RT Journal Article
SR Electronic
T1 Whole genome sequencing of pharmacogenetic drug response in racially and ethnically diverse children with asthma
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 128116
DO 10.1101/128116
A1 Angel C.Y. Mak
A1 Marquitta J. White
A1 Zachary A. Szpiech
A1 Walter L. Eckalbar
A1 Sam S. Oh
A1 Maria Pino-Yanes
A1 Donglei Hu
A1 Pagé Goddard
A1 Scott Huntsman
A1 Joshua Galanter
A1 Dara G. Torgerson
A1 Ann Chen Wu
A1 Blanca E. Himes
A1 Soren Germer
A1 Julia M. Vogel
A1 Karen L. Bunting
A1 Celeste Eng
A1 Sandra Salazar
A1 Kevin L. Keys
A1 Jennifer Liberto
A1 Thomas J. Nuckton
A1 Thomas A. Nguyen
A1 Pui-Yan Kwok
A1 Albert M. Levin
A1 Juan C. Celedón
A1 Erick Forno
A1 Hakon Hakonarson
A1 Patrick M. Sleiman
A1 Amber Dahlin
A1 Kelan G. Tantisira
A1 Scott T. Weiss
A1 Denise Serebrisky
A1 Emerita Brigino-Buenaventura
A1 Harold J. Farber
A1 Kelley Meade
A1 Michael A. Lenoir
A1 Pedro C. Avila
A1 Saunak Sen
A1 Shannon M. Thyne
A1 William Rodriguez-Cintron
A1 Cheryl A. Winkler
A1 Andrés Moreno-Estrada
A1 Karla Sandoval
A1 Jose R. Rodriguez-Santana
A1 Rajesh Kumar
A1 L. Keoki Williams
A1 Nadav Ahituv
A1 Elad Ziv
A1 Max A. Seibold
A1 Robert B. Darnell
A1 Noah Zaitlen
A1 Ryan D. Hernandez
A1 Esteban G. Burchard
A1 ,
YR 2017
UL http://biorxiv.org/content/early/2017/09/15/128116.abstract
AB Asthma 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 (NFKB1 and PLCB1), and β-adrenergic signaling pathways (ADAMTS3 and COX18). Functional analyses centered on NFKB1 revealed 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 the NFKB1 variants 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 SUMMARY Asthma 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.