Identification of Novel Single Nucleotide Polymorphisms Associated with Acute Respiratory Distress Syndrome by Exome-Seq

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.

Complex genetics of pulmonary diseases: lessons from genome-wide association studies and next-generation sequencing

“…Shortt et al 65 studied 96 patients with ARDS (70 Caucasian and 26 African Americans), and identified 76 novel ARDS susceptibility SNPs. They also selectively genotyped three of these SNPs, rs3848719 (ZNF335 gene that contributes in proliferation of neural progenitor cells and self-renewal), rs78142040 (ARSD gene that contributes to the development of cartilage and is a member of the sulfatase family), rs9605146 (in XKR3 gene that is a potential membrane transporter), in an additional 117 patients and found the correlation of rs3848719 and rs78142040 with APACHE II score quartile and 60-day mortality.…”

Novel translational approaches to the search for precision therapies for acute respiratory distress syndrome

“…45 Sequencing of genomic coding regions (socalled exome sequencing) was done in a collaborative effort sponsored by the National Heart, Lung, and Blood Institute 46 and included 96 cases of ARDS. When ARDS cases were compared with presumably healthy controls in the 1000 Genomes Project, two SNPs in the genes XK related 3 and arylsulfatase D showed differential expression in ARDS cases, 31 We refer to candidate testing when an individual known entity (SNP, specific transcript, protein, etc) is quantified, whereas medium-throughput or high-throughput discovery approaches rely on known features but are capable of multiplex assays. For example, genome-wide association studies or cDNA microarrays rely on the knowledge of a genetic sequence to generate probes that will assay each SNP or transcript.…”

“…a common alternative name in parentheses if appropriate 26,27,[30][31][32]34,35 and proteins17,29,[36][37][38] are shown using Reference Sequence abbreviations, with common alternative names in parentheses.…”

Prognostic Values of Nucleotide Polymorphism in ARDS: A Whole Exome Sequencing Association Study

“…With an extremely high hospital mortality rate among 35-46% [2], current therapeutic strategies to increase ARDS survival consist of support to prevent ventilator induced lung injury, to improve oxygenation and gas exchange, advances in etiology and pathology of ARDS are urging. Clinical factors and protocolized therapeutic strategy poorly explain the outcome of ARDS, the role of genetic locus in the pathogenesis of ARDS is increasingly recognized [3][4][5][6].…”