NHLBI GO-ESP: Lung Cohorts Exome Sequencing Project (Cystic Fibrosis): Genetic modifiers of Pseudomonas aeruginosa (Pa) lung infection acquisition in cystic fibrosis

The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO.

The major goal of this project is to apply second generation resequencing technology to identify disease causing variants influencing pediatric and adult lung diseases in a collection of two longitudinal population cohorts of cystic fibrosis patients that have been well characterized for a comprehensive set of clinical traits. Exome sequencing was performed on 43 cystic fibrosis patients with early Pseudomonas aeruginosa (Pa) infection and 48 cystic fibrosis patients with late Pa infection to identify variants influencing the time to onset of Pa infection.

• Study Weblinks:
  • NHLBI GO ESP Project
• Study Design:
  • Prospective Longitudinal Cohort
• Study Type:
  • Cohort
  • Exome Sequencing
• dbGaP estimated ancestry using GRAF-pop
• Total number of consented subjects: 91
• Subject Sample Telemetry Report (SSTR)

Extreme phenotypes:

Youngest with Pa Infection vs. Oldest without Pa Infection

Pseudomonas aeruginosa (Pa) is a ubiquitous environmental organism and the most significant pathogen in cystic fibrosis (CF) lung disease. Early Pa acquisition is a major concern for CF care providers given that chronic infection with this pathogen is associated with significant CF morbidity and mortality. Two longitudinal population cohorts of cystic fibrosis patients that have been well characterized for a comprehensive set of clinical traits for the study of Pa acquisition have contributed to this project. The first cohort, Early Pseudomonas Infection Control (CFES-CF1), the world's largest, multicenter, longitudinal, prospective cohort of early lung disease in young CF patients and consists of 1,704 CF cases who were ages ≤ 12 years old with no prior isolation of Pa or at least a two-year history of Pa negative cultures. The second cohort, the NHLBI-GWAS to Identify CF Modifiers (CFES-CF2), consists of 1,208 who are at the extremes of lung disease severity.

Exome resequencing of phenotypic extremes represents a cost-effective and robust strategy for the sensitive and specific identification of variants causing protein-coding changes influencing risk for complex traits.

• Primary Phenotype: Cystic Fibrosis

• Principal Investigators
  • Michael Bamshad, MD. University of Washington, Seattle, WA, USA.
  • Kathleen Barnes, PhD. Johns Hopkins University, Baltimore, MD, USA.
  • Michael Knowles, MD. University of North Carolina, Chapel Hill, NC, USA.
  • Ronald Gibson, MD. Seattle Children's Hospital, Seattle, WA, USA.
• Funding Source
  • 1RC2HL102923-01. National Institutes of Health, Bethesda, MD, USA.