GENETIC VARIATION IN TASTE PERCEPTION AND ITS ROLE IN FOOD LIKING AND HEALTH STATUS

2012/2013Taste has been described as the body's “nutritional gatekeeper”, affecting the identification of nutrients and toxins and guiding food choices. Genetic variation in taste receptor genes can influence perception of sweet, umami and bitter tastes, whereas less is known about the genetics of sour and salty taste. Differences in taste perception, influencing food selection and dietary behavior, have also shown important long-term health implications, especially for food-related diseases such as obesity, diabetes, cardiovascular diseases. To date, a lot of studies are focused on taste receptor genes and function but further investigations are needed to better understand which factors, including genetic ones, are involved in influencing taste and food preferences and the corresponding connections with health status. The aim of this thesis is to understand the genetic bases of taste perception and its relationship to food preferences and health outcomes. Data from ~3500 subjects coming from isolated villages located in Italy, Caucasus and Central Asia were collected. The ability to taste PROP (6-n-propylthiouracil) bitterness and NaCL saltiness, food liking and intake were measured. Additional information such as clinical parameters, professional activity, lifestyle, eating habits and family history were also collected. To learn more about taste biology the following steps were performed in this thesis: 1) genome-wide association studies (GWAS) of bitter and salty taste perception; 2) analysis of the possible impact of bitter taste perception on food preferences; 3) investigation of the relationship between differences in taste perception genes, food preferences and dental caries, as example of health outcome. The main specific results emerging from this PhD thesis work are: 1) GWAS revealed two SNPs closed to TRPV7 and KCNA5 genes associated to salty perception; 2) always through GWAS a SNP closed to GHRL gene, encoding for ghrelin and obestatin, was found to be associated to PROP bitter perception. An additional SNP closed to the 5’ region of the T2R38 gene showed association to the same phenotype; 3) ability to perceive PROP could be a marker for general perception of taste stimuli suggesting that differences in taste perception may be a driver of food liking; 4) the risk to develop dental caries is associated to genetic differences in sweet taste genes. In addition, sweet food liking but not sugar intake results linked to dental caries prevalence, suggesting that food preferences may predictive of health outcomes better than food intake. Overall, these data represent a starting point to better understand how chemosensory differences may interact to influence and predict food choices and human nutritional behavior.Il gusto può essere considerato il “guardiano alimentare” del corpo, permettendo l’identificazione di sostanze nutritive o tossiche e guidando le scelte alimentari. Variazioni genetiche nei geni che codificano per i recettori del gusto possono influenzare la percezione del gusto dolce, umami e amaro, mentre poco conosciuta è la genetica del gusto acido e salato. Differenze nella percezione gustativa, incidendo sulla scelta del cibo e sul comportamento alimentare, hanno anche mostrato importanti implicazioni a lungo termine per la salute, specialmente per malattie relate alla dieta come l’obesità, il diabete e le malattie cardiovascolari. Finora, molti studi si sono focalizzati sui geni e la funzione dei recettori del gusto, ma ulteriori indagini sono necessarie per comprendere meglio, quali fattori, inclusi quelli genetici, possono influenzare gusto e preferenze alimentari e il corrispondente legame con lo stato di salute. Lo scopo di questa tesi è di comprendere le basi genetiche della percezione del gusto e la sua connessione con le preferenze alimentari e lo stato di salute. Sono stati raccolti dati su ~3500 soggetti provenienti da villaggi isolati situati in Italia, Caucaso e Asia centrale. Sono stati misurati la capacità di percepire l'amarezza del PROP (6-n-propylthiouracile) e il gusto salato del NaCL, le preferenze e i consumi alimentari. Sono stati anche raccolti ulteriori informazioni come parametri clinici , attività professionale, stile di vita, abitudini alimentari e storia familiare. Per comprendere meglio la biologia del gusto in questa tesi sono stati svolti i seguenti steps: 1) studi di associazione su tutto il genoma (GWAS) volti a identificare nuovi geni coinvolti nella percezione del gusto amaro e salato; 2) analisi del possibile impatto della percezione del gusto amaro sulle preferenze alimentari; 3) studio della relazione tra differenze genetiche nella percezione del gusto, preferenze alimentari e carie dentale, come esempio di relazione con lo stato di salute. Le principali scoperte emerse da questa tesi sono: 1) uno studio GWA ha identificato due SNPs vicini ai geni TRPV7 e KCNA5 associati alla percezione del gusto salato; 2) sempre attraverso GWAS uno SNP vicino al gene GHRL, che codifica per la grelina e l’obestatina, è stato trovato associato alla percezione amara del PROP. Un ulteriore SNP localizzato vicino alle regione 5' del gene T2R38 mostra, inoltre, associazione con lo stesso fenotipo PROP; 3) la capacità di percepire il PROP potrebbe essere un marker per la percezione generale degli stimoli gustativi, suggerendo che le differenze nella percezione del gusto possono rappresentare un “driver” del gradimento del cibo; 4) il rischio di sviluppare carie dentali è associato a differenze nei geni che codificano per il gusto dolce. Inoltre, la preferenza per i cibi dolci, ma non il consumo di zuccheri, risulta associata alla prevalenza di carie dentale, suggerendo che le preferenze alimentari possano risultare migliori predittori dello stato di salute rispetto ai consumi alimentari. Complessivamente, questi dati rappresentano un punto di partenza per capire meglio come le differenze chemio-sensoriali possono interagire nell’influenzare e prevedere le scelte alimentari e il comportamento alimentare nell’uomo.XXVI Ciclo198

Global diversity in the TAS2R38 bitter taste receptor: Revisiting a classic evolutionary PROPosal

The ability to taste phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP) is a polymorphic trait mediated by the TAS2R38 bitter taste receptor gene. It has long been hypothesized that global genetic diversity at this locus evolved under pervasive pressures from balancing natural selection. However, recent high-resolution population genetic studies of TAS2Rs suggest that demographic events have played a critical role in the evolution of these genes. We here utilized the largest TAS2R38 database yet analyzed, consisting of 5,589 individuals from 105 populations, to examine natural selection, haplotype frequencies and linkage disequilibrium to estimate the effects of both selection and demography on contemporary patterns of variation at this locus. We found signs of an ancient balancing selection acting on this gene but no post Out-Of-Africa departures from neutrality, implying that the current observed patterns of variation can be predominantly explained by demographic, rather than selective events. In addition, we found signatures of ancient selective forces acting on different African TAS2R38 haplotypes. Collectively our results provide evidence for a relaxation of recent selective forces acting on this gene and a revised hypothesis for the origins of the present-day worldwide distribution of TAS2R38 haplotypes

Screening of lipids and kidney function in children and adolescents with Type 1 Diabetes: does age matter?

IntroductionThe purpose of this study was to evaluate lipid profile and kidney function in children and adolescents with Type 1 Diabetes.MethodsThis was a retrospective study including 324 children and adolescents with Type 1 Diabetes (48% females, mean age 13.1 ± 3.2 years). For all participants, demographic and clinical information were collected. The prevalence of dyslipidemia and kidney function markers were analyzed according to age. Multivariate linear regression analyses were performed to test the association of lipids or markers of renal function with demographic and clinical information (sex, age, disease duration, BMI SDS, HbA1c).ResultsIn our study the rate of dyslipidemia reached 32% in children <11 years and 18.5% in those ≥11 years. Children <11 years presented significantly higher triglyceride values. While the albumin-to-creatinine ratio was normal in all individuals, 17% had mildly reduced estimated glomerular filtration rate. Median of HbA1c was the most important determinant of lipids and kidney function, being associated with Total Cholesterol (p-value<0.001); LDL Cholesterol (p-value=0.009), HDL Cholesterol (p-value=0.045) and eGFR (p-value=0.001).ConclusionDyslipidemia could be present both in children and adolescents, suggesting that screening for markers of diabetic complications should be performed regardless of age, pubertal stage, or disease duration, to optimize glycemia and medical nutrition therapy and/or to start a specific medical treatment

Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity.

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

Genetic insights into resting heart rate and its role in cardiovascular disease

Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.</p

DNA mismatch repair gene MSH6 implicated in determining age at natural menopause

The length of female reproductive lifespan is associated with multiple adverse outcomes, including breast cancer, cardiovascular disease and infertility. The biological processes that govern the timing of the beginning and end of reproductive life are not well understood. Genetic variants are known to contribute to ∼50% of the variation in both age at menarche and menopause, but to date the known genes explain <15% of the genetic component. We have used genome-wide association in a bivariate meta-analysis of both traits to identify genes involved in determining reproductive lifespan. We observed significant genetic correlation between the two traits using genome-wide complex trait analysis. However, we found no robust statistical evidence for individual variants with an effect on both traits. A novel association with age at menopause was detected for a variant rs1800932 in the mismatch repair gene MSH6 (P = 1.9 × 10−9), which was also associated with altered expression levels of MSH6 mRNA in multiple tissues. This study contributes to the growing evidence that DNA repair processes play a key role in ovarian ageing and could be an important therapeutic target for infertilit

DNA mismatch repair gene MSH6 implicated in determining age at natural menopause

notes: PMCID: PMC3976329This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.The length of female reproductive lifespan is associated with multiple adverse outcomes, including breast cancer, cardiovascular disease and infertility. The biological processes that govern the timing of the beginning and end of reproductive life are not well understood. Genetic variants are known to contribute to ∼50% of the variation in both age at menarche and menopause, but to date the known genes explain <15% of the genetic component. We have used genome-wide association in a bivariate meta-analysis of both traits to identify genes involved in determining reproductive lifespan. We observed significant genetic correlation between the two traits using genome-wide complex trait analysis. However, we found no robust statistical evidence for individual variants with an effect on both traits. A novel association with age at menopause was detected for a variant rs1800932 in the mismatch repair gene MSH6 (P = 1.9 × 10(-9)), which was also associated with altered expression levels of MSH6 mRNA in multiple tissues. This study contributes to the growing evidence that DNA repair processes play a key role in ovarian ageing and could be an important therapeutic target for infertility.UK Medical Research CouncilWellcome Trus

Large-scale genomic analyses link reproductive ageing to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair

John Perry and colleagues report the results of a large genome-wide association study meta-analysis to identify variants influencing age at natural menopause. They identify 54 independent signals and find enrichment near genes involved in delayed puberty and DNA damage response