Common Genetic Variants Associated With Risk For Acute Lung Injury: A Validation Study In An ICU Cohort With SIRS

  • O'Mahony D
  • Glavan B
  • Holden T
  • et al.
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Abstract

INTRO: Through GWAS and candidate gene analyses, multiple genetic risk variants from a variety of biological pathways have been associated with development of acute lung injury (ALI). Recently developed microfluidics chip technology facilitates rapid genotyping in a medium throughput format for validation studies. Here we performed a validation study of several genetic variants previously implicated in risk for ALI to determine the robustness of the associations and to obtain better estimates of effect size. METHODS: Phenotype data and blood for DNA processing was collected from prospectively enrolled patients meeting criteria for systemic inflammatory response syndrome (SIRS) after admission to an ICU at Harborview Medical Center. Patients were screened daily for development of clinical outcomes including ALI. We selected 12 SNPs which have been associated with ALI in prior publications, which have minor allele frequencies >0.05 in HapMap Caucasian populations, and for which Taqman Genotype assays were available or could be designed. A microfluidics platform was used for Taqman allelic discrimination assays. SNP genotype associations with development of ALI were assessed in additive and recessive models through logistic regression with covariate adjustment for age, sex, and presence of ALI risk factors (sepsis, pneumonia, aspiration, pancreatitis, and multiple transfusions). RESULTS: Genotyping was completed for 863 white patients (Male 63.6%, Age 55 +/- 16 (mean +/- SD)). After enrollment, 69% (594 patients) met criteria for sepsis and 27% (234 patients) met criteria for ALI. Using an additive model, 3 SNPs had significant associations with development of ALI after adjusting for covariates. Among these SNPs were rs2515475(Ang2) OR 1.38 (95% CI 1.08-1.76), rs2069858( IL6) OR 1.76 (95% CI 1.21-2.55), and rs4073(IL8) OR 1.28 (95% CI 1.02-1.61). In a recessive model, 2 SNPs were associated with ALI including rs4444903(EGF) OR 1.81 (95% CI 1.23-2.66) and rs2069858(IL6) OR 2.64 (95% CI 1.04-6.69). Notably, the effects for the validated associations with EGF, IL6, IL8, and ANG2 were in the same direction as reported in prior studies. CONCLUSION: We confirmed associations between SNPs in 4 different genes and development of ALI in a cohort of critically ill patients with SIRS. These robust associations provide further evidence that genetic factors contribute substantially to ALI-risk.

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O’Mahony, D. S., Glavan, B. J., Holden, T. D., Christiani, D. C., & Wurfel, M. M. (2011). Common Genetic Variants Associated With Risk For Acute Lung Injury: A Validation Study In An ICU Cohort With SIRS (pp. A5535–A5535). American Thoracic Society. https://doi.org/10.1164/ajrccm-conference.2011.183.1_meetingabstracts.a5535

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