A Genome-Wide Association Scan on the Levels of Markers of Inflammation in Sardinians Reveals Associations That Underpin Its Complex Regulation
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.
Vyšlo v časopise:
A Genome-Wide Association Scan on the Levels of Markers of Inflammation in Sardinians Reveals Associations That Underpin Its Complex Regulation. PLoS Genet 8(1): e32767. doi:10.1371/journal.pgen.1002480
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002480
Souhrn
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.
Zdroje
1. DupuisJLarsonMGVasanRSMassaroJMWilsonPW 2005 Genome scan of systemic biomarkers of vascular inflammation in the Framingham Heart Study: evidence for susceptibility loci on 1q. Atherosclerosis 182 307 314
2. SannaSJacksonAUNagarajaRWillerCJChenWM 2008 Common variants in the GDF5-UQCC region are associated with variation in human height. Nat Genet 40 198 203
3. WillerCJSannaSJacksonAUScuteriABonnycastleLL 2008 Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet 40 161 169
4. SoranzoNSpectorTDManginoMKühnelBRendonA 2009 A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium. Nat Genet 41 1182 1190
5. PfeuferASannaSArkingDEMüllerMGatevaV 2009 Common variants at ten loci modulate the QT interval duration in the QTSCD Study. Nat Genet 41 407 414
6. SaxenaRHivertMFLangenbergCTanakaTPankowJS 2010 Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge. Nat Genet 42 142 148
7. BarreiroLBQuintana-MurciL 2010 From evolutionary genetics to human immunology: how selection shapes host defence genes. Nat Rev Genet 11 17 30
8. ZhernakovaAElbersCCFerwerdaBRomanosJTrynkaG 2010 Evolutionary and functional analysis of celiac risk loci reveals SH2B3 as a protective factor against bacterial infection. Am J Hum Genet 86 970 977
9. ShankerJKakkarVV 2010 Implications of genetic polymorphisms in inflammation-induced atherosclerosis. Open Cardiovasc Med J 4 30 37
10. RamanDSobolik-DelmaireTRichmondA 2011 Chemokines in health and disease. Exp Cell Res 317 575 589
11. PiliaGChenWMScuteriAOrrúMAlbaiG 2006 Heritability of cardiovascular and personality traits in 6,148 Sardinians. PLoS Genet 2 e132 doi:10.1371/journal.pgen.0020132
12. CortesABrownMA 2011 Promise and pitfalls of the Immunochip. Arthritis Res Ther 13 101
13. SannaSLiBMulasASidoreCKangHM 2011 Fine mapping of five Loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability. PLoS Genet 7 e1002198 doi:10.1371/journal.pgen.1002198
14. KulloIJDingKShameerKMcCartyCAJarvikGP 2011 Complement receptor 1 gene variants are associated with erythrocyte sedimentation rate. Am J Hum Genet 89 131 138
15. SunyaevSRamenskyVKochILatheW3rdKondrashovAS 2001 Prediction of deleterious human alleles. Hum Mol Genet 10 591 597
16. HerreraAHXiangLMartinSGLewisJWilsonJG 1998 Analysis of complement receptor type 1 (CR1) expression on erythrocytes and of CR1 allelic markers in Caucasian and African American populations. Clin Immunol Immunopathol 87 176 183
17. McCarrollSAKuruvillaFGKornJMCawleySNemeshJ 2008 Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat Genet 40 1166 1174
18. Wellcome Trust Case Control Consortium 2010 Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature 464 713 720
19. WangKLiMHadleyDLiuRGlessnerJ 2007 PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. Genome Res 17 1665 1674
20. UdaMGalanelloRSannaSLettreGSankaranVG 2008 Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia. Proc Natl Acad Sci U S A.105 1620 1625
21. SchnabelRBBaumertJBarbalicMDupuisJEllinorPT 2010 Duffy antigen receptor for chemokines (Darc) polymorphism regulates circulating concentrations of monocyte chemoattractant protein-1 and other inflammatory mediators. Blood 115 5289 5299
22. BenjaminEJDupuisJLarsonMGLunettaKLBoothSL 2007 Genome-wide association with select biomarker traits in the Framingham Heart Study. BMC Med Genet 8 Suppl 1 S11
23. RidkerPMPareGParkerAZeeRYDanikJS 2008 Loci related to metabolic-syndrome pathways including LEPR,HNF1A, IL6R, and GCKR associate with plasma C-reactive protein: the Women's Genome Health Study. Am J Hum Genet 82 1185 1192
24. ReinerAPBarberMJGuanYRidkerPMLangeLA 2008 Polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1 alpha are associated with C-reactive protein. Am J Hum Genet 82 1193 1201
25. DehghanADupuisJBarbalicMBisJCEiriksdottirG 2010 Meta-analysis of genome-wide association studies in >80,000 subjects identifies multiple loci for C-reactive protein levels. Circulation 123 731 738
26. RussellAICunninghame GrahamDSShepherdCRobertonCA 2004 Polymorphism at the C-reactive protein locus influences gene expression and predisposes to systemic lupus erythematosus. Hum Molec Genet 13 137 147
27. Arnaud-LopezLUsalaGCeresiniGMitchellBDPiliaMG 2008 Phosphodiesterase 8B gene variants are associated with serum TSH levels and thyroid function. Am J Hum Genet 82 1270 1280
28. ReichDPattersonNRameshVDe JagerPLMcDonaldGJ 2007 Admixture mapping of an allele affecting interleukin 6 soluble receptor and interleukin 6 levels. Am J Hum Genet 80 716 726
29. AulchenkoYSRipattiSLindqvistIBoomsmaDHeidIM 2009 Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat Genet 41 47 55
30. LaukensDGeorgesMLibioulleCSandorCMniMVander CruyssenBPeeters 2010 Evidence for significant overlap between common risk variants for Crohn's disease and ankylosing spondylitis. PLoS One 5 e13795 doi:10.1371/journal.pone.0013795
31. AndersonCABoucherGLeesCWFrankeAD'AmatoM 2011 Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet 43 246 252
32. DuboisPCTrynkaGFrankeLHuntKARomanosJ 2010 Multiple common variants for celiac disease influencing immune gene expression. Nat Genet 42 295 302
33. TeraoCYamadaROhmuraKTakahashiMKawaguchiT 2011 The human AIRE gene at chromosome 21q22 is a genetic determinant for the predisposition to rheumatoid arthritis in Japanese population. Hum Mol Genet 20 2680 2685
34. LoweJKMallerJBPe'erINealeBMSalitJ 2009 Genome-wide association studies in an isolated founder population from the Pacific Island of Kosrae. PLoS Genet 5 e1000365 doi:10.1371/journal.pgen.1000365
35. MelzerDPerryJRHernandezDCorsiAMStevensK 2008 A genome-wide association study identifies protein quantitative trait loci (pQTLs). PLoS Genet 4 e1000072 doi:10.1371/journal.pgen.1000072
36. ParéGChasmanDIKelloggMZeeRYRifaiN 2008 Novel association of ABO histo-blood group antigen with soluble ICAM-1: results of a genome-wide association study of 6,578 women. PLoS Genet 4 e1000118 doi:10.1371/journal.pgen.1000118
37. YuanXWaterworthDPerryJRLimNSongK 2008 Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes. Am J Hum Genet 83 520 528
38. BarbalicMDupuisJDehghanABisJCHoogeveenRC 2010 Large-scale genomic studies reveal central role of ABO in sP-selectin and sICAM-1 levels. Hum Mol Genet 19 1863 1872
39. AlkoutAMBlackwellCCWeirDM 2000 Increased inflammatory responses of persons of blood groups O to Helicobacter pylori. J Infect Dis 181 1364 1369
40. PasceriVChengJSWillersonJTYehET 2001 Modulation of C-reactive protein-mediated monocyte chemoattractant protein-1 induction in human endothelial cells by anti-atherosclerosis drugs. Circulation 103 2531 2534
41. TognottiE 1997 The spread of malaria in Sardinia: an historical perspective GreenLSDanubioME Adaptation to Malaria The interaction of biology and culture. Gordon and Breach Publishers 237 247
42. KwiatkowskiDP 2005 How malaria has affected the human genome and what human genetics can teach us about malaria. Am J Hum Genet 77 171 190
43. FryAEGriffithsMJAuburnSDiakiteMFortonJT 2008 Common variation in the ABO glycosyltransferase is associated with susceptibility to severe Plasmodium falciparum malaria. Hum Mol Genet 17 567 576
44. IwamotoSOmiTKajiiEIkemotoS 1995 Genomic organization of the glycoprotein D gene: Duffy blood group Fya/Fyb alloantigen system is associated with a polymorphism at the 44-amino acid residue. Blood 85 622 626
45. CockburnIAMackinnonMJO'DonnellAAllenSJMouldsJM 2004 A human complement receptor 1 polymorphism that reduces Plasmodium falciparum rosetting confers protection against severe malaria. Proc Natl Acad Sci U S A 101 272 277
46. KosoyRRansomMChenHMarconiMMacciardiFGloriosoNGregersenPKCusiDSeldinMF 2011 Evidence for malaria selection of a CR1 haplotype in Sardinia. Genes Immun May 19 1 7
47. SawcerSHellenthalGPirinenM International Multiple Sclerosis Genetics Consortium; Wellcome Trust Case Control Consortium 2 2011 Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476 214 9
48. BarrettJCClaytonDGConcannonPAkolkarBCooperJD 2009 Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet 41 703 707
49. MarrosuMGMotzoCMurruRLampisRCostaG 2004 The co-inheritance of type 1 diabetes and multiple sclerosis in Sardinia cannot be explained by genotype variation in the HLA region alone. Hum Mol Genet 13 2919 2924
50. PugliattiMCossuPSotgiuSRosatiGRiiseT 2009 Clustering of multiple sclerosis, age of onset and gender in Sardinia. J Neurol Sci 286 6 13
51. SannaSPitzalisMZoledziewskaMZaraISidoreC 2010 Variants within the immunoregulatory CBLB gene are associated with multiple sclerosis. Nat Genet 42 495 497
52. AmundadottirLKraftPStolzenberg-SolomonRZFuchsCSPetersenGM 2009 Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer. Nat Genet 41 986 990
53. XieJQureshiAALiYHanJ 2010 ABO blood group and incidence of skin cancer. PLoS ONE 5 e11972 doi:10.1371/journal.pone.0011972
54. ReillyMPLiMHeJFergusonJFStylianouIM 2011 Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studies. Lancet 377 383 392
55. MacyEMHayesTETracyRP 1997 Variability in the measurement of C-reactive protein in healthy subjects: implications for reference intervals and epidemiological applications. Clin Chem 43 52 58
56. ScuteriASannaSChenWMUdaMAlbaiG 2007 Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet 3 e115 doi:10.1371/journal.pgen.0030115
57. The International HapMap Consortium 2007 A second generation human haplotype map of over 3.1 million SNPs. Nature 449 851 861
58. LiYWillerCJDingJScheetPAbecasisGR 2010 MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet Epidemiol 34 816 834
59. AbecasisGRChernySSCooksonWOCardonL-R 2002 Merlin–rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 30 97 101
60. ChenWMAbecasisGR 2007 Family-based association tests for genomewide association scans. Am J Hum Genet 81 913 26
61. ProkopenkoILangenbergCFlorezJCSaxenaRSoranzoN 2009 Variants in MTNR1B influence fasting glucose levels. Nat Genet 41 77 81
62. PreussMKönigIRThompsonJRErdmannJAbsherD 2010 Design of the Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis (CARDIoGRAM) Study: A Genome-wide association meta-analysis involving more than 22000 cases and 60 000 controls. Circ Cardiovasc Genet 3 475 483
63. KangHMSulJHServiceSKZaitlenNAKongSYFreimerNBSabattiCEskinE 2010 Variance component model to account for sample structure in genome-wide association studies. Nat Genet 42 348 354
64. The Welcome Trust Case Control Consortium 2007 Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447 661 78
65. PruimRJWelchRPSannaSTeslovichTMChinesPS 2010 LocusZoom: Regional visualization of genome-wide association scan results. Bioinformatics 26 2336 2337
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
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