title: Common variants in the adiponectin gene (ADIPOQ) associated with plasma adiponectin levels, type 2 diabetes, and diabetes-related quantitative traits: the Framingham Offspring Study.
abstract: OBJECTIVE
  Variants in ADIPOQ have been inconsistently associated with adiponectin levels or diabetes. Using comprehensive linkage disequilibrium mapping, we genotyped single nucleotide polymorphisms (SNPs) in ADIPOQ to evaluate the association of common variants with adiponectin levels and risk of diabetes.
  
  
  METHODS
  Participants in the Framingham Offspring Study (n = 2,543, 53% women) were measured for glycemic phenotypes and incident diabetes over 28 years of follow-up; adiponectin levels were quantified at exam 7. We genotyped 22 tag SNPs that captured common (minor allele frequency >0.05) variation at r(2) > 0.8 across ADIPOQ plus 20 kb 5' and 10 kb 3' of the gene. We used linear mixed effects models to test additive associations of each SNP with adiponectin levels and glycemic phenotypes. Hazard ratios (HRs) for incident diabetes were estimated using an adjusted Cox proportional hazards model.
  
  
  RESULTS
  Two promoter SNPs in strong linkage disequilibrium with each other (r(2) = 0.80) were associated with adiponectin levels (rs17300539; P(nominal) [P(n)] = 2.6 x 10(-8); P(empiric) [P(e)] = 0.0005 and rs822387; P(n) = 3.8 x 10(-5); P(e) = 0.001). A 3'-untranslated region (3'UTR) SNP (rs6773957) was associated with adiponectin levels (P(n) = 4.4 x 10(-4); P(e) = 0.005). A nonsynonymous coding SNP (rs17366743, Y111H) was confirmed to be associated with diabetes incidence (HR 1.94 [95% CI 1.16-3.25] for the minor C allele; P(n) = 0.01) and with higher mean fasting glucose over 28 years of follow-up (P(n) = 0.0004; P(e) = 0.004). No other significant associations were found with other adiposity and metabolic phenotypes.
  
  
  CONCLUSIONS
  Adiponectin levels are associated with SNPs in two different regulatory regions (5' promoter and 3'UTR), whereas diabetes incidence and time-averaged fasting glucose are associated with a missense SNP of ADIPOQ.
authors.affiliation: General Medicine Division, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Hivert
authors.forename: Alisa K
authors.initials: AK
authors.lastname: Manning
authors.forename: Jarred B
authors.initials: JB
authors.lastname: McAteer
authors.forename: Jose C
authors.initials: JC
authors.lastname: Florez
authors.forename: Josée
authors.initials: J
authors.lastname: Dupuis
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Fox
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.forename: L Adrienne
authors.initials: LA
authors.lastname: Cupples
authors.forename: James B
authors.initials: JB
authors.lastname: Meigs
mesh_terms: D052242:Adiponectin / Q000097:blood* / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006801:Humans; D015994:Incidence; D015810:Linkage Disequilibrium; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci
chemical_list: D052242:Adiponectin
references.citation: Am J Epidemiol. 1979 Sep;110(3):281-90
references.pmid: 474565
references.citation: Am J Hum Genet. 1998 May;62(5):1198-211
references.pmid: 9545414
references.citation: BMC Med Genet. 2008 May 22;9:45
references.pmid: 18498634
references.citation: Hum Mol Genet. 2002 Oct 1;11(21):2607-14
references.pmid: 12354786
references.citation: Ann Med. 2005;37(2):141-50
references.pmid: 16028335
references.citation: JAMA. 2000 Jan 12;283(2):221-8
references.pmid: 10634338
references.citation: Int J Obes (Lond). 2007 Mar;31(3):500-6
references.pmid: 16953256
references.citation: J Biol Chem. 2003 Oct 10;278(41):40352-63
references.pmid: 12878598
references.citation: Nat Genet. 2001 Jan;27(1):55-8
references.pmid: 11137998
references.citation: Diabetes Res Clin Pract. 2000 Mar;47(3):177-84
references.pmid: 10741566
references.citation: Am J Hum Genet. 2000 Dec;67(6):1470-80
references.pmid: 11067779
references.citation: Diabetologia. 1985 Jul;28(7):412-9
references.pmid: 3899825
references.citation: Diabetes Care. 2006 Jun;29(6):1357-62
references.pmid: 16732021
references.citation: Diabetes. 2006 Feb;55(2):545-50
references.pmid: 16443793
references.citation: Diabetes. 2002 Apr;51(4):1247-55
references.pmid: 11916952
references.citation: Diabetes. 2005 Jan;54(1):268-74
references.pmid: 15616038
references.citation: Diabetes. 2006 Feb;55(2):375-84
references.pmid: 16443770
references.citation: Diabetes. 2004 Feb;53 Suppl 1:S31-5
references.pmid: 14749263
references.citation: Diabetes. 2007 May;56(5):1198-209
references.pmid: 17303804
references.citation: J Clin Endocrinol Metab. 2005 Feb;90(2):1137-43
references.pmid: 15562019
references.citation: Diabetologia. 2005 May;48(5):892-9
references.pmid: 15830179
references.citation: Diabetes. 2006 Jun;55(6):1537-45
references.pmid: 16731815