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J Gen Intern Med ; 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31792865


BACKGROUND: Health risk assessments (HRAs) and healthy behavior incentives are increasingly used by state Medicaid programs to promote enrollees' health. OBJECTIVE: To evaluate enrollee experiences with HRAs and healthy behavior engagement in the Healthy Michigan Plan (HMP), a state Medicaid expansion program. DESIGN: Telephone survey conducted in Michigan January-October 2016. PARTICIPANTS: A random sample of HMP enrollees aged 19-64 with ≥ 12 months of enrollment, stratified by income and geographic region. MAIN MEASURES: Self-reported completion of an HRA, reasons for completing an HRA, commitment to a healthy behavior, and choice of healthy behavior. KEY RESULTS: Among respondents (N = 4090), 49.3% (95% CI 47.3-51.2%) reported completing an HRA; among those with a primary care provider (PCP) (n = 3851), 85.2% (95% CI 83.5-86.7%) reported visiting their PCP during the last 12 months. Most enrollees having a recent PCP visit reported discussing healthy behaviors with them (91.1%, 95% CI 89.6-92.3%) and were more likely to have completed an HRA than enrollees without a recent PCP visit (52.7%, 95% CI 50.5-52.8% vs. 36.2%, 95% CI 31.7-41.1%; p < 0.01). Among enrollees completing an HRA, nearly half said they did it because their PCP suggested it (45.9%, 95% CI 43.2-48.7%), and most reported it helped their PCP understand their health needs (89.7%). Awareness of financial incentives was limited (28.1%, 95% CI 26.3-30.0%), and very few reported it as the primary reason for HRA completion (2.5%, 95% CI 1.8-3.4%). Most committed to a healthy behavior (80.7%, 95% CI 78.5-82.8%), and common behaviors chosen were nutrition/diet (57.2%, 95% CI 54.2-60.2%) and exercise/activity (52.6%, 95% CI 49.5-55.7%). CONCLUSIONS: In the Healthy Michigan Plan, PCPs appeared influential in enrollees' completion of HRAs and healthy behavior engagement, while knowledge of financial incentives was limited. Additional study is needed to understand the relative importance of financial incentives and PCP engagement in impacting healthy behaviors in state Medicaid programs.

Clin Pharmacol Ther ; 2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31869433


Warfarin is the most commonly used oral anticoagulant in sub-Saharan Africa. Dosing is challenging due to a narrow therapeutic index and high inter-individual variability in dose requirements. To evaluate the genetic factors affecting warfarin dosing in Black-Africans, we performed a meta-analysis of 48 studies (2,336 patients). Significant predictors for CYP2C9 and stable dose included rs1799853 (CYP2C9*2), rs1057910 (CYP2C9*3), rs28371686 (CYP2C9*5), rs9332131 (CYP2C9*6), and rs28371685 (CYP2C9*11) reducing dose by 6.8, 12.5, 13.4, 8.1, and 5.3 mg/week respectively. VKORC1 variants rs9923231 (-1639G>A), rs9934438 (1173C>T), rs2359612 (2255C>T), rs8050894 (1542G>C), and rs2884737 (497T>G) decreased dose by 18.1, 21.6, 17.3, 11.7, and 19.6 mg/week, respectively while rs7294 (3730G>A) increased dose by 6.9 mg/week. Finally, rs12777823 (CYP2C gene cluster) was associated with a dose reduction of 12.7 mg/week. Few studies were conducted in Africa, and patient numbers were small, highlighting the need for further work in Black Africans to evaluate genetic factors determining warfarin response.

Clin Pharmacol Ther ; 106(6): 1353-1361, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31220337


Statins can be associated with myopathy. We have undertaken a genomewide association study (GWAS) to discover and validate genetic risk factors for statin-induced myopathy in a "real-world" setting. One hundred thirty-five patients with statin myopathy recruited via the UK Clinical Practice Research Datalink were genotyped using the Illumina OmniExpress Exome version 1.0 Bead Chip and compared with the Wellcome Trust Case-Control Consortium (n = 2,501). Nominally statistically significant single nucleotide polymorphism (SNP) signals in the GWAS (P < 5 × 10-5 ) were further evaluated in several independent cohorts (comprising 332 cases and 449 drug-tolerant controls). Only one (rs4149056/c.521C>T in the SLCO1B1 gene) SNP was genomewide significant in the severe myopathy (creatine kinase > 10 × upper limit of normal or rhabdomyolysis) group (P = 2.55 × 10-9 ; odds ratio 5.15; 95% confidence interval 3.13-8.45). The association with SLCO1B1 was present for several statins and replicated in the independent validation cohorts. The data highlight the role of SLCO1B1 c.521C>T SNP as a replicable genetic risk factor for statin myopathy. No other novel genetic risk factors with a similar effect size were identified.

J Gen Intern Med ; 34(2): 325-326, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30276656
Lancet Respir Med ; 6(6): 442-450, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29551627


BACKGROUND: A serious adverse effect of corticosteroid therapy is adrenal suppression. Our aim was to identify genetic variants affecting susceptibility to corticosteroid-induced adrenal suppression. METHODS: We enrolled children with asthma who used inhaled corticosteroids as part of their treatment from 25 sites across the UK (discovery cohort), as part of the Pharmacogenetics of Adrenal Suppression with Inhaled Steroids (PASS) study. We included two validation cohorts, one comprising children with asthma (PASS study) and the other consisting of adults with chronic obstructive pulmonary disorder (COPD) who were recruited from two UK centres for the Pharmacogenomics of Adrenal Suppression in COPD (PASIC) study. Participants underwent a low-dose short synacthen test. Adrenal suppression was defined as peak cortisol less than 350 nmol/L (in children) and less than 500 nmol/L (in adults). A case-control genome-wide association study was done with the control subset augmented by Wellcome Trust Case Control Consortium 2 (WTCCC2) participants. Single nucleotide polymorphisms (SNPs) that fulfilled criteria to be advanced to replication were tested by a random-effects inverse variance meta-analysis. This report presents the primary analysis. The PASS study is registered in the European Genome-phenome Archive (EGA). The PASS study is complete whereas the PASIC study is ongoing. FINDINGS: Between November, 2008, and September, 2011, 499 children were enrolled to the discovery cohort. Between October, 2011, and December, 2012, 81 children were enrolled to the paediatric validation cohort, and from February, 2010, to June, 2015, 78 adults were enrolled to the adult validation cohort. Adrenal suppression was present in 35 (7%) children in the discovery cohort and six (7%) children and 17 (22%) adults in the validation cohorts. In the discovery cohort, 40 SNPs were found to be associated with adrenal suppression (genome-wide significance p<1 × 10-6), including an intronic SNP within the PDGFD gene locus (rs591118; odds ratio [OR] 7·32, 95% CI 3·15-16·99; p=5·8 × 10-8). This finding for rs591118 was validated successfully in both the paediatric asthma (OR 3·86, 95% CI 1·19-12·50; p=0·02) and adult COPD (2·41, 1·10-5·28; p=0·03) cohorts. The proportions of patients with adrenal suppression by rs591118 genotype were six (3%) of 214 patients with the GG genotype, 15 (6%) of 244 with the AG genotype, and 22 (25%) of 87 with the AA genotype. Meta-analysis of the paediatric cohorts (discovery and validation) and all three cohorts showed genome-wide significance of rs591118 (respectively, OR 5·89, 95% CI 2·97-11·68; p=4·3 × 10-9; and 4·05, 2·00-8·21; p=3·5 × 10-10). INTERPRETATION: Our findings suggest that genetic variation in the PDGFD gene locus increases the risk of adrenal suppression in children and adults who use corticosteroids to treat asthma and COPD, respectively. FUNDING: Department of Health Chair in Pharmacogenetics.

Corticosteroides/efeitos adversos , Insuficiência Adrenal/genética , Antiasmáticos/efeitos adversos , Asma/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Adolescente , Corticosteroides/administração & dosagem , Insuficiência Adrenal/induzido quimicamente , Adulto , Idoso , Antiasmáticos/administração & dosagem , Asma/genética , Estudos de Casos e Controles , Criança , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Hidrocortisona/análise , Linfocinas/efeitos dos fármacos , Linfocinas/genética , Masculino , Pessoa de Meia-Idade , Variantes Farmacogenômicos , Fator de Crescimento Derivado de Plaquetas/efeitos dos fármacos , Fator de Crescimento Derivado de Plaquetas/genética , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/genética , Adulto Jovem
Neurology ; 90(4): e332-e341, 2018 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-29288229


OBJECTIVE: To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs. METHODS: We conducted a case-control genome-wide association study of autosomal genotypes, including Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent. Results from each cohort were meta-analyzed. RESULTS: We report an association between a rare variant in the complement factor H-related 4 (CFHR4) gene and phenytoin-induced MPE in Europeans (p = 4.5 × 10-11; odds ratio [95% confidence interval] 7 [3.2-16]). This variant is in complete linkage disequilibrium with a missense variant (N1050Y) in the complement factor H (CFH) gene. In addition, our results reinforce the association between HLA-A*31:01 and carbamazepine hypersensitivity. We did not identify significant genetic associations with MPE among Han Chinese patients. CONCLUSIONS: The identification of genetic predictors of MPE in CFHR4 and CFH, members of the complement factor H-related protein family, suggest a new link between regulation of the complement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients.

Anticonvulsivantes/efeitos adversos , Apolipoproteínas/genética , Erupção por Droga/genética , Variação Genética , Fenitoína/efeitos adversos , Anticonvulsivantes/uso terapêutico , Grupo com Ancestrais do Continente Asiático/genética , Carbamazepina/efeitos adversos , Carbamazepina/uso terapêutico , Estudos de Casos e Controles , Fator H do Complemento/genética , Erupção por Droga/etnologia , Erupção por Droga/etiologia , Epilepsia/tratamento farmacológico , Epilepsia/genética , Grupo com Ancestrais do Continente Europeu/genética , Estudo de Associação Genômica Ampla , Antígenos HLA-A/genética , Humanos , Desequilíbrio de Ligação , Mutação de Sentido Incorreto , Variantes Farmacogenômicos , Fenitoína/uso terapêutico , Estudos Retrospectivos
Genome Med ; 8(1): 2, 2016 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-26739746


BACKGROUND: Warfarin is the most widely used oral anticoagulant worldwide, but it has a narrow therapeutic index which necessitates constant monitoring of anticoagulation response. Previous genome-wide studies have focused on identifying factors explaining variance in stable dose, but have not explored the initial patient response to warfarin, and a wider range of clinical and biochemical factors affecting both initial and stable dosing with warfarin. METHODS: A prospective cohort of 711 patients starting warfarin was followed up for 6 months with analyses focusing on both non-genetic and genetic factors. The outcome measures used were mean weekly warfarin dose (MWD), stable mean weekly dose (SMWD) and international normalised ratio (INR) > 4 during the first week. Samples were genotyped on the Illumina Human610-Quad chip. Statistical analyses were performed using Plink and R. RESULTS: VKORC1 and CYP2C9 were the major genetic determinants of warfarin MWD and SMWD, with CYP4F2 having a smaller effect. Age, height, weight, cigarette smoking and interacting medications accounted for less than 20 % of the variance. Our multifactorial analysis explained 57.89 % and 56.97 % of the variation for MWD and SMWD, respectively. Genotypes for VKORC1 and CYP2C9*3, age, height and weight, as well as other clinical factors such as alcohol consumption, loading dose and concomitant drugs were important for the initial INR response to warfarin. In a small subset of patients for whom data were available, levels of the coagulation factors VII and IX (highly correlated) also played a role. CONCLUSION: Our multifactorial analysis in a prospectively recruited cohort has shown that multiple factors, genetic and clinical, are important in determining the response to warfarin. VKORC1 and CYP2C9 genetic polymorphisms are the most important determinants of warfarin dosing, and it is highly unlikely that other common variants of clinical importance influencing warfarin dosage will be found. Both VKORC1 and CYP2C9*3 are important determinants of the initial INR response to warfarin. Other novel variants, which did not reach genome-wide significance, were identified for the different outcome measures, but need replication.

Anticoagulantes/administração & dosagem , Citocromo P-450 CYP2C9/genética , Sistema Enzimático do Citocromo P-450/genética , Vitamina K Epóxido Redutases/genética , Varfarina/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Família 4 do Citocromo P450 , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Genótipo , Humanos , Coeficiente Internacional Normatizado , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Fatores de Risco , Reino Unido , Adulto Jovem