Sucrose Liking
Sucrose liking refers to an individual’s preference for the sweet taste of sucrose, a common disaccharide found in many foods and beverages. This preference is a complex trait that varies significantly among people, influencing dietary choices and overall caloric intake. Understanding the factors that contribute to sucrose liking is crucial, as it plays a role in public health and individual well-being.
Biological Basis
Section titled “Biological Basis”The perception and preference for sweet tastes, including sucrose, are influenced by a combination of genetic and environmental factors. Genetic variations can impact taste receptor sensitivity, reward pathways in the brain, and the metabolic processing of sugars. For instance, genes involved in sugar transport and metabolism, such asSLC2A9 (also known as GLUT9), are known to play a role in how the body handles sugars like glucose and fructose. Variations inSLC2A9have been associated with serum uric acid levels, indicating a genetic link to the metabolic consequences of sugar consumption.[1] Other genetic loci, such as those near MTNR1B, have been linked to glucose-related traits, further highlighting the genetic underpinnings of sugar metabolism.[2]
Clinical Relevance
Section titled “Clinical Relevance”A strong liking for sucrose can lead to increased consumption of sugar-sweetened foods and beverages, which has significant clinical implications. High intake of sugars, particularly fructose, has been consistently linked to elevated serum uric acid levels.[3]Elevated uric acid is a well-established risk factor for conditions such as gout.[3] and kidney stones.[4]Furthermore, fructose-induced hyperuricemia has been hypothesized as a causal mechanism contributing to the epidemic of metabolic syndrome.[5]Genetic variants influencing uric acid levels, such as those inSLC2A9, ABCG2, and SLC17A3, have been identified in genome-wide association studies and are associated with a higher risk of gout.[6] High sugar intake is also broadly associated with diabetes-related traits and other metabolic health indicators.[7]
Social Importance
Section titled “Social Importance”The widespread availability and consumption of sugar-sweetened products make sucrose liking a trait with considerable social importance. Understanding individual differences in sucrose liking can help inform public health strategies aimed at promoting healthier dietary patterns and reducing the prevalence of diet-related chronic diseases. Genetic insights into sucrose liking and its metabolic consequences could lead to personalized dietary recommendations or interventions, addressing the societal challenge of excessive sugar consumption and its associated health burdens.
Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”Sample size and statistical power are critical constraints in identifying genetic associations with sucrose liking. Studies with moderate cohort sizes are susceptible to false negative findings, meaning true genetic influences might be missed due to inadequate statistical power.[8]Furthermore, the practice of sex-pooled analyses might obscure important sex-specific genetic associations, as certain variants could influence sucrose liking exclusively in males or females, remaining undetected in general population studies.[9]The reliance on a subset of SNPs from resources like HapMap in genome-wide association studies (GWAS) also limits comprehensive coverage, potentially missing novel genes or preventing a thorough investigation of candidate genes related to sucrose liking.[9]Replication of genetic findings for sucrose liking presents a significant challenge. A considerable proportion of reported associations may not replicate in independent cohorts, potentially due to false positive initial findings, differences in study populations, or inadequate statistical power in replication attempts.[8]Non-replication at the single nucleotide polymorphism (SNP) level can also arise if different studies identify distinct SNPs that are in strong linkage disequilibrium with an unknown causal variant, or if multiple causal variants exist within the same gene influencing sucrose liking.[2]Additionally, the quality of imputed genetic data, filtered by criteria such as imputation quality scores or minor allele frequency, means that associations with less reliably imputed SNPs are often excluded, which could lead to an incomplete picture of the genetic landscape of sucrose liking.[10]
Generalizability and Phenotype Definition
Section titled “Generalizability and Phenotype Definition”A major limitation concerns the generalizability of findings on sucrose liking, primarily due to the demographic characteristics of study cohorts. Many genetic studies are predominantly conducted in populations of white European descent and often include middle-aged to elderly participants.[11]Consequently, the applicability of these genetic insights to younger individuals or other diverse ethnic and racial groups remains largely unknown, limiting a universal understanding of sucrose liking’s genetic basis.[11] Additionally, the collection of biological samples at later examination points in longitudinal studies may introduce a survival bias, as only individuals who remained in the study, and thus survived to those later ages, are included, potentially skewing the genetic associations observed.[8]The precise definition and measurement of sucrose liking over time also pose challenges for genetic investigations. If sucrose liking is assessed through repeated measurements spanning many years, using potentially different methodologies or equipment, it can introduce misclassification or regression dilution bias.[11]Such averaging strategies, while aiming to characterize the phenotype better, implicitly assume that the same genetic and environmental factors influence sucrose liking consistently across a wide age range. This assumption may not hold true, potentially masking age-dependent genetic effects that could be crucial for understanding the trait’s development and variation.[11]
Environmental Confounders and Remaining Knowledge Gaps
Section titled “Environmental Confounders and Remaining Knowledge Gaps”The influence of various environmental factors and gene-environment interactions on sucrose liking represents a significant area of complexity and limitation. While some studies adjust for known covariates such as age, gender, and lifestyle factors like smoking and alcohol intake, the full spectrum of environmental confounders and their interactions with genetic predispositions is often not comprehensively captured.[10] This incomplete accounting means that observed genetic associations might be modulated by unmeasured environmental variables, or that gene-environment interactions, where a genetic effect is only apparent under specific environmental conditions, could be overlooked.[6]Consequently, the unique contribution of genetics to sucrose liking, independent of environmental influences, can be difficult to precisely delineate, contributing to the challenge of explaining all genetic variation.
Despite advances in identifying genetic loci associated with sucrose liking, substantial knowledge gaps persist regarding the full genetic architecture of the trait. A fundamental challenge in GWAS is the prioritization of identified SNPs for further functional follow-up, as statistical association does not directly equate to biological causality.[8]The ultimate validation of genetic findings requires not only replication in diverse cohorts but also functional studies to elucidate the biological mechanisms through which these genes influence sucrose liking.[8]The phenomenon of “missing heritability,” where identified genetic variants explain only a fraction of the estimated heritability for a complex trait, suggests that many genetic factors, including rare variants, structural variations, or complex epistatic interactions, remain undiscovered for sucrose liking.
Variants
Section titled “Variants”Genetic variations play a crucial role in influencing complex human traits, including sensory perception and dietary preferences like sucrose liking. Single nucleotide polymorphisms (SNPs) within or near genes involved in neurological signaling, metabolic regulation, and cellular processes can subtly alter gene function, thereby contributing to individual differences in taste perception and the rewarding aspects of food consumption. Research employing genome-wide association studies (GWAS) aims to identify these genetic markers and understand their broad impact on human health and behavior.[7]Variations in genes associated with brain function and sensory processing are particularly relevant to sucrose liking. TheRELN gene, which encodes Reelin, a protein critical for neuronal migration and synaptic plasticity in the developing and adult brain, has variants like rs10953405 and rs62485870 that could influence neural circuits involved in reward and taste perception. Similarly, the HTR5A gene, encoding a serotonin receptor, plays a role in modulating mood, cognition, and appetite, and its variant rs7795216 may alter serotonin signaling pathways, potentially affecting the hedonic response to sweet tastes. The NALT1 gene, represented by rs710411 , is also implicated in pathways that could contribute to the complex interplay between taste input and brain reward systems, thereby shaping an individual’s preference for sweet foods.[12]Other variants are found in genes related to cell structure, adhesion, and general cellular processes, which can indirectly impact taste perception or metabolic responses to sucrose. TheCLMP gene, involved in cell adhesion, has the variant rs17127163 which could affect the structural integrity of taste buds or the neural connections that transmit taste signals. Likewise, CDH20 (rs1497980 ), a cadherin family member, is crucial for cell-cell adhesion and tissue organization, potentially influencing the development or function of taste receptor cells. The GOLGA8B gene (rs2433267 ), associated with the Golgi apparatus, is involved in protein modification and transport, and alterations here could affect the processing of taste receptors or signaling molecules. These genes, through their fundamental cellular roles, can contribute to the intricate biological mechanisms underlying taste preferences.[13] Finally, genes with diverse physiological functions, such as SERPINA1 and CRABP1, also contain variants that might influence sucrose liking through broader systemic effects. TheSERPINA1 gene (rs11568814 ), which produces alpha-1 antitrypsin, is involved in inflammation and protease inhibition, and its variants could affect general metabolic health or inflammatory responses that indirectly modulate food preferences. The CRABP1 gene (rs4887033 ), encoding a cellular retinoic acid-binding protein, plays a role in cellular differentiation and metabolism, which could impact the development of taste buds or fat cells, influencing how the body processes and responds to sugars. The WSCD1 gene (rs35253088 ) also represents a locus where genetic variation could contribute to individual differences in metabolic regulation or neural signaling related to dietary choices.[14]
Key Variants
Section titled “Key Variants”Causes
Section titled “Causes”Individual differences in sucrose liking, like many other complex traits, are influenced by a complex interplay of genetic, environmental, and developmental factors. Understanding these causes involves investigating inherited predispositions, external influences, and the dynamic interactions between them.
Genetic Predisposition to Sucrose Liking
Section titled “Genetic Predisposition to Sucrose Liking”Genetic factors significantly contribute to individual variations in complex traits, including aspects of taste preference and metabolic regulation. Research often identifies common genetic variants, or single nucleotide polymorphisms (SNPs), that collectively contribute to an individual’s inherited tendencies.[7] Genome-wide association studies (GWAS) have revealed numerous loci associated with diverse metabolic profiles, demonstrating the polygenic nature of these characteristics. For instance, variants near MC4Rhave been linked to waist circumference and insulin resistance, whileSLC2A9 and ABCG2influence uric acid levels, andMTNR1Bis associated with glucose regulation.[15] These genetic influences can operate through various mechanisms, including intricate gene-gene interactions where multiple variants, such as those within the APOA1/C3/A5 region or between MYB/HBS1L and chromosome 11 SNPs, combine to exert their effects.[14] Studies also explore specific genetic models, including additive models and deviations from them, to best fit observed data, indicating the complex inherited basis of individual metabolic and physiological characteristics.[16]
Environmental and Lifestyle Influences
Section titled “Environmental and Lifestyle Influences”Beyond genetics, environmental and lifestyle factors play a crucial role in shaping complex traits. Dietary patterns, general lifestyle choices, socioeconomic conditions, and geographic location can all modulate individual characteristics.[10] For example, studies investigating metabolic traits frequently adjust for covariates such as age, gender, geographic principle components, smoking, and alcohol intake, recognizing their significant impact on observed phenotypes.[10] Furthermore, specific physiological states and external exposures, like the use of oral contraceptives or pregnancy status, are considered important covariates in research due to their known associations with metabolic traits, particularly in younger populations.[17]Body mass index (BMI) is also a powerful covariate, highlighting how broader lifestyle factors contribute to the expression of various traits.[17]
Gene-Environment Interactions and Developmental Factors
Section titled “Gene-Environment Interactions and Developmental Factors”The expression of complex traits often arises from dynamic interactions between genetic predispositions and environmental triggers. Research into gene-by-environment interactions investigates how genetic variants modify an individual’s response to specific environmental factors.[6] For instance, a genetic risk score, derived from multiple susceptibility alleles, can be assessed for its interaction with various environmental factors, providing insight into personalized risk profiles.[6]Developmental factors, particularly early life influences, can also have lasting effects on trait expression. These early experiences can lead to epigenetic modifications, such as changes in DNA methylation or histone modifications, which alter gene activity without changing the underlying DNA sequence. Such epigenetic changes can modulate how an individual’s genetic blueprint is expressed throughout their life, contributing to the variability observed in complex traits.
Biological Background
Section titled “Biological Background”Sucrose, a common disaccharide, is composed of glucose and fructose. While the direct mechanisms underlying the hedonic preference for sucrose involve complex sensory and neural pathways not extensively detailed in the provided studies, the metabolic processing of its constituent monosaccharides, particularly fructose, has significant physiological implications.[18]Understanding these metabolic pathways, the transporters involved, and their genetic underpinnings is crucial for comprehending the systemic impact of sucrose intake on human health.
Metabolic Processing of Sucrose Components
Section titled “Metabolic Processing of Sucrose Components”Upon ingestion, sucrose is hydrolyzed into glucose and fructose, with fructose primarily metabolized in the liver. This metabolic pathway is distinct from glucose metabolism and can lead to specific physiological consequences.[18]A key outcome of fructose metabolism is its ability to induce hyperuricemia, an elevation of uric acid levels in the blood.[19]This occurs because the rapid phosphorylation of fructose can deplete ATP, leading to an increase in AMP, which is subsequently catabolized into uric acid. This process highlights a direct molecular and cellular pathway linking dietary fructose to a critical metabolic byproduct. Chronic fructose consumption has also been implicated as a causal mechanism for the metabolic syndrome, a cluster of conditions that includes hypertension, dyslipidemia, and insulin resistance.[5]
The SLC2A9 (GLUT9) Gene and Urate Transport
Section titled “The SLC2A9 (GLUT9) Gene and Urate Transport”A critical biomolecule involved in the transport of both sugars and urate is the facilitative glucose transporter-like protein 9, encoded by theSLC2A9 gene, also known as GLUT9.[20] This protein exhibits substrate selectivity, a characteristic feature of membrane transporters.[20] GLUT9 has two main splice variants, which can alter its cellular trafficking and expression patterns.[20] These variants are expressed in adult liver and kidney, and their expression can be upregulated in conditions such as diabetes.[21]Beyond its role in glucose and fructose transport,SLC2A9has been newly identified as a crucial urate transporter, playing a significant role in influencing serum urate concentration and renal urate excretion.[22] This dual function positions GLUT9as a central player in both sugar metabolism and uric acid homeostasis.
Genetic and Regulatory Influences on Uric Acid Homeostasis
Section titled “Genetic and Regulatory Influences on Uric Acid Homeostasis”Genetic mechanisms play a substantial role in determining an individual’s serum uric acid levels, with variants in theSLC2A9 gene being particularly influential.[1] A common nonsynonymous variant in GLUT9has been associated with serum uric acid levels, demonstrating how specific genetic polymorphisms can impact protein function and downstream physiological traits.[1]These genetic variations can affect the efficiency of urate transport, leading to differences in how individuals process and excrete uric acid. Furthermore, the influence ofSLC2A9on uric acid concentrations can exhibit pronounced sex-specific effects, indicating complex regulatory networks and potential interactions with hormonal or other biological factors.[23]Such genetic and regulatory elements contribute to the inter-individual variability in uric acid levels, which in turn can modify an individual’s susceptibility to conditions associated with fructose consumption and hyperuricemia.[23]
Systemic Health Implications of Fructose Metabolism
Section titled “Systemic Health Implications of Fructose Metabolism”The metabolic consequences of fructose intake, channeled through pathways involving uric acid and transporters likeSLC2A9, have broad systemic implications for health. Elevated serum uric acid, often exacerbated by high fructose consumption, is a significant risk factor for conditions such as gout, a painful inflammatory arthritis.[3]Studies have consistently shown a link between intake of added sugar and sugar-sweetened drinks, which are rich in fructose, and increased serum uric acid concentrations.[24]Beyond gout, excessive fructose intake and the resulting hyperuricemia are also associated with an increased risk of kidney stones.[4]Uric acid itself is considered an ancient factor with recently found significance in renal and cardiovascular disease.[5] These pathophysiological processes underscore how disruptions in metabolic homeostasis, driven by dietary patterns and modulated by genetic factors, can lead to chronic diseases affecting multiple organ systems.
Sugar Metabolism and Transport Pathways
Section titled “Sugar Metabolism and Transport Pathways”Fructose, a key monosaccharide component derived from the disaccharide sucrose, is actively metabolized and transported within the body through specific cellular machinery. The proteinSLC2A9, also known as GLUT9, functions as a facilitative glucose transporter that also exhibits significant capacity for fructose transport ,.[6]High consumption of fructose and sugar-sweetened drinks is known to elevate serum uric acid, leading to hyperuricemia, a precursor to gout and kidney stones.[3], [4], [18], [19], [24]Beyond uric acid, genetic loci also influence plasma levels of liver enzymes.[10] lipid concentrations including LDL, HDL, and triglycerides.[14], [25] and diabetes-related traits, such as those identified in the Framingham Heart Study (e.g., rs7100927 in moderate linkage disequilibrium with TCF7L2).[7] These genetic factors, in conjunction with varying dietary sugar intake, underscore a complex interplay contributing to a spectrum of metabolic disorders.
Prognostic Value for Uric Acid-Related and Cardiometabolic Disorders
Section titled “Prognostic Value for Uric Acid-Related and Cardiometabolic Disorders”The intake of added sugar and sugar-sweetened beverages holds significant prognostic value as a modifiable environmental factor influencing disease progression and outcomes.[3], [24]Studies have demonstrated a clear association between higher consumption of these products and elevated serum uric acid levels, which in turn predicts an increased risk for conditions like gout and kidney stones.[3], [4]Furthermore, fructose-induced hyperuricemia has been hypothesized as a causal mechanism for the development and progression of metabolic syndrome.[5]Integrating information on an individual’s genetic predisposition, such as a genetic risk score for uric acid levels, with their dietary habits allows for a more refined prediction of long-term health implications and disease trajectory, highlighting populations at higher risk for these cardiometabolic complications.[6]
Risk Stratification and Personalized Prevention Strategies
Section titled “Risk Stratification and Personalized Prevention Strategies”Understanding the genetic and environmental factors influencing metabolic responses to sugar consumption is crucial for personalized medicine approaches. By identifying individuals with specific genetic variants that predispose them to elevated uric acid or dyslipidemia, clinicians can stratify risk more effectively.[6], [14]This personalized risk assessment, combining genetic insights with detailed dietary intake, facilitates targeted prevention strategies. For example, individuals with a genetic susceptibility to hyperuricemia might benefit more significantly from reduced sugar intake to mitigate their risk of gout and kidney stones.[3], [4]Such approaches can guide tailored dietary interventions and monitoring strategies, moving beyond a one-size-fits-all recommendation to optimize patient care and potentially prevent the onset or progression of sugar-related metabolic diseases.
References
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[6] Dehghan, A et al. Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study. Lancet, 2008.
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[9] Yang, Q. et al. “Genome-wide association and linkage analyses of hemostatic factors and hematological phenotypes in the Framingham Heart Study.”BMC Medical Genetics, 2007.
[10] Yuan, X et al. Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes. Am J Hum Genet, 2008.
[11] Vasan, R. S. et al. “Genome-wide association of echocardiographic dimensions, brachial artery endothelial function and treadmill exercise responses in the Framingham Heart Study.”BMC Medical Genetics, 2007.
[12] Saxena R. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science. 2007;316(5829):1331-6.
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[14] Kathiresan S. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet. 2008;40(12):1428-37.
[15] Chambers, JC et al. Common genetic variation near MC4R is associated with waist circumference and insulin resistance. Nat Genet, 2008.
[16] Uda, M et al. Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia. Proc Natl Acad Sci U S A, 2008.
[17] Sabatti, C et al. Genome-wide association analysis of metabolic traits in a birth cohort from a founder population. Nat Genet, 2009.
[18] Emmerson, B. T. “Effect of oral fructose on urate production.”Ann Rheum Dis, vol. 33, no. 3, 1974, pp. 276–80.
[19] Perheentupa, J., and K. Raivio. “Fructose-induced hyperuricaemia.”Lancet, vol. 2, no. 7515, 1967, pp. 528–31.
[20] Augustin, R., et al. “Identification and characterization of human glucose transporter-like protein-9 (GLUT9): alternative splicing alters trafficking.”J Biol Chem, vol. 279, no. 16, 2004, pp. 16229–36.
[21] Keembiyehetty, C., et al. “Mouse glucose transporter 9 splice variants are expressed in adult liver and kidney and are up-regulated in diabetes.”Mol Endocrinol, vol. 20, no. 3, 2006, pp. 686–97.
[22] Vitart, V., et al. “SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout.”Nat Genet, 2008.
[23] Döring, A., et al. “SLC2A9 influences uric acid concentrations with pronounced sex-specific effects.”Nat Genet, vol. 40, 2008, pp. 430–436.
[24] Gao, X., et al. “Intake of Added Sugar and Sugar-Sweetened Drink and Serum Uric Acid Concentration in US Men and Women.”Hypertension, vol. 50, no. 2, 2007, pp. 306–12.
[25] Willer, C. J. “Newly Identified Loci That Influence Lipid Concentrations and Risk of Coronary Artery Disease.”Nat Genet, 2008. PMID: 18193043.