Search

Statins are widely used medications for the primary and secondary prevention of cardiovascular diseases. Statin-induced musculoskeletal symptoms are the primary adverse drug events contributing to poor adherence to lipid-lowering therapy. Rosuvastatin is characterized by interindividual differences in systemic exposure among different patient population subgroups. The missense variant Q141K within ABCG2, highly prevalent in some Asian subgroups, results in decreased transporter efflux function and increased exposure to rosuvastatin. We aim to highlight the implications of ABCG2 genotype in prescribing rosuvastatin and the ramifications of interpopulation differences in Q141K frequencies in the starting dose of rosuvastatin in major Asian subgroups, using the most recent genetic-based guidelines. The high frequency of Q141K in Filipinos could warrant a lower starting rosuvastatin dose versus non-Filipinos. The Q141K genotype frequencies in Asian subgroups suggest significant interpopulation differences, reinforcing the need to move beyond race-based to genotype-based rosuvastatin dosing.

Aim: The frequencies of SLCO1B1*5 and CYP2C9*2 and *3 in specific Asian, Native Hawaiian and Pacific Islander (NHPI) subgroups are unknown. Patients & methods: Repository DNA samples from 1064 women self-identifying as Filipino, Korean, Japanese, Native Hawaiian, Marshallese or Samoan and aged 18 years or older were used for targeted sequencing of three genetic variants (rs4149056, rs1799853 and rs1057910). Results: SLCO1B1*5 was significantly less frequent in NHPI women (0.5–6%) than in Europeans (16%). Except for Koreans, CYP2C9*2 (0–1.4%) and *3 (0.5–3%) were significantly less frequent in all subgroups than in Europeans (8 and 12.7%, respectively). Prior reports showed that Asian and NHPI individuals have significantly higher ABCG2 Q141K allele frequency (13–46%) than Europeans (9.4%). Combined phenotype rates for rosuvastatin and fluvastatin revealed that Filipinos and Koreans had the highest frequencies of statin-associated myopathy symptoms risk alleles. Conclusion: Differences in ABCG2, SLCO1B1 and CYP2C9 allele frequencies among different racial and ethnic subgroups highlight the need for increased diversity in pharmacogenetic research. Risk alleles for statin-associated myopathy symptoms are more prevalent in Filipinos, underscoring the importance of genotype-based statin dosing.

Gout is one of the most common inflammatory conditions with a growing global prevalence. Individuals with gout are at higher risk of developing chronic conditions, such as diabetes, chronic kidney disease (CKD), and cardiovascular diseases. In this study, the association between urate-lowering therapy (ULT) use and the prevalence of these conditions was evaluated. This observational cross-sectional pharmacoepidemiologic study used the 2013–2018 biannual cycles of the National Health and Nutrition Examination Survey. The inclusion criteria were adults that were 30 years of age or older that had a diagnosis of gout. The association between patients’ ULT treatment status and dyslipidemia, coronary heart disease, heart failure, hypertension, and chronic kidney disease was evaluated as well as its association with select clinical laboratory biomarkers. The prevalence of ULT use was 28.9% (95% CI 24.3–33.9%). Those receiving ULT had a higher prevalence of CKD diagnoses, of a college graduate or higher and of health insurance coverage, and they were older obese males. There was no significant association between ULT use and the prevalence of heart failure, coronary heart disease, hypertension, or dyslipidemia (p > 0.05). Those receiving ULT had lower high-sensitivity c-reactive protein levels compared to those who were not on treatment (4.74 versus 7.21 mg/L, p = 0.044). LDL and total cholesterol were significantly lower among those receiving ULT treatment (p < 0.05). ULT use continues to be low among US individuals diagnosed with gout. Socioeconomic factors may influence patients’ ULT treatment status. Also, gout risk factors, including obesity, male sex, and CKD, are associated with receiving ULT. While our findings may have reflected the guideline recommendations for ULT use in CKD patients, worsening kidney functions while receiving ULT is unlikely. Gout patients receiving ULT may garner added health benefits beyond lower urate levels. Further research is necessary to determine the long-term impact of ULTs on lipid fractions, kidney functions, and other cardiovascular biomarkers.

Aim: Quantify identifiable sources of variability, including key pharmacogenetic variants in oxypurinol pharmacokinetics and their pharmacodynamic effect on serum urate. Methods: Hmong participants (n=34) received 100 mg allopurinol twice daily for 7 days followed by 150 mg allopurinol twice daily for 7 days. Serum urates (SU) were obtained pre- and post-allopurinol. Serum oxypurinol concentrations were obtained at times 0, 2, 4, and 6 hours after the last dose. A sequential population pharmacokinetic pharmacodynamics (PKPD) analysis with non-linear mixed-effects modeling evaluated the impact of anthropometrics, concomitant medications, and genetic variants on oxypurinol PKPD parameters. 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. Inhibitory of SU by oxypurinol was described with a direct inhibitory Emax model using steady-state oxypurinol concentrations. Fat-free body mass, estimated creatinine clearance and SLC22A12 rs505802 genotype were found to predict differences in oxypurinol clearance. Oxypurinol concentration required to inhibit 50% of xanthine dehydrogenase activity was affected by PDZK1 rs12129861 genotype. Most individuals with both PDZK1 rs12129861 AA and SLC22A12 rs505802 CC genotypes achieve target SU 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 alternative medications. Conclusion: The proposed allopurinol dosing guide uses individuals’ fat-free mass, renal function, and SLC22A12 rs505802 and PDZK1 rs12129861 genotypes to achieve target SU.

Low-income minority older adults are highly susceptible to drug adverse effects of medications due to aging, comorbidities, and polypharmacy. Several studies have demonstrated anticholinergic medication is associated with frailty, supporting the hypothesis for mechanistic peripheral nervous system effects. The goal of this cohort study is to determine peripheral nervous system effects of anticholinergic medication exposure with frailty by conducting a sensitivity analysis using multiple anticholinergic tools. Spearman correlation matrix and intraclass correlation coefficients (ICC) are used to determine the function of five clinical Anticholinergic Burden Scales (ACBS): Anticholinergic Burden Scale (ACB), Anticholinergic Drug Scale (ADS), total standardized daily doses (TSDD), and Cumulative Anticholinergic Burden scale (CAB). Ordinal logistic regression and area under the curve (AUC) are used to evaluate anticholinergic burden-associated frailty models. The cohort included 80 individuals (mean age = 69 years; 55.7% female, 71% African American). Among individuals prescribed anticholinergics, 33% are robust, 44% pre-frail, and 23% frail. All scales are highly correlated with each other (p < 0.001), ICC3 = 0.66 (p < 0.001, CI 95% 0.53-0.73). All five of the scales predicted pre-frail and frail status (p < 0.05) with low misclassification rates for frail individuals (AUC = 0.70 – 0.80). Considering ACBS are highly correlated and all predict frailty; all of the scales can be used in future frailty research; however, the CAB and TSDD consider both potency and dose. Additional research is necessary to understand the peripheral nervous system effects of anticholinergic drug exposure and if deprescribing can improve frailty status.

Gout is a metabolic disorder and one of the most common arthritic conditions. Hyperuricemia is the hallmark of developing gout and mostly caused by uric acid underexcretion. Gout disproportionately affects people of specific races and ethnicities. Filipinos are the second-largest Asian population in the USA and reported to have a higher prevalence of gout and hyperuricemia than non-Filipino counterparts and Filipinos residing in the Philippines. The genetic polymorphism rs2231142 GT in the ABCG2 has been strongly associated with hyperuricemia and gout across multiple populations. However, the prevalence of this variant in Filipinos is unknown. Therefore, assessing the prevalence of this variant may provide insights on the high prevalence of hyperuricemia and gout in Filipinos. A total of 190 DNA samples from pregnant females who self-identified as a Filipino from the Hawaii Biorepository Bank were genotyped for rs2231142 GT in the ABCG2. The prevalence of the gout risk allele (T) (46%) was significantly higher in Filipinos than in samples of Caucasians (12%, p 0.001), Han Chinese (29%, p = 0.014), and African Americans (3%, p 0.001). Similarly, the prevalence of the gout-risk genotype (TT) (21%) was significantly higher in Filipinos than in samples of Caucasians (1%, p 0.001), Han Chinese (9%, p = 0.002), and African Americans (0.1%, p 0.001). Though there were no gout cases in this cohort, these findings are suggestive of a genetic basis to the high prevalence of hyperuricemia and gout in Filipinos. This might also explain the reported reduced urinary uric acid excretion in Filipinos compared with Caucasians. Key Points • The Filipinos have the highest prevalence of the gout-associated risk allele (T) of the rs2231142 GT in ABCG2. • The high prevalence of the risk allele (T) of the rs2231142 GT in ABCG2 may partly explain the reduced urinary urate excretion and early-onset gout in Filipinos. • The high prevalence of the risk allele (T) of the rs2231142 GT in ABCG2 may predispose Filipinos to hyperuricemia and gout when acculturated to high-purine diet.