title: A genome-wide association scan on the levels of markers of inflammation in Sardinians reveals associations that underpin its complex regulation.
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.
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Cagliari, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Naitza
authors.forename: Eleonora
authors.initials: E
authors.lastname: Porcu
authors.forename: Maristella
authors.initials: M
authors.lastname: Steri
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Taub
authors.forename: Antonella
authors.initials: A
authors.lastname: Mulas
authors.forename: Xiang
authors.initials: X
authors.lastname: Xiao
authors.forename: James
authors.initials: J
authors.lastname: Strait
authors.forename: Mariano
authors.initials: M
authors.lastname: Dei
authors.forename: Sandra
authors.initials: S
authors.lastname: Lai
authors.forename: Fabio
authors.initials: F
authors.lastname: Busonero
authors.forename: Andrea
authors.initials: A
authors.lastname: Maschio
authors.forename: Gianluca
authors.initials: G
authors.lastname: Usala
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zoledziewska
authors.forename: Carlo
authors.initials: C
authors.lastname: Sidore
authors.forename: Ilenia
authors.initials: I
authors.lastname: Zara
authors.forename: Maristella
authors.initials: M
authors.lastname: Pitzalis
authors.forename: Alessia
authors.initials: A
authors.lastname: Loi
authors.forename: Francesca
authors.initials: F
authors.lastname: Virdis
authors.forename: Roberta
authors.initials: R
authors.lastname: Piras
authors.forename: Francesca
authors.initials: F
authors.lastname: Deidda
authors.forename: Michael B
authors.initials: MB
authors.lastname: Whalen
authors.forename: Laura
authors.initials: L
authors.lastname: Crisponi
authors.forename: Antonio
authors.initials: A
authors.lastname: Concas
authors.forename: Carlo
authors.initials: C
authors.lastname: Podda
authors.forename: Sergio
authors.initials: S
authors.lastname: Uzzau
authors.forename: Paul
authors.initials: P
authors.lastname: Scheet
authors.forename: Dan L
authors.initials: DL
authors.lastname: Longo
authors.forename: Edward
authors.initials: E
authors.lastname: Lakatta
authors.forename: Gonçalo R
authors.initials: GR
authors.lastname: Abecasis
authors.forename: Antonio
authors.initials: A
authors.lastname: Cao
authors.forename: David
authors.initials: D
authors.lastname: Schlessinger
authors.forename: Manuela
authors.initials: M
authors.lastname: Uda
authors.forename: Serena
authors.initials: S
authors.lastname: Sanna
authors.forename: Francesco
authors.initials: F
authors.lastname: Cucca
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D001799:Blood Sedimentation; D002097:C-Reactive Protein / Q000235:genetics*; D018932:Chemokine CCL2 / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D015850:Interleukin-6 / Q000235:genetics*; D007558:Italy; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics*
chemical_list: D015415:Biomarkers; D018932:Chemokine CCL2; D015850:Interleukin-6; D002097:C-Reactive Protein