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

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 ery...

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Veröffentlicht in:PLoS genetics Jg. 8; H. 1; S. e1002480
Hauptverfasser: Naitza, Silvia, Porcu, Eleonora, Steri, Maristella, Taub, Dennis D., Mulas, Antonella, Xiao, Xiang, Strait, James, Dei, Mariano, Lai, Sandra, Busonero, Fabio, Maschio, Andrea, Usala, Gianluca, Zoledziewska, Magdalena, Sidore, Carlo, Zara, Ilenia, Pitzalis, Maristella, Loi, Alessia, Virdis, Francesca, Piras, Roberta, Deidda, Francesca, Whalen, Michael B., Crisponi, Laura, Concas, Antonio, Podda, Carlo, Uzzau, Sergio, Scheet, Paul, Longo, Dan L., Lakatta, Edward, Abecasis, Gonçalo R., Cao, Antonio, Schlessinger, David, Uda, Manuela, Sanna, Serena, Cucca, Francesco
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States Public Library of Science 01.01.2012
Public Library of Science (PLoS)
Schlagworte:
Adolescent
Adult
Aged
Aged, 80 and over
Biological markers
Biology
Biomarkers
Blood Sedimentation
C-reactive protein
C-Reactive Protein - genetics
Chemokine CCL2 - genetics
Cytokines
Female
Genes
Genetic aspects
Genetics
Genome-Wide Association Study - methods
Genomes
Humans
Inflammation
Inflammation - genetics
Interleukin-6 - genetics
Italy
Male
Mathematics
Middle Aged
Physiological aspects
Polymorphism, Single Nucleotide
Population
Proteins
Quantitative Trait Loci - genetics
Risk factors
Standard deviation
Italy
ISSN:1553-7404, 1553-7390, 1553-7404
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Zusammenfassung: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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Conceived and designed the experiments: S Naitza, S Uzzau, DL Longo, E Lakatta, A Concas, GR Abecasis, D Schlessinger, M Uda, S Sanna, F Cucca. Performed the experiments: DD Taub, A Mulas, M Dei, S Lai, F Busonero, A Maschio, G Usala, M Zoledziewska. Analyzed the data: E Porcu, M Steri, X Xiao, J Strait, C Sidore, I Zara, P Sitzalis, S Sanna. Contributed reagents/materials/analysis tools: M Pitzalis, A Loi, F Virdis, R Piras, F Deidda, L Crisponi, A Concas, C Podda. Wrote the paper: S Naitza, MB Whalen, D Schlessinger, S Sanna, F Cucca.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1002480