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

NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1552-1564
Number of pages13
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume197
Issue number12
DOIs
StatePublished - Jun 15 2018

Fingerprint Dive into the research topics of 'Whole-Genome Sequencing of Pharmacogenetic Drug Response in Racially Diverse Children with Asthma'. Together they form a unique fingerprint.

Cite this