Pharmacogenomics of high-density lipoprotein-cholesterol-raising therapies

Aslibekyan, Stella; Straka, Robert J.; Irvin, Marguerite R.; Claas, Steven A.; Arnett, Donna K.

doi:10.1586/erc.12.134

Cited by 8 publications

(6 citation statements)

References 81 publications

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“…Genome-wide studies & meta-GWAS While the candidate gene studies discussed above have yielded important insights about fibrate pharmacogenomics, less than 10% of variation in fibrate responses is explained by candidate genes [33], which has motivated genomewide interrogations aimed at uncovering novel associations across the genome. Both genome-wide association and genome-wide linkage approaches have been used, with a number of successes.…”

Section: Candidate Gene Studiesmentioning

confidence: 99%

mentioning

confidence: 99%

“…While more investigation is required to understand these mixed results, the results as a whole demonstrate large interindividual variation in response to fibrate treatment [33]. Family-based studies have established that variation in lipid fibrate response is a heritable trait, with heritability values at the same order of magnitude as other complex traits [33]. The establishment of heritability is a necessary but not sufficient test to motivate further gene mapping with candidate gene or genome-wide approaches under the common disease-common variant hypothesis.…”

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confidence: 99%

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Fibrate Pharmacogenomics: Expanding Past the Genome

House

Motsinger‐Reif

2020

Pharmacogenomics

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Fibrates are a medication class prescribed for decades as ‘broad-spectrum’ lipid-modifying agents used to lower blood triglyceride levels and raise high-density lipoprotein cholesterol levels. Such lipid changes are associated with a decrease in cardiovascular disease, and fibrates are commonly used to reduce risk of dangerous cardiovascular outcomes. As with most drugs, it is well established that response to fibrate treatment is variable, and this variation is heritable. This has motivated the investigation of pharmacogenomic determinants of response, and multiple studies have discovered a number of genes associated with fibrate response. Similar to other complex traits, the interrogation of single nucleotide polymorphisms using candidate gene or genome-wide approaches has not revealed a substantial portion of response variation. However, recent innovations in technological platforms and advances in statistical methodologies are revolutionizing the use and integration of other ‘omes’ in pharmacogenomics studies. Here, we detail successes, challenges, and recent advances in fibrate pharmacogenomics.

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Section: Candidate Gene Studiesmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Fibrate Pharmacogenomics: Expanding Past the Genome

House

Motsinger‐Reif

2020

Pharmacogenomics

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“…Genome-wide pharmacogenomic studies have more recently been applied in a wide variety of clinical applications, including investigations into drug concentrations and related effects of additional cholesterol- and lipid-lowering molecules [ 12 – 14 ], anti-depressants [ 15 , 16 ], and cancer treatments [ 17 , 18 ]. While most traditional cancer genomics initiatives focused on identifying the somatic mutations that drive tumor progression, it is now also recognized that germline variation among patients may significantly impact their response to cancer treatments.…”

Section: Pharmacogenomicsmentioning

confidence: 99%

Precision medicine: from pharmacogenomics to pharmacoproteomics

Chambliss

Chan

2016

Clin Proteom

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Disease progression and drug response may vary significantly from patient to patient. Fortunately, the rapid development of high-throughput ‘omics’ technologies has allowed for the identification of potential biomarkers that may aid in the understanding of the heterogeneities in disease development and treatment outcomes. However, mechanistic gaps remain when the genome or the proteome are investigated independently in response to drug treatment. In this article, we discuss the current status of pharmacogenomics in precision medicine and highlight the needs for concordant analysis at the proteome and metabolome levels via the more recently-evolved fields of pharmacoproteomics, toxicoproteomics, and pharmacometabolomics. Integrated ‘omics’ investigations will be critical in piecing together targetable mechanisms of action for both drug development and monitoring of therapy in order to fully apply precision medicine to the clinic.

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“…Genetic variation in HCAR2 could influence niacin's effects on plasma lipids, Lp(a), or cardiovascular events, but this has not been tested [22]. First we sequenced HCAR2 in 294 healthy subjects to discover novel coding variants.…”

Section: Introductionmentioning

confidence: 99%

Genetic coding variants in the niacin receptor, hydroxyl–carboxylic acid receptor 2, and response to niacin therapy

Tuteja¹,

Wang

Dunbar³

et al. 2017

Pharmacogenetics and Genomics

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Objectives Niacin has been used for seven decades to modulate plasma lipids, but its mechanism of action is still unclear. We sought to determine whether variants in the niacin receptor gene, hydroxycarboxylic receptor 2 (HCAR2) are associated with lipid response to treatment. Methods Coding variants, rs7314976 (p.R311C) and rs2454727 (p.M317I), were genotyped in 2067 participants from the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes (AIM-HIGH) trial. AIM-HIGH was a randomized, placebo controlled trial to assess the effect of extended release (ER) niacin in patients with cardiovascular disease aggressively treated with low density lipoprotein (LDL-C) lowering therapy. Results We did not find an association of p.R311C or p.M317I with change in LDL-C, triglycerides (TG) or high-density lipoprotein cholesterol (HDL-C) at one year in groups receiving placebo or ER niacin. In white subjects, the reduction in lipoprotein(a) [Lp(a) ] in response to niacin was greater in homozygous carriers of the major 317M allele (-22.7%; p=0.005) compared with minor allele carriers (-15.3%). This was directionally consistent in the black participants. Upon combining both groups, the reduction in Lp(a) in response to niacin was significantly greater in the homozygous major allele carriers (-23.0%; p=0.003) compared with minor allele carriers (-15.2%). Conclusions Understanding the genetic contribution to variation in response to niacin therapy, including Lp(a) reduction, could uncover mechanisms by which niacin decreases Lp(a), an important independent risk factor for cardiovascular disease.

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Pharmacogenomics of high-density lipoprotein-cholesterol-raising therapies

Cited by 8 publications

References 81 publications

Fibrate Pharmacogenomics: Expanding Past the Genome

Fibrate Pharmacogenomics: Expanding Past the Genome

Precision medicine: from pharmacogenomics to pharmacoproteomics

Genetic coding variants in the niacin receptor, hydroxyl–carboxylic acid receptor 2, and response to niacin therapy

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