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 #
5R01HL060710-12
Application #
8669031
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
2014-06-01
Budget End
2015-05-31
Support Year
12
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Harvard University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
Mikacenic, Carmen; Price, Brenda L; Harju-Baker, Susanna et al. (2017) A Two-Biomarker Model Predicts Mortality in the Critically Ill with Sepsis. Am J Respir Crit Care Med 196:1004-1011
Zhang, Ruyang; Wang, Zhaoxi; Tejera, Paula et al. (2017) Late-onset moderate to severe acute respiratory distress syndrome is associated with shorter survival and higher mortality: a two-stage association study. Intensive Care Med 43:399-407
Zhu, Zhaozhong; Liang, Liming; Zhang, Ruyang et al. (2017) Whole blood microRNA markers are associated with acute respiratory distress syndrome. Intensive Care Med Exp 5:38
Bhatraju, Pavan K; Robinson-Cohen, Cassianne; Mikacenic, Carmen et al. (2017) Circulating levels of soluble Fas (sCD95) are associated with risk for development of a nonresolving acute kidney injury subphenotype. Crit Care 21:217
Bhatraju, Pavan K; Mukherjee, Paramita; Robinson-Cohen, Cassianne et al. (2016) Acute kidney injury subphenotypes based on creatinine trajectory identifies patients at increased risk of death. Crit Care 20:372
Alladina, Jehan W; Levy, Sean D; Hibbert, Kathryn A et al. (2016) Plasma Concentrations of Soluble Suppression of Tumorigenicity-2 and Interleukin-6 Are Predictive of Successful Liberation From Mechanical Ventilation in Patients With the Acute Respiratory Distress Syndrome. Crit Care Med 44:1735-43
Zhu, Zhaozhong; Zhang, Ruyang; Liang, Liming et al. (2016) Whole blood microRNAs as a prognostic classifier for acute respiratory distress syndrome 28-day mortality. Intensive Care Med 42:1824-1825
Wei, Yongyue; Wang, Zhaoxi; Su, Li et al. (2015) Platelet count mediates the contribution of a genetic variant in LRRC16A to ARDS risk. Chest 147:607-617
Ahasic, Amy M; Tejera, Paula; Wei, Yongyue et al. (2015) Predictors of Circulating Insulin-Like Growth Factor-1 and Insulin-Like Growth Factor-Binding Protein-3 in Critical Illness. Crit Care Med 43:2651-9
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

Showing the most recent 10 out of 56 publications