Lee, JTC; (2008) Angiotensin converting enzyme and interleukin-6, genetic polymorphisms and their relation to surgical outcome. Doctoral thesis , UCL (University College London).

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Abstract

Improving surgical outcome by identifying the high-risk patient has traditionally concentrated on the ability to tolerate the insult of surgery. There has been increasing interest in the inflammatory reaction to surgery, as a potential outcome predictor. Moreover, the considerable observed variation in the nature and scale of this response may be due to genotypic differences in functional cytokine polymorphisms. Thus, the Interleukin-6 (IL6) and Angiotensin-1-Converting Enzyme (ACE) expression responses to surgery were examined, along with possible association with outcome, and the influences of common functional polymorphisms (-174 G/C and I/D respectively). Twenty nine elective colorectal cancer patients were recruited. From separated peripheral blood mononuclear cells, nucleic acids were extracted. PCR of DNA was used for genotyping, and a semi-quantitative RT-PCR of RNA method for analysing gene transcription used, including an assessment of the differential I/D allelic contribution to ACE transcription. Plasma protein expression was established by ELISA. Patients were prospectively followed, with morbidity and length of stay (LOS) chosen as end-points. There was evidence of a post-operative increase (24 hour timepoint) in both IL6 gene transcription (p=0.077) and protein expression (p<0.001), but their extent associated with neither the -174 G/C polymorphism nor LOS. However, there was a trend towards C-allele carriers (p=0.077) and those launching a greater IL6 protein response (p=0.078) being less likely to experience complications. Considering ACE I/D heterozygotes, the D-allele was responsible for greater levels of gene transcription than the I-allele, both pre- (p<0.001) and post-operatively (p=0.01 24 hour timepoint). Overall, there was a post-operative rise in ACE gene transcription (p=0.042) with D/D homozygotes producing the greatest response (p=0.002), and D- allele carriers having a prolonged LOS. Conversely, plasma ACE protein levels fell post-operatively (p<0.001), and did not associate with 1/D genotype or outcome. Overall, this work contributes to previous observations that an assessment of patient genotype may aid the identification of the high-risk surgical patient.

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