Elevated concentrations of inflammatory mediators are characteristic of autoimmune disease accompanied by chronic or recurrent inflammation. disease. Genotypes were determined for 345 SNP markers in 75 genes. Association between serum analytes and single alleles was tested by linear regression. Polymorphisms in several genes were associated with IL-6 levels (including and in SLE and and in RA) or with TNFα levels (including and in SLE and and in RA). Some associations were shared between disease and control groups or between IL-6 and TNFα within a group. In conclusion variation in genes implicated in disease pathology is associated with serum IL-6 or TNFα concentration. Some genetic Resibufogenin associations are more apparent in healthy controls than in SLE or RA suggesting dysregulation of the principal mediators of chronic inflammation in disease. Susceptibility genes may affect inflammatory response with variable effect on disease etiology. and in SLE and and in RA and several including and in SLE and and in RA and and in the controls. Associations shared between serum TNFα and IL-6 concentration within a disease group included and (rs10488631) for TNFα in SLE (P=0.02) and controls (P=0.003) (rs10488631 rs4731535) for IL-6 in SLE (P=0.03 0.04 and controls Resibufogenin (P=0.01 for each) (rs5743291) for TNFα in RA (P=0.01) and controls (P=0.02) and (rs6679677 rs2476601) for TNFα in RA (P=0.05 for each) and controls (P=0.01 for each). None of the associations withstand correction for multiple testing using Bonferroni adjustment and only rs3021304 rs748855 and rs2076059 for IL-6 in RA withstand False Discovery Rate correction at 20%. We have included β coefficients as a measure of magnitude of effect and as possible support of probable marker association in Resibufogenin Tables 2 and ?and3.3. The largest coefficients (those in the 95th percentile shown in bold-face type) support some of the top-rank associations including (P=0.01) and (P=0.03) in SLE and (P=0.01) (P=0.04) and (P=0.02) in RA and also for TNFα including (P=0.03) in controls. is represented by a single SNP (rs2542151) and was not included in global haplotype estimation. Discussion Our major finding is that serum concentrations of IL-6 and TNFα principal mediators Id1 of inflammation known to be elevated in patients with SLE or RA are associated with polymorphisms in genes involved in regulation of inflammatory pathways; these genes are sometimes established susceptibility genes from genome wide association studies (GWAS) in autoimmune disorders. Such associations are seen not only in patients with SLE or RA but also to some extent in controls free of inflammatory disease. Genetic associations with inflammatory mediators noted in our study include and in RA and and in SLE as well as and several genes in the controls. Associations shared between TNFα and IL-6 concentrations are seen primarily in the RA group. Associations shared to varying extent between disease and control groups include and The limited size of our study permits only speculative conclusions regarding the contribution of particular genes Resibufogenin in the control of serum inflammatory mediator concentration but the observations that some of these associations are seen in more than one group and that biologically plausible associations are seen for the disease groups is interesting and may serve as a basis for candidate replications. It will be important to follow these observations as larger studies for which Resibufogenin both inflammation measurements and genetic data become available. To date no such studies have been reported for autoimmune disease but inflammatory markers in serum including TNFα and IL-6 have been examined in relation to genetic markers for cardiovascular disease risk in the general population.22 Genetic regulation of chronic inflammation in RA The HLA-DRB1 locus particularly the variants comprising the shared epitope (SE) has been recognized as critical in RA etiology and pathology 23 24 so that the association of markers with both TNFα and IL-6 in RA but not SLE or control groups is consistent with known pathophysiology. Given the established central role of in modulation of disease expression including the classification into pathological subsets 25 it is possible that is associated with elevated TNFα and IL-6 either by a direct effect upon the innate immune response or by an indirect association through other variables correlated with increased cytokine levels for example RA severity or disease duration. It should be noted that we did not measure SE alleles directly but the.