A genome wide linkage scan reveals CD53 as an important regulator of innate TNF-alpha levels.

Steffan Daniel Bos (1) , Nico Lakenberg (1) , Ruud van Der Breggen (1) , Jeanine Houwing-Duistermaat (1) , Margreet Kloppenburg (1) , Anton J.M. de Craen (1) , Marian Beekman (1) , Ingrid Meulenbelt (1) , P E.Slagboom (1)

1 Molecular Epidemiology

Abstract Cytokines are major immune system regulators. Previously, innate cytokine profiles determined by LPS 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 patients (The GARP study) and their innate cytokine data on IL-1β, IL-1Ra, IL-10 and TNFα. 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. A SNP gene tagging method was applied to select SNPs on the basis of highest level of gene tagging and possible functional effects. QTDT was used to identify the SNPs associated to innate cytokine production. Initial association signals were modelled 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 to TNFα levels (P = 0.001). No association of this SNP was observed to osteoarthritis. A novel gene involved in the innate immune response of TNFα is identified. Genetic variation in this gene may play a role in diseases and disorders in which TNFα is intimately involved.

Mots clés: CD53; Linkage; TNF

Steffan Daniel Bos, Nico Lakenberg, Ruud van Der Breggen, Jeanine Houwing-Duistermaat, Margreet Kloppenburg, et al.. A genome wide linkage scan reveals CD53 as an important regulator of innate TNF-alpha levels.. European Journal of Human Genetics, 2010, ⟨10.1038/ejhg.2010.52⟩. ⟨hal-00528085⟩