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Author Notes:

E-mail: jchristi@mail.med.upenn.edu

Conceived and designed the experiments: JDC MMW JB DCC RA HH.

Performed the experiments: JDC JB CK MMW JA RA HH AKM.

Analyzed the data: RF JB NJM JDC ML JA MMW HH.

Contributed reagents/materials/analysis tools: JDC MMW GEO LBW DCC CSC MJC MM KCB JS PNL AKM RA JPM HH.

Wrote the paper: JDC MMW DCC LBW CSC MM KCB JS JPM RA HH.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The authors have declared that no competing interests exist.

Subjects:

Research Funding:

This study was funded by the following NIH grants: P50HL60290, P01HL079063, HL081332, HL060710.

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • MULTIDISCIPLINARY SCIENCES
  • RESPIRATORY-DISTRESS-SYNDROME
  • MANNOSE-BINDING LECTIN
  • CHAIN-KINASE GENE
  • HUMAN-DISEASE
  • EARLY RELEASE
  • T-CELLS
  • POLYMORPHISM
  • ARDS
  • MORTALITY
  • PROTEIN
  • Pulmonary

Genome Wide Association Identifies PPFIA1 as a Candidate Gene for Acute Lung Injury Risk Following Major Trauma

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Journal Title:

PLoS ONE

Volume:

Volume 7, Number 1

Publisher:

, Pages e28268-e28268

Type of Work:

Article | Final Publisher PDF

Abstract:

Acute Lung Injury (ALI) is a syndrome with high associated mortality characterized by severe hypoxemia and pulmonary infiltrates in patients with critical illness. We conducted the first investigation to use the genome wide association (GWA) approach to identify putative risk variants for ALI. Genome wide genotyping was performed using the Illumina Human Quad 610 BeadChip. We performed a two-stage GWA study followed by a third stage of functional characterization. In the discovery phase (Phase 1), we compared 600 European American trauma-associated ALI cases with 2266 European American population-based controls. We carried forward the top 1% of single nucleotide polymorphisms (SNPs) at p<0.01 to a replication phase (Phase 2) comprised of a nested case-control design sample of 212 trauma-associated ALI cases and 283 at-risk trauma non-ALI controls from ongoing cohort studies. SNPs that replicated at the 0.05 level in Phase 2 were subject to functional validation (Phase 3) using expression quantitative trait loci (eQTL) analyses in stimulated B-lymphoblastoid cell lines (B-LCL) in family trios. 159 SNPs from the discovery phase replicated in Phase 2, including loci with prior evidence for a role in ALI pathogenesis. Functional evaluation of these replicated SNPs revealed rs471931 on 11q13.3 to exert a cis-regulatory effect on mRNA expression in the PPFIA1 gene (p = 0.0021). PPFIA1 encodes liprin alpha, a protein involved in cell adhesion, integrin expression, and cell-matrix interactions. This study supports the feasibility of future multi-center GWA investigations of ALI risk, and identifies PPFIA1 as a potential functional candidate ALI risk gene for future research.

Copyright information:

© 2012 Christie et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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