Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits: A Multi-Ethnic Meta-Analysis of 45,891 Individuals
Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10−8–1.2×10−43). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10−4). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10−3, n = 22,044), increased triglycerides (p = 2.6×10−14, n = 93,440), increased waist-to-hip ratio (p = 1.8×10−5, n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10−3, n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10−13, n = 96,748) and decreased BMI (p = 1.4×10−4, n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.
Vyšlo v časopise:
Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits: A Multi-Ethnic Meta-Analysis of 45,891 Individuals. PLoS Genet 8(3): e32767. doi:10.1371/journal.pgen.1002607
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002607
Souhrn
Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10−8–1.2×10−43). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10−4). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10−3, n = 22,044), increased triglycerides (p = 2.6×10−14, n = 93,440), increased waist-to-hip ratio (p = 1.8×10−5, n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10−3, n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10−13, n = 96,748) and decreased BMI (p = 1.4×10−4, n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.
Zdroje
1. HivertMFSullivanLMFoxCSNathanDMD'AgostinoRBSr 2008 Associations of adiponectin, resistin, and tumor necrosis factor-alpha with insulin resistance. J Clin Endocrinol Metab 93 3165 3172
2. TilgHMoschenAR 2006 Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 6 772 783
3. PischonTGirmanCJHotamisligilGSRifaiNHuFB 2004 Plasma Adiponectin Levels and Risk of Myocardial Infarction in Men. JAMA: The Journal of the American Medical Association 291 1730 1737
4. LiSShinHJDingELvan DamRM 2009 Adiponectin levels and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA 302 179 188
5. StumvollMGoldsteinBJvan HaeftenTW 2005 Type 2 diabetes: principles of pathogenesis and therapy. Lancet 365 1333 1346
6. NawrockiARRajalaMWTomasEPajvaniUBSahaAK 2006 Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor gamma agonists. J Biol Chem 281 2654 2660
7. WangYZhouMLamKSXuA 2009 Protective roles of adiponectin in obesity-related fatty liver diseases: mechanisms and therapeutic implications. Arq Bras Endocrinol Metabol 53 201 212
8. ComuzzieAGFunahashiTSonnenbergGMartinLJJacobHJ 2001 The genetic basis of plasma variation in adiponectin, a global endophenotype for obesity and the metabolic syndrome. Journal of Clinical Endocrinology and Metabolism 86 4321 4325
9. VasseurFHelbecqueNDinaCLobbensSDelannoyV 2002 Single-nucleotide polymorphism haplotypes in the both proximal promoter and exon 3 of the APM1 gene modulate adipocyte-secreted adiponectin hormone levels and contribute to the genetic risk for type 2 diabetes in French Caucasians. Hum Mol Genet 11 2607 2614
10. CesariMNarkiewiczKDe ToniRAldighieriEWilliamsCJ 2007 Heritability of plasma adiponectin levels and body mass index in twins. J Clin Endocrinol Metab 92 3082 3088
11. LiuPHJiangYDChenWJChangCCLeeTC 2008 Genetic and environmental influences on adiponectin, leptin, and BMI among adolescents in Taiwan: a multivariate twin/sibling analysis. Twin Res Hum Genet 11 495 504
12. MenzaghiCTrischittaVDoriaA 2007 Genetic influences of adiponectin on insulin resistance, type 2 diabetes, and cardiovascular disease. Diabetes 56 1198 1209
13. HivertMFManningAKMcAteerJBFlorezJCDupuisJ 2008 Common variants in the adiponectin gene (ADIPOQ) associated with plasma adiponectin levels, type 2 diabetes, and diabetes-related quantitative traits: the Framingham Offspring Study. Diabetes 57 3353 3359
14. LingHWaterworthDMStirnadelHAPollinTIBarterPJ 2009 Genome-wide Linkage and Association Analyses to Identify Genes Influencing Adiponectin Levels: The GEMS Study. Obesity (Silver Spring)
15. HeidIMHennemanPHicksACoassinSWinklerT 2010 Clear detection of ADIPOQ locus as the major gene for plasma adiponectin: results of genome-wide association analyses including 4659 European individuals. Atherosclerosis 208 412 420
16. RichardsJBWaterworthDO'RahillySHivertMFLoosRJ 2009 A genome-wide association study reveals variants in ARL15 that influence adiponectin levels. PLoS Genet 5 e1000768 doi:10.1371/journal.pgen.1000768
17. JeeSHSullJWLeeJEShinCParkJ 2010 Adiponectin concentrations: a genome-wide association study. Am J Hum Genet 87 545 552
18. WuYLiYLangeEMCroteau-ChonkaDCKuzawaCW 2010 Genome-wide association study for adiponectin levels in Filipino women identifies CDH13 and a novel uncommon haplotype at KNG1-ADIPOQ. Hum Mol Genet 19 4955 4964
19. VoightBFScottLJSteinthorsdottirVMorrisAPDinaC 2010 Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet 42 579 589
20. DupuisJLangenbergCProkopenkoISaxenaRSoranzoN 2010 New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 42 105 116
21. LindgrenCMHeidIMRandallJCLaminaCSteinthorsdottirV 2009 Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution. PLoS Genet 5 e1000508 doi:10.1371/journal.pgen.1000508
22. TeslovichTMMusunuruKSmithAVEdmondsonACStylianouIM 2010 Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466 707 713
23. KilpeläinenTOZillikensMCStančákováAFinucaneFMRiedJS 2011 Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile. Nature Genetics In press
24. MorrisAP 2011 Transethnic meta-analysis of genomewide association studies. Genetic epidemiology 35 809 822
25. NicaACPartsLGlassDNisbetJBarrettA 2011 The Architecture of Gene Regulatory Variation across Multiple Human Tissues: The MuTHER Study. PLoS Genet 7 e1002003 doi:10.1371/journal.pgen.1002003
26. NyholtDR 2004 A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am J Hum Genet 74 765 769
27. HeidIMJacksonAURandallJCWinklerTWQiL 2010 Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nat Genet 42 949 960
28. RungJCauchiSAlbrechtsenAShenLRocheleauG 2009 Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia. Nat Genet 41 1110 1115
29. TakeuchiFSerizawaMYamamotoKFujisawaTNakashimaE 2009 Confirmation of multiple risk Loci and genetic impacts by a genome-wide association study of type 2 diabetes in the Japanese population. Diabetes 58 1690 1699
30. AdachiHTsujimotoM 2002 FEEL-1, a novel scavenger receptor with in vitro bacteria-binding and angiogenesis-modulating activities. J Biol Chem 277 34264 34270
31. GraySLVidal-PuigAJ 2007 Adipose tissue expandability in the maintenance of metabolic homeostasis. Nutr Rev 65 S7 12
32. EreminaVBaeldeHJQuagginSE 2007 Role of the VEGF–a signaling pathway in the glomerulus: evidence for crosstalk between components of the glomerular filtration barrier. Nephron Physiol 106 p32 37
33. BuraczynskaMKsiazekPBaranowicz-GaszczykIJozwiakL 2007 Association of the VEGF gene polymorphism with diabetic retinopathy in type 2 diabetes patients. Nephrol Dial Transplant 22 827 832
34. HuYSunCYHuangJHongLZhangL 2007 Antimyeloma effects of resveratrol through inhibition of angiogenesis. Chin Med J (Engl) 120 1672 1677
35. SzkudelskiTSzkudelskaK 2011 Anti-diabetic effects of resveratrol. Ann N Y Acad Sci 1215 34 39
36. AhnJLeeHKimSHaT 2007 Resveratrol inhibits TNF-alpha-induced changes of adipokines in 3T3-L1 adipocytes. Biochem Biophys Res Commun 364 972 977
37. KangLHengWYuanABaolinLFangH 2010 Resveratrol modulates adipokine expression and improves insulin sensitivity in adipocytes: Relative to inhibition of inflammatory responses. Biochimie 92 789 796
38. Kiss-TothEBagstaffSMSungHYJozsaVDempseyC 2004 Human tribbles, a protein family controlling mitogen-activated protein kinase cascades. J Biol Chem 279 42703 42708
39. SungHYGuanHCzibulaAKingAREderK 2007 Human tribbles-1 controls proliferation and chemotaxis of smooth muscle cells via MAPK signaling pathways. J Biol Chem 282 18379 18387
40. WaterworthDMRickettsSLSongKChenLZhaoJH 2010 Genetic variants influencing circulating lipid levels and risk of coronary artery disease. Arterioscler Thromb Vasc Biol 30 2264 2276
41. ParkMHKimNLeeJYParkHY 2011 Genetic loci associated with lipid concentrations and cardiovascular risk factors in the Korean population. J Med Genet 48 10 15
42. ChasmanDIPareGMoraSHopewellJCPelosoG 2009 Forty-three loci associated with plasma lipoprotein size, concentration, and cholesterol content in genome-wide analysis. PLoS Genet 5 e1000730 doi:10.1371/journal.pgen.1000730
43. WillerCJSannaSJacksonAUScuteriABonnycastleLL 2008 Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet 40 161 169
44. IvanovDPhilippovaMAntropovaJGubaevaFIljinskayaO 2001 Expression of cell adhesion molecule T-cadherin in the human vasculature. Histochemistry and cell biology 115 231 242
45. WiseAFoordSMFraserNJBarnesAAElshourbagyN 2003 Molecular identification of high and low affinity receptors for nicotinic acid. J Biol Chem 278 9869 9874
46. WestphalSBoruckiKTanevaEMakarovaRLuleyC 2006 Adipokines and treatment with niacin. Metabolism 55 1283 1285
47. PlaisanceEPLukasovaMOffermannsSZhangYCaoG 2009 Niacin stimulates adiponectin secretion through the GPR109A receptor. Am J Physiol Endocrinol Metab 296 E549 558
48. EdmondsonACBraundPSStylianouIMKheraAVNelsonCP 2011 Dense Genotyping of Candidate Gene Loci Identifies Variants Associated with High-Density Lipoprotein Cholesterol. Circ Cardiovasc Genet
49. WeyerCFunahashiTTanakaSHottaKMatsuzawaY 2001 Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 86 1930 1935
50. LindsayRSFunahashiTHansonRLMatsuzawaYTanakaS 2002 Adiponectin and development of type 2 diabetes in the Pima Indian population. The Lancet 360 57 58
51. 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
52. PriceALPattersonNJPlengeRMWeinblattMEShadickNA 2006 Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38 904 909
53. MagiRMorrisAP 2010 GWAMA: software for genome-wide association meta-analysis. BMC Bioinformatics 11 288
54. HigginsJPThompsonSGDeeksJJAltmanDG 2003 Measuring inconsistency in meta-analyses. Bmj 327 557 560
55. TheodorakiEVNikopensiusTSuhorutsenkoJPeppesVFiliP 2010 Fibrinogen beta variants confer protection against coronary artery disease in a Greek case-control study. BMC Med Genet 11 28
56. StoreyJDTibshiraniR 2003 Statistical significance for genomewide studies. Proc Natl Acad Sci U S A 100 9440 9445
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2012 Číslo 3
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