Acute respiratory distress syndrome (ARDS) is a common, devastating clinical syndrome. In the last cycle of this project, we showed that candidate gene polymorphisms suggest a role for common genetic variation in determining host susceptibility to, and survival of ARDS in at-risk patients. Currently, the Principal Investigator o-leads an ongoing collaborative genome-wide association study of ALI/ARDS using patients and samples collected from the last cycle of this project. However, GWAS can only define disease-associated genomic loci with low to moderate effects and cannot identify causal mutations. Direct sequencing is regarded as the post-GWAS, ultimate approach to identifying causal mutations and defining disease candidate genes. The recent development of Next-Generation sequencing technologies enables population-based direct sequencing of much larger genomic regions, resulting in significant cost and time savings by bypassing most stages of fine mapping. This multidisciplinary competing renewal application will focus on rapidly advancing our knowledge of the genetic factors for ARDS development and related outcomes from our candidate gene research, as well as our recent large-scale genetic association study. We will conduct targeted sequencing of the promoter/exons/miRNA/regulatory elements within candidate genes/regions defined through analysis of whole exome sequencing data and existing genotyping data derived from the last cycle. We will then define ARDS candidate genes by investigating the aggregate information of functional genetic variations using our newly developed statistical method (SKAT), which addresses the specific issues related to the analysis of rare variations.
In Specific Aim 1, we will conduct whole exome sequencing on 100 ARDS cases and 100 matched controls to define target regions by integrating analysis of whole exome sequencing data with candidate genetic loci discovered in the previous cycle, as well as the current GWAS. With our collaborator, Dr. Mark Wurfel of University of Washington, we will also analyze available eQTL data to evaluate the functional relevance of the target regions.
In Specific Aim 2, we will design a molecular inversion probe (MIP) panel for resequencing promoter/exons/miRNA/regulatory elements within the target regions defined in Aim 1;identify all variations using MIP capture coupled with deep NextGen sequencing and define candidate genes by evaluating the associations of functional rare/common variations with ARDS susceptibility and outcomes using variation aggregation methods.
In Specific Aim 3, we will replicate the top-ranked genes by NextGen sequencing in a large collaborating external population with a similar study design. The project has the potential to have a high impact on our understanding of genetic factors for ARDS risk and survival outcomes.

Public Health Relevance

Acute respiratory distress syndrome (ARDS) is a common, devastating clinical syndrome caused by several direct and indirect insults to the lung, most commonly pneumonia, sepsis, and multiple traumas. This multidisciplinary competing renewal application will focus on rapidly advancing our knowledge of the genetic factors for the development of ARDS. With the completion of this project, we expect to advance our knowledge of the risk for development of ARDS and associated outcomes (especially survival) from GWAS-defined genomic loci to causal mutations in candidate genes;results will contribute significantly to our understanding of the pathogenesis of ARDS, the identification of novel targets for therapeutic intervention, and the use of novel markers for stratification of patients at risk for ARDS and related poor outcomes such as death or prolonged mechanical ventilation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL060710-10A1
Application #
8295266
Study Section
Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
Program Officer
Harabin, Andrea L
Project Start
2000-02-01
Project End
2016-05-31
Budget Start
2012-08-15
Budget End
2013-05-31
Support Year
10
Fiscal Year
2012
Total Cost
$799,058
Indirect Cost
$182,444
Name
Harvard University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
Wang, Tiehua; Liu, Zhuang; Wang, Zhaoxi et al. (2014) Thrombocytopenia is associated with acute respiratory distress syndrome mortality: an international study. PLoS One 9:e94124
Beitler, Jeremy R; Schoenfeld, David A; Thompson, B Taylor (2014) Preventing ARDS: progress, promise, and pitfalls. Chest 146:1102-13
Tejera, Paula; O'Mahony, D Shane; Owen, Caroline A et al. (2014) Functional characterization of polymorphisms in the peptidase inhibitor 3 (elafin) gene and validation of their contribution to risk of acute respiratory distress syndrome. Am J Respir Cell Mol Biol 51:262-72
Ahasic, Amy M; Zhao, Yang; Su, Li et al. (2014) Adiponectin gene polymorphisms and acute respiratory distress syndrome susceptibility and mortality. PLoS One 9:e89170
Meyer, Nuala J; Feng, Rui; Li, Mingyao et al. (2013) IL1RN coding variant is associated with lower risk of acute respiratory distress syndrome and increased plasma IL-1 receptor antagonist. Am J Respir Crit Care Med 187:950-9
de Pont, Anne-Cornelie J M (2013) Underweight, acute kidney injury, and mortality. Crit Care Med 41:e12-3
Chang, Steven Y; Dabbagh, Ousama; Gajic, Ognen et al. (2013) Contemporary ventilator management in patients with and at risk of ALI/ARDS. Respir Care 58:578-88
Lemos-Filho, Luciano B; Mikkelsen, Mark E; Martin, Greg S et al. (2013) Sex, race, and the development of acute lung injury. Chest 143:901-9
Bajwa, Ednan K; Volk, Jessica A; Christiani, David C et al. (2013) Prognostic and diagnostic value of plasma soluble suppression of tumorigenicity-2 concentrations in acute respiratory distress syndrome. Crit Care Med 41:2521-31
Ahasic, Amy M; Zhai, Rihong; Su, Li et al. (2012) IGF1 and IGFBP3 in acute respiratory distress syndrome. Eur J Endocrinol 166:121-9

Showing the most recent 10 out of 37 publications