title: A comprehensive analysis of adiponectin QTLs using SNP association, SNP cis-effects on peripheral blood gene expression and gene expression correlation identified novel metabolic syndrome (MetS) genes with potential role in carcinogenesis and systemic inflammation.
abstract: BACKGROUND
  Metabolic syndrome (MetS) is an aberration associated with increased risk for cancer and inflammation. Adiponectin, an adipocyte-produced abundant protein hormone, has countering effect on the diabetogenic and atherogenic components of MetS. Plasma levels of adiponectin are negatively correlated with onset of cancer and cancer patient mortality. We previously performed microsatellite linkage analyses using adiponectin as a surrogate marker and revealed two QTLs on chr5 (5p14) and chr14 (14q13).
  
  
  METHODS
  Using individuals from 85 extended families that contributed to the linkage and who were measured for 42 clinical and biologic MetS phenotypes, we tested QTL-based SNP associations, peripheral white blood cell (PWBC) gene expression, and the effects of cis-acting SNPs on gene expression to discover genomic elements that could affect the pathophysiology and complications of MetS.
  
  
  RESULTS
  Adiponectin levels were found to be highly intercorrelated phenotypically with the majority of MetS traits. QTL-specific haplotype-tagging SNPs associated with MetS phenotypes were annotated to 14 genes whose function could influence MetS biology as well as oncogenesis or inflammation. These were mechanistically categorized into four groups: cell-cell adhesion and mobility, signal transduction, transcription and protein sorting. Four genes were highly prioritized: cadherin 18 (CDH18), myosin X (MYO10), anchor protein 6 of AMPK (AKAP6), and neuronal PAS domain protein 3 (NPAS3). PWBC expression was detectable only for the following genes with multi-organ or with multi-function properties: NPAS3, MARCH6, MYO10 and FBXL7. Strong evidence of cis-effects on the expression of MYO10 in PWBC was found with SNPs clustered near the gene's transcription start site. MYO10 expression in PWBC was marginally correlated with body composition (p = 0.065) and adipokine levels in the periphery (p = 0.064). Variants of genes AKAP6, NPAS3, MARCH6 and FBXL7 have been previously reported to be associated with insulin resistance, inflammatory markers or adiposity studies using genome-wide approaches whereas associations of CDH18 and MYO10 with MetS traits have not been reported before.
  
  
  CONCLUSIONS
  Adiponectin QTLs-based SNP association and mRNA expression identified genes that could mediate the association between MetS and cancer or inflammation.
authors.affiliation: TOPS Obesity and Metabolic Research Center, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. yzhang@mcw.edu
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jack W
authors.initials: JW
authors.lastname: Kent
authors.forename: Michael
authors.initials: M
authors.lastname: Olivier
authors.forename: Omar
authors.initials: O
authors.lastname: Ali
authors.forename: Diana
authors.initials: D
authors.lastname: Cerjak
authors.forename: Ulrich
authors.initials: U
authors.lastname: Broeckel
authors.forename: Reham M
authors.initials: RM
authors.lastname: Abdou
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Dyer
authors.forename: Anthony
authors.initials: A
authors.lastname: Comuzzie
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Curran
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Carless
authors.forename: David L
authors.initials: DL
authors.lastname: Rainwater
authors.forename: Harald H H
authors.initials: HH
authors.lastname: Göring
authors.forename: John
authors.initials: J
authors.lastname: Blangero
authors.forename: Ahmed H
authors.initials: AH
authors.lastname: Kissebah
mesh_terms: D054758:A Kinase Anchor Proteins / Q000235:genetics; D052242:Adiponectin / Q000097:blood / Q000235:genetics*; D051792:Basic Helix-Loop-Helix Proteins; D015820:Cadherins / Q000235:genetics; D002471:Cell Transformation, Neoplastic; D002883:Chromosomes, Human, Pair 14; D002895:Chromosomes, Human, Pair 5; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D024821:Metabolic Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009218:Myosins / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics
chemical_list: D054758:A Kinase Anchor Proteins; D052242:Adiponectin; D051792:Basic Helix-Loop-Helix Proteins; D015820:Cadherins; D009218:Myosins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; C093173:AKAP6 protein, human; C104822:CDH18 protein, human; C498718:MYO10 protein, human; C502963:NPAS3 protein, human