Identification of novel single nucleotide polymorphisms associated with acute respiratory distress syndrome by exome-seq.

Pubmed ID: 25372662

Pubmed Central ID: PMC4221189

Journal: PloS one

Publication Date: Nov. 5, 2014

Affiliation: Department of Pediatrics, Division of Experimental and Translational Genetics, Children's Mercy Hospital, University of Missouri - Kansas City School of Medicine, Kansas City, Missouri, United States of America; Department of Biomedical and Health Informatics, University of Missouri - Kansas City School of Medicine, Kansas City, Missouri, United States of America.

MeSH Terms: Humans, Male, Female, Case-Control Studies, Alleles, Adolescent, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Young Adult, Child, Comorbidity, Signal Transduction, Child, Preschool, Genetic Association Studies, High-Throughput Nucleotide Sequencing, Exome, Genomics, Respiratory Distress Syndrome

Grants: HL080042, HL080042-S1, R01 HL080042

Authors: Shortt K, Chaudhary S, Grigoryev D, Heruth DP, Venkitachalam L, Zhang LQ, Ye SQ

Cite As: Shortt K, Chaudhary S, Grigoryev D, Heruth DP, Venkitachalam L, Zhang LQ, Ye SQ. Identification of novel single nucleotide polymorphisms associated with acute respiratory distress syndrome by exome-seq. PLoS One 2014 Nov 5;9(11):e111953. doi: 10.1371/journal.pone.0111953. eCollection 2014.

Studies:

Abstract

Acute respiratory distress syndrome (ARDS) is a lung condition characterized by impaired gas exchange with systemic release of inflammatory mediators, causing pulmonary inflammation, vascular leak and hypoxemia. Existing biomarkers have limited effectiveness as diagnostic and therapeutic targets. To identify disease-associating variants in ARDS patients, whole-exome sequencing was performed on 96 ARDS patients, detecting 1,382,399 SNPs. By comparing these exome data to those of the 1000 Genomes Project, we identified a number of single nucleotide polymorphisms (SNP) which are potentially associated with ARDS. 50,190SNPs were found in all case subgroups and controls, of which89 SNPs were associated with susceptibility. We validated three SNPs (rs78142040, rs9605146 and rs3848719) in additional ARDS patients to substantiate their associations with susceptibility, severity and outcome of ARDS. rs78142040 (C>T) occurs within a histone mark (intron 6) of the Arylsulfatase D gene. rs9605146 (G>A) causes a deleterious coding change (proline to leucine) in the XK, Kell blood group complex subunit-related family, member 3 gene. rs3848719 (G>A) is a synonymous SNP in the Zinc-Finger/Leucine-Zipper Co-Transducer NIF1 gene. rs78142040, rs9605146, and rs3848719 are associated significantly with susceptibility to ARDS. rs3848719 is associated with APACHE II score quartile. rs78142040 is associated with 60-day mortality in the overall ARDS patient population. Exome-seq is a powerful tool to identify potential new biomarkers for ARDS. We selectively validated three SNPs which have not been previously associated with ARDS and represent potential new genetic biomarkers for ARDS. Additional validation in larger patient populations and further exploration of underlying molecular mechanisms are warranted.