A Phenomics-Based Strategy Identifies Loci on , , and Associated with Metabolic Syndrome Phenotype Domains
Despite evidence of the clustering of metabolic syndrome components, current approaches for identifying unifying genetic mechanisms typically evaluate clinical categories that do not provide adequate etiological information. Here, we used data from 19,486 European American and 6,287 African American Candidate Gene Association Resource Consortium participants to identify loci associated with the clustering of metabolic phenotypes. Six phenotype domains (atherogenic dyslipidemia, vascular dysfunction, vascular inflammation, pro-thrombotic state, central obesity, and elevated plasma glucose) encompassing 19 quantitative traits were examined. Principal components analysis was used to reduce the dimension of each domain such that >55% of the trait variance was represented within each domain. We then applied a statistically efficient and computational feasible multivariate approach that related eight principal components from the six domains to 250,000 imputed SNPs using an additive genetic model and including demographic covariates. In European Americans, we identified 606 genome-wide significant SNPs representing 19 loci. Many of these loci were associated with only one trait domain, were consistent with results in African Americans, and overlapped with published findings, for instance central obesity and FTO. However, our approach, which is applicable to any set of interval scale traits that is heritable and exhibits evidence of phenotypic clustering, identified three new loci in or near APOC1, BRAP, and PLCG1, which were associated with multiple phenotype domains. These pleiotropic loci may help characterize metabolic dysregulation and identify targets for intervention.
Vyšlo v časopise:
A Phenomics-Based Strategy Identifies Loci on , , and Associated with Metabolic Syndrome Phenotype Domains. PLoS Genet 7(10): e32767. doi:10.1371/journal.pgen.1002322
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002322
Souhrn
Despite evidence of the clustering of metabolic syndrome components, current approaches for identifying unifying genetic mechanisms typically evaluate clinical categories that do not provide adequate etiological information. Here, we used data from 19,486 European American and 6,287 African American Candidate Gene Association Resource Consortium participants to identify loci associated with the clustering of metabolic phenotypes. Six phenotype domains (atherogenic dyslipidemia, vascular dysfunction, vascular inflammation, pro-thrombotic state, central obesity, and elevated plasma glucose) encompassing 19 quantitative traits were examined. Principal components analysis was used to reduce the dimension of each domain such that >55% of the trait variance was represented within each domain. We then applied a statistically efficient and computational feasible multivariate approach that related eight principal components from the six domains to 250,000 imputed SNPs using an additive genetic model and including demographic covariates. In European Americans, we identified 606 genome-wide significant SNPs representing 19 loci. Many of these loci were associated with only one trait domain, were consistent with results in African Americans, and overlapped with published findings, for instance central obesity and FTO. However, our approach, which is applicable to any set of interval scale traits that is heritable and exhibits evidence of phenotypic clustering, identified three new loci in or near APOC1, BRAP, and PLCG1, which were associated with multiple phenotype domains. These pleiotropic loci may help characterize metabolic dysregulation and identify targets for intervention.
Zdroje
1. IsomaaBAlmgrenPTuomiTForsenBLahtiK 2001 Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 24 683 689
2. GrundySM 2006 Drug therapy of the metabolic syndrome: minimizing the emerging crisis in polypharmacy. Nat Rev Drug Discov 5 295 309
3. AlbertiKGZimmetPShawJ 2006 Metabolic syndrome–a new world-wide definition. A Consensus Statement from the International Diabetes Federation. Diabet Med 23 469 480
4. TreatmentPanelATPIII 2002 Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 106 3143 3421
5. BalkauBCharlesMA 1999 Comment on the provisional report from the WHO consultation. European Group for the Study of Insulin Resistance (EGIR). Diabet Med 16 442 443
6. EinhornDReavenGMCobinRHFordEGandaOP 2003 American College of Endocrinology position statement on the insulin resistance syndrome. Endocr Pract 9 237 252
7. GrundySMCleemanJIDanielsSRDonatoKAEckelRH 2005 Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 112 2735 2752
8. Bosy-WestphalAOnurSGeislerCWolfAKorthO 2007 Common familial influences on clustering of metabolic syndrome traits with central obesity and insulin resistance: the Kiel obesity prevention study. Int J Obes (Lond) 31 784 790
9. LinHFBoden-AlbalaBJuoSHParkNRundekT 2005 Heritabilities of the metabolic syndrome and its components in the Northern Manhattan Family Study. Diabetologia 48 2006 2012
10. ZabanehDBaldingDJ 2010 A genome-wide association study of the metabolic syndrome in Indian Asian men. PLoS ONE 5 e11961 doi:10.1371/journal.pone.0011961
11. KrajaATVaidyaDPankowJSGoodarziMOAssimesTL 2011 A Bivariate Genome-Wide Approach to Metabolic Syndrome: STAMPEED Consortium. Diabetes 60 1329 1339
12. MullerMJBosy-WestphalAKrawczakM 2010 Genetic studies of common types of obesity: a critique of the current use of phenotypes. Obes Rev 11 612 618
13. HouleDGovindarajuDROmholtS 2010 Phenomics: the next challenge. Nat Rev Genet 11 855 866
14. HegeleRA 2004 Phenomics, lipodystrophy, and the metabolic syndrome. Trends Cardiovasc Med 14 133 137
15. BilderRMSabbFWCannonTDLondonEDJentschJD 2009 Phenomics: The systematic study of phenotypes on a genome-wide scale. Neuroscience 164 30 42
16. AmosCILaingAE 1993 A comparison of univariate and multivariate tests for genetic linkage. Genet Epidemiol 10 671 676
17. JiangCZengZB 1995 Multiple trait analysis of genetic mapping for quantitative trait loci. Genetics 140 1111 1127
18. BilderRM 2008 Phenomics: building scaffolds for biological hypotheses in the post-genomic era. Biol Psychiatry 63 439 440
19. FreimerNSabattiC 2003 The human phenome project. Nat Genet 34 15 21
20. SmithNLChenMHDehghanAStrachanDPBasuS 2010 Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium. Circulation 121 1382 1392
21. DupuisJLangenbergCProkopenkoISaxenaRSoranzoN 2010 New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 42 105 116
22. WaterworthDMRickettsSLSongKChenLZhaoJH 2010 Genetic variants influencing circulating lipid levels and risk of coronary artery disease. Arterioscler Thromb Vasc Biol 30 2264 2276
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. KamataniYMatsudaKOkadaYKuboMHosonoN 2010 Genome-wide association study of hematological and biochemical traits in a Japanese population. Nat Genet 42 210 215
25. KolzMJohnsonTSannaSTeumerAVitartV 2009 Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations. PLoS Genet 5 e1000504 doi:10.1371/journal.pgen.1000504
26. MatschinskyFMGlaserBMagnusonMA 1998 Pancreatic beta-cell glucokinase: closing the gap between theoretical concepts and experimental realities. Diabetes 47 307 315
27. KathiresanSWillerCJPelosoGMDemissieSMusunuruK 2009 Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet 41 56 65
28. OkadaYTakahashiAOhmiyaHKumasakaNKamataniY 2011 Genome-wide association study for C-reactive protein levels identified pleiotropic associations in the IL6 locus. Hum Mol Genet 20 1224 1231
29. VoightBFScottLJSteinthorsdottirVMorrisAPDinaC 2010 Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet 42 579 589
30. WillerCJSannaSJacksonAUScuteriABonnycastleLL 2008 Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet 40 161 169
31. KathiresanSMelanderOGuiducciCSurtiABurttNP 2008 Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet 40 189 197
32. ElliottPChambersJCZhangWClarkeRHopewellJC 2009 Genetic Loci associated with C-reactive protein levels and risk of coronary heart disease. JAMA 302 37 48
33. DehghanADupuisJBarbalicMBisJCEiriksdottirG 2011 Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels. Circulation 123 731 738
34. LiWHTanimuraMLuoCCDattaSChanL 1988 The apolipoprotein multigene family: biosynthesis, structure, structure-function relationships, and evolution. J Lipid Res 29 245 271
35. JongMCVosholPJMuurlingMDahlmansVERomijnJA 2001 Protection from obesity and insulin resistance in mice overexpressing human apolipoprotein C1. Diabetes 50 2779 2785
36. SoutarAKGarnerCWBakerHNSparrowJTJacksonRL 1975 Effect of the human plasma apolipoproteins and phosphatidylcholine acyl donor on the activity of lecithin: cholesterol acyltransferase. Biochemistry 14 3057 3064
37. LiSKuCYFarmerAACongYSChenCF 1998 Identification of a novel cytoplasmic protein that specifically binds to nuclear localization signal motifs. J Biol Chem 273 6183 6189
38. MathenySAChenCKortumRLRazidloGLLewisRE 2004 Ras regulates assembly of mitogenic signalling complexes through the effector protein IMP. Nature 427 256 260
39. OrySMorrisonDK 2004 Signal transduction: implications for Ras-dependent ERK signaling. Curr Biol 14 R277 278
40. CuiRKamataniYTakahashiAUsamiMHosonoN 2009 Functional variants in ADH1B and ALDH2 coupled with alcohol and smoking synergistically enhance esophageal cancer risk. Gastroenterology 137 1768 1775
41. 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
42. CooperJDSmythDJSmilesAMPlagnolVWalkerNM 2008 Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci. Nat Genet 40 1399 1401
43. LevyDEhretGBRiceKVerwoertGCLaunerLJ 2009 Genome-wide association study of blood pressure and hypertension. Nat Genet 41 677 687
44. ChoYSGoMJKimYJHeoJYOhJH 2009 A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat Genet 41 527 534
45. Lastres-BeckerIBrodesserSLutjohannDAzizovMBuchmannJ 2008 Insulin receptor and lipid metabolism pathology in ataxin-2 knock-out mice. Hum Mol Genet 17 1465 1481
46. LiWDDongCLiDZhaoHPriceRA 2004 An obesity-related locus in chromosome region 12q23-24. Diabetes 53 812 820
47. BerridgeMJIrvineRF 1984 Inositol trisphosphate, a novel second messenger in cellular signal transduction. Nature 312 315 321
48. LiaoHJKumeTMcKayCXuMJIhleJN 2002 Absence of erythrogenesis and vasculogenesis in Plcg1-deficient mice. J Biol Chem 277 9335 9341
49. HeZOplandDMWayKJUekiKBodyakN 2006 Regulation of vascular endothelial growth factor expression and vascularization in the myocardium by insulin receptor and PI3K/Akt pathways in insulin resistance and ischemia. Arterioscler Thromb Vasc Biol 26 787 793
50. XiangGSchusterMDSekiTKocherAAEshghiS 2004 Down-regulation of plasminogen activator inhibitor 1 expression promotes myocardial neovascularization by bone marrow progenitors. J Exp Med 200 1657 1666
51. MouquetFCuilleretFSusenSSautiereKMarboeufP 2009 Metabolic syndrome and collateral vessel formation in patients with documented occluded coronary arteries: association with hyperglycaemia, insulin-resistance, adiponectin and plasminogen activator inhibitor-1. Eur Heart J 30 840 849
52. PollexRLHegeleRA 2006 Genetic determinants of the metabolic syndrome. Nat Clin Pract Cardiovasc Med 3 482 489
53. MeigsJB 2000 Invited commentary: insulin resistance syndrome? Syndrome X? Multiple metabolic syndrome? A syndrome at all? Factor analysis reveals patterns in the fabric of correlated metabolic risk factors. Am J Epidemiol 152: 908-911; discussion 912
54. MeigsJBWilsonPWNathanDMD'AgostinoRBSrWilliamsK 2003 Prevalence and characteristics of the metabolic syndrome in the San Antonio Heart and Framingham Offspring Studies. Diabetes 52 2160 2167
55. MatiseTCAmbiteJLBuyskeSColeSACrawfordDC 2010 The next PAGE in understanding complex traits: study design for analysis of Population Architecture using Genetics and Epidemiology. Am J Epidemiol. In press
56. MusunuruKLettreGYoungTFarlowDNPirruccelloJP 2010 Candidate gene association resource (CARe): design, methods, and proof of concept. Circ Cardiovasc Genet 3 267 275
57. PendergrassSABrown-GentryKDDudekSAmbiteJLAveryCL 2010 Phenotype-wide association study (PheWAS) for exploration of novel SNP and phenotype relationships within PAGE. Genet Epidemiol 35 410 422
58. KeatingBJTischfieldSMurraySSBhangaleTPriceTS 2008 Concept, design and implementation of a cardiovascular gene-centric 50 k SNP array for large-scale genomic association studies. PLoS ONE 3 e3583 doi:10.1371/journal.pone.0003583
59. LiYWillerCJDingJScheetPAbecasisGR 2010 MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet Epidemiol 34 816 834
60. GrundySMBrewerHBJrCleemanJISmithSCJrLenfantC 2004 Definition of metabolic syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 109 433 438
61. PriceALPattersonNJPlengeRMWeinblattMEShadickNA 2006 Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38 904 909
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2011 Číslo 10
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
Najčítanejšie v tomto čísle
- The Glycobiome Reveals Mechanisms of Pentose and Hexose Co-Utilization in Bacteria
- Global Mapping of Cell Type–Specific Open Chromatin by FAIRE-seq Reveals the Regulatory Role of the NFI Family in Adipocyte Differentiation
- Genetic Determinants of Serum Testosterone Concentrations in Men
- MicroRNA Expression and Regulation in Human, Chimpanzee, and Macaque Brains