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.

Keywords: Latinos; NFKB1; albuterol; asthma; minority.

Figure 1.

An overview of the main analyses performed in the current study. More detailed descriptions of the discovery and replication cohort demographics and analyses performed for common and rare variant analysis can be found in the Methods section and the Methods section in the online supplement. AA = African American; BDR = bronchodilator drug response; BSMC = bronchial smooth muscle cell; ChIP-seq = chromatin immunoprecipitation sequencing; CHOP = Children’s Hospital of Philadelphia; DiCE = Diverse Convergent Evidence; GALA I = Genetics of Asthma in Latino Americans; GALA II = Genes-Environments and Admixture in Latino Americans; HPR = Hartford–Puerto Rico cohort; MX = Mexican; PR = Puerto Rican; SAGE = Study of African Americans, Asthma, Genes and Environments; SAPPHIRE = Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity; WGS = whole-genome sequencing.

Figure 2.

(A) Manhattan plot of the transethnic meta-analysis of single locus bronchodilator drug response association testing. Top 10 bronchodilator drug response–associated loci are circled. The black line indicates the universal genome-wide significance threshold (5.00 × 10⁻⁸), the red line indicates the adjusted genome-wide significance threshold (3.53 × 10⁻⁷), and the blue line indicates the suggestive significance threshold (7.06 × 10⁻⁶). (B) Forest plot of the two most significantly associated SNPs, rs17834628 and rs35661809. The R² between these two SNPs is 0.93 in Puerto Ricans, 0.96 in Mexicans, and 0.66 in African Americans. (C) The most significantly associated SNP (rs17834628) is plotted with 400-kb flanking regions on either side. Dot color shows each SNP linkage disequilibrium with rs17834628 based on the 1,000 Genomes November 2014 admixed American population. Multiple SNPs in high linkage disequilibrium (R² > 0.8, red) reached a suggestive significance level.

Figure 3.

Manhattan plot of SKAT-O analysis of biallelic common and rare SNPs grouped by 1-kb windows sliding across chromosome 1–22 in (A) Puerto Ricans, (B) Mexicans, (C) African Americans, and (D) all populations combined. Bonferroni-corrected genome-wide and suggestive significance levels are marked by red and blue lines, respectively.