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.

Association of rs2075876 polymorphism of AIRE gene with rheumatoid arthritis risk

“…The C-reactive protein (CRP) level reflects the acute phase response under acute or chronic inflammatory condition, and it mainly used as a marker of status of inflammation in clinical diagnosis. Naitza and colleagues identified a SNP rs113459440 near AIRE gene had great impact on the level of high-sensitivity C-reactive protein (hsCRP) [25]. And it was an appealing result that rs7065875 was also correlated with CRP concentration.…”

Rare variant genotype imputation with thousands of study-specific whole-genome sequences: implications for cost-effective study designs

“…Data from the Affymetrix 6.0 array were instead not combined with the Illumina arrays, given the smaller number of samples available (1072 vs 6602); for this set, quality control filters have been already described. 13 From the QCed set of markers, we extracted a subset of 227 745 SNPs representing most of the content of the Illumina HumanCore array (78.9% prior QC), a low-density genome-wide array. Given the extensive overlap, and considering that after quality control filtering the effective content of an array is always reduced, we treated this subset of markers as an approximation of the genomic content accessible with the HumanCore array that we refer to here as 'pseudo-HumanCore'.…”

<b><i>VPS13D</i></b> Gene Variant Is Associated with Altered IL-6 Production and Mortality in Septic Shock

“…The VPS13C rs17271305 SNP was identified in the discovery phase of a GWAS that measured insulin responses to an oral glucose load [26], potentially related to the observation that Vps proteins are involved in the delivery of insulin receptors to the cell surface membrane in yeast [21]. Despite no identification of an overlap of SNPs in our cytomix-stimulated in vitro IL-6 GWAS and previously reported pQTL GWAS using baseline IL-6 in noncritically ill populations [27,28], VPS13D SNPs have also been identified in a GWAS of peripheral arterial disease defined by lower limb claudication [29] (specifically rs235243 G/T and rs3765337 T/G). Based on HapMap data, the minor allele frequency of rs3765337, marking peripheral arterial disease, is much less than that of rs6685273, the SNP that we have identified.…”