Please describe the research questions of your lab.
Our airways diseases genetics research laboratory is located within the Department of Internal Medicine and the Center for Precision Medicine at the Wake Forest School of Medicine. Our primary research questions relate to the effects of rare genetic variants on asthma severity and the response to beta2-adrenergic receptor agonist therapy with a focus on the role of rare functional variants within the beta2-adrenergic receptor (ADRB2), genes within the G protein-coupled receptor pathway. We have also performed ancestry-based genetic studies in African American asthma and COPD cohorts enriched for severe disease to understand the genetic determinants of lung function, disease severity, and drug responsiveness inherited from a common ancestry. Our group developed the analytical methods for analyzing genetic ancestry for effects on therapeutic responses to LABA and inhaled corticosteroid-containing combination therapies in African descent subjects from the NHLBI AsthmaNet Best African American Response to Asthma Drugs (BARD) trial. Our group has also analyzed rare variants identified through targeted resequencing of the gene coding for alpha1-antitrypsin, the strongest genetic factor for COPD, to determine if rare variation influences disease severity in both asthma and COPD cohorts.
What genetics/genomics techniques do you utilize in your lab?
The genomics laboratory in the Center for Precision Medicine operates a genotyping core with multiple platforms which we use for genotyping, including the Sequenom MassARRAY SNP genotyping system for genotyping of candidate genes and the Illumina HiScan for high throughput whole-genome genotyping. Most of our asthma and COPD cohorts have had whole-genome genotyping performed with a combination of different Chip platforms designed to tag/scan whole-genomes (for genome-wide association studies or GWAS [ie Illumina OmniExpress BeadChip]) and/or provide comprehensive coverage of genetic variants within the coding exons (ie Illumina HumanExome or Multi-Ethnic Global [MEGA] BeadChip). Our group is also active in two NHLBI-sponsored network study cohorts that will have whole-genome sequencing data through the NHLBI TopMed program: the NHLBI Severe Asthma Research Program (SARP1-3) and the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS). The Center also has access to next-generation sequencing technologies, including an Ion Torrent PGM, the Illumina NextSeq 500, and the Illumina MiSeq Dx.
Describe a key technique/assay/instrument utilized in your lab, and what novel insights does it bring to your research question?
Our genetics research group has participated in different NHBLI-sponsored network studies for airways diseases, including NHLBI Asthma Clinical Research Network (ACRN), AsthmaNet, SARP1-3, and SPIROMICS. These cohorts and partnerships with industry-sponsored asthma clinical trials have resulted in a unique resource for our group consisting of more than 8,000 asthma and COPD subjects from eleven ethnically diverse cohorts who have whole-genome genetic data from a combination of sources (mainly comprehensively genotyping and next-generation sequencing). As a participating site for these large NHLBI networks and clinical trial, we have the capacity to recruit and characterize subjects while performing data analysis of large cohorts that focus on pharmacogenetic studies and the genetics of disease severity in asthma and COPD while allowing for validation of genetic discoveries across ethnically diverse cohorts.
At what point in your life did you decide you wanted to be a scientist/physician?
My grandmother was an asthmatic who died of a life-threatening asthma exacerbation on December 1994, the year I graduated from high school. I will never forget about this rare outcome among asthmatics, an asthma-related death. My grandmother was Puerto Rican, a member of the ethnic group that experiences the greatest burden of morbidity and mortality in the United States. Since my pulmonary fellowship training began 10 years ago, my mentored research path led me from the study of genetic variation in individuals with asthma from different ethnic populations, including Puerto Ricans, to the study of rare variants that may define a small subgroup susceptible to altered beta agonist response and an increased risk for severe exacerbations with the use of long-acting beta agonists (Ortega VE, Lancet Resp Med 2014). After my fellowship was completed in 2010, I became a scholar for the K12 Program in the Genetics and Genomics of Lung Diseases (PI: Deborah A Meyers, PhD) from the NHLBI for three years. I was subsequently awarded a K08 career development award from the NHLBI (PI: VE Ortega) which has protected 75% effort for research and the completion of a PhD degree in Molecular Medicine and Translational Sciences through the Wake Forest University Graduate School. I am also fortunate to have been a recipient of a NIH Loan Repayment Program for seven consecutive years which eliminated by medical school student loan debt and allowed me to focus on my research. My early life experience with the rare severe consequences of asthma initiated a career path which has been recently supported by my mentors (Eugene Bleecker, MD; Deborah Meyers, PhD; Stephen Peters, MD, PhD) and the generosity of the NHLBI career development programs.
In your opinion, what is one of the most important discoveries in the field of respiratory illness/disease/function that was dependent on genomics or similar techniques?
Since the initial sequencing of the human genome in 2001, the amount of information available for genetic studies has expanded rapidly from early family-based based studies to genome-wide association studies (GWAS) which have now demonstrated that at least approximately 69 genes possibly influence asthma risk. Among the most important and rapidly evolving discoveries in the field of respiratory diseases relates to numerous recent publications highlighting these complex genetic determinants and how environmental factors influence susceptibility of common airways disease such as asthma and COPD. More recent, larger GWAS highlight how more comprehensive genotyping platforms that evaluate variation in diverse human population, the inclusion of more ethnically diverse cohorts, and how the study of disease-related phenotypes (such as markers of disease severity [i.e. lung function]) has led to the discovery of an expanding catalogue of genetic determinants for these common, complex airways disease. Since the variation discovered to date does not completely account for the observed heritability of asthma or COPD, the use of next-generation DNA sequencing, RNA sequencing (gene expression), and epigenetic methods (i.e. bisulfite sequencing for DNA methylation studies) in relevant target tissues is beginning to show the potential role of infrequent or rare variants and gene-by-environment epigenetic interactions in determining disease risk and progression.
Briefly describe your favorite publication involving genomics/omics that you were involved with in general-audience terms.
Our genetic study of rare variants within the ADRB2 gene is the first demonstrating major rare variant pharmacogenetics effects in asthma as it relates to the potential for rare, life-threatening responses to long-acting beta agonist (LABA) therapy in different ethnic groups (Ortega VE, Lancet Resp Med 2014). This safety issue with LABA has been the focus of an FDA-mandated international safety study consisting of 46,800 asthmatics, in which our group was a participating site (Peters SP, N Engl J Med 2016). The resulting editorials and manuscripts of the LABA safety study (two published in the New England Journal of Medicine) have resulted in the FDA removing their black box safety warning from LABA-containing inhalers and cited our work on rare variants as the next step in understanding ethnic group-specific differences in LABA responsiveness.
What is your favorite aspect of ATS?
I have had the opportunity to present different genetic studies at the ATS international conference for the past 10 consecutive years. Each abstract I have presented has provided different and unique opportunities to meet investigators within the NHLBI-sponsored networks that I actively participate in such as the Asthma Clinical Research Network, AsthmaNet, the Severe Asthma Research Program, the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS), and the Cystic Fibrosis Therapeutics Development Network. These presentations and my participation at each ATS conference also allowed me to further expand my professional network as I also meet and network with investigators from across the United States and Europe. This has resulted in collaborative relationships which have formed the basis for my participation in publications as a co-author or reviewer for the American Journal of Respiratory and Critical Care Medicine, a successful K08 career development award application, and a pending R01 application. Throughout these past 10 years, I have served on the Respiratory Structure and Function Assembly Program Committee, the ATS/NHLBI Workshop on Addressing Healthcare Disparities in Respiratory Diseases, and am currently a Nominating Committee Member for the Section of Genetics and Genomics. These leadership opportunities have allowed me to contribute my evolving expertise as an early career investigator and work with other investigators with a broad range of interests and senior expertise.
How could your research assist scientists and clinicians in other assemblies at ATS?
The strength of our genetics research group is that we participate in different NHBLI-sponsored networks for airways diseases and have partnerships with industry-sponsored asthma clinical trials. Thus, we have access to eleven ethnically diverse asthma or COPD cohorts with comprehensive clinical phenotype data and whole-genome genetic data. Such data could potentially assist scientists or clinicians who are trying to expand current clinical or genetic studies for larger, multi-ethnic meta-analyses or can provide an opportunity to confirm or replicate of genetic associations found in GWAS from in other, outside cohorts from similar or different ethnic backgrounds. In addition, our genomics laboratory has the ability to perform genotyping or sequencing in new cohorts where DNA or RNA samples have been collected.
Victor Ortega (vortega@wakehealth.edu)
