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Novel haplotypes and polymorphisms of interleukin-10 and interleukin-18 pathway genes in complex inflammatory diseases Shaw, David M.


Complex diseases such as critical illness and post-cardiopulmonary bypass inflammation are characterized by inappropriate activation of the inflammatory response. Polymorphisms of key inflammatory mediator genes can alter the amount of that mediator produced and the severity of response to the stimulus. Interleukin-I 0 is a key down-regulator of the inflammatory response, dampening pro-inflammatory cytokine production follow injury. In opposition, interleukin-18 is a key pro-inflammatory cytokine, up-regulating the type I T cell response following activation. We hypothesized that polymorphisms and haplotypes of these genes are likely to contribute to alterations among patients in the response to stimuli such as critical illness and cardiopulmonary bypass surgery. A haplotype-based approach, grounded in linkage disequilibrium, is used for selection of polymorphisms to genotype in our patient cohorts, allowing great flexibility in choice of haplotype tagging polymorphisms. Novel haplotypes and polymorphisms of the interleukin-l 0 gene and interleukin-l S pathway genes (including the interleukin-18 binding protein and the interleukin-18 receptors 1 and receptor-accessory protein) were found to be associated with altered outcomes from cardiopulmonary bypass surgery as well as altered serum cytokine levels, indicating biologic plausibility. Significant results with novel polymorphisms of the interleukin-18 pathway genes in the cardiopulmonary bypass surgery cohort were not replicated in the critical illness cohort. This failure to reproduce initial findings may represent a lack of functionality of the identified polymorphisms, or the fact that effects of polymorphisms of the interleukin-I S pathway genes are not strong enough to affect survival or organ dysfunction in critical illness. The strong effects of these novel haplotypes and polymorphisms in the interleukin-I 0 and interleukin-l S pathway genes, including altered outcomes and intermediate phenotypes, indicate that these are attractive targets for further investigation in inflammatory diseases. The use of linkage disequilibrium and haplotypes for selection of polymorphisms in disease association studies is shown to be a powerful method of identifying markers of altered outcomes from inflammatory diseases.

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