The association between the insertion/deletion polymorphism of the angiotensin converting enzyme gene and hypertension, as well as environmental, biochemical and anthropometric factors.

Rocz Panstw Zakl Hig. 2020;71(2):207-214

Authors: Pachocka L, Włodarczyk M, Kłosiewicz-Latoszek L, Stolarska I

Abstract
Background: Arterial hypertension is caused by environmental factors and genetic predisposition.
Objective: The aim of this study was to assess the association between the angiotensin converting enzyme (ACE) gene variants and environmental factors, biochemical and anthropometric parameters and the incidence of hypertension.
Material and methods: A total of 73 patients, aged 24 to 68, with Body Mass Index (BMI) above 25 kg/m2 took part in this study. Nutrient intake was assessed with a diet based on consumption records. The ACE gene insertion/deletion (I/D) polymorphism was determined by the polymerase chain reaction (PCR) method.
Results: Normal pressure predominated in persons with genotype II (59.1%), whereas hypertension in persons with genotype ID (55.2%). The frequency of the D allele was 5% higher in the hypertensive group (53% vs. 48%), but this difference was not statistically significant. The percentage of patients who consumed alcohol and smoked cigarettes in the D allele group was higher than in the I allele group. People with the D allele had lower vitamin D intake and higher copper intake than carriers of the allele I. The highest vitamin D intake was found in people with genotype II, and the differences were significant compared to patients with ID genotype. People with the D allele consumed more carbohydrates and less protein than those with the I allele, but these differences were not statistically significant.
Conclusions: Hypertensive subjects were more frequent DD and ID genotypes, whereas normotensive subjects - the II genotype. People with the D allele had lower vitamin D and protein intake, while the carbohydrate and copper intake was higher than those with the I allele. The group with the D allele had a higher percentage of smokers and alcohol drinkers. Our studies have shown a relationship between environmental and genetic factors and hypertension, but more research is needed.

PMID: 32519825 [PubMed - as supplied by publisher]

CYP2D6 genetic polymorphisms and risperidone pharmacokinetics: a systematic review and meta-analysis.

Pharmacotherapy. 2020 Jun 10;:

Authors: Zhang L, Brown SJ, Shan Y, Lee AM, Allen JD, Eum S, de Leon J, Bishop JR

Abstract
BACKGROUND: Risperidone is a second-generation antipsychotic drug metabolized to an active metabolite, 9-hydroxyrisperidone, primarily by cytochrome P4502D6 (CYP2D6) and to a lesser extent by CYP3A4. The extent to which drug metabolism genetics impacts risperidone and 9-hydroxyrisperidone exposure has not been clarified.
OBJECTIVE: A systematic review and meta-analysis evaluated the impact of genetically defined CYP2D6 function on risperidone pharmacokinetics applying a standardized genotype-phenotype translation system.
METHODS: A comprehensive electronic database search identified studies reporting relationships between genetically determined CYP2D6 metabolism and risperidone pharmacokinetic properties. The exposure of risperidone or active moiety (risperidone+9-hydroxyrisperidone) was measured by dose-adjusted steady-state serum/plasma concentration (C/D) or area under the concentration-time curve (AUC0-t ) as primary outcomes. Subjects were assigned to CYP2D6 poor metabolizer (PM), intermediate metabolizer (IM) normal metabolizer (NM) or ultrarapid metabolizer (UM) groups using a standardized genotype-phenotype translation method. Effect sizes between groups were pooled and stratified by single or multiple dosing regimens.
RESULTS: Fifteen studies involving 2125 adult subjects were included in the meta-analysis. Following multiple-dose oral administration, as compared to CYP2D6 NMs, risperidone C/D was 2.35-fold higher in IMs (95% CI [1.77-3.13], P<0.0001) and 6.20-fold higher in PMs (95% CI [5.05-7.62], P<0.0001); the active moiety C/D was 1.18-fold higher in IMs (95% CI [1.11-1.25], P<0.0001) and 1.44-fold higher in PM (95% CI [1.23-1.69], P<0.0001). Higher AUC0-t of risperidone and active moiety was also found in single-dose studies.
CONCLUSION: Genetically defined impaired CYP2D6 activity is associated with increased exposure of both risperidone and risperidone+9-hydroxyrisperidone in adults receiving oral formulations. Additional studies are needed to quantify clinical impact of these relationships.

PMID: 32519344 [PubMed - as supplied by publisher]

Do Indian patients with schizophrenia need half the recommended clozapine dose to achieve therapeutic serum level? An exploratory study.

Schizophr Res. 2020 Jun 06;:

Authors: Suhas S, Kumar V, Damodharan D, Sharma P, Rao NP, Varambally S, Venkatasubramanian G, Murthy P, Gangadhar BN

Abstract
Inter-racial differences in serum clozapine have received less scientific importance, as there are fewer studies on therapeutic drug monitoring (TDM) from Asia. We measured the serum clozapine levels in 142 patients with schizophrenia and related disorders at a tertiary care psychiatric institute in India. The clozapine concentration per milligram (mg) of oral clozapine dose (C/D ratio) was calculated, and the C/D ratio was used to estimate oral clozapine dose needed to achieve therapeutic serum clozapine level (350 ng/ml). This study examined Indian patients only and compared the results with weighted mean serum clozapine and its correlates in Caucasian population, based on published scientific literature. The median C/D ratio in our sample was 2.5 (n = 142), and the clozapine dose needed to achieve therapeutic serum clozapine level was 140 mg/d. The median C/D ratio of our subjects was nearly two and a half times higher than the weighted mean C/D ratio of Caucasians (2.5 v/s 1.07) reported elsewhere. After excluding the significant pharmacokinetic interactions and stratifying according to gender and smoking status, the estimated clozapine dose to achieve therapeutic serum level in male smokers (n = 9) and female non-smokers (n = 38) were 238 mg/d (C/D ratio; 1.47) and 120 mg/d (C/D ratio:2.93) respectively. On comparing, male smokers (600 mg/d versus 238 mg/d) and female non-smokers (300 mg/d versus 120 mg/d) in our study needed about 40% of the recommended clozapine dose for Caucasians to achieve therapeutic serum clozapine level. The pharmacogenetic correlates of lesser clozapine dose requirement in the Indian population require further research.

PMID: 32518001 [PubMed - as supplied by publisher]

Targeted therapies for cancer during the COVID-19 pandemic: a threat or a blessing?

Pharmacogenomics. 2020 Jun 10;:

Authors: Moujaess E, Kourie HR, Kattan J

PMID: 32517540 [PubMed - as supplied by publisher]

Rural Community Perceptions and Interests in Pharmacogenomics.

Healthcare (Basel). 2020 Jun 05;8(2):

Authors: Stegelmeier J, Nartker C, Barnes C, Rayo H, Hoover R, Boyle J, O'Connor S, Barrott J

Abstract
Pharmacogenomics testing is a rapidly expanding field with increasing importance to individualized patient care. However, it remains unclear whether the general public in rural areas would be willing to engage in this service. The objective of this survey was to determine rural community-dwelling members' perceptions of pharmacogenomics. A questionnaire was developed consisting of five Likert-style questions on knowledge and perceptions of pharmacogenomics, a single multiple-choice question on cost of testing, and a free-response question. Two cohorts received the same questionnaire: attendees at a university-sponsored health fair and patients presenting to two independent community pharmacies in southeastern Idaho. While both showed positive reception to the implementation and value of pharmacogenomics, those at the health fair were more in favor of pharmacogenomics, suggesting a need for greater outreach and education to the general public. The findings suggest that interest of rural community-dwelling individuals may be amenable to the expansion of pharmacogenomics testing.

PMID: 32516951 [PubMed]

Cost avoidance related to a pharmacist-led pharmacogenomics service for the Program of All-inclusive Care for the Elderly.

Pharmacogenomics. 2020 Jun 09;:

Authors:

Abstract
Aim: Estimate cost avoidance of pharmacist recommendations for participants enrolled in the Program of All-inclusive Care for the Elderly. Materials & methods: Convenience sample of 200 pharmacogenomics consultations from the PHARM-GENOME-PACE study. Genetic variants, drug-gene interactions, drug-drug-gene interactions and phenoconversions were interrogated. Cost avoidance was estimated and adjusted for inflation. Results: In total, 165 participants had at least one actionable drug-gene pair totaling 429 drug-gene pairs, of which 158 (36.8%) were clinically actionable. Most (70.5%) pharmacists' recommendations were accepted. Estimated cost avoidance was $233,945 when all recommendations were included but conservatively $162,031 based on acceptance rates. Overall mean cost avoidance per actionable drug-gene pair was $1063 or $1983 per participant. Conclusion: Pharmacist-led pharmacogenomics services added to the traditional medication review can avoid substantial costs for payers. Clinical trial registration number: NCT03257605.

PMID: 32515286 [PubMed - as supplied by publisher]

Combinatorial PharmacogenomicTesting Improves Outcomes for Older Adults With Depression.

Am J Geriatr Psychiatry. 2020 May 19;:

Authors: Forester BP, Parikh SV, Weisenbach S, Ajilore O, Vahia I, Rothschild AJ, Thase ME, Dunlop BW, DeBattista C, Conway CR, Shelton RC, Macaluso M, Li J, Traxler P, Logan J, Brown L, Dechairo B, Greden JF

Abstract
OBJECTIVE: Evaluate the clinical utility of combinatorial pharmacogenomic testing for informing medication selection among older adults who have experienced antidepressant medication failure for major depressive disorder (MDD).
DESIGN: Post hoc analysis of data from a blinded, randomized controlled trial comparing two active treatment arms.
SETTING: Psychiatry specialty and primary care clinics across 60 U.S. community and academic sites.
PARTICIPANTS: Adults age 65 years or older at baseline (n = 206), diagnosed with MDD and inadequate response to at least one medication on the combinatorial pharmacogenomic test report during the current depressive episode.
INTERVENTION: Combinatorial pharmacogenomic testing to inform medication selection (guided-care), compared with treatment as usual (TAU).
OUTCOMES: Mean percent symptom improvement, response rate, and remission rateat week 8, measured using the 17-item Hamilton Depression Rating Scale; medication switching; and comorbidity moderator analysis.
RESULTS: At week 8, symptom improvement was not significantly different for guided-care than for TAU (∆ = 8.1%, t = 1.64, df = 187; p = 0.102); however, guided-care showed significantly improved response (∆ = 13.6%, t = 2.16, df = 187; p = 0.032) and remission (∆ = 12.7%, t = 2.49, df = 189; p = 0.014) relative to TAU. By week 8, more than twice as many patients in guided-care than in TAU were on medications predicted to have no gene-drug interactions (χ2 = 19.3, df = 2; p <0.001). Outcomes in the guided-care arm showed consistent improvement through the end of the open-design 24-week trial, indicating durability of the effect. Differences in outcomes between arms were not significantly impacted by comorbidities.
CONCLUSIONS: Combinatorial pharmacogenomic test-informed medication selection improved outcomes over TAU among older adults with depression.

PMID: 32513518 [PubMed - as supplied by publisher]

Epidrugs: targeting epigenetic marks in cancer treatment.

Epigenetics. 2019 12;14(12):1164-1176

Authors: Miranda Furtado CL, Dos Santos Luciano MC, Silva Santos RD, Furtado GP, Moraes MO, Pessoa C

Abstract
Growing evidence suggests that aberrant epigenetic regulation of gene function is strongly related to the genesis of cancer. Unlike genetic mutations, the ability to reprogram the epigenetic landscape in the cancer epigenome is one of the most promising target therapies in both treatment and reversibility of drug resistance. Epigenetic alterations in cancer development and progression may be the basis for the individual variation in drug response. Thus, this review focuses on the emerging area of pharmaco(epi)genomics, specifically highlighting epigenetic reprogramming during tumorigenesis and how epigenetic markers are targeted as a therapy (epidrugs) and the clinical implications of this for cancer treatment.

PMID: 31282279 [PubMed - indexed for MEDLINE]

EGFR mutation status in a series of Turkish non-small cell lung cancer patients.

Biomed Rep. 2020 Aug;13(2):2

Authors: Calibasi-Kocal G, Amirfallah A, Sever T, Umit Unal O, Gurel D, Oztop I, Ellidokuz H, Basbinar Y

Abstract
Epidermal growth factor receptor (EGFR) mutations are potential markers driving carcinogenesis, and may alter the response to EGFR tyrosine kinase inhibitors in patients with non-small cell lung cancer (NSCLC). The frequency of EGFR mutations in patients with NSCLC differs according to sex, smoking habits and regional-based ethnicity differences. The aim of the present study was to determine the frequency of EGFR mutations in Turkish patients with NSCLC to highlight the importance of regional differences, and their associations with patient characteristics. Genomic DNA was extracted from formalin-fixed and paraffin-embedded tumor tissue sections of 409 NSCLC patients. The most common EGFR mutations in exons 18, 19, 20 and 21 were detected using BioFilmChip-based microarray assay. The overall EGFR mutation frequency was 16.6%, and the highest mutation frequencies were observed in exon 19 (6.4%) and exon 21 (7.3%). There was a higher frequency of EGFR mutations in females compared with males and in never-smokers compared with smokers (both P≤0.05). These results were similar to other European population-based studies, but not consistent Middle-Eastern based studies. The present study may contribute to understanding the gradient frequency of EGFR mutation across different ethnicities, and in designing genome wide-based collaborations that may reveal novel decision making and susceptibility mutations in EGFR in patients with NSCLC.

PMID: 32509305 [PubMed]

Response to fluoxetine in children and adolescents: a weighted gene co-expression network analysis of peripheral blood.

Am J Transl Res. 2020;12(5):2028-2040

Authors: Torres T, Boloc D, Rodríguez N, Blázquez A, Plana MT, Varela E, Gassó P, Martinez-Pinteño A, Lázaro L, Arnaiz JA, Mas S

Abstract
The inconclusive and non-replicated results of pharmacogenetic studies of antidepressant response could be related to the lack of acknowledgement of its mechanism of action. In this scenario, gene expression studies provide and interesting framework to reveal new candidate genes for pharmacogenetic studies or peripheral biomarkers of fluoxetine response. We propose a system biology approach to analyse changes in gene expression induced by eight weeks of treatment with fluoxetine in peripheral blood. 21 naïve child and adolescents participated in the present study. Our analysis include the identification of gene co-expression modules, using Weighted Gene Co-expression Network Analysis (WGCNA), followed by protein-protein interaction (PPi) network construction coupled with functional annotation. Our results revealed two modules of co-expression genes related to fluoxetine treatment. The constructed networks from these modules were enriched for biological processes related to cellular and metabolic processes, cell communication, immune system processes, cell death, response to stimulus and neurogenesis. Some of these processes, such as immune system, replicated previous findings in the literature, whereas, neurogenesis, a mechanism proposed to be involved in fluoxetine response, had been identified for first time using peripheral tissues. In conclusion, our study identifies several biological processes in relation to fluoxetine treatment in peripheral blood, offer new candidate genes for pharmacogenetic studies and valuable markers for peripheral moderator biomarkers discovery.

PMID: 32509197 [PubMed]

Genotype-Guided Dosing of Warfarin in Chinese Adults: A Multicenter Randomized Clinical Trial.

Circ Genom Precis Med. 2020 Jun 08;:

Authors: Guo C, Kuang Y, Zhou H, Yuan H, Pei Q, Li J, Jiang W, Ng CM, Chen X, Huo Y, Cui Y, Wang X, Yu J, Sun X, Yu W, Chen P, Miao D, Liu W, Yu Z, Ouyang Z, Shi X, Lv C, Peng Z, Xiong G, Zeng G, Zeng J, Dai H, Peng J, Zhang Y, Xu F, Wu J, Chen X, Gong H, Yang Z, Wu X, Fang Q, Yang L, Li H, Tan H, Huang Z, Tang X, Yang Q, Tu S, Wang X, Xiang Y, Huang J, Wang X, Cai J, Jiang S, Huang L, Peng J, Gong L, Zou C, Yang G

Abstract
Background - Warfarin is an effective treatment for thromboembolic disease but has a narrow therapeutic index; optimal anticoagulation dosage can differ tremendously among individuals. We aimed to evaluate whether genotype-guided warfarin dosing is superior to routine clinical dosing for the outcomes of interest in Chinese patients. Methods - We conducted a multicenter, randomized, single-blind, parallel-controlled trial from September 2014 to April 2017 in 15 hospitals in China. Eligible patients were 18 years or older, with atrial fibrillation or deep vein thrombosis without previous treatment of warfarin or a bleeding disorder. Nine follow-up visits were performed during the 12-week study period. The primary outcome measure was the percentage of time in the therapeutic range (%TTR) of the international normalized ratio (INR) during the first 12 weeks after starting warfarin therapy. Results - A total of 660 participants were enrolled and randomly assigned to a genotype-guided dosing group or a control group under standard dosing. The genotype-guided dosing group had a significantly higher %TTR than the control group (58.8% vs. 53.2%, 95% confidence interval of group difference (95%CI): 1.1-10.2; P=0.01). The genotype-guided dosing group also achieved the target INR sooner than the control group. In subgroup analyses, warfarin normal sensitivity group had an even higher %TTR during the first 12 weeks compared to the control group (60.8% vs. 48.9%; 95% CI: 1.1-24.4). The incidence of adverse events was low in both groups. Conclusions - The outcomes of genotype-guided warfarin dosing were superior to those of clinical standard dosing. These findings raise the prospect of precision warfarin treatment in China.

PMID: 32510984 [PubMed - as supplied by publisher]

An update on CYP2C9 polymorphisms and phenytoin metabolism: implications for adverse effects.

Expert Opin Drug Metab Toxicol. 2020 Jun 08;:

Authors: Chang WC, Hung SI, Carleton B, Chung WH

Abstract
INTRODUCTION: Phenytoin is a frequently used drug treatment for epilepsy. Genetic polymorphisms in the metabolism of phenytoin, particularly CYP2C9, are strongly associated with increased plasma concentrations and can result in toxicity. Human leukocyte antigen (HLA) alleles are well-known genetic predictors of certain antiepileptic drug-associated severe cutaneous adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Recent pharmacogenomic studies show genetic polymorphisms in CYP2C9, as well as HLA alleles, are significantly associated with phenytoin-related SCAR.
AREAS COVERED: Updated pharmacogenomic information of CYP2C9 variants and HLA alleles involved in phenytoin-associated cutaneous adverse drug reactions (cADRs) are discussed in this article.
EXPERT OPINION: CYP2C9*3 has been identified as the most significant genetic variant associated with increased phenytoin concentrations and adverse events. Recent pharmacogenomic findings reveal that CYP2C9*3 and HLA alleles, i.e. HLA-B*15:02, HLA-B*13:01, and HLA-B*51:01, are important genetic variants in the occurrence of phenytoin-induced cADRs or SCAR. A phenotype- and population-specific multigene panel can be used before prescribing to predict phenytoin-induced cADRs and further guide optimal dose selection.

PMID: 32510242 [PubMed - as supplied by publisher]

CYP2C19 allele frequencies in over 2.2 million direct-to-consumer genetics research participants and the potential implication for prescriptions in a large health system.

Clin Transl Sci. 2020 Jun 07;:

Authors: Ionova Y, Ashenhurst J, Zhan J, Nhan H, Kosinski C, Tamraz B, Chubb A

Abstract
Understanding the prevalence of clinically relevant pharmacogenetic variants using large unselected populations is critical for gauging the potential clinical impact of widespread preemptive pharmacogenetic testing. To this end, we assessed the frequencies and ethnic distribution of the three most common CYP2C19 alleles (*2, *3, and *17) in 2.29 million direct-to-consumer genetics research participants (23andMe, Inc. Sunnyvale, CA). The overall frequencies of *2, *3, and *17 were 15.2%, 0.3%, and 20.4%, respectively, but varied by ethnicity. The most common variant diplotypes were *1/*17 at 26% and *1/*2 at 19.4%. The less common *2/*17, *17/*17 and *2/*2 genotypes occurred at 6.0%, 4.4%, and 2.5%, respectively. Overall, 58.3% of participants had at least one increased-function or no-function CYP2C19 allele. To better understand how this high frequency might impact a real patient population, we examined the prescription rates (Rx) of high-pharmacogenetic-risk medications metabolized by CYP2C19 using the University of California at San Francisco (UCSF) health system's anonymized database of over 1.25 million patients. Between 2012 and 2019, a total of 151,068 UCSF patients (15.8%) representing five self-reported ethnicities were prescribed one or more high-pharmacogenetic-risk CYP2C19 medications: proton pump inhibitors (145,243 Rx), three SSRI antidepressants (54,463 Rx), clopidogrel (14,376 Rx), and voriconazole (2,303 Rx).

PMID: 32506666 [PubMed - as supplied by publisher]

Pharmacogenetic-guided and clinical warfarin dosing algorithm assessments with bleeding outcomes risk-stratified by genetic and covariate subgroups.

Int J Cardiol. 2020 Mar 21;:

Authors: Dietz N, Ruff C, Giugliano RP, Mercuri MF, Antman EM

Abstract
BACKGROUND: Safe administration of warfarin presents challenges due to a narrow therapeutic INR range and significant variability in inter-individual dose response. Bleeding secondary to warfarin use is a leading cause of hospitalization.
METHODS: Five warfarin dosing algorithms were assessed for accuracy of predicted compared to the INR target dose for patients with a HAS-BLED score ≥3 participating in the ENGAGE-AF TIMI 48 trial. Three warfarin metabolism subgroups (normal, sensitive, and highly sensitive responders) were established based on genotype. Mean differences between calculated and prescribed dose were determined for each algorithm across groups.
RESULTS: A total of 7036 patients were analyzed and 1846 participants with HAS-BLED ≥3 were genotyped. The mean absolute error of predicted versus INR target dose for warfarin ranged from 8.1 mg/week on the pharmacogenetic-guided International Warfarin Pharmacogenetics Consortium (IWPC) and Gage algorithms to 11.3 mg/week on fixed dose. Overestimation of INR target dose occurred in 98% of highly sensitive responders by 21 mg/week for subjects on fixed dose. Pharmacogenetic-guided IWPC saw 89% overestimation with mean difference of 8.3 mg/week for highly sensitive responders. Major or clinically relevant non-major bleeding in the first 90 days of beginning warfarin was 3.27 times more likely for highly sensitive than normal responders.
CONCLUSIONS: Initial doses were higher than INR target doses in high-risk bleeding subpopulations as defined by the modified HAS-BLED and genotype sensitivity analysis when compared to established algorithms. Clinical and pharmacogenetic-guided algorithms improved dosing in highly sensitive responders with HAS-BLED ≥3 compared to fixed dosing.

PMID: 32505370 [PubMed - as supplied by publisher]

Interview with Prof. Collet Dandara: A Pioneer and Advocate of Multiomics Science and Health Innovation in Africa.

OMICS. 2019 12;23(12):603-606

Authors: Dandara C

PMID: 31755849 [PubMed - indexed for MEDLINE]

CYP17A1 Polymorphisms Are Linked to the Risk of Coronary Heart Disease in a Case-Control Study.

J Cardiovasc Pharmacol. 2019 08;74(2):98-104

Authors: Lu S, Zhong J, Zhang Y, Huang K, Wu M, Zhou Y, Li Q, Chen Z, Zhang S, Zhou H

Abstract
BACKGROUND: Cytochrome P450 17A1 (CYP17A1) catalyzes the formation and metabolism of steroid hormones and is required for cortisol and androgens. There is increasing evidence that CYP17A1 plays an important role in the development of coronary heart disease (CHD). However, the association of CYP17A1 polymorphisms and CHD susceptibility is still not clear.
METHODS: We conducted a case-control study with 396 CHD cases and 461 healthy controls from Hainan province, China. Using the Agena MassARRAY platform, we genotyped 4 genetic variants (rs3740397, rs1004467, rs4919687, and rs3781286) in CYP17A1. Logistic regression analysis was used to assess the association of CYP17A1 polymorphisms with CHD risk by odds ratios (ORs) and 95% confidence intervals (CIs).
RESULTS: It showed that A allele of CYP17A1 rs4919687 carried with a 1.59-fold increased risk of CHD (OR = 1.59; 95% CI = 1.26-1.99; P < 0.001). Also, rs4919687 was significantly associated with CHD risk under various models (homozygote: OR = 3.60; 95% CI = 1.64-7.83; P = 0.001; dominant: OR = 1.51; 95% CI = 1.06-2.13; P = 0.021; recessive: OR = 3.28; 95% CI = 1.51-7.14; P = 0.003; additive: OR = 1.56; 95% CI = 1.17-2.07; P = 0.002). Moreover, analysis showed that Ars1004467 Ars4919687 haplotype was a protective factor of CHD (OR = 0.64; 95% CI = 0.48-0.86; P = 0.002).
CONCLUSIONS: Our study suggests that CYP17A1 polymorphisms are associated with CHD susceptibility in the Hainan Han Chinese population.

PMID: 31356544 [PubMed - indexed for MEDLINE]

Pharmacogenetics of hypoglycemia associated with sulfonylurea therapy in usual clinical care.

Pharmacogenomics J. 2020 Jun 05;:

Authors: Mitchell SL, Leon DAC, Chaugai S, Kawai VK, Levinson RT, Wei WQ, Stein CM

Abstract
Hypoglycemia is a common complication among type 2 diabetes mellitus (T2DM) patients receiving sulfonylurea therapy. The aim of this study was to determine if genetic contributions to sulfonylurea pharmacokinetics or pharmacodynamics substantially affect the risk of hypoglycemia in these patients. In a retrospective case-control study in European American patients with T2DM, we examined the potential association between CYP2C9 reduced-function variants and sulfonylurea-related hypoglycemia. We also explored the relationship between sulfonylurea-related hypoglycemia and several candidate genetic variants previously reported to alter the response to sulfonylureas. We detected no evidence of association between CYP2C9 reduced-function alleles or any of the candidate genetic variants and sulfonylurea-related hypoglycemia. In conclusion, we identified no clinically significant predictors of hypoglycemia among genes associated with sulfonylurea pharmacokinetics or pharmacodynamics.

PMID: 32504053 [PubMed - as supplied by publisher]

Multi-trait analysis of rare-variant association summary statistics using MTAR.

Nat Commun. 2020 Jun 05;11(1):2850

Authors: Luo L, Shen J, Zhang H, Chhibber A, Mehrotra DV, Tang ZZ

Abstract
Integrating association evidence across multiple traits can improve the power of gene discovery and reveal pleiotropy. Most multi-trait analysis methods focus on individual common variants in genome-wide association studies. Here, we introduce multi-trait analysis of rare-variant associations (MTAR), a framework for joint analysis of association summary statistics between multiple rare variants and different traits. MTAR achieves substantial power gain by leveraging the genome-wide genetic correlation measure to inform the degree of gene-level effect heterogeneity across traits. We apply MTAR to rare-variant summary statistics for three lipid traits in the Global Lipids Genetics Consortium. 99 genome-wide significant genes were identified in the single-trait-based tests, and MTAR increases this to 139. Among the 11 novel lipid-associated genes discovered by MTAR, 7 are replicated in an independent UK Biobank GWAS analysis. Our study demonstrates that MTAR is substantially more powerful than single-trait-based tests and highlights the value of MTAR for novel gene discovery.

PMID: 32503972 [PubMed - as supplied by publisher]

PHARMACOGENOMICS OF ANTI-CANCER DRUGS: personalizing the CHOICE AND dose TO managE drug response.

Br J Clin Pharmacol. 2020 Jun 05;:

Authors: Carr DF, Turner RM, Pirmohamed M

Abstract
The field of pharmacogenomics has made great strides in oncology over the last 20 years and indeed a significant number of pre-emptive genetic tests are now routinely undertaken prior to anti-cancer drug administration. Many of these gene-drug interactions are the fruits of candidate gene and genome-wide association studies which have largely focused on common genetic variants (allele frequency>1%). Examples where there is clinical utility include genotyping or phenotyping for G6PD to prevent rasburicase-induced RBC haemolysis, and TPMT to prevent thiopurine-induced bone marrow suppression. Other associations such as CYP2D6 status in determining the efficacy of tamoxifen are more controversial because of contradictory evidence from different sources, which has led to variability in the implementation of testing. As genomic technology becomes ever cheaper and more accessible, we must look to the additional data our genome can provide to explain inter-individual variability in anti-cancer drug response. Clearly genes do not act on their own and it is therefore important to investigate genetic factors in conjunction with clinical factors, interacting concomitant drug therapies, and other factors such as the microbiome, which can all affect drug disposition. Taking account of all of these factors, in conjunction with the somatic genome, is more likely to provide better predictive accuracy in determining anti-cancer drug response, both efficacy and safety. This review summarises the existing knowledge related to the pharmacogenomics of anti-cancer drugs and discusses areas of opportunity for further advances in personalisation of therapy in order to improve both drug safety and efficacy.

PMID: 32501544 [PubMed - as supplied by publisher]

Angiotensin converting enzyme 2 (ACE2) and COVID-19: using antihypertensive medications, pharmacogenetic considerations.

Pharmacogenomics. 2020 Jun 05;:

Authors: Snyder EM, Johnson BD

Abstract
COVID-19 utilizes the angiotensin-converting enzyme-2 (ACE2) pathway as a means of infection. Early data on COVID-19 suggest heterogeneity in the severity of symptoms during transmission and infection ranging from no symptoms to death. The source of this heterogeneity is likely multifaceted and may have a genetic component. Demographic and clinical comorbidities associated with the severity of infection suggest that possible variants known to influence the renin-angiotensin-aldosterone system pathway (particularly those that influence ACE2) may contribute to the heterogenous infection response. ACE2 and angiotensin(1-7) (the product of ACE2) seem to have a protective effect on the pulmonary and cardiac systems. Hypertension medication modulation, may alter ACE2 and angiotensin(1-7), particularly in variants that have been shown to influence renin-angiotensin-aldosterone system function, which could be clinically useful in patients with COVID-19.

PMID: 32501190 [PubMed - as supplied by publisher]