Identification of novel coding single nucleotide polymorphisms associated with acute respiratory distress syndrome
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Abstract
ARDS is a lung condition characterized by impaired gas exchange with systemic release of inflammatory mediators, causing inflammation, hypoxemia and multiple organ failure. Disease susceptibility and progression are poorly understood and there are few effective therapeutic options. Existing biomarkers have limited effectiveness as diagnostic and therapeutic targets. Whole-exome sequencing is an effective tool in detection of disease-causing genetic variants in complex genetic conditions such as acute respiratory distress syndrome (ARDS). To identify disease-causing variants in ARDS patients, whole-exome sequencing was performed on 96 patient DNA samples from the National Heart, Lung and Blood Institute's ARDS Network (ARDSnet). By comparing these exome data with 625 participants of the 1000 Genomes Project, we have tentatively identified a number of single nucleotide polymorphisms (SNP) which are potentially associated with ARDS. In this study, we validated three SNPs (rs78142040, rs9605146, and rs3848719) in an additional 117 ARDS patients using TaqMan SNP genotyping assays (Life Technologies) to substantiate their associations with the susceptibility, severity and outcome of ARDS. rs78142040 (C>T) occurs within a histone mark in intron 6 of the Arylsulfatase D gene. rs9605146 (G>A)(also known as rs114989947) causes a coding change (proline to leucine) with a deleterious effect in the XK, Kell blood group complex subunit-related family, member 3 gene. rs3848719 (G>A) is a synonymous SNP in exon 5 of gene Zinc-Finger/Leucine-Zipper Co-Transducer NIF1. rs78142040 and rs9605146 are significantly associated with susceptibility to ARDS[minor allele frequency (MAF): 0.219 versus 0.003 (control), p<2.95×10-7 and 0.386 versus 0.046 (control), p<2.95×10-7; respectively]. rs3848719 (MAF 0.394 in cases, 0.287 in controls) is associated with APACHE II score when the score quartiles are compared (p=0.032 OR=0.549, 95%CI=0.313-0.96) and Rs78142040 approaches significant association with APACHE II score (p=0.061). rs78142040 is associated with the 60-day mortality in the 213 ARDS patient population (p=0.017, OR=2.039, 95%CI=1.130-3.681). The same trends hold by stratification of patient population and comorbidity variables. All SNPs are in Hardy-Weinberg Equilibrium (HWE p>1×10-4) in our cases. These 3 SNPs have not been previously associated with ARDS and represent potential new genetic biomarkers for ARDS. More validations in larger patient populations and further exploration of underlying molecular mechanisms are warranted
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Abstract -- List of illustrations -- List of tables -- Glossary -- Acknowledgments -- Introduction - Review of the literature -- Research question -- Methods -- Results -- Discussion -- Conclusions -- Supplementary figures and tables -- Reference list
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M. S.