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

被引：125

作者：

Naitza, Silvia ^{[1
]}

Porcu, Eleonora ^{[1
]}

Steri, Maristella ^{[1
]}

Taub, Dennis D. ^{[2
]}

Mulas, Antonella ^{[1
]}

Xiao, Xiang ^{[3
]}

Strait, James ^{[2
]}

Dei, Mariano ^{[1
]}

Lai, Sandra ^{[1
]}

Busonero, Fabio ^{[1
]}

Maschio, Andrea ^{[1
]}

Usala, Gianluca ^{[1
]}

Zoledziewska, Magdalena ^{[4
]}

Sidore, Carlo ^{[1
,4
,5
]}

Zara, Ilenia ^{[6
]}

Pitzalis, Maristella ^{[4
]}

Loi, Alessia ^{[1
]}

Virdis, Francesca ^{[1
]}

Piras, Roberta ^{[1
]}

Deidda, Francesca ^{[4
]}

Whalen, Michael B. ^{[6
]}

Crisponi, Laura ^{[1
]}

Concas, Antonio ^{[7
]}

Podda, Carlo ^{[7
]}

Uzzau, Sergio ^{[4
,8
]}

Scheet, Paul ^{[3
]}

Longo, Dan L. ^{[2
]}

Lakatta, Edward ^{[2
]}

Abecasis, Goncalo R. ^{[5
]}

Cao, Antonio ^{[1
]}

Schlessinger, David ^{[2
]}

Uda, Manuela ^{[1
]}

Sanna, Serena ^{[1
]}

Cucca, Francesco ^{[1
,4
]}

机构：

[1] CNR, Ist Ric Genet & Biomed, Cagliari, Italy

[2] NIA, Intramural Res Program, Baltimore, MD 21224 USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA

[4] Univ Sassari, Dipartimento Sci Biomed, I-07100 Sassari, Italy

[5] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA

[6] Ctr Adv Studies Res & Dev Sardinia CRS4, AGCT Program, Pula, Italy

[7] CRS4, High Performance Comp & Network, Pula, Italy

[8] Porto Conte Ric, Localita Tramariglio, Sassari, Italy

来源：

PLOS GENETICS | 2012年 / 8卷 / 01期

基金：

美国国家卫生研究院;

关键词：

C-REACTIVE PROTEIN; MONOCYTE CHEMOATTRACTANT PROTEIN-1; COMMON VARIANTS; GENE VARIANTS; LOCI; RISK; POLYMORPHISM; RECEPTOR; SUSCEPTIBILITY; NUMBER;

D O I：

10.1371/journal.pgen.1002480

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 = 2.13x10(-29)); for ESR, at the HBB (rs4910472, p = 2.31x10(-11)) and UCN119B/SPPL3 (rs11829037, p = 8.91x10(-10)) loci; for MCP-1, near its receptor CCR2 (rs17141006, p = 7.53x10(-13)) and in CADM3 (rs3026968, p = 7.63x10(-13)); for hsCRP, within the CRP gene (rs3093077, p = 5.73x10(-21)), near DARC (rs3845624, p = 1.43x10(-10)), UNC119B/SPPL3 (rs11829037, p = 1.50x10(-14)), and ICOSLG/AIRE (rs113459440, p = 1.54x10(-08)) loci. Confirmatory evidence was found for IL-6 in the IL6R 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.

引用

页数：12

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