A two-step tagging single nucleotide polymorphism approach for the identification of genetic variants of interleukin-6 associated with acute lung injury.

Rationale Interleukin-6 (IL-6) is a key proinflammatory cytokine in the inflammatory diseases including acute lung injury (ALI) and sepsis. Genetic associations of IL-6 variants with disease have focused on the -174 G>C single nucleotide polymorphism (SNP) within the IL-6 promoter. However, it is not clear whether these associations are due to linkage disequilibrium to flanking regions or to other SNPs of the gene. Methods Eighty-four healthy controls (H), 91 septic (S), and 64 ALI patients of European American descent (ED) were analyzed for association. A set of seven evenly distributed intergenic SNPs covering ≈74 kb plus the -174 SNP were chosen to evaluate the associations with the flanking regions of IL-6 gene. TagIT software (http://www.genome.duke.edu/resourses/computation/software>) was used to select IL-6 cosmopolitan tagging SNPs (tSNPs) from 23 ED and 24 African American descent (AD) individuals. SNP dropping with resampling method was used to predict the properties of tSNPs covering variation. Results Only the -174 G>C SNP was significantly associated with ALI (ALI vs H: OR = 0.28, 95% CI 0.08-0.96, p = .039; ALI vs S: OR = 0.26, 95% CI 0.08-0.87, p = .038). Additionally, a set of 14 cosmopolitan tSNPs were identified covering more than 85% of known and unknown ED or AD common variations in the IL-6 gene. Conclusion Our data demonstrate that variants in the IL-6 gene, but not flanking regions, are involved in susceptibility to ALI. The analysis of haplotypes defined by tSNPs within the IL-6 gene may confirm whether genetic variants other than -174 G>C SNP may be associated with ALI. This approach will allow us to delimitate the search for causal variants in the IL-6 gene. Funding Specialized Centers of Clinically Oriented Research P50 HL-073994 and Fundacion Canaria Dr. Manuel Morales.