A Genome-Wide Association Scan on the Levels of Markers of Inflammation in Sardinians Reveals Associations That Underpin Its Complex Regulation

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dc.contributor.authorNaitza, Silvia
dc.contributor.authorPorcu, Eleonora
dc.contributor.authorSteri, Maristella
dc.contributor.authorTaub, Dennis Daniel
dc.contributor.authorMulas, Antonella
dc.contributor.authorXiao, Xiang
dc.contributor.authorStrait, James
dc.contributor.authorDei, Mariano
dc.contributor.authorLai, Sandra
dc.contributor.authorBusonero, Fabio
dc.contributor.authorMaschio, Andrea
dc.contributor.authorUsala, Gianluca
dc.contributor.authorZoledziewska, Magdalena
dc.contributor.authorSidore, Carlo
dc.contributor.authorZara, Ilenia
dc.contributor.authorPitzalis, Maristella
dc.contributor.authorLoi, Alessia
dc.contributor.authorVirdis, Francesca
dc.contributor.authorPiras, Roberta
dc.contributor.authorDeidda, Francesca
dc.contributor.authorWhalen, Michael B.
dc.contributor.authorCrisponi, Laura
dc.contributor.authorConcas, Antonio
dc.contributor.authorPodda, Carlo
dc.contributor.authorUzzau, Sergio
dc.contributor.authorScheet, Paul
dc.contributor.authorLongo, Dan L.
dc.contributor.authorLakatta, Edward
dc.contributor.authorAbecasis, Gonçalo
dc.contributor.authorCao, Antonio
dc.contributor.authorSchlessinger, David
dc.contributor.authorUda, Manuela
dc.contributor.authorSanna, Serena
dc.contributor.authorCucca, Francesco
dc.date.accessioned2014-12-16T13:38:27Z
dc.date.available2014-12-16T13:38:27Z
dc.date.issued2012-01-26
dc.description.abstractIdentifying the genes that influence levels of pro-inflammatory molecules can help to elucidate the mechanisms underlying this process. We first conducted a two-stage genome-wide association scan (GWAS) for the key inflammatory biomarkers Interleukin-6 (IL-6), the general measure of inflammation erythrocyte sedimentation rate (ESR), monocyte chemotactic protein-1 (MCP-1), and high-sensitivity C-reactive protein (hsCRP) in a large cohort of individuals from the founder population of Sardinia. By analysing 731,213 autosomal or X chromosome SNPs and an additional ,1.9 million imputed variants in 4,694 individuals, we identified several SNPs associated with the selected quantitative trait loci (QTLs) and replicated all the top signals in an independent sample of 1,392 individuals from the same population. Next, to increase power to detect and resolve associations, we further genotyped the whole cohort (6,145 individuals) for 293,875 variants included on the ImmunoChip and MetaboChip custom arrays. Overall, our combined approach led to the identification of 9 genome-wide significant novel independent signals—5 of which were identified only with the custom arrays—and provided confirmatory evidence for an additional 7. Novel signals include: for IL-6, in the ABO gene (rs657152, p = 2.13610229); for ESR, at the HBB (rs4910472, p = 2.31610211) and UCN119B/SPPL3 (rs11829037, p = 8.91610210) loci; for MCP-1, near its receptor CCR2 (rs17141006, p = 7.53610213) and in CADM3 (rs3026968, p = 7.63610213); for hsCRP, within the CRP gene (rs3093077, p = 5.73610221), near DARC (rs3845624, p = 1.43610210), UNC119B/SPPL3 (rs11829037, p = 1.50610214), and ICOSLG/AIRE (rs113459440, p = 1.54610208) loci. Confirmatory evidence was found for IL-6 in the IL- 6R gene (rs4129267); for ESR at CR1 (rs12567990) and TMEM57 (rs10903129); for MCP-1 at DARC (rs12075); and for hsCRP at CRP (rs1205), HNF1A (rs225918), and APOC-I (rs4420638). Our results improve the current knowledge of genetic variants underlying inflammation and provide novel clues for the understanding of the molecular mechanisms regulating this complex process.IT
dc.description.statusPubblicatoIT
dc.identifier.doi10.1371/journal.pgen.1002480IT
dc.identifier.eissn1553-7404
dc.identifier.issn1553-7390
dc.identifier.urihttp://hdl.handle.net/11050/1138
dc.language.isoenIT
dc.publisherPublic Library of ScienceIT
dc.relation.ispartofPLoS GeneticsIT
dc.relation.ispartofseries8;1
dc.rightsAttribuzione - Non commerciale - Non opere derivate 3.0 Italia*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/it/*
dc.subjectGenome-wide association scan (GWAS)IT
dc.subjectpro-inflammatory moleculesIT
dc.subjecterythrocyte sedimentation rate (ESR)IT
dc.subject.een-cordisEEN CORDIS::SCIENZE BIOLOGICHE ::Ricerca sul genoma ::Espressione genica, ricerca proteomicaIT
dc.titleA Genome-Wide Association Scan on the Levels of Markers of Inflammation in Sardinians Reveals Associations That Underpin Its Complex RegulationIT
dc.typeArticoloIT
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