Dataset Information

Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

ABSTRACT: 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.

SUBMITTER: Dastani Z

PROVIDER: S-EPMC3315470 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

Dastani Zari Z Hivert Marie-France MF Timpson Nicholas N Perry John R B JR Yuan Xin X Scott Robert A RA Henneman Peter P Heid Iris M IM Kizer Jorge R JR Lyytikäinen Leo-Pekka LP Fuchsberger Christian C Tanaka Toshiko T Morris Andrew P AP Small Kerrin K Isaacs Aaron A Beekman Marian M Coassin Stefan S Lohman Kurt K Qi Lu L Kanoni Stavroula S Pankow James S JS Uh Hae-Won HW Wu Ying Y Bidulescu Aurelian A Rasmussen-Torvik Laura J LJ Greenwood Celia M T CM Ladouceur Martin M Grimsby Jonna J Manning Alisa K AK Liu Ching-Ti CT Kooner Jaspal J Mooser Vincent E VE Vollenweider Peter P Kapur Karen A KA Chambers John J Wareham Nicholas J NJ Langenberg Claudia C Frants Rune R Willems-Vandijk Ko K Oostra Ben A BA Willems Sara M SM Lamina Claudia C Winkler Thomas W TW Psaty Bruce M BM Tracy Russell P RP Brody Jennifer J Chen Ida I Viikari Jorma J Kähönen Mika M Pramstaller Peter P PP Evans David M DM St Pourcain Beate B Sattar Naveed N Wood Andrew R AR Bandinelli Stefania S Carlson Olga D OD Egan Josephine M JM Böhringer Stefan S van Heemst Diana D Kedenko Lyudmyla L Kristiansson Kati K Nuotio Marja-Liisa ML Loo Britt-Marie BM Harris Tamara T Garcia Melissa M Kanaya Alka A Haun Margot M Klopp Norman N Wichmann H-Erich HE Deloukas Panos P Katsareli Efi E Couper David J DJ Duncan Bruce B BB Kloppenburg Margreet M Adair Linda S LS Borja Judith B JB Wilson James G JG Musani Solomon S Guo Xiuqing X Johnson Toby T Semple Robert R Teslovich Tanya M TM Allison Matthew A MA Redline Susan S Buxbaum Sarah G SG Mohlke Karen L KL Meulenbelt Ingrid I Ballantyne Christie M CM Dedoussis George V GV Hu Frank B FB Liu Yongmei Y Paulweber Bernhard B Spector Timothy D TD Slagboom P Eline PE Ferrucci Luigi L Jula Antti A Perola Markus M Raitakari Olli O Florez Jose C JC Salomaa Veikko V Eriksson Johan G JG Frayling Timothy M TM Hicks Andrew A AA Lehtimäki Terho T Smith George Davey GD Siscovick David S DS Kronenberg Florian F van Duijn Cornelia C Loos Ruth J F RJ Waterworth Dawn M DM Meigs James B JB Dupuis Josee J Richards J Brent JB Voight Benjamin F BF Scott Laura J LJ Steinthorsdottir Valgerdur V Dina Christian C Welch Ryan P RP Zeggini Eleftheria E Huth Cornelia C Aulchenko Yurii S YS Thorleifsson Gudmar G McCulloch Laura J LJ Ferreira Teresa T Grallert Harald H Amin Najaf N Wu Guanming G Willer Cristen J CJ Raychaudhuri Soumya S McCarroll Steve A SA Hofmann Oliver M OM Segrè Ayellet V AV van Hoek Mandy M Navarro Pau P Ardlie Kristin K Balkau Beverley B Benediktsson Rafn R Bennett Amanda J AJ Blagieva Roza R Boerwinkle Eric E Bonnycastle Lori L LL Boström Kristina Bengtsson KB Bravenboer Bert B Bumpstead Suzannah S Burtt Noël P NP Charpentier Guillaume G Chines Peter S PS Cornelis Marilyn M Crawford Gabe G Doney Alex S F AS Elliott Katherine S KS Elliott Amanda L AL Erdos Michael R MR Fox Caroline S CS Franklin Christopher S CS Ganser Martha M Gieger Christian C Grarup Niels N Green Todd T Griffin Simon S Groves Christopher J CJ Guiducci Candace C Hadjadj Samy S Hassanali Neelam N Herder Christian C Isomaa Bo B Jackson Anne U AU Johnson Paul R V PR Jørgensen Torben T Kao Wen H L WH Kong Augustine A Kraft Peter P Kuusisto Johanna J Lauritzen Torsten T Li Man M Lieverse Aloysius A Lindgren Cecilia M CM Lyssenko Valeriya V Marre Michel M Meitinger Thomas T Midthjell Kristian K Morken Mario A MA Narisu Narisu N Nilsson Peter P Owen Katharine R KR Payne Felicity F Petersen Ann-Kristin AK Platou Carl C Proença Christine C Prokopenko Inga I Rathmann Wolfgang W Rayner N William NW Robertson Neil R NR Rocheleau Ghislain G Roden Michael M Sampson Michael J MJ Saxena Richa R Shields Beverley M BM Shrader Peter P Sigurdsson Gunnar G Sparsø Thomas T Strassburger Klaus K Stringham Heather M HM Sun Qi Q Swift Amy J AJ Thorand Barbara B Tichet Jean J Tuomi Tiinamaija T van Dam Rob M RM van Haeften Timon W TW van Herpt Thijs T van Vliet-Ostaptchouk Jana V JV Walters G Bragi GB Weedon Michael N MN Wijmenga Cisca C Witteman Jacqueline J Bergman Richard N RN Cauchi Stephane S Collins Francis S FS Gloyn Anna L AL Gyllensten Ulf U Hansen Torben T Hide Winston A WA Hitman Graham A GA Hofman Albert A Hunter David J DJ Hveem Kristian K Laakso Markku M Morris Andrew D AD Palmer Colin N A CN Rudan Igor I Sijbrands Eric E Stein Lincoln D LD Tuomilehto Jaakko J Uitterlinden Andre A Walker Mark M Watanabe Richard M RM Abecasis Goncalo R GR Boehm Bernhard O BO Campbell Harry H Daly Mark J MJ Hattersley Andrew T AT Pedersen Oluf O Barroso Inês I Groop Leif L Sladek Rob R Thorsteinsdottir Unnur U Wilson James F JF Illig Thomas T Froguel Philippe P van Duijn Cornelia M CM Stefansson Kari K Altshuler David D Boehnke Michael M McCarthy Mark I MI Soranzo Nicole N Wheeler Eleanor E Glazer Nicole L NL Bouatia-Naji Nabila N Mägi Reedik R Randall Joshua J Elliott Paul P Rybin Denis D Dehghan Abbas A Hottenga Jouke Jan JJ Song Kijoung K Goel Anuj A Lajunen Taina T Doney Alex A Cavalcanti-Proença Christine C Kumari Meena M Timpson Nicholas J NJ Zabena Carina C Ingelsson Erik E An Ping P O'Connell Jeffrey J Luan Jian'an J Elliott Amanda A McCarroll Steven A SA Roccasecca Rosa Maria RM Pattou François F Sethupathy Praveen P Ariyurek Yavuz Y Barter Philip P Beilby John P JP Ben-Shlomo Yoav Y Bergmann Sven S Bochud Murielle M Bonnefond Amélie A Borch-Johnsen Knut K Böttcher Yvonne Y Brunner Eric E Bumpstead Suzannah J SJ Chen Yii-Der Ida YD Chines Peter P Clarke Robert R Coin Lachlan J M LJ Cooper Matthew N MN Crisponi Laura L Day Ian N M IN de Geus Eco J C EJ Delplanque Jerome J Fedson Annette C AC Fischer-Rosinsky Antje A Forouhi Nita G NG Franzosi Maria Grazia MG Galan Pilar P Goodarzi Mark O MO Graessler Jürgen J Grundy Scott S Gwilliam Rhian R Hallmans Göran G Hammond Naomi N Han Xijing X Hartikainen Anna-Liisa AL Hayward Caroline C Heath Simon C SC Hercberg Serge S Hillman David R DR Hingorani Aroon D AD Hui Jennie J Hung Joe J Kaakinen Marika M Kaprio Jaakko J Kesaniemi Y Antero YA Kivimaki Mika M Knight Beatrice B Koskinen Seppo S Kovacs Peter P Kyvik Kirsten Ohm KO Lathrop G Mark GM Lawlor Debbie A DA Le Bacquer Olivier O Lecoeur Cécile C Li Yun Y Mahley Robert R Mangino Massimo M Martínez-Larrad María Teresa MT McAteer Jarred B JB McPherson Ruth R Meisinger Christa C Melzer David D Meyre David D Mitchell Braxton D BD Mukherjee Sutapa S Naitza Silvia S Neville Matthew J MJ Orrù Marco M Pakyz Ruth R Paolisso Giuseppe G Pattaro Cristian C Pearson Daniel D Peden John F JF Pedersen Nancy L NL Pfeiffer Andreas F H AF Pichler Irene I Polasek Ozren O Posthuma Danielle D Potter Simon C SC Pouta Anneli A Province Michael A MA Rayner Nigel W NW Rice Kenneth K Ripatti Samuli S Rivadeneira Fernando F Rolandsson Olov O Sandbaek Annelli A Sandhu Manjinder M Sanna Serena S Sayer Avan Aihie AA Scheet Paul P Seedorf Udo U Sharp Stephen J SJ Shields Beverley B Sigurðsson Gunnar G Sijbrands Eric J G EJ Silveira Angela A Simpson Laila L Singleton Andrew A Smith Nicholas L NL Sovio Ulla U Swift Amy A Syddall Holly H Syvänen Ann-Christine AC Tönjes Anke A Uitterlinden André G AG van Dijk Ko Willems KW Varma Dhiraj D Visvikis-Siest Sophie S Vitart Veronique V Vogelzangs Nicole N Waeber Gérard G Wagner Peter J PJ Walley Andrew A Ward Kim L KL Watkins Hugh H Wild Sarah H SH Willemsen Gonneke G Witteman Jaqueline C M JC Yarnell John W G JW Zelenika Diana D Zethelius Björn B Zhai Guangju G Zhao Jing Hua JH Zillikens M Carola MC Borecki Ingrid B IB Meneton Pierre P Magnusson Patrik K E PK Nathan David M DM Williams Gordon H GH Silander Kaisa K Bornstein Stefan R SR Schwarz Peter P Spranger Joachim J Karpe Fredrik F Shuldiner Alan R AR Cooper Cyrus C Serrano-Ríos Manuel M Lind Lars L Palmer Lyle J LJ Hu Frank B FB Franks Paul W PW Ebrahim Shah S Marmot Michael M Kao W H Linda WH Pramstaller Peter Paul PP Wright Alan F AF Stumvoll Michael M Hamsten Anders A Buchanan Thomas A TA Valle Timo T TT Rotter Jerome I JI Penninx Brenda W J H BW Boomsma Dorret I DI Cao Antonio A Scuteri Angelo A Schlessinger David D Uda Manuela M Ruokonen Aimo A Jarvelin Marjo-Riitta MR Peltonen Leena L Mooser Vincent V Sladek Robert R Musunuru Kiran K Smith Albert V AV Edmondson Andrew C AC Stylianou Ioannis M IM Koseki Masahiro M Pirruccello James P JP Chasman Daniel I DI Johansen Christopher T CT Fouchier Sigrid W SW Peloso Gina M GM Barbalic Maja M Ricketts Sally L SL Bis Joshua C JC Feitosa Mary F MF Orho-Melander Marju M Melander Olle O Li Xiaohui X Li Mingyao M Cho Yoon Shin YS Go Min Jin MJ Kim Young Jin YJ Lee Jong-Young JY Park Taesung T Kim Kyunga K Sim Xueling X Ong Rick Twee-Hee RT Croteau-Chonka Damien C DC Lange Leslie A LA Smith Joshua D JD Ziegler Andreas A Zhang Weihua W Zee Robert Y L RY Whitfield John B JB Thompson John R JR Surakka Ida I Spector Tim D TD Smit Johannes H JH Sinisalo Juha J Scott James J Saharinen Juha J Sabatti Chiara C Rose Lynda M LM Roberts Robert R Rieder Mark M Parker Alex N AN Pare Guillaume G O'Donnell Christopher J CJ Nieminen Markku S MS Nickerson Deborah A DA Montgomery Grant W GW McArdle Wendy W Masson David D Martin Nicholas G NG Marroni Fabio F Lucas Gavin G Luben Robert R Lokki Marja-Liisa ML Lettre Guillaume G Launer Lenore J LJ Lakatta Edward G EG Laaksonen Reijo R Kyvik Kirsten O KO König Inke R IR Khaw Kay-Tee KT Kaplan Lee M LM Johansson Åsa Å Janssens A Cecile J W AC Igl Wilmar W Hovingh G Kees GK Hengstenberg Christian C Havulinna Aki S AS Hastie Nicholas D ND Harris Tamara B TB Haritunians Talin T Hall Alistair S AS Groop Leif C LC Gonzalez Elena E Freimer Nelson B NB Erdmann Jeanette J Ejebe Kenechi G KG Döring Angela A Dominiczak Anna F AF Demissie Serkalem S Deloukas Panagiotis P de Faire Ulf U Crawford Gabriel G Chen Yii-der I YD Caulfield Mark J MJ Boekholdt S Matthijs SM Assimes Themistocles L TL Quertermous Thomas T Seielstad Mark M Wong Tien Y TY Tai E-Shyong ES Feranil Alan B AB Kuzawa Christopher W CW Taylor Herman A HA Gabriel Stacey B SB Holm Hilma H Gudnason Vilmundur V Krauss Ronald M RM Ordovas Jose M JM Munroe Patricia B PB Kooner Jaspal S JS Tall Alan R AR Hegele Robert A RA Kastelein John J P JJ Schadt Eric E EE Strachan David P DP Reilly Muredach P MP Samani Nilesh J NJ Schunkert Heribert H Cupples L Adrienne LA Sandhu Manjinder S MS Ridker Paul M PM Rader Daniel J DJ Kathiresan Sekar S

PLoS genetics 20120329 3

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 no ...[more]

PMID: 22479202

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Project description:Aims/hypothesisType 2 diabetes is a growing global public health challenge. Investigating quantitative traits, including fasting glucose, fasting insulin and HbA1c, that serve as early markers of type 2 diabetes progression may lead to a deeper understanding of the genetic aetiology of type 2 diabetes development. Previous genome-wide association studies (GWAS) have identified over 500 loci associated with type 2 diabetes, glycaemic traits and insulin-related traits. However, most of these findings were based only on populations of European ancestry. To address this research gap, we examined the genetic basis of fasting glucose, fasting insulin and HbA1c in participants of the diverse Population Architecture using Genomics and Epidemiology (PAGE) Study.MethodsWe conducted a GWAS of fasting glucose (n = 52,267), fasting insulin (n = 48,395) and HbA1c (n = 23,357) in participants without diabetes from the diverse PAGE Study (23% self-reported African American, 46% Hispanic/Latino, 40% European, 4% Asian, 3% Native Hawaiian, 0.8% Native American), performing transethnic and population-specific GWAS meta-analyses, followed by fine-mapping to identify and characterise novel loci and independent secondary signals in known loci.ResultsFour novel associations were identified (p < 5 × 10-9), including three loci associated with fasting insulin, and a novel, low-frequency African American-specific locus associated with fasting glucose. Additionally, seven secondary signals were identified, including novel independent secondary signals for fasting glucose at the known GCK locus and for fasting insulin at the known PPP1R3B locus in transethnic meta-analysis.Conclusions/interpretationOur findings provide new insights into the genetic architecture of glycaemic traits and highlight the continued importance of conducting genetic studies in diverse populations.Data availabilityFull summary statistics from each of the population-specific and transethnic results are available at NHGRI-EBI GWAS catalog ( https://www.ebi.ac.uk/gwas/downloads/summary-statistics ).

Project description:BackgroundAdiponectin Q is a hormone that modulates several metabolic processes and contributes to the suppression of biochemical pathways leading to metabolic syndrome. Hence, polymorphic changes in the adiponectin Q (ADIPOQ) gene are likely to contribute to metabolic disorders, and consequently lead to atherosclerosis. In the present study, we performed a population-based association study for 8 SNPs in 4646 Saudi individuals (2339 CAD cases versus angiographed 2307 controls) by real-time PCR.MethodsLinkage analysis was done by the Affymetrix Gene Chip array, sequencing by the MegaBACE DNA analysis system and genotyping accomplished by TaqMan chemistry with the Applied Biosystem real-time Prism 7900HT Sequence Detection System.ResultsThe rs2241766 (TG + GG) [Odds ratio(95% Confidence Interval = 1.35(1.01-1.72); p = 0.015] and rs9842733A > T [1.48(1.01-2.07); p = 0.042] were associated with hypertension [HTN; 3541 cases vs 1101 controls), following adjustment for the presence of other cardiovascular risk traits. The rs2241766 (TG + GG) was further implicated in harbouring of low high density lipoprotein levels (LHDL; 1353 versus 2156 controls) [1.35(1.10-1.67); p = 0.005], but lost its association with obesity after the adjustment for confounders. Besides, low high density lipoprotein was also linked with rs6444174 (TC + CC) [1.28(1.05-1.59)]. On the other hand, while initial univariate logistic regression analysis pointed to rs1063537 C > T (p = 0.010), rs2082940 C > T (p = 0.035) and rs1063539 G > C (p = 0.035) as being associated with myocardial infarction, significance levels of these relationships were diminished following adjustment for the influence of confounding covariates. Interestingly, haplotyping showed that an 8-mer haplotype GTGCCTCA and several of its derivatives constructed from the studied SNPs were commonly implicated in MI (χ² = 4.12; p = 0.042), HTN (χ² = 6.40; p = 0.011) and OBS (χ² = 5.18; p = 0.023).ConclusionThese results demonstrate that the ADIPOQ 3'UTR harbours common susceptibility variants for metabolic risk traits and CAD, pointing to the importance of this region in atherosclerosis disease pathways.

Dataset Information

Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

Publications

Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

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