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. BMC Med Genomics 2013 Apr 29;6:14
Date
05/01/2013Pubmed ID
23628382Pubmed Central ID
PMC3643849DOI
10.1186/1755-8794-6-14Scopus ID
2-s2.0-84876807719 (requires institutional sign-in at Scopus site) 27 CitationsAbstract
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.
Author List
Zhang Y, Kent JW Jr, Olivier M, Ali O, Cerjak D, Broeckel U, Abdou RM, Dyer TD, Comuzzie A, Curran JE, Carless MA, Rainwater DL, Göring HH, Blangero J, Kissebah AHAuthor
Ulrich Broeckel MD Chief, Center Associate Director, Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
A Kinase Anchor ProteinsAdiponectin
Cadherins
Cell Transformation, Neoplastic
Chromosomes, Human, Pair 14
Chromosomes, Human, Pair 5
Genotype
Haplotypes
Humans
Inflammation
Leukocytes
Metabolic Syndrome
Myosins
Nerve Tissue Proteins
Phenotype
Polymorphism, Single Nucleotide
Quantitative Trait Loci
RNA, Messenger
Transcription Factors
