Cytokines are major immune system regulators. Previously, innate cytokine profiles determined by lipopolysaccharide stimulation were shown to be highly heritable. To identify regulating genes in innate immunity, we analyzed data from a genome-wide linkage scan using microsatellites in osteoarthritis (OA) patients (The GARP study) and their innate cytokine data on interleukin (IL)-1Β, IL-1Ra, IL-10 and tumor necrosis factor (TNF)α. A confirmation cohort consisted of the Leiden 85-Plus study. In this study, a linkage analysis was followed by manual selection of candidate genes in linkage regions showing LOD scores over 2.5. An single-nucleotide polymorphism (SNP) gene tagging method was applied to select SNPs on the basis of the highest level of gene tagging and possible functional effects. QTDT was used to identify the SNPs associated with innate cytokine production. Initial association signals were modeled by a linear mixed model. Through these analyses, we identified 10 putative genes involved in the regulation of TNFα. SNP rs6679497 in gene CD53 showed significant association with TNFα levels (P0.001). No association of this SNP was observed with OA. A novel gene involved in the innate immune response of TNFα is identified. Genetic variation in this gene may have a role in diseases and disorders in which TNFα is closely involved.