Genetics and Genomics Research at the National Heart, Lung, and Blood Institute: Cashell Jaquish, PhD and Weiniu Gan, PhD

Dr. Cashell Jaquish and Dr. Weiniu Gan
Dr. Cashell Jaquish and Dr. Weiniu Gan

The National Heart, Lung and Blood Institute (NHLBI)’s mission is to provide global leadership for a research, training, and education program to promote the prevention and treatment of heart, lung and blood diseases and enhance the health of all individuals so that they can live longer and more fulfilling lives. The third largest institute at NIH, NHLBI supports one of the largest portfolios of human genome research. We spoke with Dr. Cashell Jaquish, Program Director in NHLBI’s Division of Cardiovascular Sciences, and Dr. Weiniu Gan, Program Director for Genetics, Genomics and Advanced Technologies in NHLBI’s Division of Lung Diseases, to learn more about the Institute’s current directions pertaining to genetics, genomics, and precision medicine research.

ASHG: NHLBI has a strong interest in precision medicine and sponsors the Trans-Omics for Precision Medicine (TOPMed) program.  What are we learning from this program and what do you see as the promise of precision medicine for improving the treatment of heart, lung, blood, and sleep diseases?

Jaquish: The TOPMed program integrates whole-genome sequencing and other omics data (e.g., metabolic profiles, epigenomics, protein and RNA expression patterns) with laboratory, behavioral, imaging, environmental, and clinical data. So far, it has amassed nearly four petabytes of de-identified data from more than 161,000 racially and ethnically diverse participants in 80 studies, including the NHLBI’s landmark Framingham Heart Study, the Jackson Heart Study, the Hispanic Community Health Study/Study of Latinos, and many others. Just last month, a study published in Nature described the analysis of more than 53,000 whole genomes using TOPMed data, primarily from people of non-European ancestry. Within this data, 400 million genetic variants were identified, more than 78 percent of which had not been described before. These findings provide new insights into genetic variants that can influence disease susceptibility and responses to treatment. For example, the analysis found more than 30 change-of-function variants in the CYP2D6 gene, which encodes an enzyme that metabolizes an estimated 25 percent of prescription drugs.

TOPMed fills a need for high-quality genomic data from people of non-European ancestry who have been previously underrepresented in genome sequencing efforts. So far, this diverse population structure is supporting more than 40 percent of TOPMed publications. We are expecting more to come. TOPMed offers an Imputation Reference Panel, among the most diverse available, that enables researchers to fill gaps in the sequencing data from their own genomic studies, saving time and resources. The panel, as well as other datasets, are accessible through NHLBI’s secure, cloud-based platform called the BioData Catalyst. The BioData Catalyst includes tools for analyzing large datasets and sharing results among users in real time. It also provides a virtual collaborative workspace that makes data findable, accessible, interoperable, and reusable to all qualified researchers, the vast majority of whom lack their own data science resources.

 ASHG: What do you see as significant advances in recent years in our understanding of the genetic underpinnings of some of the more common heart, lung, blood, and sleep disorders?

Gan: When NHLBI started its TOPMed program, it was estimated that 96 percent of genome wide association study (GWAS) participants were of European ancestry. This lack of diversity was a missed opportunity for scientific discovery in other racial and ethnic populations and was a huge gap in genomic medicine. TOPMed was designed to reverse this trend and, so far, has recruited nearly 60 percent of its participants from underrepresented populations, including 31 percent of African descent, 15 percent Hispanic/Latino, 9 percent Asian, and 4 percent others.

We are beginning to reap the benefits of this diversity. For example, a TOPMed study involving Puerto Rican youth identified a genomic region at 1q32 that was significantly associated with a decrease in the lung volume of exhaled air. This result suggests that genetic ancestry should be considered when determining a standard lung function reference for healthy individuals. In another example, the gene GSDMB in 17q21 locus was found to be associated with asthma in a 2007 GWAS that used a Caucasian population. However, because of lack of single nucleotide polymorphisms (SNPs) near the gene among this population, the function of this gene in asthma remained unknown, until a recent TOPMed study using whole genome sequencing data from African Americans successfully identified a potential functional SNP that causes an alternative splicing form of GSDMB. This insight which will likely lead to a better understanding of GSDMB’s role in asthma development.

ASHG: What other precision medicine efforts is NHLBI supporting? 

Gan: Within its lung disease portfolio, NHLBI continues to support the Precision Interventions for Severe and Exacerbation Prone Asthma (PrecISE) clinical trial network. With 30 locations across the country, PrecISE is evaluating several novel and approved treatments for asthma by targeting them to defined groups of patients who share similar genetic characteristics or biomarkers.

In idiopathic pulmonary fibrosis (IPF), NHLBI is working with the Pulmonary Fibrosis Foundation to support the PRECISIONS study, which is using genetic testing to identify those with IPF most likely to respond to experimental treatment with the antioxidant N-acetylcysteine (NAC). This precision medicine trial builds on an earlier retrospective analysis suggesting that a gene called TOLLIP influences patients’ responses to NAC. The study is enrolling only those patients who carry the NAC-responsive TOLLIP variant to increase the likelihood of detecting a benefit.

ASHG: What is NHLBI’s current focus on genetic diseases such as sickle cell disease, familial hypercholesterolemia, and congenital heart disease?

Gan: NHLBI is making significant investments in identifying treatments and potential cures for sickle cell disease (SCD). Of note, NHLBI launched the  Cure Sickle Cell Initiative in 2018 to support the development of gene-based cures for SCD that will work for all patients, including those ineligible for bone marrow transplants. And in early 2020, the NHLBI also became an integral part of a collaboration between NIH and the Bill & Melinda Gates Foundation to develop affordable, safe, and effective gene-based cures for SCD in sub-Saharan Africa.

We know that familial hypercholesterolemia (FH) frequently goes undiagnosed, but screening family members of people with FH can help find those undiagnosed cases. However, this “cascade screening” is often limited in reach due to patient privacy laws and lack of availability of FH genetic testing. In 2019, NHLBI issued a funding opportunity to develop solutions that address these real-world barriers. Applications are due in March 2021.

NHLBI’s Bench to Bassinet Program, which comprises the Pediatric Heart Network (PHN), the Cardiovascular Development Consortium, and the Pediatric Cardiac Genomics Consortium (PCGC), is studying the genetic underpinnings of congenital heart disease (CHD). The PCGC is also investigating the genomic basis of learning disabilities and developmental delays associated with CHD, and is leveraging the NIH Gabriella Miller Kids First Program and the TOPMed Program to conduct whole-genome sequencing of hundreds of children with CHD and their parents. NHLBI also co-leads the trans-NIH INvestigating Co-occurring conditions across the Lifespan to Understand Down syndrome (INCLUDE) Project, which includes genome sequencing studies to better define the genetic causes of CHD in people with and without Down syndrome.

ASHG: What are some of the challenges associated with conducting and supporting genomics research, and how is NHLBI working to address them?

Jaquish: There are some significant challenges associated with sharing data and making it accessible to researchers, especially among populations that grapple with the legacy of being mistreated by the medical or scientific research establishment. Many vulnerable populations are understandably uncomfortable with the idea of their genetic data being shared. In addition, past consent issues may limit the use of some valuable legacy data sets, and consent details may be inconsistent from one data set to another. There are also logistical challenges associated with promoting and supporting the analysis of existing genomic data sets, as well as breaking down silos between and among individual investigators. Finally, we are also still working to better pinpoint when genomic findings for common complex diseases are ready for translation and implementation into practice.

As we work through these challenges, we are investing in training opportunities for young and early-stage investigators that will improve genomics research down the line. For example, the BioData Catalyst Fellows Program, currently supporting more than 30 uniquely skilled individuals, provides funding to early-stage investigators for research on novel and innovative data science research problems, including genomic data. Other training opportunities for early-career investigators, such as the Programs to Increase Diversity Among Individuals Engaged in Health Related Research (PRIDE), and the Maximizing Opportunities for Scientific and Academic Independent Careers (MOSAIC) program, include training in genetics and genetic epidemiology for heart, lung, blood and sleep disorders.

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