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 = 2.13610229); for ESR, at the HBB (rs4910472, p = 2.31610211) and UCN119B/SPPL3 (rs11829037, p = 8.91610210) loci; for
MCP-1, near its receptor CCR2 (rs17141006, p = 7.53610213) and in CADM3 (rs3026968, p = 7.63610213); for hsCRP, within
the CRP gene (rs3093077, p = 5.73610221), near DARC (rs3845624, p = 1.43610210), UNC119B/SPPL3 (rs11829037,
p = 1.50610214), and ICOSLG/AIRE (rs113459440, p = 1.54610208) 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.