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. 2012 Jan;8(1):e1002480.
doi: 10.1371/journal.pgen.1002480. Epub 2012 Jan 26.

A genome-wide association scan on the levels of markers of inflammation in Sardinians reveals associations that underpin its complex regulation

Silvia Naitza  1 , Eleonora Porcu, Maristella Steri, Dennis D Taub, Antonella Mulas, Xiang Xiao, James Strait, Mariano Dei, Sandra Lai, Fabio Busonero, Andrea Maschio, Gianluca Usala, Magdalena Zoledziewska, Carlo Sidore, Ilenia Zara, Maristella Pitzalis, Alessia Loi, Francesca Virdis, Roberta Piras, Francesca Deidda, Michael B Whalen, Laura Crisponi, Antonio Concas, Carlo Podda, Sergio Uzzau, Paul Scheet, Dan L Longo, Edward Lakatta, Gonçalo R Abecasis, Antonio Cao, David Schlessinger, Manuela Uda, Serena Sanna, Francesco Cucca
Affiliations

A genome-wide association scan on the levels of markers of inflammation in Sardinians reveals associations that underpin its complex regulation

Silvia Naitza et al. PLoS Genet. 2012 Jan.

Abstract

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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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Manhattan plot and QQ plot of association findings.
The figure summarizes the association results obtained on the ImmunoChip and MetaboChip markers (Step 3). The blue dotted line marks the Bonferroni threshold significance levels (1.7×10−7), and SNPs in loci exceeding this threshold are highlighted in green. The bottom panel represents the QQ plot, where the red line corresponds to all test statistics, and the blue line to results after excluding statistics at top markers (highlighted in green in the Manhattan Plot). The gray area corresponds to the 90% confidence region from a null distribution of P values (generated from 100 simulations).
Figure 2
Figure 2. Zoom views of the association results in the loci associated with IL-6 and ESR.
Each panel shows the association curve around the strongest SNP, which is highlighted with a purple dot. The SNPs are coloured according to their linkage disequilibrium (r2) with the top variant in the 1000 Genomes European data set, with symbols that reflect genomic annotation as indicated in the legend. Arrows highlight independent signals, if any, described in the manuscript; while light blue lines indicate the recombination rate, according to the right-hand Y axis. Genomic positions are as in build 37. Gene transcripts are annotated in the lower box. Plots were drawn using the standalone LocusZoom version .
Figure 3
Figure 3. Zoom views of the association results in the loci associated with MCP-1 and hsCRP.
Each panel shows the association curve around the strongest SNP, which is highlighted with a purple dot. The SNPs are coloured according to their linkage disequilibrium (r2) with the top variant in the 1000 Genomes European data set, with symbols that reflect genomic annotation as indicated in the legend. Arrows highlight independent signals, if any, described in the manuscript; while light blue lines indicate the recombination rate, according to the right-hand Y axis. Genomic positions are as in build 37. Gene transcripts are annotated in the lower box. Plots were drawn using the standalone LocusZoom version .
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