Whole genome sequencing of pharmacogenetic drug response in racially and ethnically diverse children with asthma
Authors: Mak Angel C.Y. , White Marquitta J. , Szpiech Zachary A. , Eckalbar Walter L. , Oh Sam S. , Pino-Yanes Maria , Hu Donglei , Goddard Pagé , Huntsman Scott , Galanter Joshua , Torgerson Dara G. , Wu Ann Chen , Himes Blanca E. , Germer Soren , Vogel Julia M. , Bunting Karen L. , Eng Celeste , Salazar Sandra , Keys Kevin L. , Liberto Jennifer , Nuckton Thomas J. , Nguyen Thomas A. , Kwok Pui-Yan , Levin Albert M. , Celedón Juan C. , Forno Erick , Hakonarson Hakon , Sleiman Patrick M. , Dahlin Amber , Tantisira Kelan G. , Weiss Scott T. , Serebrisky Denise , Brigino-Buenaventura Emerita , Farber Harold J. , Meade Kelley , Lenoir Michael A. , Avila Pedro C. , Sen Saunak , Thyne Shannon M. , Rodriguez-Cintron William , Winkler Cheryl A. , Moreno-Estrada Andrés , Sandoval Karla , Rodriguez-Santana Jose R. , Kumar Rajesh , Williams L. Keoki , Ahituv Nadav , Ziv Elad , Seibold Max A. , Darnell Robert B. , Zaitlen Noah , Hernandez Ryan D. , Burchard Esteban G. 
Published: April 2017

ABSTRACTAsthma is the most common chronic disease of children, with significant racial/ethnic differences in prevalence, morbidity, mortality and therapeutic response. Albuterol, a bronchodilator medication, is the first-line therapy for asthma treatment worldwide. We performed the largest whole genome sequencing (WGS) pharmacogenetics study to date using data from 1,441 minority children with asthma who had extremely high or low bronchodilator drug response (BDR). We identified population-specific and shared pharmacogenetic variants associated with BDR, including genome-wide significant (p < 3.53 x 10-7) and suggestive (p < 7.06 x 10-6) loci near genes previously associated with lung capacity (DNAH5), immunity (NFKB1andPLCB1), and β-adrenergic signaling pathways (ADAMTS3andCOX18). Functional analyses centered onNFKB1revealed potential regulatory function of our BDR-associated SNPs in bronchial smooth muscle cells. Specifically, these variants are in linkage disequilibrium with SNPs in a functionally active enhancer, and are also expression quantitative trait loci (eQTL) for a neighboring gene,SLC39A8. Given the lack of other asthma study populations with WGS data on minority children, replication of our rare variant associations is infeasible. We attempted to replicate our common variant findings in five independent studies with GWAS data. The age-specific associations previously found in asthma and asthma-related traits suggest that the over-representation of adults in our replication populations may have contributed to our lack of statistical replication, despite the functional relevance of theNFKB1variants demonstrated by our functional assays. 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.AUTHOR SUMMARYAsthma is the most common chronic disease among children. Albuterol, a bronchodilator medication, is the first-line therapy for asthma treatment worldwide. In the U.S., asthma prevalence is the highest among Puerto Ricans, intermediate among African Americans and lowest in Whites and Mexicans. Asthma disparities extend to mortality, which is four- to five-fold higher in Puerto Ricans and African Americans compared to Mexicans [1]. Puerto Ricans and African Americans, the populations with the highest asthma prevalence and death rate, also have the lowest albuterol bronchodilator drug response (BDR). We conducted the largest pharmacogenetic study using whole genome sequencing data from 1,441 minority children with asthma who had extremely high or low albuterol bronchodilator drug response. We identified population-specific and shared pharmacogenetic variants associated with BDR. Our findings help inform the direction of future development of asthma medications and our study advances the foundation of precision medicine for at-risk, yet understudied, racially/ethnically diverse populations.