title: Genome wide association identifies PPFIA1 as a candidate gene for acute lung injury risk following major trauma.
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.
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Christie
authors.forename: Mark M
authors.initials: MM
authors.lastname: Wurfel
authors.forename: Rui
authors.initials: R
authors.lastname: Feng
authors.forename: Grant E
authors.initials: GE
authors.lastname: O'Keefe
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bradfield
authors.forename: Lorraine B
authors.initials: LB
authors.lastname: Ware
authors.forename: David C
authors.initials: DC
authors.lastname: Christiani
authors.forename: Carolyn S
authors.initials: CS
authors.lastname: Calfee
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Cohen
authors.forename: Michael
authors.initials: M
authors.lastname: Matthay
authors.forename: Nuala J
authors.initials: NJ
authors.lastname: Meyer
authors.forename: Cecilia
authors.initials: C
authors.lastname: Kim
authors.forename: Mingyao
authors.initials: M
authors.lastname: Li
authors.forename: Joshua
authors.initials: J
authors.lastname: Akey
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Barnes
authors.forename: Jonathan
authors.initials: J
authors.lastname: Sevransky
authors.forename: Paul N
authors.initials: PN
authors.lastname: Lanken
authors.forename: Addison K
authors.initials: AK
authors.lastname: May
authors.forename: Richard
authors.initials: R
authors.lastname: Aplenc
authors.forename: James P
authors.initials: JP
authors.lastname: Maloney
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
mesh_terms: D055371:Acute Lung Injury / Q000150:complications* / Q000235:genetics*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D002460:Cell Line; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D014947:Wounds and Injuries / Q000150:complications*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C094398:PPFIA1 protein, human