Home
|
Inbox
|
Search
|
View Abstract
iSPAAR: Genome-Wide Pathway Analysis Reveals Hypoxia-Inducible Factor Pathway Is Associated with Acute Respiratory Distress Syndrome Survival
Description
.abstract img { width:300px !important; height:auto; display:block; text-align:center; margin-top:10px } .abstract { overflow-x:scroll } .abstract table { width:100%; display:block; border:hidden; border-collapse: collapse; margin-top:10px } .abstract td, th { border-top: 1px solid #ddd; padding: 4px 8px; } .abstract tbody tr:nth-child(even) td { background-color: #efefef; } .abstract a { overflow-wrap: break-word; word-wrap: break-word; }
A2977 - iSPAAR: Genome-Wide Pathway Analysis Reveals Hypoxia-Inducible Factor Pathway Is Associated with Acute Respiratory Distress Syndrome Survival
Author Block: S. Shen1, R. Zhang2, Y. Wei3, Z. Zhu4, L. Su5, F. Chen6, D. C. Christiani7; 1Harvard School of Public Health, Boston, MA, United States, 2Environmental Health, Harvard School of Public Health, Boston, MA, United States, 3Biostatistics, Nanjing Medical University, Nanjing, China, 4Environmental Health, Harvard T.H.Chan School of Public Health, Boston, MA, United States, 5Harvard Sch of Public Health, Boston, MA, United States, 6Nanjing Medical University, Nanjing, China, 7Harvard Sch of Public Hlth, Boston, MA, United States.
Background: Genetics is believed to contribute to acute respiratory distress syndrome (ARDS) progression and outcome, including biological pathways, genes and single-nucleotide polymorphisms (SNPs). We aim to investigate the role of pathways in ARDS 28-day mortality and survival.
Methods: The Identification of SNPs Predisposing to Altered ALI Risk (iSPAAR) consortium of 983 ARDS cases were recruited from the intensive care unit (ICU) including 367 patients from the Harvard School of Public Health (HSPH) cohort and 616 patients from the ARDSNet cohort. Genotypes were generated using the Illumina Human610-Quad Bead-Chips.
Results: In the gene set enrichment analysis for SNP (GSEA-SNP) analysis, we identified the HIF pathway (Hypoxia-Inducible Factor in the Cardiovascular System) was associated with ARDS mortality in both cohorts (normalized enrichment score [NES]HSPH = 1.286, P = 0.011; NESARDSNet = 1.261, P = 0.027). Of the 13 genes in the HIF pathway, HIF1A showed a significant joint association with ARDS mortality (P = 0.016). Further, we identified rs12435848 within the HIF1A gene was significantly associated with ARDS 28-day survival (hazard ratio [HR] = 1.43, 95% confidence interval [CI]:1.17-1.75, P = 5.14×10-4, FDR-q = 0.004). In addition, white blood cell (WBC) count was also associated with worse survival [HR per log(109/L) increment = 1.55, 95% CI: 1.11-2.15, P = 0.008]. We found rs12435848 was significantly associated with WBC count using linear regression model (β = 0.10, 95%CI: 0.01-0.20, P = 0.032). Using the casual mediation analysis, we detected a significant indirect effect for SNP rs12435848 on worse ARDS 28-day survival that was mediated through WBC count (Pdirect = 0.010, Pindirect = 0.040, 10.40% effects mediated).
Conclusions: Our study suggests the important role of HIF pathway and HIF1A in ARDS outcomes, which could be a novel drug target in the future.
Keywords: ARDS outcome; pathway; SNP; white blood cell count
Author Block: S. Shen1, R. Zhang2, Y. Wei3, Z. Zhu4, L. Su5, F. Chen6, D. C. Christiani7; 1Harvard School of Public Health, Boston, MA, United States, 2Environmental Health, Harvard School of Public Health, Boston, MA, United States, 3Biostatistics, Nanjing Medical University, Nanjing, China, 4Environmental Health, Harvard T.H.Chan School of Public Health, Boston, MA, United States, 5Harvard Sch of Public Health, Boston, MA, United States, 6Nanjing Medical University, Nanjing, China, 7Harvard Sch of Public Hlth, Boston, MA, United States.
Background: Genetics is believed to contribute to acute respiratory distress syndrome (ARDS) progression and outcome, including biological pathways, genes and single-nucleotide polymorphisms (SNPs). We aim to investigate the role of pathways in ARDS 28-day mortality and survival.
Methods: The Identification of SNPs Predisposing to Altered ALI Risk (iSPAAR) consortium of 983 ARDS cases were recruited from the intensive care unit (ICU) including 367 patients from the Harvard School of Public Health (HSPH) cohort and 616 patients from the ARDSNet cohort. Genotypes were generated using the Illumina Human610-Quad Bead-Chips.
Results: In the gene set enrichment analysis for SNP (GSEA-SNP) analysis, we identified the HIF pathway (Hypoxia-Inducible Factor in the Cardiovascular System) was associated with ARDS mortality in both cohorts (normalized enrichment score [NES]HSPH = 1.286, P = 0.011; NESARDSNet = 1.261, P = 0.027). Of the 13 genes in the HIF pathway, HIF1A showed a significant joint association with ARDS mortality (P = 0.016). Further, we identified rs12435848 within the HIF1A gene was significantly associated with ARDS 28-day survival (hazard ratio [HR] = 1.43, 95% confidence interval [CI]:1.17-1.75, P = 5.14×10-4, FDR-q = 0.004). In addition, white blood cell (WBC) count was also associated with worse survival [HR per log(109/L) increment = 1.55, 95% CI: 1.11-2.15, P = 0.008]. We found rs12435848 was significantly associated with WBC count using linear regression model (β = 0.10, 95%CI: 0.01-0.20, P = 0.032). Using the casual mediation analysis, we detected a significant indirect effect for SNP rs12435848 on worse ARDS 28-day survival that was mediated through WBC count (Pdirect = 0.010, Pindirect = 0.040, 10.40% effects mediated).
Conclusions: Our study suggests the important role of HIF pathway and HIF1A in ARDS outcomes, which could be a novel drug target in the future.
Keywords: ARDS outcome; pathway; SNP; white blood cell count
|
Home
|
Inbox
|
Search
|