cohort of centenarian and near-centenarian subjects and two control cohorts were determined. Results show in the centenarian cohort an increased frequency of subjects carrying the homozygous genotype for the functional variant of TAS2R38 (PAV/PAV) and a decreased frequency of those having homozygous genotype for the non-functional form (AVI/AVI), as compared to those determined in the two control cohorts. In conclusion, our data providing evidence of an association between genetic variants of TAS2R38 gene and human longevity, suggest that TAS2R38 bitter receptor can be involved in the molecular physiological mechanisms implied in the biological process of aging.

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.

Background: Three inter-related and consistent factors emerging from the epidemiological literature for colorectal adenoma are cigarette smoking, alcohol intake, and dietary folate levels. Oxidative damage caused by these three factors can be repaired through the base excision repair pathway (BER). The ability to repair such damage may be modified by common genetic variants in BER pathway genes. In a sigmoidoscopy based study, we examined associations between 182 haplotype tagging single nucleotide polymorphisms (SNPs), which captured common genetic variation in 14 BER genes, and colorectal adenoma risk. Additionally, the interaction effects between SNPs and cigarette smoking, alcohol intake, and dietary folate levels were examined. Methods: We used data and samples from 721 cases and 736 controls enrolled in a University of Southern California/Kaiser Permanente sigmoidoscopy-based study of risk factors for colorectal adenomas. Genotype data on 182 haplotype tagging SNPs were obtained using the Golden Gate Assay (Illumina, Inc). Using logistic regression, per allele odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for the association between SNPs and colorectal adenoma risk. Using multinomial logistic regression, per allele ORs and 95% CIs for each SNP were calculated after stratifying on adenoma location (rectal versus left colon) and adenoma size (&amp;lt; 1 cm versus ≥ 1cm). Adenoma, adenoma location and adenoma size associations were corrected for multiple testing for all SNPs within each gene using the multiple testing correction method implemented in the R package PACT, and additionally for the 14 different genes within the BER pathway using the Bonferroni method. Interaction effects between SNPs and smoking, alcohol and dietary folate intake on colorectal adenoma risk were tested using logistic regression models and corrected for within each gene and additionally for the 14 different genes within the BER pathway using the Bonferroni method. Results: Among African-Americans we observed an increased risk of adenoma with APEX1 rs17111750 (OR = 2.19; 95%CI = 1.36-3.55; pACT = 0.013). Among Asian-Pacific Islanders we observed an increased risk of adenoma with FEN1 rs108499 (OR = 2.12; 95%CI = 1.30-3.45; pACT = 0.009). Among the entire study population, an increased risk of rectal adenoma was observed for two unlinked SNPs in the NEIL2 gene: NEIL2 rs7015453 (OR = 1.72; 95%CI = 1.24-2.39; pACT =0.025) and rs3757949 (OR=1.58; 95%CI= 1.18-2.13; pACT = 0.044). Both NEIL2 SNPs showed evidence of statistically significant heterogeneity of the ORs by adenoma location (rs7015453, p = 0.003; rs3757949, p = 0.004). The association between smoking (pack-years) and adenoma risk was modified by MUTYH rs10890324 (interaction pgene = 0.009). The association between alcohol intake and adenoma risk was modified by LIG3 rs1052536 (interaction pgene = 0.028). The association between dietary folate intake and adenoma risk was modified by two unlinked LIG3 SNPs (rs1052536 interaction pgene = 0.009; rs3744358 interaction pgene = 0.048) and one XRCC1 SNP (rs3213344 interaction pgene = 0.046). Conclusions: The findings support our hypothesis that genetic variation in DNA repair genes can modify the association of key colorectal adenoma risk factors. Our findings support a role for oxidative damage induced by these exposures on colorectal cancer formation. Citation Format: Roman Corral, Juan Pablo Lewinger, Amit D. Joshi, A. Joan Levine, David Van Den Berg, Robert W. Haile, Mariana C. Stern. Genetic variation in the base excision repair pathway, environmental risk factors, and colorectal adenoma risk. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B85.

Addiction as a Coping Response: Hyperkatifeia, Deaths of Despair, and COVID-19.

P.6.a.008 Neuropeptide S receptor gene variant and stressful life events: associations with alcohol use disorder and alcohol consumption