Marquitta J White
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Researcher at University of California San Francisco
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American Journal of Respiratory and Critical Care Medicine, 2018-06-15
Video Abstract (AI generated)
Paper
Preprint
American Journal of Respiratory and Critical Care Medicine
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.
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PLOS Medicine, 2015-12-15
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Paper
Preprint
PLOS Medicine
Summary Points Health disparities persist across race/ethnicity for the majority of Healthy People 2010 health indicators. Most physicians and scientists are informed by research extrapolated from a largely homogenous population, usually White and male. A growing proportion of Americans are not fully benefiting from clinical and biomedical advances since racial and ethnic minorities make up nearly 40% of the U.S. population. Ignoring the racial/ethnic diversity of the U.S. population is a missed scientific opportunity to fully understand the factors that lead to disease or health. U.S. biomedical research and study populations must better reflect the country's changing demographics. Adequate representation of diverse populations in scientific research is imperative as a matter of social justice, economics, and science.