Dataset Information

Whole-Genome Sequencing of Pharmacogenetic Drug Response in Racially Diverse Children with Asthma.

ABSTRACT:

Rationale

Albuterol, a bronchodilator medication, is the first-line therapy for asthma worldwide. There are significant racial/ethnic differences in albuterol drug response.

Objectives

To identify genetic variants important for bronchodilator drug response (BDR) in racially diverse children.

Methods

We performed the first whole-genome sequencing pharmacogenetics study from 1,441 children with asthma from the tails of the BDR distribution to identify genetic association with BDR.

Measurements and main results

We identified population-specific and shared genetic variants associated with BDR, including genome-wide significant (P < 3.53 × 10^-7) and suggestive (P < 7.06 × 10^-6) loci near genes previously associated with lung capacity (DNAH5), immunity (NFKB1 and PLCB1), and β-adrenergic signaling (ADAMTS3 and COX18). Functional analyses of the BDR-associated SNP in NFKB1 revealed potential regulatory function in bronchial smooth muscle cells. The SNP is also an expression quantitative trait locus for a neighboring gene, SLC39A8. The lack of other asthma study populations with BDR and whole-genome sequencing data on minority children makes it impossible to perform replication of our rare variant associations. Minority underrepresentation also poses significant challenges to identify age-matched and population-matched cohorts of sufficient sample size for replication of our common variant findings.

Conclusions

The lack of minority data, despite a collaboration of eight universities and 13 individual laboratories, highlights the urgent need for a dedicated national effort to prioritize diversity in research. Our study expands the understanding of pharmacogenetic analyses in racially/ethnically diverse populations and advances the foundation for precision medicine in at-risk and understudied minority populations.

SUBMITTER: Mak ACY

PROVIDER: S-EPMC6006403 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Whole-Genome Sequencing of Pharmacogenetic Drug Response in Racially Diverse Children with Asthma.

Mak Angel C Y ACY White Marquitta J MJ Eckalbar Walter L WL Szpiech Zachary A ZA Oh Sam S SS Pino-Yanes Maria M Hu Donglei D Goddard Pagé P Huntsman Scott S Galanter Joshua J Wu Ann Chen AC Himes Blanca E BE Germer Soren S Vogel Julia M JM Bunting Karen L KL Eng Celeste C Salazar Sandra S Keys Kevin L KL Liberto Jennifer J Nuckton Thomas J TJ Nguyen Thomas A TA Torgerson Dara G DG Kwok Pui-Yan PY Levin Albert M AM Celedón Juan C JC Forno Erick E Hakonarson Hakon H Sleiman Patrick M PM Dahlin Amber A Tantisira Kelan G KG Weiss Scott T ST Serebrisky Denise D Brigino-Buenaventura Emerita E Farber Harold J HJ Meade Kelley K Lenoir Michael A MA Avila Pedro C PC Sen Saunak S Thyne Shannon M SM Rodriguez-Cintron William W Winkler Cheryl A CA Moreno-Estrada Andrés A Sandoval Karla K Rodriguez-Santana Jose R JR Kumar Rajesh R Williams L Keoki LK Ahituv Nadav N Ziv Elad E Seibold Max A MA Darnell Robert B RB Zaitlen Noah N Hernandez Ryan D RD Burchard Esteban G EG

American journal of respiratory and critical care medicine 20180601 12

<h4>Rationale</h4>Albuterol, a bronchodilator medication, is the first-line therapy for asthma worldwide. There are significant racial/ethnic differences in albuterol drug response.<h4>Objectives</h4>To identify genetic variants important for bronchodilator drug response (BDR) in racially diverse children.<h4>Methods</h4>We performed the first whole-genome sequencing pharmacogenetics study from 1,441 children with asthma from the tails of the BDR distribution to identify genetic association with ...[more]

PMID: 29509491

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Project description:BackgroundChildren with medical complexity (CMC) are a priority pediatric population, with high resource use and associated costs. Genome-wide sequencing is increasingly organized for CMC early in life as a diagnostic test. Polypharmacy becomes common as CMC age. Clinically relevant pharmacogenetic (PGx) information can be extracted from existing genome sequencing (GS) data via GS-PGx profiling. The role of GS-PGx profiling in the CMC population is unclear.MethodsPrescribed medications were extracted from care plans of 802 eligible CMC enrolled in a structured Complex Care Program over a 10-year period. Drug-gene associations were annotated using curated Clinical Pharmacogenetics Implementation Consortium data. GS-PGx profiling was then performed for a subset of 50 CMC.ResultsOverall, 546 CMC (68%) were prescribed at least one medication with an established PGx association. In the GS-PGx subgroup, 24 (48%) carried variants in pharmacogenes with drug-gene guidelines for one or more of their current medications. All had findings of potential relevance to some medications, including 32 (64%) with variants in CYP2C19 that could affect their metabolism of proton-pump inhibitors.ConclusionGS-PGx profiling at the time of diagnostics-focused genetic testing could be an efficient way to incorporate precision prescribing practices into the lifelong care of CMC.ImpactPolypharmacy and genetic test utilization are both common in children with medical complexity. The role of repurposing genome sequencing data for pharmacogenetic profiling in children with medical complexity was previously unclear. We identified a high rate of medication use with clinically relevant drug-gene associations in this priority pediatric population and demonstrated that relevant pharmacogenetic information can be extracted from their existing genome sequencing data. Pharmacogenetic profiling at the time of diagnostics-focused genetic testing could be an efficient way to incorporate precision prescribing practices into the lifelong care of children with medical complexity.

Project description:ObjectiveMultiple linear regression (MLR) and machine learning techniques in pharmacogenetic algorithm-based warfarin dosing have been reported. However, performances of these algorithms in racially diverse group have never been objectively evaluated and compared. In this literature-based study, we compared the performances of eight machine learning techniques with those of MLR in a large, racially-diverse cohort.MethodsMLR, artificial neural network (ANN), regression tree (RT), multivariate adaptive regression splines (MARS), boosted regression tree (BRT), support vector regression (SVR), random forest regression (RFR), lasso regression (LAR) and Bayesian additive regression trees (BART) were applied in warfarin dose algorithms in a cohort from the International Warfarin Pharmacogenetics Consortium database. Covariates obtained by stepwise regression from 80% of randomly selected patients were used to develop algorithms. To compare the performances of these algorithms, the mean percentage of patients whose predicted dose fell within 20% of the actual dose (mean percentage within 20%) and the mean absolute error (MAE) were calculated in the remaining 20% of patients. The performances of these techniques in different races, as well as the dose ranges of therapeutic warfarin were compared. Robust results were obtained after 100 rounds of resampling.ResultsBART, MARS and SVR were statistically indistinguishable and significantly out performed all the other approaches in the whole cohort (MAE: 8.84-8.96 mg/week, mean percentage within 20%: 45.88%-46.35%). In the White population, MARS and BART showed higher mean percentage within 20% and lower mean MAE than those of MLR (all p values < 0.05). In the Asian population, SVR, BART, MARS and LAR performed the same as MLR. MLR and LAR optimally performed among the Black population. When patients were grouped in terms of warfarin dose range, all machine learning techniques except ANN and LAR showed significantly higher mean percentage within 20%, and lower MAE (all p values < 0.05) than MLR in the low- and high- dose ranges.ConclusionOverall, machine learning-based techniques, BART, MARS and SVR performed superior than MLR in warfarin pharmacogenetic dosing. Differences of algorithms' performances exist among the races. Moreover, machine learning-based algorithms tended to perform better in the low- and high- dose ranges than MLR.

Project description:BACKGROUND:Pharmacogenetic testing may change clinical medicine by allowing clinicians to tailor medications based on a patient's genetic makeup, however, these tests must first be validated in large, real-life populations of subjects that include children. A dearth of knowledge exists for whether pediatric populations are as willing as adult populations to provide samples for such studies. OBJECTIVE:(1) To assess whether pediatric and adult patients with persistent asthma are willing to provide specimens for DNA extraction and genetic studies. (2) To assess whether patients' willingness to provide blood as compared to buccal smear specimens differ. METHODS:Of 644 patients ages 4-38 years who had three or more prescription fills for inhaled corticosteroids in one year, 60% (385) were randomized to the blood specimen group and 40% (259) were randomized to the buccal smear group in order to study acceptance of different biospecimen collection methods. Research assistants contacted subjects to obtain consent, perform a phone survey, and request a specimen. RESULTS:There were no baseline differences between subjects randomized to the blood specimen group versus buccal smear group with respect to age, gender, or number of dispensings of inhaled corticosteroids. Of 259 subjects in the buccal smear group, 30% (78) provided samples, and of 385 subjects in the blood specimen group, 16% (60) provided samples. Subjects randomized to the buccal smear group were more likely to provide specimens for genetic study compared to subjects randomized to the blood specimen group (RR 1.21; 95% CI 1.10 - 1.32), even after adjusting for age. Pediatric subjects were more likely to provide specimens for genetic study than adult subjects with 23% (113) of pediatric subjects providing samples and 15% (25) of adult subjects providing samples (p=0.03). CONCLUSION:Children with asthma are as likely to participate in genetic studies as adults. Both children and adult subjects are more likely to provide buccal smear specimens rather than blood specimens for genetic study.

Dataset Information

Whole-Genome Sequencing of Pharmacogenetic Drug Response in Racially Diverse Children with Asthma.

Rationale

Objectives

Methods

Measurements and main results

Conclusions

Publications

Whole-Genome Sequencing of Pharmacogenetic Drug Response in Racially Diverse Children with Asthma.

Similar Datasets

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