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Background and Aims: The disintegrin and metalloproteinase ADAM17, also known as tumor necrosis factor alpha converting enzyme, is expressed in adipocytes. Importantly, elevated levels of ADAM17 expression have been linked to obesity and insulin resistance. Therefore, the aim of this study was to evaluate the association of six ADAM17 single nucleotide polymorphisms (SNPs) (m1254A>G, i14121C>A, i33708A>G, i48827A>C, i53440C>T, and i62781G>T) with insulin-resistance phenotypes and obesity risk, and their potential interactions with dietary polyunsaturated fatty acids (PUFA).Methods and Results: ADAM17 SNPs were genotyped in 936 subjects (448 men/488 women) who participated in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study. Anthropometrical and biochemical measurements were determined by standard procedures. PUFA intake was estimated using a validated questionnaire. G allele carriers at the ADAM17_m1254A>G polymorphism exhibited significantly higher risk of obesity (P=0.003), were shorter (P=0.017), had higher insulin (P=0.016), and lower HDL-C concentrations (P=0.027) than AA subjects. For the ADAM17_i33708A>G SNP, homozygotes for the A allele displayed higher risk of obesity (P=0.001), were heavier (P=0.011), had higher BMI (P=0.005), and higher waist measurements (P=0.023) than GG subjects. A significant gene-diet interaction was found (P=0.030), in which the deleterious association of the i33708A allele with obesity was observed in subjects with low intakes from (n-6) PUFA (P<0.001), whereas no differences in obesity risk were seen among subjects with high (n-6) PUFA intake (P>0.5)Conclusion: These findings support that ADAM17 (m1254A>G and i33708A>G) SNPs may contribute to obesity risk. For the ADAM17_i33708A>G SNP, this risk may be further modulated by (n-6) PUFA intake. [ABSTRACT FROM AUTHOR]

BACKGROUND: Several genome-wide association studies have identified novel loci (KCTD10, MVK, and MMAB) that are associated with HDL-cholesterol concentrations. Of the environmental factors that determine HDL cholesterol, high-carbohydrate diets have been shown to be associated with low concentrations. OBJECTIVE: The objective was to evaluate the associations of 8 single nucleotide polymorphisms (SNPs) located within the KCTD10, MVK, and MMAB loci with lipids and their potential interactions with dietary carbohydrates. DESIGN: KCTD10, MVK, and MMAB SNPs were genotyped in 920 subjects (441 men and 479 women) who participated in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study. Biochemical measurements were made by using standard procedures. Dietary intakes were estimated by using a validated questionnaire. RESULTS: For the SNPs KCTD10_i5642G-->C and MVK_S52NG-->A, homozygotes for the major alleles (G) had lower HDL-cholesterol concentrations than did carriers of the minor alleles (P = 0.005 and P = 0.019, respectively). For the SNP 12inter_108466061A-->G, homozygotes for the minor allele (G) had higher total cholesterol and LDL-cholesterol concentrations than did AG subjects (P = 0.030 and P = 0.034, respectively). Conversely, homozygotes for the major allele (G) at MMAB_3U3527G-->C had higher LDL-cholesterol concentrations than did carriers of the minor allele (P = 0.034). Significant gene-diet interactions for HDL cholesterol were found (P < 0.001-0.038), in which GG subjects at SNPs KCTD10_i5642G-->C and MMAB_3U3527G-->C and C allele carriers at SNP KCTD10_V206VT-->C had lower concentrations only if they consumed diets with a high carbohydrate content (P < 0.001-0.011). CONCLUSION: These findings suggest that the KCTD10 (V206VT-->C and i5642G-->C) and MMAB_3U3527G-->C variants may contribute to the variation in HDL-cholesterol concentrations, particularly in subjects with high carbohydrate intakes. Copyright © 2009 American Society for Nutrition [ABSTRACT FROM AUTHOR]

Objective: C-reactive protein (CRP) is an inflammatory marker that contributes to the prediction of cardiovascular disease. We investigated the influences of CRP polymorphisms on baseline CRP levels and fenofibrate-induced CRP changes in subjects with the metabolic syndrome.Research Design and Methods: We examined the association of CRP single nucleotide polymorphisms (SNPs) (m772A>G, m301G>A >T, i178T>A, 3u1273C>T, and 3u2131C>T) with baseline plasma CRP levels among 1,123 white U.S. participants in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study and the modulating effect of these SNPs on CRP response to a 3-week fenofibrate treatment among 290 participants with the metabolic syndrome.Results: There were strong associations of m301G>A>T (rs3091244; P = 0.003), i178T>A (rs1417938; P = 0.001), 3u1273C>T (rs1130864; P = 0.001), and 3u2131C>T (rs1205; P < 0.001) with baseline CRP levels. Moreover, among subjects with the metabolic syndrome, fenofibrate induced the greatest reduction in CRP levels for TT subjects of the i178T>A compared with TA and AA subjects (-30 for TT, -19 for TA, and -11% for AA; P = 0.004). Similarly, for the m301G>A>T, major allele carriers displayed maximal reduction of CRP over noncarriers (-20 for GG, -15 for GA and GT, and -0.3% for TA and AA; P = 0.020).Conclusions: Our results demonstrate that common genetic variants within the CRP gene affect baseline CRP levels and further modulate CRP response in subjects with the metabolic syndrome treated with fenofibrate. This knowledge could contribute to a better prediction of therapeutic success. [ABSTRACT FROM AUTHOR]

Objective: The clinical literature suggests that atorvastatin therapy achieves a reduction in major cardiovascular events within the first year of therapy. Aside from obvious clinical benefits, economic advantage may also result from this observation. The present analysis modeled the clinical and economic consequences of initiating atorvastatin versus generic simvastatin in defined US managed care organization patient populations.Research Design and Methods: A cost-consequence model was developed to estimate the differential rate and associated costs of cardiovascular events occurring over 2 years using real world price and adherence data. Four defined patient populations were included from representative atorvastatin trials: (1) diabetes mellitus; (2) multiple risk factors; (3) coronary heart disease; and (4) acute coronary syndrome. Costs of care included drug costs and costs of managing cardiovascular events. Univariate sensitivity analyses and multivariate sensitivity analysis via Monte Carlo simulation were conducted to test the robustness of the results.Main Outcome Measures: The number of cardiovascular events avoided per 100,000 patients initiated on atorvastatin as compared with simvastatin, and total treatment costs.Results: The model predicts that, relative to simvastatin, atorvastatin will prevent 941 (95% confidence interval [CI] 481-1367) cardiovascular events after 1 year and 1426 (95% CI 833-1987) events after 2 years, per 100,000 patients. This is expected to reduce the cost of cardiovascular events by $365 (95% CI $192-$527) and $552 (95% CI $327-$763) per patient (US$ 2006), respectively, offsetting 80% and 75% of the medication cost difference between atorvastatin and simvastatin after 1 and 2 years, respectively. The incremental costs associated with atorvastatin treatment were estimated at $94 (95% CI -$68 to $267) and $175 (95% CI -$37 to $399) per patient after 1 and 2 years, respectively. Results were sensitive to assumptions regarding simvastatin efficacy and drug acquisition costs.Conclusions: Although the present analysis is based in part on indirect comparisons and on trials not designed or statistically powered to specifically test the early benefits hypothesis, it suggests that atorvastatin's assumed early reduction of cardiovascular events partly offsets the acquisition price difference between atorvastatin and generic simvastatin in various groups of high-risk patients newly initiated on statin treatment. [ABSTRACT FROM AUTHOR]

Polymorphisms of N-acetyltransferase 2 (NAT2) acetylation may influence drug toxicities and efficacy and are associated with a differential susceptibility to select cancers. Acetylation phenotype may have clinical implications. The purposes of this study were to determine the genetic basis of an apparent predominance of slow acetylation phenotype and to assess concordance with genotype in a population of Hmong residing in Minnesota. Urine and DNA obtained from unrelated Hmong 18 to 65 years of age were used to determine phenotype from caffeine metabolites, whereas direct nucleotide sequencing of the NAT2 coding region, followed by cloning, identified all known allelic variants. From 61 subjects (27 men, 30 +/- 11 years), analysis of 50 urine-DNA pairs identified 46 (92%) slow acetylators and 4 (8%) rapid acetylators by phenotype. Genotypic analysis inferred 5 (10%) slow acetylators and 45 (90%) rapid acetylators. There is 86% discordance between phenotype and genotype. A predominance of NAT2 slow acetylation phenotype in the Hmong is confirmed, and a significant discordance between NAT2 phenotype and genotype is identified. In this population, slow acetylation phenotype determined by a metabolic probe would not have been predicted by genotype alone. Environmental, genetic, or phenotypic anomalies that may contribute to this discordance should be considered and evaluated in future studies within this unique population. [ABSTRACT FROM AUTHOR]

In addition to intensive treatment of CHD, a major focus of the revised guidelines of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) for cholesterol testing and management is on primary prevention in persons with multiple risk factors. NCEP ATP III now guides in the determination of risk based on designations of CHD risk equivalents and the Framingham 10-year risk assessment for patients who have 2 or more risk factors and there-fore require more intensive therapy. The updated guidelines also identify patients who fit criteria for the metabolic syndrome. The guidelines now establish the optimal low-density lipoprotein cholesterol (LDL-C) level as <100 mg/dL and the minimally acceptable high-density lipoprotein cholesterol (HDL-C) level as 40 mg/dL. Other new recommendations include step-by-step risk management to assess the need for therapeutic lifestyle changes or drug therapy to lower LDL-C levels. This introduction will focus on new features of the guidelines and their application to prospective patients. [ABSTRACT FROM AUTHOR]

Recent studies have shown an association between the use of calcium channel antagonists for the treatment of hypertension and an increased risk of myocardial infarction, gastrointestinal hemorrhage and cancer. The interpretation of the results of these studies and their application to clinical practice requires an understanding of study design constraints, conflicting results and limitations in extrapolating study findings to other dosage strengths, formulations or agents within the calcium channel antagonist class. A review and critique of these studies provides background information on the controversial subject of using calcium channel antagonists for the treatment of hypertension. Despite the limitations of these studies, clinicians may want to select other classes of agents, including diuretics and beta blockers, as first-line therapy until the morbidity and mortality effects related to the use of calcium channel antagonists are clearly known. [ABSTRACT FROM AUTHOR]

The accumulation of (+)- and (-)-propranolol was investigated in nine subjects who received 160 mg of racemic propranolol as a single dose and then once daily for 7 days. The serum concentrations of propranolol enantiomers were measured by h.p.l.c. using a novel chiral stationary phase allowing direct resolution of underivatized propranolol. The (+)- propranolol AUC increased from 412 +/- 223 ng ml-1 h after single doses (0-infinity) to 584 +/- 279 ng ml-1 h at steady-state (0-24 h) (P less than 0.05). Similarly, (-)-propranolol AUC increased from 609 +/- 304 to 777 +/- 370 ng ml-1 h (P less than 0.05). The AUC ratio (-)/(+) was 1.52 +/- 0.36 and 1.32 +/- 0.17 after single doses and steady-state, respectively (P greater than 0.05). Therefore, nonlinear accumulation occurs with both enantiomers although there is a trend for the (-)/(+) ratio to decrease at steady-state. [ABSTRACT FROM AUTHOR]

Introduction: In collaboration with the Minnesota Hmong community, we have previously discovered significant differences in allele frequencies for key Single Nucleotide Variations (SNVs) within Very Important Pharmacogenes (VIPs) between Hmong and East Asians. Recognizing the potential clinical implications of these observed differences, we sought to validate these observations in a Hmong cohort residing in California, the state with the largest Hmong population in the US. Robust validation of these differences would affect motivation for clinicians treating individuals who identify as Hmong to consider pharmacogenomic (PGx) testing as a means to improve clinical decision making when using therapeutic agents in this unique population., Method: Guided by California Hmong community leaders and utilizing the basic approach of community-based participatory research, demographic, clinical information and a buccal swab was obtained from Hmong adults residing in California. A commercial PGx testing panel was performed on these samples and specific allele frequencies of interest were compared between California and Minnesota Hmong. Allele frequency differences between California Hmong, East Asians and Europeans, were also compared. Return-of-PGx-results and presentations of group data were made to members of the Hmong along with PGx educational sessions to help interpret the observations., Results: In 118 California Hmong who completed the study, the allele frequencies for SNV's were similar to previous Minnesota Hmong results. Furthermore, out of the 18 SNVs that were not previously reported in Hmong, allele frequencies were statistically different in 38% (7/18) of SNVs comparing California Hmong to East Asians, and in 77.8% (14/18) SNVs comparing California Hmong to Europeans., Conclusion: These results validate the original study's findings that Hmong people living in different US locations have similar allele frequencies for key PGx genes. Further, for many of these PGx genes, their allele frequencies are significantly different compared to either East Asians or Europeans. Clinicians should consider these important differences when prescribing medications for people who identify as Hmong., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sun, Thao, Culhane-Pera, Yang, Thor, Yang, Xiong, Vang and Straka.)

Several bacterial taxa enriched in inflammatory bowel diseases and colorectal cancer (CRC) are found in the oral cavity. We conducted a pilot study nested within a six-week aspirin intervention in a randomized placebo-controlled trial to test their response to aspirin intervention. Fifty healthy subjects, 50-75 years old, were randomized to receive 325 mg aspirin (n = 30) or placebo (n = 20) orally once daily for six weeks. Oral tongue swabs were collected at baseline and week six. We estimated the association between aspirin use and the temporal changes in the relative abundance of pre-specified genus level taxa from pre- to post-treatment. The temporal change in relative abundance differed for eight genus level taxa between the aspirin and placebo groups. In the aspirin group, there were significant increases in the relative abundances of Neisseria , Streptococcus , Actinomyces , and Rothia and significant decreases in Prevotella , Veillonella , Fusobacterium , and Porphyromonas relative to placebo. The log ratio of Neisseria to Fusobacterium declined more in the aspirin group than placebo, signaling a potential marker associated with aspirin intervention. These preliminary findings should be validated using metagenomic sequencing and may guide future studies on the role of aspirin on taxa in various oral ecological niches.

Statin-associated muscle symptoms (SAMS) can lead to statin nonadherence. This paper aims to develop a pharmacological SAMS risk stratification (PSAMS-RS) score using a previously developed PSAMS phenotyping algorithm that distinguishes objective vs. nocebo SAMS using electronic health record (EHR) data. Using our PSAMS phenotyping algorithm, SAMS cases and controls were identified from Minnesota Fairview EHR, with the statin user cohort divided into derivation (January 1, 2010, to December 31, 2018) and validation (January 1, 2019, to December 31, 2020) cohorts. A Least Absolute Shrinkage and Selection Operator regression model was applied to identify significant features for PSAMS. PSAMS-RS scores were calculated and the clinical utility of stratifying PSAMS risk was assessed by comparing hazard ratios (HRs) between fourth vs. first score quartiles. PSAMS cases were identified in 1.9% (310/16,128) of the derivation and 1.5% (64/4,182) of the validation cohorts. Sixteen out of 38 clinical features were determined to be significant predictors for PSAMS risk. Patients within the fourth quartile of the PSAMS scores had an over sevenfold (HR: 7.1, 95% confidence interval (CI): 4.03-12.45, derivation cohort) or sixfold (HR: 6.1, 95% CI: 2.15-17.45, validation cohort) higher hazard of developing PSAMS vs. those in their respective first quartile. The PSAMS-RS score is a simple tool to stratify patients' risk of developing PSAMS after statin initiation which could inform clinician-guided pre-emptive measures to prevent PSAMS-related statin nonadherence., (© 2024 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Ginger has been associated with a decreased incidence of colorectal cancer (CRC) through reduction in inflammatory pathways and inhibition of tumor growth. Recent pre-clinical models have implicated changes in the gut microbiome as a possible mediator of the ginger effect on CRC. We hypothesized that, in adults previously diagnosed with a colorectal adenoma, ginger supplementation would alter the fecal microbiome in the direction consistent with its CRC-inhibitory effect. Sixty-eight adults were randomized to take either ginger or placebo daily for 6 weeks, with a 6-week washout and longitudinal stool collection throughout. We performed 16S rRNA sequencing and evaluated changes in overall microbial diversity and the relative abundances of pre-specified CRC-associated taxa using mixed-effects logistic regression. Ginger supplementation showed no significant effect on microbial community structure through alpha or beta diversity. Of 10 pre-specified CRC-associated taxa, there were significant decreases in the relative abundances of the genera Akkermansia (p < 0.001), Bacteroides (p = 0.018), and Ruminococcus (p = 0.013) after 6-week treatment with ginger compared to placebo. Ginger supplementation led to decreased abundances of Akkermansia and Bacteroides, which suggests that ginger may have an inhibitory effect on CRC-associated taxa. Overall, ginger supplementation appears to have a limited effect on gut microbiome in patients with colorectal adenomas., (© 2024. The Author(s).)

Importance: Statins are widely prescribed cholesterol-lowering medications in the United States, but their clinical benefits can be diminished by statin-associated muscle symptoms (SAMS), leading to discontinuation., Objectives: In this study, we aimed to develop and validate a pharmacological SAMS clinical phenotyping algorithm using electronic health records (EHRs) data from Minnesota Fairview., Materials and Methods: We retrieved structured and unstructured EHR data of statin users and manually ascertained a gold standard set of SAMS cases and controls using the published SAMS-Clinical Index tool from clinical notes in 200 patients. We developed machine learning algorithms and rule-based algorithms that incorporated various criteria, including ICD codes, statin allergy, creatine kinase elevation, and keyword mentions in clinical notes. We applied the best-performing algorithm to the statin cohort to identify SAMS., Results: We identified 16 889 patients who started statins in the Fairview EHR system from 2010 to 2020. The combined rule-based (CRB) algorithm, which utilized both clinical notes and structured data criteria, achieved similar performance compared to machine learning algorithms with a precision of 0.85, recall of 0.71, and F1 score of 0.77 against the gold standard set. Applying the CRB algorithm to the statin cohort, we identified the pharmacological SAMS prevalence to be 1.9% and selective risk factors which included female gender, coronary artery disease, hypothyroidism, and use of immunosuppressants or fibrates., Discussion and Conclusion: Our study developed and validated a simple pharmacological SAMS phenotyping algorithm that can be used to create SAMS case/control cohort to enable further analysis which can lead to the development of a SAMS risk prediction model., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Aims: The aim of this study was to quantify identifiable sources of variability, including key pharmacogenetic variants in oxypurinol pharmacokinetics and their pharmacodynamic effect on serum urate (SU)., Methods: Hmong participants (n = 34) received 100 mg allopurinol twice daily for 7 days followed by 150 mg allopurinol twice daily for 7 days. A sequential population pharmacokinetic pharmacodynamics (PKPD) analysis with non-linear mixed effects modelling was performed. Allopurinol maintenance dose to achieve target SU was simulated based on the final PKPD model., Results: A one-compartment model with first-order absorption and elimination best described the oxypurinol concentration-time data. Inhibition of SU by oxypurinol was described with a direct inhibitory E max model using steady-state oxypurinol concentrations. Fat-free body mass, estimated creatinine clearance and SLC22A12 rs505802 genotype (0.32 per T allele, 95% CI 0.13, 0.55) were found to predict differences in oxypurinol clearance. Oxypurinol concentration required to inhibit 50% of xanthine dehydrogenase activity was affected by PDZK1 rs12129861 genotype (-0.27 per A allele, 95% CI -0.38, -0.13). Most individuals with both PDZK1 rs12129861 AA and SLC22A12 rs505802 CC genotypes achieve target SU (with at least 75% success rate) with allopurinol below the maximum dose, regardless of renal function and body mass. In contrast, individuals with both PDZK1 rs12129861 GG and SLC22A12 rs505802 TT genotypes would require more than the maximum dose, thus requiring selection of alternative medications., Conclusions: The proposed allopurinol dosing guide uses individuals' fat-free mass, renal function and SLC22A12 rs505802 and PDZK1 rs12129861 genotypes to achieve target SU., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

The Pharmacogene Variation Consortium (PharmVar) is now providing star (*) allele nomenclature for the highly polymorphic human SLCO1B1 gene encoding the organic anion transporting polypeptide 1B1 (OATP1B1) drug transporter. Genetic variation within the SLCO1B1 gene locus impacts drug transport, which can lead to altered pharmacokinetic profiles of several commonly prescribed drugs. Variable OATP1B1 function is of particular importance regarding hepatic uptake of statins and the risk of statin-associated musculoskeletal symptoms. To introduce this important drug transporter gene into the PharmVar database and serve as a unified reference of haplotype variation moving forward, an international group of gene experts has performed an extensive review of all published SLCO1B1 star alleles. Previously published star alleles were self-assigned by authors and only loosely followed the star nomenclature system that was first developed for cytochrome P450 genes. This nomenclature system has been standardized by PharmVar and is now applied to other important pharmacogenes such as SLCO1B1. In addition, data from the 1000 Genomes Project and investigator-submitted data were utilized to confirm existing haplotypes, fill knowledge gaps, and/or define novel star alleles. The PharmVar-developed SLCO1B1 nomenclature has been incorporated by the Clinical Pharmacogenetics Implementation Consortium (CPIC) 2022 guideline on statin-associated musculoskeletal symptoms., (© 2022 The Authors. Clinical Pharmacology & Therapeutics © 2022 American Society for Clinical Pharmacology and Therapeutics.)

Background: Hmong men in Minnesota exhibit a high prevalence of gout and hyperuricemia. Although evidence of vitamin C's effectiveness as a treatment for gout is mixed, analysis of therapeutic benefit based on an individual's multiomic signature may identify predictive markers of treatment success., Objectives: The primary objective of the Hmong Microbiome ANd Gout, Obesity, Vitamin C (HMANGO-C) study was to assess the effectiveness of vitamin C on serum urate in Hmong adults with and without gout/hyperuricemia. The secondary objectives were to assess if 1) vitamin C impacts the taxonomic and functional patterns of microbiota; 2) taxonomic and functional patterns of microbiota impact vitamin C's urate-lowering effects; 3) genetic variations impact vitamin C's urate-lowering effects; 4) differential microbial biomarkers exist for patients with or without gout; and 5) there is an association between obesity, gut microbiota and gout/hyperuricemia., Methods: This prospective open-labelled clinical trial was guided by community-based participatory research principles and conducted under research safety restrictions for SARS-CoV-2. We aimed to enroll a convenient sample of 180 Hmong adults (120 with gout/hyperuricemia and 60 without gout/hyperuricemia) who provided medical, demographic, dietary and anthropometric information. Participants took vitamin C 500mg twice daily for 8 weeks and provided pre-and post- samples of blood and urine for urate measurements as well as stool samples for gut microbiome. Salivary DNA was also collected for genetic markers relevant to uric acid disposition., Expected Results: We expected to quantify the impact of vitamin C on serum urate in Hmong adults with and without gout/hyperuricemia. The outcome will enhance our understanding of how gut microbiome and genomic variants impact the urate-lowering of vitamin C and associations between obesity, gut microbiota and gout/hyperuricemia. Ultimately, findings may improve our understanding of the causes and potential interventions that could be used to address health disparities in the prevalence and management of gout in this underserved population., Trial Registration: ClinicalTrials.gov NCT04938024 (first posted: 06/24/2021)., Competing Interests: D.K. serves as CEO and holds equity in CoreBiome, a company involved in the commercialization of microbiome analysis. The University of Minnesota also has financial interests in CoreBiome under the terms of a license agreement with CoreBiome. These interests have been reviewed and managed by the University of Minnesota in accordance with its Conflict-of-Interest policies. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Wen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Underrepresentation of subpopulations within geo-ancestral groups engaged in research can exacerbate health disparities and impair progress toward personalized medicine. This is particularly important when implementing pharmacogenomics which uses genomic-based sources of variability to guide medication selection and dosing. This mini-review focuses on pharmacogenomic findings with Hmong in the United States and their potential clinical implications. By actively engaging Hmong community in pharmacogenomic-based research, several clinically relevant differences in allele frequencies were observed within key pharmacogenes such as CYP2C9 and CYP2C19 in Hmong compared to those in either East Asians or Europeans. Additionally, using state-of-the-art genome sequencing approaches, Hmong appear to possess novel genetic variants within CYP2D6 , a critical pharmacogene affecting pharmacokinetics of a broad range of medications. The allele frequency differences and novel alleles in Hmong have translational impact and real-world clinical consequences. For example, Hmong patients exhibited a lower warfarin stable dose requirement compared to East Asian patients. This was predicted based on Hmong's unique genetic and non-genetic factors and confirmed using real-world data from clinical practice settings. By presenting evidence of the genetic uniqueness and its translational impact within subpopulations, such as the Hmong, we hope to inspire greater inclusion of other geo-ancestrally underrepresented subpopulations in pharmacogenomic-based research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sun, Wen, Culhane-Pera, Lo and Straka.)

Background Previous research predicted that Hmong, an understudied East Asian subpopulation, might require significantly lower warfarin doses than East Asian patients partially due to their unique genetic and clinical factors. However, such findings have not been corroborated using real-world data. Methods This was a retrospective cohort study of Hmong and East Asian patients receiving warfarin. Warfarin stable doses (WSD) and time to the composite outcome, including international normalized ratio (INR) greater than four incidences or major bleeding within six months of warfarin initiation, were compared. Results This cohort study included 55 Hmong and 100 East Asian patients. Compared to East Asian patients, Hmong had a lower mean WSD (14.5 vs. 20.4 mg/week, p<0.05). In addition, Hmong had a 3.1-fold (95% CI: 1.1-9.3, p<0.05) higher hazard of the composite outcome. Conclusion Using real-world data, significant differences in warfarin dosing and hazard for the composite outcome of INR>4 and major bleeding were observed between Hmong and East Asian patients. These observations further underscore the importance of recognizing subpopulation-based differences in warfarin dosing and outcomes., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Sun et al.)

Statins reduce cholesterol, prevent cardiovascular disease, and are among the most commonly prescribed medications in the world. Statin-associated musculoskeletal symptoms (SAMS) impact statin adherence and ultimately can impede the long-term effectiveness of statin therapy. There are several identified pharmacogenetic variants that impact statin disposition and adverse events during statin therapy. SLCO1B1 encodes a transporter (SLCO1B1; alternative names include OATP1B1 or OATP-C) that facilitates the hepatic uptake of all statins. ABCG2 encodes an efflux transporter (BCRP) that modulates the absorption and disposition of rosuvastatin. CYP2C9 encodes a phase I drug metabolizing enzyme responsible for the oxidation of some statins. Genetic variation in each of these genes alters systemic exposure to statins (i.e., simvastatin, rosuvastatin, pravastatin, pitavastatin, atorvastatin, fluvastatin, lovastatin), which can increase the risk for SAMS. We summarize the literature supporting these associations and provide therapeutic recommendations for statins based on SLCO1B1, ABCG2, and CYP2C9 genotype with the goal of improving the overall safety, adherence, and effectiveness of statin therapy. This document replaces the 2012 and 2014 Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for SLCO1B1 and simvastatin-induced myopathy., (© 2022 The Authors. Clinical Pharmacology & Therapeutics © 2022 American Society for Clinical Pharmacology and Therapeutics.)

Objective: Hmong individuals represent a unique East Asian subpopulation in whom limited information concerning pharmacogenetic variation exists. The objectives of this study were to comprehensively characterize the highly polymorphic CYP2D6 gene in Hmong, estimate allele and phenotype frequencies and to compare results between two testing platforms. Methods: DNA from 48 self-identified Hmong participants were sequenced using a targeted next-generation sequencing (NGS) panel. Star allele calls were made using Astrolabe, manual inspection of NGS variant calls and confirmatory Sanger sequencing. Structural variation was determined by long-range (XL)-PCR and digital droplet PCR (ddPCR). The consensus diplotypes were subsequently translated into phenotype utilizing the activity score system. Clinical grade pharmacogenetic testing was obtained for 12 of the 48 samples enabling an assessment of concordance between the consensus calls and those determined by clinical testing platforms. Results: A total of 13 CYP2D6 alleles were identified. The most common alleles were CYP2D6*10 and its structural arrangements (37.5%, 36/96) and the *5 gene deletion (13.5%, 13/96). Three novel suballeles ( *10.007 , *36.004 , and *75.002 ) were also identified. Phenotype frequencies were as follows: ultrarapid metabolizers (4.2%, 2/48), normal metabolizers (41.7%, 20/48) and intermediate metabolizers (52.1%, 25/48); none of the 48 participants were predicted to be poor metabolizers. Concordance of diplotype and phenotype calls between the consensus and clinical testing were 66.7 and 50%, respectively. Conclusion: Our study to explore CYP2D6 genotypes in the Hmong population suggests that this subpopulation is unique regarding CYP2D6 allelic variants; also, a higher portion of Hmong participants (50%) are predicted to have an intermediate metabolizer phenotype for CYP2D6 compared to other East Asians which range between 27 and 44%. Results from different testing methods varied considerably. These preliminary findings underscore the importance of thoroughly interrogating unique subpopulations to accurately predict a patient's CYP2D6 metabolizer status., Competing Interests: AG was the Director of PharmVar. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wen, Gaedigk, Boone, Wang and Straka.)

Several healthcare organizations across Minnesota have developed formal pharmacogenomic (PGx) clinical programs to increase drug safety and effectiveness. Healthcare professional and student education is strong and there are multiple opportunities in the state for learners to gain workforce skills and develop advanced competency in PGx. Implementation planning is occurring at several organizations and others have incorporated structured utilization of PGx into routine workflows. Laboratory-based and translational PGx research in Minnesota has driven important discoveries in several therapeutic areas. This article reviews the state of PGx activities in Minnesota including educational programs, research, national consortia involvement, technology, clinical implementation and utilization and reimbursement, and outlines the challenges and opportunities in equitable implementation of these advances.

Individuals of distinct Asian backgrounds are commonly aggregated as Asian, which could mask the differences in the etiology and prevalence of health conditions in the different Asian subgroups. The Hmong are a growing Asian subgroup in the United States with a higher prevalence of gout and gout-related comorbidities than non-Hmong. Genetic explorations in the Hmong suggest a higher prevalence of genetic polymorphisms associated with an increased risk of hyperuricemia and gout. History of immigration, acculturation, lifestyle factors, including dietary and social behavioral patterns, and the use of traditional medicines in the Hmong community may also increase the risk of developing gout and lead to poor gout management outcomes. Engaging minorities such as the Hmong population in biomedical research is a needed step to reduce the burden of health disparities within their respective communities, increase diversity in genomic studies, and accelerate the adoption of precision medicine to clinical practice.

Introduction: Warfarin's narrow therapeutic index and high variability in dosage requirements make dosage selection critical. Genetic factors are known to impact warfarin dosage selection. The Hmong are a unique Asian subpopulation numbering over 278,000 in the United States whose participation in genetics-based research is virtually nonexistent. The translational significance of early reports of warfarin pharmacogene differences in Hmong has not been evaluated., Objectives: (i) To validate previously identified allele frequency differences relevant to warfarin dosing in Hmong versus East Asians and (ii) to compare predicted warfarin sensitivity and maintenance doses between a Hmong population and an East Asian cohort., Method: DNA collected from two independent cohorts (n=236 and n=198) of Hmong adults were genotyped for CYP2C9 (*2, *3), VKORC1 (G-1639A), and CYP4F2 (*3). Allele frequencies between the combined Hmong cohort (n=433) and East Asians (n=1165) from the 2009 International Warfarin Pharmacogenetics Consortium (IWPC) study were compared using a χ 2 test. Percentages of Hmong and East Asian participants predicted to be very sensitive to warfarin were compared using a χ 2 test, and the predicted mean warfarin maintenance dose was compared with a t test., Results: The allele frequencies of CYP2C9*3 in the combined Hmong cohort and CYP4F2*3 in the VIP-Hmong cohort are significantly different from those in East Asians (18.9% vs 3.0%, p<0.001 and 9.8% vs 22.1%, p<0.001, respectively). Comparing the combined Hmong cohort to the East Asian cohort, the percentage of participants predicted to be very sensitive to warfarin was significantly higher (28% vs 5%, p<0.01) and the mean predicted warfarin maintenance dose was significantly lower (19.8 vs 21.3 mg/week, p<0.001), respectively., Conclusion: The unique allele frequencies related to warfarin when combined with nongenetic factors observed in the Hmong translate into clinically relevant differences in predicted maintenance dose requirements for Hmong versus East Asians., (© 2020 Pharmacotherapy Publications, Inc.)

Pharmacogenetic research has historically lacked racial and ethnic diversity, limiting the application of findings to minority populations. Recent studies, including the Hmong, have gauged communities' interest in participating in genomic research and receiving their individual results. This study was conducted to create a culturally and linguistically appropriate format to return pharmacogenomic results and identify Minnesota Hmong research participants' reactions to their personal and collective results. Using a community-based participatory research approach, researchers collaborated with Hmong community members to format the pharmacogenetic disclosure process. Three focus groups were completed with 24 Hmong participants and three major themes emerged using thematic analysis. Many Hmong focus group participants viewed the results positively, finding them useful for themselves and their community as a means to optimize responses to and avoid harms from medicines. However, some participants expressed concerns about harms that the pharmacogenetic information could bring, including anxiety, misunderstanding, discrimination, exploitation, and lack of a clinician involvement in interpreting and applying the result. Many participants interpreted their results through an experiential lens, trusting their experience of medicines more than trusting genetic information, and through a cultural lens, expressing the belief that environmental factors may influence how people's bodies respond to medicines by influencing their inherited flesh and blood (roj ntsha). Lastly, participants stressed the importance of disseminating the information while acknowledging the complex linguistic, educational, and cultural factors that limit understanding of the results. Researchers, genetic counselors, pharmacists, and healthcare providers should strive to return results in meaningful ways to all members of society.

Background: Aspirin is associated with decreased risk of colorectal cancer (CRC), potentially by modulating the gut microbiome., Aims: To evaluate the effect of aspirin on the gut microbiome in a double-blinded, randomised placebo-controlled pilot trial., Methods: Healthy volunteers aged 50-75 received a standard dose of aspirin (325 mg, N = 30) or placebo (N = 20) once daily for 6 weeks and provided stool samples every 3 weeks for 12 weeks. Serial measurements of gut microbial community composition and bacterial abundance were derived from 16S rRNA sequences. Linear discriminant analysis of effect size (LEfSe) was tested for between-arm differences in bacterial abundance. Mixed-effect regression with binomial distribution estimated the effect of aspirin use on changes in the relative abundance of individual bacterial taxa via an interaction term (treatment × time)., Results: Over the study period, there were differences in microbial composition in the aspirin vs placebo arm. After treatment, four taxa were differentially abundant across arms: Prevotella, Veillonella, Clostridium XlVa and Clostridium XVIII clusters. Of pre-specified bacteria associated with CRC (n = 8) or aspirin intake (n = 4) in published studies, interactions were significant for four taxa, suggesting relative increases in Akkermansia, Prevotella and Ruminococcaceae and relative decreases in Parabacteroides, Bacteroides and Dorea in the aspirin vs placebo arm., Conclusion: Compared to placebo, aspirin intake influenced several microbial taxa (Ruminococcaceae, Clostridium XlVa, Parabacteroides and Dorea) in a direction consistent with a priori hypothesis based on their association with CRC. This suggests that aspirin may influence CRC development through an effect on the gut microbiome. The findings need replication in a larger trial., (© 2020 John Wiley & Sons Ltd.)

Background: Copy number variation (CNV) in the salivary amylase gene (AMY1) modulates salivary α-amylase levels and is associated with postprandial glycemic traits. Whether AMY1-CNV plays a role in age-mediated change in insulin resistance (IR) is uncertain., Methods: We measured AMY1-CNV using duplex quantitative real-time polymerase chain reaction in two studies, the Boston Puerto Rican Health Study (BPRHS, n = 749) and the Genetics of Lipid-Lowering Drug and Diet Network study (GOLDN, n = 980), and plasma metabolomic profiles in the BPRHS. We examined the interaction between AMY1-CNV and age by assessing the relationship between age with glycemic traits and type 2 diabetes (T2D) according to high or low copy numbers of the AMY1 gene. Furthermore, we investigated associations between metabolites and interacting effects of AMY1-CNV and age on T2D risk., Results: We found positive associations of IR with age among subjects with low AMY1-copy-numbers in both studies. T2D was marginally correlated with age in participants with low AMY1-copy-numbers but not with high AMY1-copy-numbers in the BPRHS. Metabolic pathway enrichment analysis identified the pentose metabolic pathway based on metabolites that were associated with both IR and the interactions between AMY1-CNV and age. Moreover, in older participants, high AMY1-copy-numbers tended to be associated with lower levels of ribonic acid, erythronic acid, and arabinonic acid, all of which were positively associated with IR., Conclusions: We found evidence supporting a role of AMY1-CNV in modifying the relationship between age and IR. Individuals with low AMY1-copy-numbers tend to have increased IR with advancing age., (Published by Oxford University Press on behalf of the American Association for Clinical Chemistry 2020. This work is written by US Government employees and is in the public domain in the US.)

Objectives: Implementing pharmacogenetics for very important pharmacogenes (VIPs) holds the promise of improving clinical outcomes through optimal medication selection and dosing. However, significant differences in the frequency of actionable variants in VIPs may exist within subpopulations of a given ancestral group. Furthermore, these differences can potentially impact drug selection and dosing. The purpose of this study was to ascertain allele frequencies for VIPs and to predict medication requirements using Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines in Hmong and compare with published data for East Asians., Methods: Using a community-based participatory action research approach, DNA collected from 194 Hmong adults living in the United States was analyzed for 22 genetic variants within eight VIPs (CYP2C9, CYP2C19, CYP4F2, DPYD, G6PD, SLCO1B1, TPMT, VKORC1). Allele frequencies for VIPs and predicted medication requirements using CPIC guidelines were compared between Hmong participants and East Asians., Results: Significant differences in allele frequencies between the Hmong and East Asians were found for 23% (5/22) of the CPIC-actionable variants tested. Allele frequencies for VIPs in Hmong versus East Asians were 16.6% versus 3.4% in CYP2C9*3A, 42.2% versus 29.0% for CYP2C19*2, 0.3% versus 8.3% in CYP2C19*3, 6.5% versus 22.1% in CYP4F2*3, and 3.6% versus 0.1% in SLCO1B1*5, respectively. These differences significantly influenced predicted medication usage recommendations in warfarin, simvastatin, and phenytoin between Hmong and East Asians., Conclusions: Important differences in allele frequencies for key genetic variants influencing selection of medications and dosages were found between the Hmong and East Asians. The magnitude and nature of these differences can be expected to result in different medication recommendations for the Hmong relative to East Asians., (© 2019 Pharmacotherapy Publications, Inc.)

Allopurinol, a common medication to treat gout, is associated with severe cutaneous adverse reactions, and the occurrence is highly predicted by an individual's HLA-B*58:01 carrier status. Guidelines endorse preemptive testing in select Asian populations before initiating allopurinol. The Hmong, an Asian subpopulation originally from China who now live dispersed around the world, have a 2.5-fold higher risk of gout when compared to non-Hmong in Minnesota. Given the concern for severe cutaneous adverse reactions when prescribing allopurinol, we quantified the carrier status of HLA-B*58:01 in Hmong from two independent cohorts in Minnesota. Using a community-based participatory research approach, HLA-B*58:01 carrier status was determined in 49 US-born Hmong without a history of gout or allopurinol use. Further, 47 Hmong patients undergoing clinical evaluation to receive gout pharmacotherapy were also tested. The frequency of HLA-B*58:01 positive carrier status in these two cohorts were compared to published data from a Han Chinese (n = 2910) and a Korean cohort (n = 485) using a Fisher's exact test with a Bonferroni-corrected P-value <0.025 for significance. With one uninterpretable result, we identified two out of 95 people (2.1%) who carried HLA-B*58:01. This 2.1% incidence in these Hmong adults is notably lower than Han Chinese (19.6%, P < 0.0001) and Korean (12.2%, P = 0.0016) populations. Though commonly understood to be of Chinese descent, the lower prevalence within the Hmong underscores the risk of generalizing genotypic findings from Chinese to Asian subpopulations. We suggest no change to the current guidelines recommending which populations should be tested for HLA-B*58:01 before allopurinol use until further validation.

It remains largely unknown as to why some individuals experience substantial weight loss with obesity interventions, while others receiving these same interventions do not. Person-specific characteristics likely play a significant role in this heterogeneity in treatment response. The practice of precision medicine accounts for an individual's genes, environment, and lifestyle when deciding upon treatment type and intensity in order to optimize benefit and minimize risk. In this review, we first discuss biopsychosocial determinants of obesity, as understanding the complexity of this disease is necessary for appreciating how difficult it is to develop individualized treatment plans. Next, we present literature on person-specific characteristics associated with, and predictive of, weight loss response to various obesity treatments including lifestyle modification, pharmacotherapy, metabolic and bariatric surgery, and medical devices. Finally, we discuss important gaps in our understanding of the causes of obesity in relation to the suboptimal treatment outcomes in certain patients, and offer solutions that may lead to the development of more effective and targeted obesity therapies., Competing Interests: Conflict of interest statement: J.R.R. received research support in the form of drug/placebo from Boehringer Ingelheim. C.K.F. received research support from Novo Nordisk. S.D.S. received grant funding from Astra Zeneca Pharmaceuticals. A.S.K. received research support (drug/placebo) from Astra Zeneca Pharmaceuticals and served as a consultant for Novo Nordisk, WW, and Vivus Pharmaceuticals but did not accept personal or professional income for these activities. The other authors have no disclosures.

Background: Associations of both common and rare genetic variants with fasting blood lipids have been extensively studied. However, most of the rare coding variants associated with lipids are population-specific, and exploration of genetic data from diverse population samples may enhance the identification of novel associations with rare variants. Results: We searched for novel coding genetic variants associated with fasting lipid levels in 894 samples from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) with exome-wide sequencing-based genotype data. In single variant tests, one variant (rs11171663 in ITGA7 ) was associated with fasting triglyceride levels ( P = 7.66E-08), explaining approximately 3.2% of the total trait variance. In gene-based tests, we found statistically significant associations between ITGA7 ( P = 1.77E-07) and SLCO2A1 ( P = 7.18E-07) and triglycerides, as well as between POT1 ( P = 3.00E-07) and low-density lipoprotein cholesterol. In another independent replication cohort consisting of 3,183 African American samples from Hypertension Genetic Epidemiology Network (HyperGEN) and the Genetic Epidemiology Network of Arteriopathy (GENOA), the top genes achieved P -values of 0.04 ( ITGA7 ), 0.08 ( SLCO2A1 ), and 0.02 ( POT1 ). In GOLDN, gene transcript levels of ITGA7 and SLCO2A1 were associated with fasting triglycerides ( P = 0.07 and P = 0.02), highlighting functional relevance of our findings. Conclusion: In this study, we present preliminary evidence of novel rare variant determinants of fasting lipids, and reveal potential underlying molecular mechanisms. Moreover, these results were replicated in an independent cohort. Our findings may inform novel biomarkers of disease risk and treatment targets.

Our understanding of genetic influences on the response of lipids to specific interventions is limited. In this study, we sought to elucidate effects of rare genetic variants on lipid response to a high-fat meal challenge and fenofibrate (FFB) therapy in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) cohort using an exome-wide sequencing-based association study. Our results showed that the rare coding variants in ITGA7 , SIPA1L2 , and CEP72 are significantly associated with fasting LDL cholesterol response to FFB ( P = 1.24E-07), triglyceride postprandial area under the increase (AUI) ( P = 2.31E-06), and triglyceride postprandial AUI response to FFB ( P = 1.88E-06), respectively. We sought to replicate the association for SIPA1L2 in the Heredity and Phenotype Intervention (HAPI) Heart Study, which included a high-fat meal challenge but not FFB treatment. The associated rare variants in GOLDN were not observed in the HAPI Heart study, and thus the gene-based result was not replicated. For functional validation, we found that gene transcript level of SIPA1L2 is associated with triglyceride postprandial AUI ( P < 0.05) in GOLDN. Our study suggests unique genetic mechanisms contributing to the lipid response to the high-fat meal challenge and FFB therapy.

Blood lipids are associated with cardiovascular disease (CVD) risk. Moreover, circulating lipid and fatty acid levels vary between men and women, and evidence demonstrates these traits may be influenced by single nucleotide polymorphisms (SNP). Sex-genotype interactions related to blood lipids and fatty acids have been poorly investigated and may help elucidate sex differences in CVD risk. The goal of this study was to investigate if the influence of SNPs previously associated with blood lipids and fatty acids varies in a sex-specific manner. Lipids and fatty acids were measured in serum and red blood cells (RBC), respectively, in 94 adults (18-30 years) from the GONE FISHIN' cohort and 118 age-matched individuals from the GOLDN cohort. HDL-c levels were higher and the total cholesterol/HDL-c (TC/HDL-c) ratio was lower in women versus men (p < 0.01). RBC palmitoleic acid and the stearoyl-CoA desaturase index were both higher in women (p < 0.01). Fatty acid desaturase (FADS) pathway activity (estimated using the ratio of eicosapentaenoic acid/alpha-linolenic acid) was higher in men (p < 0.01). The AA genotype for rs1800775 in CETP had a lower TC/HDL-c ratio in men, but not women (p int  = 0.03). Independent of sex, major alleles for rs174537 in FADS1 (GG) and rs3211956 in CD36 (TT) had higher arachidonic acid, lower dihomo-γ-linoleic acid, and a higher FADS1 activity compared to minor alleles. The current study showed that blood lipid and fatty acid levels vary between healthy young men and women, but that the observed sex differences are not associated with common variants in candidate lipid metabolism genes.

Switching branded to generic medications has become a common cost-containment measure. Although this is an important objective for health care systems worldwide, the impact of this practice on patient outcomes needs to be carefully considered. We reviewed the literature summarizing the potential clinical and economic consequences of switching from branded to generic medications on patient outcomes. A literature search of peer-reviewed articles published 2003-2013 using key words of "generic switching" or "substitution" was conducted using PubMed, OvidSP, and ScienceDirect. Of 30 articles identified and reviewed, most were related to the diseases of the central nervous system, especially epilepsy. Based on our review, potential impacts of switching fell into 3 broad categories: patient attitudes and adherence, clinical and safety outcomes, and cost and resource utilization. Although in many cases generics may represent an appropriate alternative to branded products, this may not always be the case. Specifically, several studies suggested that switching may negatively impact medication adherence, whereas other studies found that generic switching was associated with poorer clinical outcomes and more adverse events. In some instances, switching accomplished cost savings but did so at increased total cost of care because of increased physician visits or hospitalizations. Although in many cases generics may represent an appropriate alternative, mandatory generic switching may lead to unintended consequences, especially in certain therapeutic areas. Although further study is warranted, based on our review, it may be medically justifiable for physicians and patients to retain the right to request the branded product in certain cases.

Advancing precision medicine relies in part on examining populations that may exhibit unique genetic variants that impact clinical outcomes. Failure to include diverse populations in genomic-based research represents a health disparity. We implemented a community-based participatory research (CBPR) process with the Hmong community in Minnesota, who were refugees from Laos, in order to assess the feasibility of conducting genomic and pharmacogenomic-based research for genetic variants that are relevant to the Hmong community. Our Hmong Genomics Board, consisting of Hmong and non-Hmong professionals, used CBPR principles and built on previous formative research to create and implement culturally and linguistically appropriate informed consent processes for Hmong people at six community venues. The Board chose genetic variants for diabetes risk and warfarin response as relevant to the community. The Institutional Review Board approved aggregate but not individual return of results. Two hundred thirty-seven Hmong participants with mean (range) age of 30.2 (18-81) years and diverse levels of education (22% without and 75% with high-school education) provided saliva for genetic (DNA) analyses. Eighty-five percent of participants agreed to store DNA for future analyses, 82% agreed to share DNA with other researchers, and 78% agreed to be contacted for future studies. Twenty-five elders refused to participate because they wanted individual results. Aggregate results were shared with all participants. This CBPR approach proved highly successful to obtain informed consent and recruit a sample from the Hmong community for a genomic and pharmacogenomic study. Investment in the CBPR process may prove successful to address the gap of genomic information in under-represented communities.

Historically, Hmong refugees in the USA were distrustful of Western medicine, medicines, and medical research due to concerns about harm and experimentation. Current Hmong concerns about genomics research are not well known. Our research aims were to identify cultural and ethical issues about conducting genomic studies in the Hmong community. Using a community-based participatory action process, the West Side Hmong Genomics Research Board conducted a qualitative exploratory research study that included semistructured interviews with five Hmong key informants and five focus groups with 42 Hmong adults near Saint Paul, Minnesota. We used a thematic analysis approach to qualitatively analyze the data. Identified concepts of heredity included characteristics that are passed between the generations: physical features; character traits; some behaviors; some diseases; and probably not response to medicines, although individual variations to medicines are known. Most participants were willing to join genomic research projects to help themselves and community. Others refused to participate: they did not want to know future disease risk; did not want doctors to know their genes; did not trust doctors with their blood; and did not know if they would benefit from results. Ethically, many participants were in favor of confidentiality, but wanted to know their personal results; many were willing to agree to genetic storage of anonymous samples; all agreed with individual consent, not family or community consent; and none were concerned about social stigma from genetic testing about chronic diseases and medications. The Hmong Genomics Board will build upon these concepts to create, conduct, and evaluate culturally-appropriate genomic and pharmacogenomic research projects relevant to community interests., Competing Interests: Compliance with ethical standards Funding This study was funded by University of Minnesota’s Program in Health Disparity Research for funding in 2007–2008 (Grant# PHDR-2007-005). Conflict of interest Kathleen A. Culhane-Pera MD MA declares that she has no conflict of interest. MaiKia Moua RN MPH PHN declares that she has no conflict of interest. Pachia Vue MPH declares that she has no conflict of interest. Kang Xiaaj MD declares that she has no conflict of interest. May Xia Lo Pharm D declares that she has no conflict of interest. Robert J. Straka Pharm D declares that he has no conflict of interest. Ethical approval for research involving human participants All procedures performed in studies involving human participants were in accordance with the ethical standards of the University of Minnesota institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The research project was approved by the University of Minnesota Committee on the Use of Human Subjects in Research (IRB 0711 M21884). Informed consent Informed consent was obtained from all individual participants included in the study.

Background: Previous studies have suggested that for clinical purposes, subjects with fasting triglycerides (TGs) between 89-180 mg/dl (1-2 mmol/l) would benefit from postprandial TGs testing., Objective: To determine the postprandial TG response in 2 independent studies and validate who should benefit diagnostically from an oral-fat tolerance test (OFTT) in clinical practice., Methods: A population of 1002 patients with coronary heart disease (CHD) from the CORDIOPREV clinical trial and 1115 white US subjects from the GOLDN study underwent OFTTs. Subjects were classified into 3 groups according to fasting cut points of TGs to predict the usefulness of OFTT: (1) TG < 89 mg/dl (<1 mmol/l); (2) TG, 89-180 mg/dl (1-2 mmol/l); and (3) TG > 180 mg/dl (>2 mmol/l). Postprandial TG concentration at any point > 220 mg/dl (>2.5 mmol/l) has been pre-established as an undesirable postprandial response., Results: Of the total, 49% patients with CHD and 42% from the general population showed an undesirable response after the OFTT. The prevalence of undesirable postprandial TG in the CORDIOPREV clinical trial was 12.8, 50.3, and 89.7%, in group 1, 2, and 3, respectively (P < .001) and 11.2, 58.1, and 97.5% in group 1, 2, and 3, respectively (P < .001) in the GOLDN study., Conclusions: These two studies validate the predictive values reported in a previous consensus. Moreover, the findings of the CORDIOPREV and GOLDN studies show that an OFTT is useful to identify postprandial hyperlipidemia in subjects with fasting TG between 1-2 mmol/l (89-180 mg/dL), because approximately half of them have hidden postprandial hyperlipidemia, which may influence treatment. An OFTT does not provide additional information regarding postprandial hyperlipidemia in subjects with low TG (<1 mmol/l, <89 mg/dL) or increased TG (>2 mmol/l, >180 mg/dl)., (Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Aim: Hyperuricemia commonly causes gout. Minnesota Hmong exhibit a two- to fivefold higher prevalence of gout versus non-Hmong. To elucidate a possible genomic contribution to this disparity, prevalence of risk alleles for hyperuricemia in Hmong was compared with European (CEU) and Han-Chinese (CHB)., Methods: In total, 235 Hmong were genotyped for eight SNPs representing five candidate genes ( SLC22A12 , SLC2A9 , ABCG2 , SLC17A1 and PDZK1 )., Results: The frequency of seven out of eight risk alleles in the Hmong was significantly different than CEU; six higher and one with lower prevalence. The frequency of three out of eight risk alleles in the Hmong was significantly different than CHB; two higher and one with lower prevalence., Conclusion: Hyperuricemia risk alleles are more prevalent in the Hmong than CEU and HB., Competing Interests: Competing interests disclosure The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Background: Fibrates are commonly prescribed for hypertriglyceridemia, but they also lower LDL cholesterol and increase HDL cholesterol. Large interindividual variations in lipid response suggest that some patients may benefit more than others and genetic studies could help identify such patients., Methods: We carried out the first genome-wide association study of lipid response to fenofibrate using data from two well-characterized clinical trials: the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study. Genome-wide association study data from both studies were imputed to the 1000 Genomes CEU reference panel (phase 1). Lipid response was modeled as the log ratio of the post-treatment lipid level to the pretreatment level. Linear mixed models (GOLDN, N=813 from 173 families) and linear regression models (ACCORD, N=781) adjusted for pretreatment lipid level, demographic variables, clinical covariates, and ancestry were used to evaluate the association of genetic markers with lipid response. Among Caucasians, the results were combined using inverse-variance weighted fixed-effects meta-analyses. The main findings from the meta-analyses were examined in other ethnic groups from the HyperTG study (N=267 Hispanics) and ACCORD (N=83 Hispanics, 138 African Americans)., Results: A known lipid locus harboring the pre-B-cell leukemia homeobox 4 (PBX4) gene on chromosome 19 is important for LDL cholesterol response to fenofibrate (smallest P=1.5×10). The main results replicated with nominal statistical significance in Hispanics from ACCORD (P<0.05)., Conclusion: Future research should evaluate the usefulness of this locus to refine clinical strategies for lipid-lowering treatments.

Cost-effective identification of novel pharmacogenetic variants remains a pressing need in the field. Using data from the Genetics of Lipid Lowering Drugs and Diet Network, we identified genomic regions of relevance to fenofibrate response in a sample of 173 families. Our approach included a multipoint linkage scan, followed by selection of the families showing evidence of linkage. We identified a strong signal for changes in LDL-cholesterol (LDL-C) on chromosome 7 (peak logarithm of odds score = 4.76) in the full sample (n = 821). The signal for LDL-C response remained even after adjusting for baseline LDL-C. Restricting analyses only to the families contributing to the linkage signal for LDL-C (N = 19), we observed a peak logarithm of odds score of 5.17 for chromosome 7. Two genes under this peak (ABCB4 and CD36) were of biological interest. These results suggest that linked family analyses might be a useful approach to gene discovery in the presence of a complex (e.g. multigenic) phenotype.

Background: Treatment of opiate use disorders with methadone is complicated by wide interindividual variability in pharmacokinetics. To identify potentially contributing covariates in methadone pharmacokinetics, we used population pharmacokinetic modeling to estimate clearance (CL/F) and volume of distribution (V/F) for each methadone enantiomer in an ethnically diverse methadone maintained population., Methods: Plasma levels of the opiate-active R-methadone and opiate-inactive S-methadone were measured in 206 methadone maintained subjects approximately two and twenty-three hours after a daily oral dose of rac-methadone. A linear one-compartment population pharmacokinetic model with first-order conditional estimation with interaction (FOCE-I) was used to evaluate methadone CL/F and V/F. The influence of covariates on parameter estimates was evaluated using stepwise covariate modeling. Covariates included ethnicity, gender, weight, BMI, age, methadone dose, and 21 single nucleotide polymorphisms in genes implicated in methadone pharmacokinetics., Results: In the final model, for each enantiomer, Hmong ethnicity reduced CL/F by approximately 30% and the rs2032582 (ABCB1 2677G>T/A) GG genotype was associated with a 20% reduction in CL/F. The presence of the rs3745274 minor allele (CYP2B6 515G>T) reduced CL/F by up to 20% for S-methadone only. A smaller effect of age was noted on CL/F for R-methadone., Conclusion: This is the first report showing the influence of the rs2032582 and rs3745274 variants on methadone pharmacokinetics rather than simply dose requirements or plasma levels. Population pharmacokinetics is a valuable method for identifying the influences on methadone pharmacokinetic variability., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Lipoprotein subclass concentrations are modifiable markers of cardiovascular disease risk. Fenofibrate is known to show beneficial effects on lipoprotein subclasses, but little is known about the role of genetics in mediating the responses of lipoprotein subclasses to fenofibrate. A recent genomewide association study (GWAS) associated several single nucleotide polymorphisms (SNPs) with lipoprotein measures, and validated these associations in two independent populations. We used this information to construct genetic risk scores (GRSs) for fasting lipoprotein measures at baseline (pre-fenofibrate), and aimed to examine whether these GRSs also associated with the responses of lipoproteins to fenofibrate. Fourteen lipoprotein subclass measures were assayed in 817 men and women before and after a three week fenofibrate trial. We set significance at a Bonferroni corrected alpha <0.05 (p < 0.004). Twelve subclass measures changed with fenofibrate administration (each p = 0.003 to <0.0001). Mixed linear models which controlled for age, sex, body mass index (BMI), smoking status, pedigree and study-center, revealed that GRSs were associated with eight baseline lipoprotein measures (p < 0.004), however no GRS was associated with fenofibrate response. These results suggest that the mechanisms for changes in lipoprotein subclass concentrations with fenofibrate treatment are not mediated by the genetic risk for fasting levels.

Non-high-density lipoprotein cholesterol(NHDL) is an independent and superior predictor of CVD risk as compared to low-density lipoprotein alone. It represents a spectrum of atherogenic lipid fractions with possibly a distinct genomic signature. We performed genome-wide association studies (GWAS) to identify loci influencing baseline NHDL and its postprandial lipemic (PPL) response. We carried out GWAS in 4,241 participants of European descent. Our discovery cohort included 928 subjects from the Genetics of Lipid-Lowering Drugs and Diet Network Study. Our replication cohorts included 3,313 subjects from the Heredity and Phenotype Intervention Heart Study and Family Heart Study. A linear mixed model using the kinship matrix was used for association tests. The best association signal was found in a tri-genic region at RHOQ-PIGF-CRIPT for baseline NHDL (lead SNP rs6544903, discovery p = 7e-7, MAF = 2 %; validation p = 6e-4 at 0.1 kb upstream neighboring SNP rs3768725, and 5e-4 at 0.7 kb downstream neighboring SNP rs6733143, MAF = 10 %). The lead and neighboring SNPs were not perfect surrogate proxies to each other (D' = 1, r (2) = 0.003) but they seemed to be partially dependent (likelihood ration test p = 0.04). Other suggestive loci (discovery p < 1e-6) included LOC100419812 and LOC100288337 for baseline NHDL, and LOC100420502 and CDH13 for NHDL PPL response that were not replicated (p > 0.01). The current and first GWAS of NHDL yielded an interesting common variant in RHOQ-PIGF-CRIPT influencing baseline NHDL levels. Another common variant in CDH13 for NHDL response to dietary high-fat intake challenge was also suggested. Further validations for both loci from large independent studies, especially interventional studies, are warranted.

Introduction: Cardiovascular diseases are the leading causes of disability and death in the United States. Primary prevention of these events may be achieved through aspirin use. The ability of a community-based intervention to increase aspirin use has not been evaluated. The objective of this study was to evaluate an educational intervention implemented to increase aspirin use for primary prevention of cardiovascular disease in a small city in Minnesota., Methods: A community-based intervention was implemented during 16 months in a medium-sized community in Minnesota. Messages for aspirin use were disseminated to individuals, health care professionals, and the general population. Independent cross-sectional samples of residents (men aged 45-79, women aged 55-79) were surveyed by telephone to identify candidates for primary prevention aspirin use, examine their characteristics, and determine regular aspirin use at baseline and after the campaign at 4 months and 16 months., Results: In primary prevention candidates, regular aspirin use rates increased from 36% at baseline to 54% at 4 months (odds ratio = 2.05; 95% confidence interval, 1.09-3.88); the increase was sustained at 52% at 16 months (odds ratio = 1.89; 95% confidence interval, 1.02-3.49). The difference in aspirin use rates at 4 months and 16 months was not significant (P = .77)., Conclusion: Aspirin use rates for primary prevention remain low. A combined public health and primary care approach can increase and sustain primary prevention aspirin use in a community setting.

Glucuronidation, catalyzed by uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes, detoxifies cholestatic bile acids (BAs). We aimed to (i) characterize the circulating BA-glucuronide (BA-G) pool composition in humans, (ii) determine how sex and UGT polymorphisms influence this composition, and (iii) analyze the effects of the lipid-lowering drug fenofibrate on the circulating BA-G profile in 300 volunteers and 5 cholestatic patients. Eleven BA-Gs were determined in pre- and postfenofibrate samples. Men exhibited higher BA-G concentrations, and various genotype/BA-G associations were discovered in relevant UGT genes. The chenodeoxycholic acid-3G (CDCA-3G) concentration was associated with the UGT2B7 802C>T polymorphism. Glucuronidation assays confirmed the predominant role of UGT2B7 and UGT1A4 in CDCA-3G formation. Fenofibrate exposure increased the serum levels of five BA-G species, including CDCA-3G, and upregulated expression of UGT1A4, but not UGT2B7, in hepatic cells. This study demonstrated that fenofibrate stimulates BA glucuronidation in humans and thus reduces BA toxicity in the liver.

Background and Aims: Adiponectin is an adipose-secreted protein that has been linked to changes in insulin sensitivity, high-density lipoprotein cholesterol levels, and inflammatory patterns. Although fenofibrate therapy can raise adiponectin levels, treatment response is heterogeneous and heritable, suggesting a role for genetic mediators. This is the first genome-wide association study of fenofibrate effects on circulating adiponectin., Methods and Results: Plasma adiponectin was measured in participants of the Genetics of Lipid Lowering Drugs and Diet Network (n = 793) before and after a 3-week daily treatment with 160 mg of fenofibrate. Associations between variants on the Affymetrix Genome-Wide Human SNP Array 6.0 and adiponectin were assessed using mixed linear models, adjusted for age, sex, site, and family. We observed a statistically significant (P = 5 × 10⁻⁸) association between rs2384207 in 12q24, a region previously linked to several metabolic traits, and the fenofibrate-induced change in circulating adiponectin. Additionally, our genome-wide analysis of baseline adiponectin levels replicated the previously reported association with CDH13 and suggested novel associations with markers near the PCK1, ZBP1, TMEM18, and SCUBE1 genes. The findings from the single marker tests were corroborated in gene-based analyses. Biological pathway analyses suggested a borderline significant association between the EGF receptor signaling pathway and baseline adiponectin levels., Conclusions: We present preliminary evidence linking several biologically relevant genetic variants to adiponectin levels at baseline and in response to fenofibrate therapy. Our findings provide support for fine-mapping of the 12q24 region to investigate the shared biological mechanisms underlying levels of circulating adiponectin and susceptibility to metabolic disease., (Copyright © 2012 Elsevier B.V. All rights reserved.)

As a peroxisome proliferator-activated receptor alpha (PPARα) agonist, fenofibrate favorably modulates dyslipidemia and inflammation markers, which are associated with cardiovascular risk. To determine whether variation in the PPARα receptor gene was associated with lipid and inflammatory marker response, we conducted a 3-week trial of fenofibrate in 861 men and women. Mixed linear models that controlled for age and sex, as well as family pedigree and study center, were constructed using single-nucleotide polymorphisms (SNPs) in the PPARα gene as predictors and changes in fasting triglycerides (TGs), cholesterol and inflammatory markers as outcomes. Significant associations with low-density cholesterol and interleukin-2 (P<0.001) responses to fenofibrate were found. Although there were suggestive associations with tumor necrosis factor-alpha and TG responses (P<0.05), these did not survive the correction for multiple testing. We conclude that variants in the PPARα gene may contribute to future pharmacogenomic paradigms seeking to predict fenofibrate responders from both an anti-dyslipidemic and anti-inflammatory perspective.

Specific constellations of lipoprotein particle features, reflected as differences in mean lipoprotein particle diameters, are associated with risk of insulin resistance (IR) and cardiovascular disease (CVD). The associations of lipid profiles with disease risk differ by race/ethnicity, the reason for this is not clear. We aimed to examine whether there were additional genetic differences between racial/ethnic groups on lipoprotein profile. Genotypes were assessed using the Affymetrix 6.0 array in 817 related Caucasian participants of the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN). Association analysis was conducted on fasting mean particle diameters using linear models, adjusted for age, sex and study center as fixed effects, and pedigree as a random effect. Replication of associations reaching P < 1.97 × 10(-05) (the level at which we achieved at least 80% power to replicate SNP-phenotype associations) was conducted in the Caucasian population of the Multi-Ethnic Study of Atherosclerosis (MESA; N = 2,430). Variants which replicated across both Caucasian populations were subsequently tested for association in the African-American (N = 1,594), Chinese (N = 758), and Hispanic (N = 1,422) populations of MESA. Variants in the APOB gene region were significantly associated with mean VLDL diameter in GOLDN, and in the Caucasian and Hispanic populations of MESA, while variation in the hepatic lipase (LIPC) gene was associated with mean HDL diameter in both Caucasians populations only. Our findings suggest that the genetic underpinnings of mean lipoprotein diameter differ by race/ethnicity. As lipoprotein diameters are modifiable, this may lead new strategies to modify lipoprotein profiles during the reduction of IR that are sensitive to race/ethnicity.

High levels of HDL cholesterol (HDL-C) have traditionally been linked to lower incidence of cardiovascular disease, prompting the search for effective and safe HDL-C raising pharmaceutical agents. Although drugs such as niacin and fibrates represent established therapeutic approaches, HDL-C response to such therapies is variable and heritable, suggesting a role for pharmacogenomic determinants. Multiple genetic polymorphisms, located primarily in genes encoding lipoproteins, cholesteryl ester transfer protein, transporters and CYP450 proteins have been shown to associate with HDL-C drug response in vitro and in epidemiologic studies. However, few of the pharmacogenomic findings have been independently validated, precluding the development of clinical tools that can be used to predict HDL-C response and leaving the goal of personalized medicine to future efforts.

Sixteen nuclear magnetic resonance (NMR) spectroscopy lipoprotein measurements of more than 1,000 subjects of GOLDN study, at fasting and at 3.5 and 6 h after a postprandial fat (PPL) challenge at visits 2 and 4, before and after a 3 weeks Fenofibrate (FF) treatment, were included in 6 time-independent multivariate factor analyses. Their top 1,541 unique SNPs were assessed for association with GOLDN NMR-particles and classical lipids. Several SNPs with -log₁₀ p > 7.3 and MAF ≥ 0.10, mostly intergenic associated with NMR-single traits near genes FAM84B (8q24.21), CRIPT (2p21), ACOXL (2q13), BCL2L11 (2q13), PCDH10 (4q28.3), NXPH1 (7p22), and SLC24A4 (14q32.12) in association with NMR-LDLs; HOMER1 (5q14.2), KIT (4q11-q12), VSNL1 (2p24.3), QPRT (16p11.2), SYNPR (3p14.2), NXPH1 (7p22), NELL1 (11p15.1), and RUNX3 (1p36) with NMR-HDLs; and DOK5-CBLN4-MC3R (20q13), NELL1 (11p15.1), STXBP6 (14q12), APOB (2p24-p23), GPR133 (12q24.33), FAM84B (8q24.21) and NR5A2 (1q32.1) in association with NMR-VLDLs particles. NMR single traits associations produced 75 % of 114 significant candidates, 7 % belonged to classical lipids and 18 % overlapped, and 16 % matched for time of discovery between NMR- and classical traits. Five proxy genes, (ACOXL, FAM84B, NXPH1, STK40 and VAPA) showed pleiotropic effects. While tagged for significant associations in our study and with some extra evidence from the literature, candidates as CBNL4, FAM84B, NXPH1, SLC24A4 remain unclear for their functional relation to lipid metabolism. Although GOLDN study is one of the largest in studying PPL and FF treatment effects, the relatively small samples (over 700-1,000 subjects) in association tests appeals for a replication of such a study. Thus, further investigation is needed.