Acute Respiratory Distress Syndrome (ARDS) and Acute Lung Injury
Introduction Acute respiratory distress syndrome (ARDS) is characterized by impaired gas exchange...
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Introduction Acute respiratory distress syndrome (ARDS) is characterized by impaired gas exchange with a systemic release of inflammatory mediators, hypoxemia, multiple organ failure and high mortality rates (30-50%). The etiology and pathogenesis of ARDS are still not fully understood and there are few effective therapeutic options. It is increasingly recognized that genetic predisposition significantly contributes to the pathogenesis of ARDS. Our objective of this study was to identify novel genetic markers for susceptibility, severity and mortality associated with ARDS. Methods The outcomes of interest in ARDS cases are described in Table 2. three that associated susceptibility (rs78142040, rs9605146, and rs3848719), severity (rs3848719) and outcome (rs78142040) of ARDS(Table 3). Profile of the 3 potential SNP markers are described in Table 4 • rs78142040 (C>T) is suspected to occur within a histone mark in intron 6 of the Arylsulfatase D gene • rs9605146 (G>A) causes a coding change from 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 the 5th exon of the Zinc-Finger/Leucine-Zipper Co- Summary In our study cohort, 49,834 SNPs were common across the ARDS subgroups (all ARDS, Caucasian ARDS, African American ARDS, all sepsis, and all pneumonia) and the 1000 Genomes Project. • Of these, the significance level for association with susceptibility was p<0.01 for 156 SNPs, and p<2.95x10 -7 for 102 SNPs • 53 of the 102 SNPs were located in coding regions - 24 caused nonsynonymous changes in amino acid coding; 10 of these changes had a negative predicted functional effect. •Of the 27 SNPs analyzed (24 nonsynonymous , 2 synonymous, 1 splice variant), the following SNPs emerged as potential markers to be associated with: • Susceptibility: rs78142040, rs9605146, rs3848719 • Severity (APACHEII): rs3848719 • Outcome (60-day Mortality): rs7814204 Conclusion In our cohort of ARDS patients, we identified three novel genetic biomarkers of susceptibility, severity, and mortality to ARDS. Further studies are warranted to validate these findings in larger populations and to identify the underlying molecular mechanisms. Table 4. Profile of the 3 SNPs ARDS Patients Participants (N) ARDS Total 213 Caucasian 145 African American 43 Other ancestry 25 ARDS with Sepsis total 107 Caucasian 71 African American 20 Other ancestry 16 ARDS with Pneumonia total 106 Caucasian 74 African American 23 Other ancestry 9 Secondary Controls from the 1000 Genomes Project Participants (N) 1000 genomes Total Control 1092 1000 genomes European Ancestry Control 379 1000 genomes African Ancestry Control 246 ARDS cases APACHE II Score mean ±SD Ventilator- free days/28 days mean ±SD 60-day mortalit y (%) 213(Total) 101.6± 31.9 12.3± 10.3 30.2 96(by Exome- Seq) 97.2±30.4 12.6±10.2 29.4 117(by TaqMan) 105.1±32. 7 12.0±10.5 31 Table 1. Distribution of Race/Ethnicity Table 2. Outcomes among ARDS cases NK: Not known, HWE: Hardy-Weinberg equilibrium, AA: alternate genotype or homozygous minor genotype, Ar: heterozygous genotype, rr: reference genotype or homozygous major genotype 1:http://provean.jcvi.org/genome_submit.php, 2:http://genetics.bwh.harvard.edu/pph2/ Data collectio n • SNP Data of 96 patients were obtained using exome-sequencing (Illumina HiScanSQ) • Selected SNPs were validated in additional 117 patients using the TaqMan Assay Study sample • Test association of SNPs with ARDS using SNP & Variation Suite 7 software package (Golden Helix, Bozeman, MT) for: • Susceptibility: Presence of disease • Severity: APACHE II score, Ventilator-free days/28 days • Outcome: Mortality at 60 days Data analysis • Cases: 213 ARDS patients in total • Controls: 1092 participants from the 1000 Genomes Project rs3848719 rs9605146 Location 20:4459654 5 22:17265194 X:2832771 Gene ID ZNF335 XKR3 ARSD Call Rate (Cases + Controls) 0.981 0.998 0.995 Call Rate (Cases) 0.883 0.986 0.972 HWE P-value (Cases) 2.86E-04 4.22E-01 1.18E-03 HWE P-value (Controls) 6.69E-10 7.80E-19 1.81E-239 HWE P-value (Cases + Controls) 6.14E-15 2.06E-30 7.47E-02 Reference: Alternate Allele G>A G>A C>T Alt. Allele Freq. (Cases) 39.4% 38.6% 22.0% Alt. Allele Freq. (Controls) 22.0% 3.4% 0.2% Number AA(%) (Cases) 41(21.8%) 34(16.2%) 2(1.0%) Number AA(%) (Controls) 88(8.1%) 11(1.0%) 2(0.2%) Number Ar(%) (Cases) 66(35.1%) 94(44.8%) 87(42.0%) Number Ar(%) (Controls) 305(27.9%) 53(4.9%) 0(0.0%) Number rr(%) (Cases) 81(45.1%) 82(39.1%) 118(57.0%) Number rr(%) (Controls) 699(64.0%) 1028(94.1%) 1090(99.8% ) SNP classification Coding Coding Coding Coding classification Synonymous Nonsynonymous Intronic Reference amino acid S P NK Alternate amino acid S L NK Provean prediction (cutoff=-25) 1 Neutral Deleterious NK rs3848719 rs9605146 rs78142040 Susceptibility(cases vs. controls) Chi-squared p- value 5.47E-13 2.44E-116 4.38E-104 Odds Ratio (95% CI) 1 2.30(1.83- 2.89) 17.66(13.04- 23.90) 153.54(56.03- 420.77) Severity(ventilator-free days/28 days) p-value NS NS NS Odds Ratio(95% CI) 2 NS NS NS Severity(APACHE II score) p-value 0.032 NS 0.061 Odds Ratio(95% CI) 2 0.55(0.31- 0.96) NS NS Outcome(60-day mortality) p-value NS* NS 0.017 Odds Ratio(95% CI) 2 NS NS 2.04(1.13-3.68) Table 3. Overall Associations of 3 SNPs NS: Not significant; * Significantly associated in genotyped Caucasian, pneumonia, and Caucasian pneumonia subgroups; 1:Odds ratio for alternate allele (allelic test); 2:additive genotypic model Identification of Three Novel SNPs Associated With ARDS by Exome-Seq K. Shortt 1,2 , S. Chaudhary 2 , D. Grigoryev 1,2 , D.P. Heruth 2 , L.Venkitachalam 1 , L.Q. Zhang 2 , and S.Q. Ye 1,2 . Department of Biomedical and Health Informatics 1 and Department of Pediatrics 2 , Children's Mercy Hospitals and Clinics, University of Missouri, Kansas City, MO. Contact: Katherine Shortt( [email protected]) IRB Approval: This study protocol was determined to be IRB exempt. Funded By: NHLBI/NIH Grant (HL080042 & HL080042-S1, Ye, SQ), start-up fund of Children's Mercy Hospitals and Clinics, UMKC (Ye, SQ), and a Sarah Morrison Results The distribution of race/ethnicity in the study sample is given in Table 1. • Among ARDS cases, 68% are Caucasian, 20% are African American, and 12% are other races. • Among controls, 35% are of European Ancestry, 23% are of African ancestry, and 43% are of other ancestries.
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Transcript of Introduction Acute respiratory distress syndrome (ARDS) is characterized by impaired gas exchange...
IntroductionAcute respiratory distress syndrome (ARDS) is characterized by impaired gas exchange with a systemic release of inflammatory mediators, hypoxemia, multiple organ failure and high mortality rates (30-50%).
The etiology and pathogenesis of ARDS are still not fully understood and there are few effective therapeutic options.
It is increasingly recognized that genetic predisposition significantly contributes to the pathogenesis of ARDS. Our objective of this study was to identify novel genetic markers for susceptibility, severity and mortality associated with ARDS.
Methods
The outcomes of interest in ARDS cases are described in Table 2.
These three novel SNPs that are associated with susceptibility (rs78142040, rs9605146, and rs3848719), severity (rs3848719) and outcome (rs78142040) of ARDS(Table 3).
Profile of the 3 potential SNP markers are described in Table 4
• rs78142040 (C>T) is suspected to occur within a histone mark in intron 6 of the Arylsulfatase D gene
• rs9605146 (G>A) causes a coding change from 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 the 5th exon of the Zinc-Finger/Leucine-Zipper Co-Transducer NIF1 gene.
Summary In our study cohort, 49,834 SNPs were common across the ARDS subgroups (all ARDS, Caucasian ARDS, African American ARDS, all sepsis, and all pneumonia) and the 1000 Genomes Project.
• Of these, the significance level for association with susceptibility was p<0.01 for 156 SNPs, and p<2.95x10-7 for 102 SNPs
• 53 of the 102 SNPs were located in coding regions - 24 caused nonsynonymous changes in amino acid coding; 10 of these changes had a negative predicted functional effect.
•Of the 27 SNPs analyzed (24 nonsynonymous , 2 synonymous, 1 splice variant), the following SNPs emerged as potential markers to be associated with:• Susceptibility: rs78142040, rs9605146,
rs3848719• Severity (APACHEII): rs3848719• Outcome (60-day Mortality): rs7814204
ConclusionIn our cohort of ARDS patients, we identified three novel genetic biomarkers of susceptibility, severity, and mortality to ARDS. Further studies are warranted to validate these findings in larger populations and to identify the underlying molecular mechanisms.
Table 4. Profile of the 3 SNPs
ARDS Patients Participants (N)ARDS Total 213 Caucasian 145 African American 43 Other ancestry 25ARDS with Sepsis total 107Caucasian 71African American 20Other ancestry 16ARDS with Pneumonia total 106Caucasian 74African American 23Other ancestry 9
Secondary Controls from the 1000 Genomes Project
Participants(N)
1000 genomes Total Control 10921000 genomes European Ancestry Control 3791000 genomes African Ancestry Control 246
ARDS casesAPACHE II
Scoremean ±SD
Ventilator-free days/28 days
mean ±SD
60-day mortality
(%) 213(Total) 101.6± 31.9 12.3± 10.3 30.2 96(by Exome-Seq) 97.2±30.4 12.6±10.2 29.4
117(by TaqMan) 105.1±32.7 12.0±10.5 31
Table 1. Distribution of Race/Ethnicity
Table 2. Outcomes among ARDS cases
NK: Not known, HWE: Hardy-Weinberg equilibrium, AA: alternate genotype or homozygous minor genotype, Ar: heterozygous genotype, rr: reference genotype or homozygous major genotype
1:http://provean.jcvi.org/genome_submit.php, 2:http://genetics.bwh.harvard.edu/pph2/
Data collection
•SNP Data of 96 patients were obtained using exome-sequencing (Illumina HiScanSQ)
•Selected SNPs were validated in additional 117 patients using the TaqMan Assay
Study
sample
•Test association of SNPs with ARDS using SNP & Variation Suite 7 software package (Golden Helix, Bozeman, MT) for:•Susceptibility: Presence of disease•Severity: APACHE II score, Ventilator-free
days/28 days•Outcome: Mortality at 60 days
Data analy
sis
• Cases: 213 ARDS patients in total• Controls: 1092 participants from the 1000 Genomes Project
rs3848719 rs9605146 rs78142040Location 20:44596545 22:17265194 X:2832771Gene ID ZNF335 XKR3 ARSDCall Rate (Cases + Controls) 0.981 0.998 0.995Call Rate (Cases) 0.883 0.986 0.972HWE P-value (Cases) 2.86E-04 4.22E-01 1.18E-03HWE P-value (Controls) 6.69E-10 7.80E-19 1.81E-239HWE P-value (Cases + Controls) 6.14E-15 2.06E-30 7.47E-02Reference: Alternate Allele G>A G>A C>TAlt. Allele Freq. (Cases) 39.4% 38.6% 22.0%Alt. Allele Freq. (Controls) 22.0% 3.4% 0.2%Number AA(%) (Cases) 41(21.8%) 34(16.2%) 2(1.0%)Number AA(%) (Controls) 88(8.1%) 11(1.0%) 2(0.2%)Number Ar(%) (Cases) 66(35.1%) 94(44.8%) 87(42.0%)Number Ar(%) (Controls) 305(27.9%) 53(4.9%) 0(0.0%)Number rr(%) (Cases) 81(45.1%) 82(39.1%) 118(57.0%)Number rr(%) (Controls) 699(64.0%) 1028(94.1%) 1090(99.8%)SNP classification Coding Coding CodingCoding classification Synonymous Nonsynonymous IntronicReference amino acid S P NKAlternate amino acid S L NKProvean prediction (cutoff=-25)1 Neutral Deleterious NKSift prediction (cutoff=0.05)1 Tolerated Tolerated NKPph2 prediction2 NK benign NK
rs3848719 rs9605146 rs78142040Susceptibility(cases vs. controls)
Chi-squared p-value 5.47E-13 2.44E-116 4.38E-104Odds Ratio (95% CI)1 2.30(1.83-2.89) 17.66(13.04-23.90) 153.54(56.03-420.77)
Severity(ventilator-free days/28 days)p-value NS NS NSOdds Ratio(95% CI)2 NS NS NS
Severity(APACHE II score)p-value 0.032 NS 0.061Odds Ratio(95% CI)2 0.55(0.31-0.96) NS NS
Outcome(60-day mortality)p-value NS* NS 0.017Odds Ratio(95% CI)2 NS NS 2.04(1.13-3.68)
Table 3. Overall Associations of 3 SNPs
NS: Not significant; * Significantly associated in genotyped Caucasian, pneumonia, and Caucasian pneumonia subgroups; 1:Odds ratio for alternate allele (allelic test); 2:additive genotypic model
Identification of Three Novel SNPs Associated With ARDS by Exome-SeqK. Shortt1,2, S. Chaudhary2, D. Grigoryev1,2, D.P. Heruth2, L.Venkitachalam1, L.Q. Zhang2, and S.Q. Ye1,2. Department of Biomedical and Health Informatics1
and Department of Pediatrics2, Children's Mercy Hospitals and Clinics, University of Missouri, Kansas City, MO.
Contact: Katherine Shortt( [email protected])
IRB Approval: This study protocol was determined to be IRB exempt.
Funded By: NHLBI/NIH Grant (HL080042 & HL080042-S1, Ye, SQ), start-up fund of Children's Mercy Hospitals and Clinics, UMKC (Ye, SQ), and a Sarah Morrison Student Research Award of UMKC (Shortt, K).
Results The distribution of race/ethnicity in the study sample is given in Table 1.
• Among ARDS cases, 68% are Caucasian, 20% are African American, and 12% are other races.
• Among controls, 35% are of European Ancestry, 23% are of African ancestry, and 43% are of other ancestries.
