Naitza, Silvia and Porcu, Elenora and Steri, Maristella and Taub, Dennis Daniel and Mulas, Antonella and Xiao, Xiang and Strait, James and Dei, Mariano and Lai, Sandra and Busonero, Fabio and Maschio, Andrea and Usala, Gianluca and Zoledziewska, Magdalena and Sidore, Carlo and Zara, Ilenia and Pitzalis, Maristella and Loi, Alessia and Virdis, Francesca and Piras, Roberta and Deidda, Francesca and Whalen, Michael B. and Crisponi, Laura and Concas, Antonio and Podda, Carlo and Uzzau, Sergio and Scheet, Paul and Longo, Dan L. and Lakatta, Edward G. and Abecasis, Gonçalo and Cao, Antonio and Schlessinger, David and Uda, Manuela and Sanna, Serena and Cucca, Francesco (2012) A Genome-wide association scan on the levels of markers of inflammation in Sardinians reveals associations that underpin its complex regulation. Plos Genetics, Vol. 8 (1), e1002480. ISSN 1553-7390. Article.
Identifying 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 = 2.13×10−29); for ESR, at the HBB (rs4910472, p = 2.31×10−11) and UCN119B/SPPL3 (rs11829037, p = 8.91×10−10) loci; for MCP-1, near its receptor CCR2 (rs17141006, p = 7.53×10−13) and in CADM3 (rs3026968, p = 7.63×10−13); for hsCRP, within the CRP gene (rs3093077, p = 5.73×10−21), near DARC (rs3845624, p = 1.43×10−10), UNC119B/SPPL3 (rs11829037, p = 1.50×10−14), and ICOSLG/AIRE (rs113459440, p = 1.54×10−08) 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.
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