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1.
Clin Pharmacol Ther ; 102(2): 254-264, 2017 Aug.
Article in English | MEDLINE | ID: mdl-28390138

ABSTRACT

Advances in pharmacogenomics (PGx) have the potential to transform healthcare by allowing precision medicine to become a reality. However, PGx knowledge is new, complex, and evolving, and relying on the cognition of clinicians alone is insufficient for clinical implementation. Integrating clinical decision support (CDS) tools in the electronic health record (EHR) is critical for translating PGx into clinical practice. Herein, we review current strategies to implement PGx using EHR-CDS functionalities.


Subject(s)
Decision Support Systems, Clinical , Electronic Health Records , Pharmacogenetics/methods , Precision Medicine/methods , Decision Support Systems, Clinical/trends , Electronic Health Records/trends , Humans , Pharmacogenetics/trends , Precision Medicine/trends
3.
Diabet Med ; 33(7): 985-91, 2016 07.
Article in English | MEDLINE | ID: mdl-26937608

ABSTRACT

AIMS: To test the hypothesis that soluble cellular adhesion molecules would be positively and independently associated with risk of diabetes. METHODS: Soluble levels of six cellular adhesion molecules (ICAM-1, E-selectin, VCAM-1, E-cadherin, L-selectin and P-selectin) were measured in participants in the Multi-Ethnic Study of Atherosclerosis, a prospective cohort study. Participants were then followed for up to 10 years to ascertain incident diabetes. RESULTS: Sample sizes ranged from 826 to 2185. After adjusting for age, sex, race/ethnicity, BMI and fasting glucose or HbA1c , four cellular adhesion molecules (ICAM-1, E-selectin, VCAM-1 and E-cadherin) were positively associated with incident diabetes and there was a statistically significant trend across quartiles. Comparing the incidence of diabetes in the highest and lowest quartiles of each cellular adhesion molecule, the magnitude of association was largest for E-selectin (hazard ratio 2.49; 95% CI 1.26-4.93) and ICAM-1 (hazard ratio 1.76; 95% CI 1.22-2.55) in fully adjusted models. Tests of effect modification by racial/ethnic group and sex were not statistically significant for any of the cellular adhesion molecules (P > 0.05). CONCLUSIONS: The finding of significant associations between multiple cellular adhesion molecules and incident diabetes may lend further support to the hypothesis that microvascular endothelial dysfunction contributes to risk of diabetes.


Subject(s)
Cadherins/blood , Diabetes Mellitus, Type 2/epidemiology , E-Selectin/blood , Intercellular Adhesion Molecule-1/blood , L-Selectin/blood , P-Selectin/blood , Vascular Cell Adhesion Molecule-1/blood , Antigens, CD , Cohort Studies , Diabetes Mellitus, Type 2/blood , Female , Humans , Incidence , Male , Middle Aged , Proportional Hazards Models , Prospective Studies , Risk , United States/epidemiology
4.
Clin Pharmacol Ther ; 100(2): 160-9, 2016 08.
Article in English | MEDLINE | ID: mdl-26857349

ABSTRACT

Genetic variation can affect drug response in multiple ways, although it remains unclear how rare genetic variants affect drug response. The electronic Medical Records and Genomics (eMERGE) Network, collaborating with the Pharmacogenomics Research Network, began eMERGE-PGx, a targeted sequencing study to assess genetic variation in 82 pharmacogenes critical for implementation of "precision medicine." The February 2015 eMERGE-PGx data release includes sequence-derived data from ∼5,000 clinical subjects. We present the variant frequency spectrum categorized by variant type, ancestry, and predicted function. We found 95.12% of genes have variants with a scaled Combined Annotation-Dependent Depletion score above 20, and 96.19% of all samples had one or more Clinical Pharmacogenetics Implementation Consortium Level A actionable variants. These data highlight the distribution and scope of genetic variation in relevant pharmacogenes, identifying challenges associated with implementing clinical sequencing for drug treatment at a broader level, underscoring the importance for multifaceted research in the execution of precision medicine.


Subject(s)
Databases, Genetic , Genetic Variation , Genomics , Pharmacogenetics , Aged , Electronic Health Records , Female , Humans , Male , Middle Aged , Precision Medicine/methods
5.
Clin Pharmacol Ther ; 96(4): 482-9, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24960519

ABSTRACT

We describe here the design and initial implementation of the eMERGE-PGx project. eMERGE-PGx, a partnership of the Electronic Medical Records and Genomics Network and the Pharmacogenomics Research Network, has three objectives: (i) to deploy PGRNseq, a next-generation sequencing platform assessing sequence variation in 84 proposed pharmacogenes, in nearly 9,000 patients likely to be prescribed drugs of interest in a 1- to 3-year time frame across several clinical sites; (ii) to integrate well-established clinically validated pharmacogenetic genotypes into the electronic health record with associated clinical decision support and to assess process and clinical outcomes of implementation; and (iii) to develop a repository of pharmacogenetic variants of unknown significance linked to a repository of electronic health record-based clinical phenotype data for ongoing pharmacogenomics discovery. We describe site-specific project implementation and anticipated products, including genetic variant and phenotype data repositories, novel variant association studies, clinical decision support modules, clinical and process outcomes, approaches to managing incidental findings, and patient and clinician education methods.


Subject(s)
Databases, Genetic , Electronic Health Records/organization & administration , Genetic Variation , Adolescent , Aged , Child , Drug Therapy , Female , Genetic Association Studies , Genotype , Humans , Knowledge Bases , Male , Middle Aged , Pharmacogenetics , Phenotype , Pilot Projects , Sequence Analysis, DNA , Young Adult
6.
Clin Genet ; 86(1): 50-5, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24588254

ABSTRACT

We provide a mini-review of how biobanks can support clinical genetics in the era of personalized medicine. We discuss types of biobanks, including disease specific and general biobanks not focused on one disease. We present considerations in setting up a biobank, including consenting and governance, biospecimens, risk factor and related data, informatics, and linkage to electronic health records for phenotyping. We also discuss the uses of biobanks and ongoing considerations, including genotype-driven recruitment, investigations of gene-environment associations, and the re-use of data generated from studies. Finally, we present a brief discussion of some of the unresolved issues, such as return of research results and sustaining biobanks over time. In summary, carefully designed biobanks can provide critical research and infrastructure support for clinical genetics in the era of personalized medicine.


Subject(s)
Biological Specimen Banks/organization & administration , Biological Specimen Banks/trends , Computational Biology/methods , Databases, Genetic/trends , Genetics, Medical/methods , Precision Medicine/methods , Genetics, Medical/trends , Genotype , Humans , Precision Medicine/trends
7.
Diabetologia ; 55(11): 2970-84, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22893027

ABSTRACT

AIMS/HYPOTHESIS: Hyperglycaemia disproportionately affects African-Americans (AfAs). We tested the transferability of 18 single-nucleotide polymorphisms (SNPs) associated with glycaemic traits identified in European ancestry (EuA) populations in 5,984 non-diabetic AfAs. METHODS: We meta-analysed SNP associations with fasting glucose (FG) or insulin (FI) in AfAs from five cohorts in the Candidate Gene Association Resource. We: (1) calculated allele frequency differences, variations in linkage disequilibrium (LD), fixation indices (F(st)s) and integrated haplotype scores (iHSs); (2) tested EuA SNPs in AfAs; and (3) interrogated within ± 250 kb around each EuA SNP in AfAs. RESULTS: Allele frequency differences ranged from 0.6% to 54%. F(st) exceeded 0.15 at 6/16 loci, indicating modest population differentiation. All iHSs were <2, suggesting no recent positive selection. For 18 SNPs, all directions of effect were the same and 95% CIs of association overlapped when comparing EuA with AfA. For 17 of 18 loci, at least one SNP was nominally associated with FG in AfAs. Four loci were significantly associated with FG (GCK, p = 5.8 × 10(-8); MTNR1B, p = 8.5 × 10(-9); and FADS1, p = 2.2 × 10(-4)) or FI (GCKR, p = 5.9 × 10(-4)). At GCK and MTNR1B the EuA and AfA SNPs represented the same signal, while at FADS1, and GCKR, the EuA and best AfA SNPs were weakly correlated (r(2) <0.2), suggesting allelic heterogeneity for association with FG at these loci. CONCLUSIONS/INTERPRETATION: Few glycaemic SNPs showed strict evidence of transferability from EuA to AfAs. Four loci were significantly associated in both AfAs and those with EuA after accounting for varying LD across ancestral groups, with new signals emerging to aid fine-mapping.


Subject(s)
Blood Glucose/genetics , Diabetes Mellitus, Type 2/ethnology , Diabetes Mellitus, Type 2/genetics , Hyperglycemia/ethnology , Hyperglycemia/genetics , Insulin/genetics , Adult , Black or African American/genetics , Black or African American/statistics & numerical data , Aged , Aged, 80 and over , Databases, Genetic/statistics & numerical data , Delta-5 Fatty Acid Desaturase , Female , Gene Frequency , Genetic Predisposition to Disease/ethnology , Genetic Predisposition to Disease/genetics , Humans , Linkage Disequilibrium , Male , Middle Aged , Polymorphism, Single Nucleotide/genetics , Quantitative Trait Loci/genetics , Risk Factors , White People/genetics , White People/statistics & numerical data , Young Adult
8.
Eur Respir J ; 36(2): 379-84, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20110399

ABSTRACT

The aim of the present study was to compare the prevalence of sleep-disordered breathing among Hispanic and white Americans and Japanese. A 1-night sleep study using a single-channel airflow monitor was performed on 211 Hispanics and 246 Whites from the Minnesota field centre (St Paul, MN, USA) of the Multi-Ethnic Study of Atherosclerosis (MESA), and 978 Japanese from three community-based cohorts of the Circulatory Risk in Communities Study (CIRCS) in Japan. The respiratory disturbance index and sleep-disordered breathing, defined as a respiratory disturbance index of > or =15 events x h(-1), were estimated. The prevalence of sleep-disordered breathing was higher in males (34.2%) than females (14.7%), and among Hispanics (36.5%) and Whites (33.3%) than among Japanese (18.4%), corresponding to differences in body mass index. Within body mass index strata, the race difference in sleep-disordered breathing was attenuated. This was also true when body mass index was adjusted for instead of stratification. The strong association between body mass index and sleep-disordered breathing was similar in Japanese and Americans. The prevalence of sleep-disordered breathing was lower among Japanese than among Americans. However, the association of body mass index with sleep-disordered breathing was strong, and similar among the race/ethnic groups studied. The majority of the race/ethnic difference in sleep-disordered breathing prevalence was explained by a difference in body mass index distribution.


Subject(s)
Sleep Apnea Syndromes/epidemiology , Aged , Asian People , Cross-Cultural Comparison , Female , Hispanic or Latino , Humans , Japan , Male , Middle Aged , Prevalence , Sex Factors , Sleep Apnea Syndromes/complications , United States , White People
9.
Diabetologia ; 51(6): 968-70, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18437354

ABSTRACT

AIMS/HYPOTHESIS: We hypothesised that TCF7L2 single nucleotide polymorphisms (SNPs) are associated with cardiovascular disease (CVD) and that the associations differ in diabetic and non-diabetic persons. METHODS: Our analysis included black and white participants from the Atherosclerosis Risk in Communities study who were free of prevalent CVD at baseline and had been genotyped for rs7903146, rs12255372, rs7901695, rs11196205 and rs7895340 (n=13,369). Cox proportional hazard regression was used to estimate the associations between polymorphisms and incident events; logistic and linear regression were used for associations with baseline risk factor levels. RESULTS: TCF7L2 SNPs were not significantly associated with incident coronary heart disease, ischaemic stroke, CVD, prevalent peripheral artery disease (PAD) or all-cause mortality in the full cohort or when stratified by race. CONCLUSIONS/INTERPRETATION: In the whole cohort, TCF7L2 SNPs were not associated with incident CVD, all-cause mortality or prevalent PAD. This result suggests that the increased health risk associated with rs7903146 genotype is specific to diabetes.


Subject(s)
Atherosclerosis/genetics , Atherosclerosis/mortality , Cardiovascular Diseases/genetics , Cardiovascular Diseases/mortality , Diabetic Angiopathies/genetics , Polymorphism, Single Nucleotide , TCF Transcription Factors/genetics , Black People/genetics , Coronary Disease/genetics , Coronary Disease/mortality , Diabetic Angiopathies/mortality , Female , Glycated Hemoglobin/analysis , Humans , Male , Middle Aged , Proportional Hazards Models , Racial Groups , Transcription Factor 7-Like 2 Protein , White People/genetics
10.
Genes Immun ; 8(8): 684-90, 2007 Dec.
Article in English | MEDLINE | ID: mdl-17917677

ABSTRACT

Atherogenesis is a chronic inflammatory process. Critical in the inflammation process is monocyte chemoattractant protein-1 (MCP-1). To locate genomic regions that affect circulating MCP-1 levels, a genome-wide linkage scan was conducted in a sample of whites and blacks. Phenotype and genetic marker data were available for 2501 white and 513 black participants in the National Heart Lung Blood Institute Family Heart Study follow-up examination. Heritability for MCP-1 was 0.37 in whites and 0.47 in blacks after adjusting for the effects of sex, age, age-sex interaction, smoking status, lifetime smoking exposure (pack-years) and field center. Significant linkage was observed for MCP-1 in a combined black and white sample on chromosome 3 (logarithm of the odds ratio (LOD)=3.5 at 78 cM, P=0.0001) and suggestive linkage was observed in whites on chromosome 5 (LOD=1.8 at 128 cM, P=0.002). Located under the linkage peak on chromosome 3 is the chemokine receptor gene cluster, including CCR2, the receptor for MCP-1. This study provides preliminary evidence linking genetic variation in a receptor to circulating levels of its ligand, as previously demonstrated for the low-density lipoprotein receptor. Further characterization of these chromosomal regions is needed to identify the functional mutations associated with circulating levels of MCP-1.


Subject(s)
Atherosclerosis/genetics , Chemokine CCL2/blood , Chromosomes, Human, Pair 3/genetics , Genetic Linkage , Receptors, Chemokine/genetics , Adult , Aged , Aged, 80 and over , Black People/genetics , Female , Humans , Male , Middle Aged , Multigene Family , National Heart, Lung, and Blood Institute (U.S.) , United States/ethnology , White People/genetics
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