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1.
BMJ Open ; 9(11): e032707, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31699749

RESUMO

PURPOSE: The Mayo Clinic Biobank was established to provide a large group of patients from which comparison groups (ie, controls) could be selected for case-control studies, to create a prospective cohort with sufficient power for common outcomes and to support electronic health record (EHR) studies. PARTICIPANTS: A total of 56 862 participants enrolled (21% response rate) into the Mayo Clinic Biobank from Rochester, Minnesota (77%, n=43 836), Jacksonville, Florida (18%, n=10 368) and La Crosse, Wisconsin (5%, n=2658). Participants were all Mayo Clinic patients, 18 years of age or older and US residents. FINDINGS TO DATE: Overall, 43% of participants were 65 years of age or older and female participants were more frequent (59%) than males at all sites. Most participants resided in the Upper Midwest regions of the USA (Minnesota, Iowa, Illinois or Wisconsin), Florida or Georgia. Self-reported race among Biobank participants was 90% white. Here we provide examples of the types of studies that have successfully utilised the resource, including (1) investigations of the population itself, (2) provision of controls for case-control studies, (3) genotype-driven research, (4) EHR-based research and (5) prospective recruitment to other studies. Over 270 projects have been approved to date to access Biobank data and/or samples; over 200 000 sample aliquots have been approved for distribution. FUTURE PLANS: The data and samples in the Mayo Clinic Biobank can be used for various types of epidemiological and clinical studies, especially in the setting of case-control studies for which the Biobank samples serve as control samples. We are planning cohort studies with additional follow-up and acquisition of genetic information on a large scale.

2.
Genet Med ; 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31591509

RESUMO

PURPOSE: To examine the evidence on the cost-effectiveness of implementing pharmacogenomics (PGx) in cardiovascular disease (CVD) care. METHODS: We conducted a systematic review using multiple databases from inception to 2018. The titles and abstracts of cost-effectiveness studies on PGx-guided treatment in CVD care were screened, and full texts were extracted. RESULTS: We screened 909 studies and included 46 to synthesize. Acute coronary syndrome and atrial fibrillation were the predominantly studied conditions (59%). Most studies (78%) examined warfarin-CYP2C9/VKORC1 or clopidogrel-CYP2C19. A payer's perspective was commonly used (39%) for cost calculations, and most studies (46%) were US-based. The majority (67%) of the studies found PGx testing to be cost-effective in CVD care, but cost-effectiveness varied across drugs and conditions. Two studies examined PGx panel testing, of which one examined pre-emptive testing strategies. CONCLUSION: We found mixed evidence on the cost-effectiveness of PGx in CVD care. Supportive evidence exists for clopidogrel-CYP2C19 and warfarin-CYP2C9/VKORC1, but evidence is limited in other drug-gene combinations. Gaps persist, including unclear explanation of perspective and cost inputs, underreporting of study design elements critical to economic evaluations, and limited examination of PGx panel and pre-emptive testing for their cost-effectiveness. This review identifies the need for further research on economic evaluations of PGx implementation.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31591640

RESUMO

Pharmacogenomics (PGx) clinical decision support integrated into the electronic health record (EHR) has the potential to provide relevant knowledge to clinicians to enable individualized care. However, past experience implementing PGx clinical decision support into multiple EHR platforms has identified important clinical, procedural, and technical challenges. Commercial EHRs have been widely criticized for the lack of readiness to implement precision medicine. Herein, we share our experiences and lessons learned implementing new EHR functionality charting PGx phenotypes in a unique repository, genomic indicators, instead of using the problem or allergy list. The Gen-Ind has additional features including a brief description of the clinical impact, a hyperlink to the original laboratory report, and links to additional educational resources. The automatic generation of genomic indicators from interfaced PGx test results facilitates implementation and long-term maintenance of PGx data in the EHR and can be used as criteria for synchronous and asynchronous CDS.

4.
Eur Respir J ; 54(3)2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31371443

RESUMO

Adhesion molecules may contribute to the development of interstitial lung disease (ILD) and have been proposed as prognostic biomarkers in idiopathic pulmonary fibrosis. Our objective was to determine whether the circulating adhesion molecules soluble intracellular adhesion molecule (sICAM)-1, soluble vascular cell adhesion molecule (sVCAM)-1 and P-selectin are associated with subclinical ILD in community-dwelling adults.The Multi-Ethnic Study of Atherosclerosis enrolled males and females aged 45-84 years from six communities in the United States in 2000-2002. High attenuation areas were defined as the percentage of imaged lung volume with attenuation -600--250 HU on cardiac computed tomography (CT). Interstitial lung abnormalities were visually assessed on full-lung CT. Spirometry was performed on a subset of individuals. ILD hospitalisations and deaths were adjudicated.In fully adjusted analyses, higher levels of sICAM-1, sVCAM-1 and P-selectin were associated with greater high attenuation areas (2.94%, 95% CI 1.80-4.07%; 1.24%, 95% CI 0.14-2.35%; and 1.58%, 95% CI 0.92-2.23%, respectively), and greater rate of ILD hospitalisations (HR 1.36, 95% CI 1.03-1.80; 1.40, 95% CI 1.07-1.85; and 2.03, 95% CI 1.16-3.5, respectively). sICAM-1 was associated with greater prevalence of interstitial lung abnormalities (OR 1.39, 95% CI 1.13-1.71). sICAM-1 and P-selectin were associated with lower forced vital capacity (44 mL, 95% CI 12-76 mL and 29 mL, 95% CI 8-49 mL, respectively). sVCAM-1 and P-selectin were associated with increased risk of ILD death (HR 2.15, 95% CI 1.26-3.64 and 3.61, 95% CI 1.54-8.46, respectively).Higher levels of circulating sICAM-1, sVCAM-1 and P-selectin are independently associated with CT and spirometric measures of subclinical ILD, and increased rate of adjudicated ILD events among community-dwelling adults.

7.
Am Heart J ; 213: 30-34, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31085382

RESUMO

Hepatocyte growth factor (HGF) is associated with subclinical and clinical atherosclerosis. However, the significance of change in HGF and development of atherosclerotic disease is unknown. In a large and diverse population-based cohort, we report that change in the biomarker HGF is an independent predictor of incident CHD.

8.
PLoS One ; 14(5): e0216222, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31075152

RESUMO

BACKGROUND: Fibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies. METHODS AND FINDINGS: We evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score used a meta-analysis of 11 European-ancestry prospective cohorts, free of CHD and MI at baseline, to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI). In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models. CONCLUSIONS: A small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.

9.
Drug Metab Dispos ; 47(4): 425-435, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30745309

RESUMO

CYP2C9 and CYP2C19 are highly polymorphic pharmacogenes; however, clinically actionable genetic variability in drug metabolism due to these genes has been limited to a few common alleles. The identification and functional characterization of less-common open reading frame sequence variation might help to individualize therapy with drugs that are substrates for the enzymes encoded by these genes. The present study identified seven uncharacterized variants each in CYP2C9 and CYP2C19 using next-generation sequence data for 1013 subjects, and functionally characterized the encoded proteins. Constructs were created and transiently expressed in COS-1 cells for the assay of protein concentration and enzyme activities using fluorometric substrates and liquid chromatography- tandem mass spectrometry with tolbutamide (CYP2C9) and (S)-mephenytoin (CYP2C19) as prototypic substrates. The results were compared with the SIFT, Polyphen, and Provean functional prediction software programs. Cytochrome P450 oxidoreductase (CPR) activities were also determined. Positive correlations were observed between protein content and fluorometric enzyme activity for variants of CYP2C9 (P < 0.05) and CYP2C19 (P < 0.0005). However, CYP2C9 709G>C and CYP2C19 65A>G activities were much lower than predicted based on protein content. Substrate intrinsic clearance values for CYP2C9 218C>T, 343A>C, and CYP2C19 337G>A, 518C>T, 556C>T, and 557G>A were less than 25% of wild-type allozymes. CPR activity levels were similar for all variants. In summary, sequencing of CYP2C9 and CYP2C19 in 1013 subjects identified low-frequency variants that had not previously been functionally characterized. In silico predictions were not always consistent with functional assay results. These observations emphasize the need for high-throughput methods for pharmacogene variant mutagenesis and functional characterization.

10.
Am J Hum Genet ; 104(1): 112-138, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30595373

RESUMO

Mitochondria (MT), the major site of cellular energy production, are under dual genetic control by 37 mitochondrial DNA (mtDNA) genes and numerous nuclear genes (MT-nDNA). In the CHARGEmtDNA+ Consortium, we studied genetic associations of mtDNA and MT-nDNA associations with body mass index (BMI), waist-hip-ratio (WHR), glucose, insulin, HOMA-B, HOMA-IR, and HbA1c. This 45-cohort collaboration comprised 70,775 (insulin) to 170,202 (BMI) pan-ancestry individuals. Validation and imputation of mtDNA variants was followed by single-variant and gene-based association testing. We report two significant common variants, one in MT-ATP6 associated (p ≤ 5E-04) with WHR and one in the D-loop with glucose. Five rare variants in MT-ATP6, MT-ND5, and MT-ND6 associated with BMI, WHR, or insulin. Gene-based meta-analysis identified MT-ND3 associated with BMI (p ≤ 1E-03). We considered 2,282 MT-nDNA candidate gene associations compiled from online summary results for our traits (20 unique studies with 31 dataset consortia's genome-wide associations [GWASs]). Of these, 109 genes associated (p ≤ 1E-06) with at least 1 of our 7 traits. We assessed regulatory features of variants in the 109 genes, cis- and trans-gene expression regulation, and performed enrichment and protein-protein interactions analyses. Of the identified mtDNA and MT-nDNA genes, 79 associated with adipose measures, 49 with glucose/insulin, 13 with risk for type 2 diabetes, and 18 with cardiovascular disease, indicating for pleiotropic effects with health implications. Additionally, 21 genes related to cholesterol, suggesting additional important roles for the genes identified. Our results suggest that mtDNA and MT-nDNA genes and variants reported make important contributions to glucose and insulin metabolism, adipocyte regulation, diabetes, and cardiovascular disease.


Assuntos
DNA Mitocondrial/genética , Genes Mitocondriais/genética , Variação Genética/genética , Metabolismo/genética , Mitocôndrias/genética , Mitocôndrias/metabolismo , Adipócitos/metabolismo , Índice de Massa Corporal , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Estudos de Coortes , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Glucose/metabolismo , Hemoglobina A Glicada/metabolismo , Humanos , Insulina/metabolismo , Locos de Características Quantitativas , Relação Cintura-Quadril
11.
PLoS One ; 13(7): e0200486, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30044860

RESUMO

Current knowledge of the genetic architecture of key reproductive events across the female life course is largely based on association studies of European descent women. The relevance of known loci for age at menarche (AAM) and age at natural menopause (ANM) in diverse populations remains unclear. We investigated 32 AAM and 14 ANM previously-identified loci and sought to identify novel loci in a trans-ethnic array-wide study of 196,483 SNPs on the MetaboChip (Illumina, Inc.). A total of 45,364 women of diverse ancestries (African, Hispanic/Latina, Asian American and American Indian/Alaskan Native) in the Population Architecture using Genomics and Epidemiology (PAGE) Study were included in cross-sectional analyses of AAM and ANM. Within each study we conducted a linear regression of SNP associations with self-reported or medical record-derived AAM or ANM (in years), adjusting for birth year, population stratification, and center/region, as appropriate, and meta-analyzed results across studies using multiple meta-analytic techniques. For both AAM and ANM, we observed more directionally consistent associations with the previously reported risk alleles than expected by chance (p-valuesbinomial≤0.01). Eight densely genotyped reproductive loci generalized significantly to at least one non-European population. We identified one trans-ethnic array-wide SNP association with AAM and two significant associations with ANM, which have not been described previously. Additionally, we observed evidence of independent secondary signals at three of six AAM trans-ethnic loci. Our findings support the transferability of reproductive trait loci discovered in European women to women of other race/ethnicities and indicate the presence of additional trans-ethnic associations both at both novel and established loci. These findings suggest the benefit of including diverse populations in future studies of the genetic architecture of female growth and development.

12.
Artigo em Inglês | MEDLINE | ID: mdl-29874848

RESUMO

We investigated the effect of candidate variants in AS3MT (arsenic (III) methyltransferase) with urinary arsenic metabolites and their principal components in a subset of 264 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Urinary arsenic species, including inorganic arsenic (iAs), monomethylarsonate (MMA), dimethylarsinate (DMA), and arsenobetaine (Ab), were measured using high performance liquid chromatography-inductively coupled plasma mass spectrometry (HPLC-ICPMS) and corrected for organic sources from seafood consumption by regressing Ab on arsenic species using a validated method. Principal components of arsenic metabolism were also used as independent phenotypes. We conducted linear regression of arsenic traits with allelic dosage of candidate single nucleotide polymorphisms (SNPs) rs12768205 (G > A), rs3740394 (A > G), and rs3740393 (G > C) measured using Illumina MetaboChip. Models were stratified by non-Hispanic white vs. all other race/ethnicity and adjusted for age, sex, arsenic exposure, study site, and population stratification. Consistent with previous studies, rs12768205 showed evidence for strongest association (non-Hispanic white: iAs% -0.14 (P 0.83), MMA% -0.66 (0.49), DMA% 0.81(0.49); other race/ethnicity: 0.13 (0.71), -1.21 (0.09), 1.08 (0.20)). No association, however, passed the strict Bonferroni p-value. This was a novel study among an ethnically diverse population exposed to low arsenic levels.

13.
Atherosclerosis ; 272: 162-167, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29609131

RESUMO

BACKGROUND AND AIMS: Hepatocyte growth factor (HGF) has previously been associated with risk of stroke, coronary heart disease, and atherosclerosis. We hypothesized that higher circulating HGF is associated with greater progression of measures of atherosclerosis: coronary artery calcium (CAC) and carotid plaque. METHODS: Participants aged 45-84 years from the prospective cohort study Multi-Ethnic Study of Atherosclerosis had HGF measured at baseline (between 2000 and 2002) and were followed for progression of atherosclerosis for up to 12 years. CAC was measured at all five exams using the Agatston method. Mixed-effects models were used to examine the association of HGF and CAC progression among 6695 participants with available data. Relative risk regression was used to assess the association between HGF and new or additional carotid plaque between exams 1 and 5 in 3400 participants with available data. All point estimates were adjusted for potential confounding variables. RESULTS: Each standard deviation higher HGF at baseline was associated with 2.9 Agatston units/year greater CAC progression (95% CI: 1.6-4.2, p < 0.0001), and the magnitude of this association differed by race/ethnicity (p value for interaction by race = 0.003). Each standard deviation higher HGF at baseline was associated with a 4% higher risk of new or additional carotid plaque (95% CI: 1.01-1.08, p = 0.005). CONCLUSIONS: Higher levels of HGF were significantly associated with greater progression of atherosclerosis in this large and diverse population. Circulating HGF continues to show promise as a potential clinical biomarker for cardiovascular disease.

14.
PLoS One ; 12(12): e0189858, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29253899

RESUMO

In whites, the minor G allele of the atrial natriuretic peptide (ANP) genetic variant rs5068 is associated with higher circulating levels of ANP and B-type natriuretic peptide (BNP), lower risk of hypertension, higher high-density lipoprotein (HDL) cholesterol plasma levels, and lower prevalence of obesity and metabolic syndrome. The observed phenotype is consistent with the blood pressure lowering and metabolic properties of ANP and BNP. The cardiovascular and metabolic phenotype associated with rs5068 genotypes in African Americans is undefined. We genotyped 1631 African Americans in the Multi-Ethnic Study of Atherosclerosis (MESA) for rs5068 and investigated their phenotype. Genotype frequencies of rs5068 were 93.2% AA (n = 1520), 6.7% AG (n = 110) and 0.1% GG (n = 1). All subsequent analyses are AG + GG versus AA genotype. Using a Bonferroni corrected level of significance of 0.005, the prevalence of metabolic syndrome (23% vs 38%, age-sex-adjusted p = 0.002) and triglycerides plasma values (76 vs 90 mg/dl, age-sex-BMI adjusted p = 0.004) were both significantly lower in the AG+GG genotypes. In the AG+GG genotypes, the prevalence of diabetes (8% vs 18%, age-sex-BMI-adjusted p = 0.02) and insulin plasma levels tended to be lower (4.8 vs 5.7 µU/ml, age-sex-BMI adjusted p = 0.04) whereas HDL-cholesterol levels tended to be higher (55 vs 50 mg/dl, age-sex-BMI-adjusted p = 0.04). No association was found with hypertension. The association between the rs5068 G allele and a favorable metabolic phenotype is now shown in African Americans. The rs5068 AG+GG genotypes are associated with lower prevalence of metabolic syndrome and lower triglycerides values.


Assuntos
Aterosclerose/etnologia , Aterosclerose/genética , Fator Natriurético Atrial/genética , Doenças Cardiovasculares/etnologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/prevenção & controle , Afro-Americanos , Idoso , Idoso de 80 Anos ou mais , Alelos , Sistema Cardiovascular , HDL-Colesterol/sangue , Estudos de Coortes , Grupos Étnicos , Feminino , Genótipo , Geografia , Humanos , Insulina/sangue , Masculino , Síndrome Metabólica/sangue , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Obesidade/sangue , Obesidade/genética , Fenótipo , Prevalência , Triglicerídeos/sangue , Estados Unidos
15.
Pharmgenomics Pers Med ; 10: 217-227, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28769582

RESUMO

BACKGROUND: Variation in the CYP2D6 gene may affect response to opioids in both poor and ultrarapid metabolizers, but data demonstrating such associations have been mixed, and the impact of variants on toxicity-related symptoms (e.g., nausea) is unclear. Therefore, we examined the association between CYP2D6 phenotype and poor pain control or other adverse symptoms related to the use of opioids in a sample of primary care patients. MATERIALS AND METHODS: We identified all patients in the Mayo Clinic RIGHT Protocol who were prescribed an opioid medication between July 01, 2013 and June 30, 2015, and categorized patients into three phenotypes: poor, intermediate to extensive, or ultrarapid CYP2D6 metabolizers. We reviewed the electronic health record of these patients for indications of poor pain control or adverse symptoms related to medication use. Associations between phenotype and outcomes were assessed using Chi-square tests and logistic regression. RESULTS: Overall, 257 (25% of RIGHT Protocol participants) patients received at least one opioid prescription; of these, 40 (15%) were poor metabolizers, 146 (57%) were intermediate to extensive metabolizers, and 71 (28%) were ultrarapid metabolizers. We removed patients that were prescribed a CYP2D6 inhibitor medication (n=38). After adjusting for age and sex, patients with a poor or ultrarapid phenotype were 2.7 times more likely to experience either poor pain control or an adverse symptom related to the prescription compared to patients with an intermediate to extensive phenotype (odds ratio: 2.68; 95% CI: 1.39, 5.17; p=0.003). CONCLUSION: Our results suggest that >30% of patients with a poor or ultrarapid CYP2D6 phenotype may experience an adverse outcome after being prescribed codeine, tramadol, oxycodone, or hydrocodone. These medications are frequently prescribed for pain relief, and ~39% of the US population is expected to carry one of these phenotypes, suggesting that the population-level impact of these gene-drug interactions could be substantial.

16.
J Clin Lipidol ; 11(4): 955-963.e3, 2017 Jul - Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28666711

RESUMO

BACKGROUND: High-density lipoproteins (HDL) are well characterized for their role in reverse cholesterol transport but may confer other cardiovascular benefits-specifically, HDL may suppress the endothelial activation cascade in the initiating stages of atherogenesis. OBJECTIVE: It was the primary aim of this study to examine the relations of HDL cholesterol (HDL-C), total HDL particle (HDL-P) concentrations, and HDL-P subclasses with circulating levels of endothelial activation markers in a subcohort of Multi-Ethnic Study of Atherosclerosis participants. METHODS: HDL-C was measured by enzymatic assay, and total HDL-P and subclass concentrations were assessed by nuclear magnetic resonance spectroscopy. Concentrations of circulating endothelial activation markers were determined through immunoassay. Multivariable linear regression was used to determine the cross-sectional associations between HDL variables and endothelial markers with statistical adjustment for age, race/ethnicity, sex, education, systolic blood pressure, hypertension medication use, body mass index, smoking status, lipid-lowering medication use, serum creatinine, diabetes, low-density lipoprotein cholesterol, and coronary artery calcium. RESULTS: HDL-C and HDL-P were found to be inversely associated with soluble vascular cell adhesion molecule-1, soluble vascular intracellular adhesion molecule-1, sL-selectin, and sP-selectin; HDL-P was additionally inversely associated with sE-selectin. Participants with low levels of HDL-C (<40 mg/dL) or HDL-P (<25th percentile) showed 3%-12% higher mean levels of soluble vascular cell adhesion molecule and compared with those above these levels (all P < .01). CONCLUSION: Coupled with previous evidence, our findings suggest a modest to moderate relation of HDL and circulating levels of endothelial activation markers in humans. Whether this relationship may have clinical implications in suppressing atherogenesis or coronary heart disease development requires additional research.


Assuntos
Aterosclerose/etnologia , Aterosclerose/patologia , Lipoproteínas HDL/sangue , Idoso , Idoso de 80 Anos ou mais , Aterosclerose/sangue , Aterosclerose/metabolismo , Transporte Biológico , Biomarcadores/sangue , Estudos Transversais , Endotélio/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
17.
Heart ; 103(15): 1185-1193, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28572400

RESUMO

OBJECTIVE: To determine if hepatocyte growth factor (HGF), a promising biomarker of coronary heart disease (CHD) given its release into circulation in response to endothelial damage, is associated with subclinical and clinical CHD in a racial/ethnic diverse population. METHODS: HGF was measured in 6738 participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Highest mean HGF values (pg/mL) were observed in Hispanic, followed by African, non-Hispanic white, then Chinese Americans. RESULTS: In all races/ethnicities, HGF levels were associated with older age, higher systolic blood pressure (SBP) and body mass index, lower high-density lipoprotein, diabetes and current smoking. In fully adjusted models, each SD higher HGF was associated with an average increase in coronary artery calcium (CAC) of 55 Agatston units for non-Hispanic whites (p<0.001) and 51 Agatston units for African-Americans (p=0.007) but was not in the other race/ethnic groups (interaction p=0.02). There were 529 incident CHD events, and CHD risk was 41% higher in African (p<0.001), 17% in non-Hispanic white (p=0.026) and Chinese (p=0.36), and 6% in Hispanic Americans (p=0.56) per SD increase in HGF. CONCLUSION: In a large and diverse population-based cohort, we report that HGF is associated with subclinical and incident CHD. We demonstrate evidence of racial/ethnic heterogeneity within these associations, as the results are most compelling in African-Americans and non-Hispanic white Americans. We provide evidence that HGF is a biomarker of atherosclerotic disease that is independent of traditional risk factors.


Assuntos
Grupos de Populações Continentais , Doença da Artéria Coronariana/sangue , Fator de Crescimento de Hepatócito/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Doença da Artéria Coronariana/etnologia , Grupos Étnicos , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Morbidade , Estados Unidos/epidemiologia
18.
Pharmgenomics Pers Med ; 10: 39-47, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28243137

RESUMO

BACKGROUND: Cytochrome P450 2D6 (CYP2D6) is responsible for the metabolism of clinically used drugs and other environmental exposures, but it is unclear whether the CYP2D6 phenotype is associated with adverse health outcomes. The aim was to determine the association of CYP2D6 phenotype with the risk of hospitalization or an emergency department (ED) visit among a group of primary care patients. METHODS: In this study, 929 adult patients underwent CYP2D6 testing. The primary outcome was risk of hospitalization or an ED visit from January 2005 through September 2014. CYP2D6 genotypes were interpreted as 1 of 7 clinical phenotypes, from ultrarapid to poor metabolizer, and patients with the extensive metabolizer phenotype were used as the reference group. The hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for finding the association of CYP2D6 phenotypes with the risk of hospitalization or an ED visit by using Cox proportional hazard models and adjusting for age and sex. RESULTS: The median age was 49 years (interquartile range, 46-52 years); 74% of patients had 3 or fewer chronic conditions, 285 had at least 1 hospitalization, and 496 had at least 1 ED visit. The risk of hospitalization was higher among patients who were ultrarapid metabolizers compared to extensive metabolizers (47% vs 30%; HR, 1.69; 95% CI, 1.11-2.57), as was the risk of an ED visit (62% vs 49%; HR, 1.50; 95% CI, 1.05-2.14). For poor metabolizers compared to extensive metabolizers, there was no difference in the risk of hospitalization (HR, 0.95; 95% CI, 0.58-1.56), but there was an increase in the risk of an ED visit (HR, 1.38; 95% CI, 0.96-1.98) (the difference was not statistically significant). CONCLUSION: We found an increased risk of hospitalization or an ED visit among ultrarapid compared to extensive CYP2D6 metabolizers. Further research identifying the mechanisms of the association and ultimate clinical utility is warranted.

19.
Thromb Res ; 153: 1-6, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28267600

RESUMO

INTRODUCTION: Peripheral artery disease (PAD) affects 8.5 million Americans and thus improving our understanding of PAD is critical to developing strategies to reduce disease burden. The objective of the study was to determine the association of ABO blood type with ankle brachial index (ABI) as well as prevalent and incident PAD in a multi-ethnic cohort. METHODS: The Multi-Ethnic Study of Atherosclerosis includes non-Hispanic White, African, Hispanic, and Chinese Americans aged 45-84. ABO blood type was estimated using ABO genotypes in 6027 participants who had ABI assessed at the baseline exam. Associations with ABO blood type were evaluated categorically and under an additive genetic model by number of major ABO alleles. After excluding those with ABI>1.4, prevalent PAD was defined as ABI≤0.9 at baseline and incident PAD as ABI≤0.9 for 5137 participants eligible for analysis. RESULTS: There were 222 prevalent cases and 239 incident cases of PAD. In African Americans, each additional copy of the A allele was associated with a 0.02 lower baseline ABI (p=0.006). Each copy of the A allele also corresponded to 1.57-fold greater odds of prevalent PAD (95% CI, 1.17-2.35; p=0.004), but was not associated with incident PAD. No associations were found in other racial/ethnic groups for ABI, prevalent PAD, or incident PAD across all races/ethnicities. CONCLUSIONS: Blood type A and the A allele count were significantly associated with baseline ABI and prevalent PAD in African Americans. Further research is needed to confirm and study the mechanisms of this association in African Americans.


Assuntos
Sistema do Grupo Sanguíneo ABO/genética , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/genética , Afro-Americanos/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Índice Tornozelo-Braço , Americanos Asiáticos/genética , Aterosclerose/diagnóstico , Aterosclerose/epidemiologia , Aterosclerose/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Genótipo , Hispano-Americanos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/epidemiologia , Prevalência , Fatores de Risco
20.
Eur J Hum Genet ; 25(4): 410-415, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28145427

RESUMO

Knowledge of variant pathogenicity is key to implementing genomic medicine. We describe variability between expert reviewers in assigning pathogenicity to sequence variants in LDLR, the causal gene in the majority of cases of familial hypercholesterolemia. LDLR was sequenced on the Illumina HiSeq platform (average read depth >200 × ) in 1013 Mayo Biobank participants recruited from 2012 to 2013. Variants with a minor allele frequency (MAF) <5% predicted to be functional or referenced in HGMD (Human Gene Mutation Database) or NCBI-ClinVar databases were reviewed. To assign pathogenicity, variant frequency in population data sets, computational predictions, reported observations and patient-level data including electronic health record-based post hoc phenotyping were leveraged. Of 178 LDLR variants passing quality control, 25 were selected for independent review using either an in-house protocol or a disease/gene-specific semi-quantitative framework based on the American College of Medical Genetics and Genomics-recommended lines of evidence. NCBI-ClinVar included interpretations for all queried variants with 74% (14/19) of variants with >1 submitter showing inconsistency in classification and 26% (5/19) appearing with conflicting clinical actionability. The discordance rate (one-step level of disagreement out of five classes in variant interpretation) between the reviewers was 40% (10/25). Two LDLR variants were independently deemed clinically actionable and returnable. Interpretation of LDLR variants was often discordant among ClinVar submitters and between expert reviewers. A quantitative approach based on strength of each predefined criterion in the context of specific genes and phenotypes may yield greater consistency between different reviewers.


Assuntos
Bases de Dados Genéticas/normas , Registros Eletrônicos de Saúde/normas , Testes Genéticos/normas , Hiperlipoproteinemia Tipo II/genética , Receptores de LDL/genética , Idoso , Feminino , Frequência do Gene , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Achados Incidentais , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Polimorfismo Genético
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