Background Surgery necessitating cardiopulmonary bypass (snCPB) induces a systemic inflammatory response which can lead to organ dysfunction, including acute lung injury (ALI). Polymorphisms in inflammatory genes have been linked to adverse clinical outcomes following snCPB. The receptor for advanced glycation end products (RAGE) is an inflammation-perpetuating pattern recognition receptor. We investigated the hypothesis that polymorphisms in genes encoding RAGE or RAGE ligands predispose patients to a more severe systemic inflammatory response and the development of ALI after snCPB.
Methods In a nested unmatched case–control study 187 UK Caucasian patients undergoing cardiac surgery necessitating CPB were genotyped for eight biallelic single nucleotide polymorphisms (SNPs) in the RAGE, S100A8 and HMGB1 genes using sequence-specific primer polymerase chain reactions. Intensive care unit length of stay, duration of level 3 care, post-operative neutrophil and white blood cell count (WCC), C-reactive protein (CRP) and PaO2:FiO2 ratio were used as clinical outcome measures.
Results All SNPs conformed to Hardy–Weinberg equilibrium. Patients carrying the C alleles of rs3795391 and rs3806232 SNPs, in linkage disequilibrium in the S100A8 gene, had a higher neutrophil and WCC (p=0.019, p=0.039 respectively) and a lower PaO2:FiO2 (p=0.01) on post-operative day 3. Median post-operative PiO2:FiO2 of patients carrying the C alleles versus those not was 123.5 mm Hg vs 204.4 mm Hg. Patients carrying the GG genotype of the rs2070600 (Gly82Ser) SNP in the RAGE gene had a higher neutrophil count on post-operative day 2 (p=0.025). Patients carrying the T allele of the RAGE rs1800624 (−374T/A) SNP had higher CRP levels on post-operative day 1 (p=0.015).
Conclusion SNPs in the RAGE and S100A8 genes are associated with the intensity of the systemic inflammatory response and patient oxygenation levels in our cohort of patients following snCPB. Patients carrying the C alleles of the S100A8 SNPs had significantly impaired oxygenation in the early post-operative period compared to patients carrying the TT genotype, suggesting a genetic influence on the degree of lung injury arising as a result of snCPB. Pre-operative genotyping for polymorphisms associated with adverse outcomes may be used to stratify patients' risk from snCPB, allowing the development of interventions designed to reduce post-operative morbidity and mortality.
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