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 signals5 of which were identified only with the custom arraysand provided confirmatory evidence for an additional 7. Novel signals include: for IL-6, in the ABO gene (rs657152, p=2.1310 29 ); for ESR, at the HBB (rs4910472, p=2.3110 11 ) and UCN119B / SPPL3 (rs11829037, p=8.9110 10 ) loci; for MCP-1, near its receptor CCR2 (rs17141006, p=7.5310 13 ) and in CADM3 (rs3026968, p=7.6310 13 ); for hsCRP, within the CRP gene (rs3093077, p=5.7310 21 ), near DARC (rs3845624, p=1.4310 10 ), UNC119B / SPPL3 (rs11829037, p=1.5010 14 ), and ICOSLG/AIRE (rs113459440, p=1.5410 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.

... SardiNIA). MCP-1 The GWAS results for MCP-1 levels revealed strong association signals on chromosome 1q22-q23 ( Table S1 ). The associated region encompassed 500 kb and contained several genes, with the top signal detected in the DARC ( Duffy blood group chemokine receptor ) gene at marker rs12075 (p=1.6810 30 , 36.78 pg/ml average increase per A allele), as also shown in a recent meta-analysis ( Table 1 ) [21] . The association curve encompasses several other genes, including the CADM3 ( cell adhesion molecule 3 ) locus upstream of DARC , as well as in the FCER1A ( Fc fragment of IgE, high affinity I, receptor for alpha polypeptide ), OR10J1 ( olfactory receptor, family 10, subfamily J, member 1 ), and OR10J5 , that have been previously reported to be associated with MCP-1 levels ( Table S1 ) [22] . Interestingly, when we performed a conditional analysis on the top SNP in the DARC gene, SNP rs3026968 in the CADM3 gene still showed a strong association (p=4.2610 08 ), indicating that this marker

... ), as well as 3 additional SNPs including the 2 independent signals in the CADM3 and DARC loci (rs3026968 and rs3845624), and one suggestive SNP with p<10 06 near HLA-DRB9 (rs9268858), in a group of 1,392 Sardinians enrolled in the same SardiNIA study but unrelated to the individuals analyzed in Step 1 GWAS. This independent cohort has been previously described as SardiNIA stage 2 [27] . Table 1 provides a summary of the follow-up results for the SNPs with the strongest association signal at each

... likely due to the fact that it was imputed with a modest imputation score in the initial GWAS, whereas it was directly genotyped in the replication cohort. The association signal at rs3026968 in CADM3 was also confirmed in SardiNIA stage 2 (p=0.0147, Table 1 ), whereas the association at rs9405112 in the HLA-DRB9 region was not (p=0.59). Neither the signal in the CDH4 gene, or that at rs3918357 in the CCR2 gene were followed up; however, the latter supports a previously reported suggestive

.... Our study thus refines the association and points to CCR2 as the most likely candidate for a role in the levels of MCP-1. We also carried out a search for independent SNPs by conditioning on the strongest associated variant, but this analysis did not reveal any evidence. The independent signal in CADM3 or an adequate proxy were not included on the custom arrays, and thus it could not be tested in this data set. However, since the SNP was available in both the SardiNIA discovery cohort (Step 1) and

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Gene: CADM3 - cell adhesion molecule 3 - (NCBI)

Protein : 1z9m

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