Using a Pharmacokinetic Model to Relate an Individual’s Susceptibility to Alcohol Dependence to Genotypes

Mustavich, Laura F.; Miller, Perry L.; Kídd, Kenneth K.; Zhao, Hongyu

doi:10.1159/000317056

Cited by 8 publications

(3 citation statements)

References 47 publications

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“…For example, phenotypic markers of TAS2R variation predict beer intake, but only during the first year of drinking (Intranuovo & Powers, 1998). Likewise, modeling of gene-gene interactions suggest bitter taste genes may act as a stage gate for other genetic risk factors; that is, if you never learn to drink alcohol because of an aversive taste, other risk alleles may be largely irrelevant (Mustavich, Miller, Kidd, & Zhao, 2010). Thus, our group and others have explored the potential role of other SNPs near this region as predictors of alcohol use, rather than abuse.…”

Section: Bitter Taste Differencesmentioning

confidence: 99%

Do polymorphisms in chemosensory genes matter for human ingestive behavior?

Hayes

Feeney

Allen

2013

Food Quality and Preference

147

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In the last decade, basic research in chemoreceptor genetics and neurobiology have revolutionized our understanding of individual differences in chemosensation. From an evolutionary perspective, chemosensory variations appear to have arisen in response to different living environments, generally in the avoidance of toxins and to better detect vital food sources. Today, it is often assumed that these differences may drive variable food preferences and choices, with downstream effects on health and wellness. A growing body of evidence indicates chemosensory variation is far more complex than previously believed. However, just because a genetic polymorphism results in altered receptor function in cultured cells or even behavioral phenotypes in the laboratory, this variation may not be sufficient to influence food choice in free living humans. Still, there is ample evidence to indicate allelic variation in TAS2R38 predicts variation in bitterness of synthetic pharmaceuticals (e.g., propylthiouracil) and natural plant compounds (e.g., goitrin), and this variation associates with differential intake of alcohol and vegetables. Further, this is only one of 25 unique bitter taste genes (TAS2Rs) in humans, and emerging evidence suggests other TAS2Rs may also contain polymorphisms that a functional with respect to ingestive behavior. For example, TAS2R16 polymorphisms are linked to the bitterness of naturally occurring plant compounds and alcoholic beverage intake, a TAS2R19 polymorphism predicts differences in quinine bitterness and grapefruit bitterness and liking, and TAS2R31 polymorphisms associate with differential bitterness of plant compounds like aristolochic acid and the sulfonyl amide sweeteners saccharin and acesulfame-K. More critically with respect to food choices, these polymorphisms may vary independently from each other within and across individuals, meaning a monolithic one-size-fits-all approach to bitterness needs to be abandoned. Nor are genetic differences restricted to bitterness. Perceptual variation has also been associated with polymorphisms in genes involved in odors associated with meat defects (boar taint), green/grassy notes, and cilantro, as well as umami and sweet tastes (TAS1R1/2/3). Here, a short primer on receptor genetics is provided, followed by a summary of current knowledge, and implications for human ingestive behavior are discussed.

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Section: Bitter Taste Differencesmentioning

confidence: 99%

Do polymorphisms in chemosensory genes matter for human ingestive behavior?

Hayes

Feeney

Allen

2013

Food Quality and Preference

147

View full text Add to dashboard Cite

show abstract

“…For example, four parameters are needed to describe drug response of a genotype at four dose levels if traditional approaches are used, while the pharmacodynamic model only uses three parameters to do the same thing. Moreover, the pharmacodynamic model, such as the Emax model 36 and differential equations, 44,45 contains biologically meaningful aspects of drug response in terms of body-drug interactions. Applied to GWAS of response to corticosteroids for asthma intervention, this model can not only facilitate the interpretation and elucidation of the pharmacogenomics architecture of this important clinical problem, but also increase the statistical power of significant association detection.…”

Section: Discussionmentioning

confidence: 99%

Pharmacodynamic genome-wide association study identifies new responsive loci for glucocorticoid intervention in asthma

Wang

Mauger

et al. 2015

Pharmacogenomics J

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Asthma is a chronic lung disease that has a high prevalence. The therapeutic intervention of this disease can be made more effective if genetic variability in patients’ response to medications is implemented. However, a clear picture of the genetic architecture of asthma intervention response remains elusive. We conducted a genome-wide association study (GWAS) to identify drug response-associated genes for asthma, in which 909,622 SNPs were genotyped for 120 randomized participants who inhaled multiple doses of glucocorticoids. By integrating pharmacodynamic properties of drug reactions, we implemented a mechanistic model to analyze the GWAS data, enhancing the scope of inference about the genetic architecture of asthma intervention. Our pharmacodynamic model observed associations of genome-wide significance between dose-dependent response to inhaled glucocorticoids (measured as %FEV1) and five loci (p = 5.315 × 10−7 to 3.924 × 10−9), many of which map to metabolic genes related to lung function and asthma risk. All significant SNPs detected indicate a recessive effect, at which the homozygotes for the mutant alleles drive variability in %FEV1. Significant associations were well replicated in three additional independent GWAS studies. Pooled together over these three trials, two SNPs, chr6 rs6924808 and chr11 rs1353649, display an increased significance level (p = 6.661 ×10−16 and 5.670×10−11). Our study reveals a general picture of pharmacogenomic control for asthma intervention. The results obtained help to tailor an optimal dose for individual patients to treat asthma based on their genetic makeup.

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“…This model was then conceptualized as a theory for computational pharmacogenetics and pharmacogenomics [24][25][26] , which has been effectively used in practice. For example, Mustavich et al 27 used it to detect loci that control susceptibility to alcohol dependence, and Wang et al 28 applied it to identify important pharmacological genes for glucocorticoid intervention in asthma. This theory can be extended to model how SBP and DBP respond differently to drugs and how their derived variables, MAP and PP, are dynamically related with drug treatments.…”

Section: Introductionmentioning

confidence: 99%

A unified mapping framework of multifaceted pharmacodynamic responses to hypertension interventions

Wang

Gan

Wei

et al. 2019

Drug Discovery Today

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Increasing studies suggest that the best therapy for hypertension not only needs to control systolic (SBP) and diastolic blood pressure (DBP), but also requires the simultaneous control of the pulsatile component (pulse pressure, PP, defined as SBP minus DBP) and steady component (mean arterial pressure, MAP, defined as 1/3 SBP plus 2/3 DBP). However, the genetic basis of how these blood pressure measures respond singly or in combination to drug intervention is unclear, thus limiting the translation of personalized hypertension medicine. We propose a unified functional mapping framework for identifying specific quantitative trait loci (QTLs) that mediate multivariate response-dose curves of blood pressure. The mapping framework integrates the pharmacodynamic mechanisms of drug response into a genetic association study setting to characterize how QTLs govern PP and MAP through jointly regulating systolic and diastolic pressures. The framework can quantify the genetic effects of individual QTLs on maximal drug effect, the maximal rate of drug response, and the dose window of maximal drug response. In conclusion, the unified mapping framework provides a powerful tool for identifying pharmacological genes responsible for blood pressure and can potentially help to design the right medication and right dose for right patients based on their genetic makeup.

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Using a Pharmacokinetic Model to Relate an Individual’s Susceptibility to Alcohol Dependence to Genotypes

Cited by 8 publications

References 47 publications

Do polymorphisms in chemosensory genes matter for human ingestive behavior?

Do polymorphisms in chemosensory genes matter for human ingestive behavior?

Pharmacodynamic genome-wide association study identifies new responsive loci for glucocorticoid intervention in asthma

A unified mapping framework of multifaceted pharmacodynamic responses to hypertension interventions

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