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

Shortt K, Chaudhary S, Grigoryev D, Heruth DP, Venkitachalam L, Zhang LQ, Ye SQ - PLoS ONE (2014)

Bottom Line: 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.Additional validation in larger patient populations and further exploration of underlying molecular mechanisms are warranted.

View Article: PubMed Central - PubMed

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.

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.

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Related in: MedlinePlus

Pipeline of the exome-seq data analysis workflow.After processing the data using the GATK pipeline, this filtering workflow was derived to identify SNPs which were associated with measures of susceptibility across the racial and etiology groups of cases. SNPs were filtered based on strength of association, coding effect, and functional prediction prior to testing for association with other ARDS phenotypes. *, The sample contains African American and Caucasian patients, so the EUR and ASW healthy controls from 1000 Genomes were used for comparison; **, In the 1000 Genomes Project exome sequence, the same 714,074 SNPs are present for all 440 EUR and ASW; §, HWE = Hardy Weinberg Equilibrium, p>0.0001; +, African American with pneumonia, African American with sepsis, Caucasian with pneumonia, Caucasian with sepsis; + +, χ2 test of ARDS vs. respective 1000 Genomes Project control groups; ‡, SNPs with P-value <0.01 in the overall comparison, Caucasian ARDS comparison, and African American comparison with 1000 Genomes were filtered further by p<0.01 in the sepsis comparison and pneumonia comparison; ‡ ‡, All ARDS cases, all pneumonia cases, all sepsis cases, all African American cases, all Caucasian cases.
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pone-0111953-g001: Pipeline of the exome-seq data analysis workflow.After processing the data using the GATK pipeline, this filtering workflow was derived to identify SNPs which were associated with measures of susceptibility across the racial and etiology groups of cases. SNPs were filtered based on strength of association, coding effect, and functional prediction prior to testing for association with other ARDS phenotypes. *, The sample contains African American and Caucasian patients, so the EUR and ASW healthy controls from 1000 Genomes were used for comparison; **, In the 1000 Genomes Project exome sequence, the same 714,074 SNPs are present for all 440 EUR and ASW; §, HWE = Hardy Weinberg Equilibrium, p>0.0001; +, African American with pneumonia, African American with sepsis, Caucasian with pneumonia, Caucasian with sepsis; + +, χ2 test of ARDS vs. respective 1000 Genomes Project control groups; ‡, SNPs with P-value <0.01 in the overall comparison, Caucasian ARDS comparison, and African American comparison with 1000 Genomes were filtered further by p<0.01 in the sepsis comparison and pneumonia comparison; ‡ ‡, All ARDS cases, all pneumonia cases, all sepsis cases, all African American cases, all Caucasian cases.

Mentions: In order to identify novel coding SNPs associated with the ARDS susceptibility, we performed the exome-seq of 96 ARDS patient DNAs. These patients consisted of 70 Caucasian and 26 African Americans (Table 1). In Caucasian patients, 37 cases were due to the initiating etiology of sepsis and 33 were due to pneumonia. In African American patients, 11 cases were due to the initiating etiology of sepsis and 15 were due to pneumonia. We detected 1,382,399 SNPs in 96 ARDS patients by exome-seq (Table 2) and 490,015 SNPs per person on average (Figure 1). Among them, 169,376 SNPs matched records from 625 healthy control subjects in the 1000 human genome project. From 169,376 SNPs, there are 49,723 bi-allelic SNPs out of 50,190 total SNPs in all ARDS patient subgroups based on race and initiating etiologies: Caucasian sepsis, Caucasian pneumonia, African-American sepsis and African American pneumonia. Of our 1,382,399 ARDS SNPs, 608,723 were common between the sepsis and pneumonia cases while 369,639 and 404,037 are non-overlapping SNPs, respectively. There are 442,235 common SNPs between our African American cases and Caucasian cases while 337,738 and 602,426 are non-overlapping SNPs, respectively. 87.8% of the 1,382,399 ARDS SNPs (i.e., 1,213,023 ARDS SNPs) are not found in the 1000 Genomes Project Exome, but 85.4% of the 1,213,023 ARDS SNPs (i.e., 1,035,921 SNPs) were assigned RS numbers, suggesting our data collection and processing are reliable. By comparing the frequencies of the minor alleles in those newly detected SNPs in 96 ARDS patients with those in 440 Caucasian and African-Americans from the Southwest healthy control subjects of the 1000 human genome project, we found that there are 3,867 differential SNPs (p<0.01) (Figure 2). In Caucasians, between ARDS patients and healthy controls, there are 788 differential SNPs (p<0.01). In African-Americans, between ARDS patients and healthy controls, there are 948 differential SNPs (p<0.01). There are 122 common differential SNPs (p<0.01) between either Caucasian or African American patients or healthy controls. When we examined sepsis- or pneumonia-initiated ARDS separately, we found that 106 and 109 differential SNPs (p<0.01), respectively. Between them, there are 99 common differential SNPs (p<0.01). When the Bonferroni correction (p<2.95×10−7) was applied, 76SNPs remains significantly different. These SNPs are potentially novel coding SNPs associated with the ARDS susceptibility.


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

Shortt K, Chaudhary S, Grigoryev D, Heruth DP, Venkitachalam L, Zhang LQ, Ye SQ - PLoS ONE (2014)

Pipeline of the exome-seq data analysis workflow.After processing the data using the GATK pipeline, this filtering workflow was derived to identify SNPs which were associated with measures of susceptibility across the racial and etiology groups of cases. SNPs were filtered based on strength of association, coding effect, and functional prediction prior to testing for association with other ARDS phenotypes. *, The sample contains African American and Caucasian patients, so the EUR and ASW healthy controls from 1000 Genomes were used for comparison; **, In the 1000 Genomes Project exome sequence, the same 714,074 SNPs are present for all 440 EUR and ASW; §, HWE = Hardy Weinberg Equilibrium, p>0.0001; +, African American with pneumonia, African American with sepsis, Caucasian with pneumonia, Caucasian with sepsis; + +, χ2 test of ARDS vs. respective 1000 Genomes Project control groups; ‡, SNPs with P-value <0.01 in the overall comparison, Caucasian ARDS comparison, and African American comparison with 1000 Genomes were filtered further by p<0.01 in the sepsis comparison and pneumonia comparison; ‡ ‡, All ARDS cases, all pneumonia cases, all sepsis cases, all African American cases, all Caucasian cases.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4221189&req=5

pone-0111953-g001: Pipeline of the exome-seq data analysis workflow.After processing the data using the GATK pipeline, this filtering workflow was derived to identify SNPs which were associated with measures of susceptibility across the racial and etiology groups of cases. SNPs were filtered based on strength of association, coding effect, and functional prediction prior to testing for association with other ARDS phenotypes. *, The sample contains African American and Caucasian patients, so the EUR and ASW healthy controls from 1000 Genomes were used for comparison; **, In the 1000 Genomes Project exome sequence, the same 714,074 SNPs are present for all 440 EUR and ASW; §, HWE = Hardy Weinberg Equilibrium, p>0.0001; +, African American with pneumonia, African American with sepsis, Caucasian with pneumonia, Caucasian with sepsis; + +, χ2 test of ARDS vs. respective 1000 Genomes Project control groups; ‡, SNPs with P-value <0.01 in the overall comparison, Caucasian ARDS comparison, and African American comparison with 1000 Genomes were filtered further by p<0.01 in the sepsis comparison and pneumonia comparison; ‡ ‡, All ARDS cases, all pneumonia cases, all sepsis cases, all African American cases, all Caucasian cases.
Mentions: In order to identify novel coding SNPs associated with the ARDS susceptibility, we performed the exome-seq of 96 ARDS patient DNAs. These patients consisted of 70 Caucasian and 26 African Americans (Table 1). In Caucasian patients, 37 cases were due to the initiating etiology of sepsis and 33 were due to pneumonia. In African American patients, 11 cases were due to the initiating etiology of sepsis and 15 were due to pneumonia. We detected 1,382,399 SNPs in 96 ARDS patients by exome-seq (Table 2) and 490,015 SNPs per person on average (Figure 1). Among them, 169,376 SNPs matched records from 625 healthy control subjects in the 1000 human genome project. From 169,376 SNPs, there are 49,723 bi-allelic SNPs out of 50,190 total SNPs in all ARDS patient subgroups based on race and initiating etiologies: Caucasian sepsis, Caucasian pneumonia, African-American sepsis and African American pneumonia. Of our 1,382,399 ARDS SNPs, 608,723 were common between the sepsis and pneumonia cases while 369,639 and 404,037 are non-overlapping SNPs, respectively. There are 442,235 common SNPs between our African American cases and Caucasian cases while 337,738 and 602,426 are non-overlapping SNPs, respectively. 87.8% of the 1,382,399 ARDS SNPs (i.e., 1,213,023 ARDS SNPs) are not found in the 1000 Genomes Project Exome, but 85.4% of the 1,213,023 ARDS SNPs (i.e., 1,035,921 SNPs) were assigned RS numbers, suggesting our data collection and processing are reliable. By comparing the frequencies of the minor alleles in those newly detected SNPs in 96 ARDS patients with those in 440 Caucasian and African-Americans from the Southwest healthy control subjects of the 1000 human genome project, we found that there are 3,867 differential SNPs (p<0.01) (Figure 2). In Caucasians, between ARDS patients and healthy controls, there are 788 differential SNPs (p<0.01). In African-Americans, between ARDS patients and healthy controls, there are 948 differential SNPs (p<0.01). There are 122 common differential SNPs (p<0.01) between either Caucasian or African American patients or healthy controls. When we examined sepsis- or pneumonia-initiated ARDS separately, we found that 106 and 109 differential SNPs (p<0.01), respectively. Between them, there are 99 common differential SNPs (p<0.01). When the Bonferroni correction (p<2.95×10−7) was applied, 76SNPs remains significantly different. These SNPs are potentially novel coding SNPs associated with the ARDS susceptibility.

Bottom Line: 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.Additional validation in larger patient populations and further exploration of underlying molecular mechanisms are warranted.

View Article: PubMed Central - PubMed

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.

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.

Show MeSH
Related in: MedlinePlus