TY - JOUR
T1 - A genome-wide association scan on the levels of markers of inflammation in sardinians reveals associations that underpin its complex regulation
AU - Naitza, Silvia
AU - Porcu, Eleonora
AU - Steri, Maristella
AU - Taub, Dennis D.
AU - Mulas, Antonella
AU - Xiao, Xiang
AU - Strait, James
AU - Dei, Mariano
AU - Lai, Sandra
AU - Busonero, Fabio
AU - Maschio, Andrea
AU - Usala, Gianluca
AU - Zoledziewska, Magdalena
AU - Sidore, Carlo
AU - Zara, Ilenia
AU - Pitzalis, Maristella
AU - Loi, Alessia
AU - Virdis, Francesca
AU - Piras, Roberta
AU - Deidda, Francesca
AU - Whalen, Michael B.
AU - Crisponi, Laura
AU - Concas, Antonio
AU - Podda, Carlo
AU - Uzzau, Sergio
AU - Scheet, Paul
AU - Longo, Dan L.
AU - Lakatta, Edward
AU - Abecasis, Gonçalo R.
AU - Cao, Antonio
AU - Schlessinger, David
AU - Uda, Manuela
AU - Sanna, Serena
AU - Cucca, Francesco
PY - 2012/1
Y1 - 2012/1
N2 - 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.
AB - 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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U2 - 10.1371/journal.pgen.1002480
DO - 10.1371/journal.pgen.1002480
M3 - Article
C2 - 22291609
AN - SCOPUS:84857467976
SN - 1553-7390
VL - 8
JO - PLoS genetics
JF - PLoS genetics
IS - 1
M1 - e1002480
ER -