Article

Interactions between noncontiguous haplotypes in the adiponectin gene ACDC are associated with plasma adiponectin

Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
Diabetes (Impact Factor: 8.47). 03/2006; 55(2):523-9. DOI: 10.2337/diabetes.55.02.06.db05-0446
Source: PubMed

ABSTRACT Adiponectin, an adipocyte protein important in insulin sensitization and cardioprotection, has a strong genetic component. We hypothesized that variants in the adiponectin gene (adipocyte collagen-domain containing [ACDC]) contribute to adiponectin levels in a biracial adolescent cohort. We genotyped 11 ACDC single nucleotide polymorphisms (SNPs) in 631 non-Hispanic white and 553 African-American unrelated adolescents in grades 5-12 randomly selected from the Princeton School District Study. ACDC SNPs -11,391 (A allele), -10,068 (G allele), and +276 (T allele) were associated with higher adiponectin, adjusting for sex, puberty stage, BMI Z score, and waist Z score. Contiguous two-SNP haplotypes of promoter variants -11,391/-10,068 were significantly associated with adiponectin levels in whites and African Americans (P < 0.0001 and 0.03, respectively). Extended haplotypes from the promoter through the second intron (-11,391 to +349) strongly associated with adiponectin in whites (P = 6 x 10(-11)) and African Americans (P = 0.004), but haplotypes of first intron SNPs -4,521 to -657 did not (P > 0.2). Noncontiguous haplotypes or interactions between two-SNP (-11,391/-10,068) and three-SNP (+45, +276, and +349) haplotypes predicted adiponectin better than either region alone. Variants of ACDC are associated with adiponectin levels in whites and African Americans. Interactions between noncontiguous ACDC haplotypes strongly influence adiponectin levels, suggesting nonadditive and potentially cis relationships between these regions.

0 Bookmarks
 · 
92 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Type 2 diabetes mellitus is the result of resistance to insulin function along with inadequate insulin secretion, leading to a number of dysfunctions characterized by hyperglycemia, and it is associated with microvascular, macrovascular, and neuropathic complications. There is compelling evidence that the decline in both insulin sensitivity and insulin secretion has a genetic component. In addition, increasing evidence suggests that microRNAs (miRNAs) as key regulators of gene expression play significant roles in insulin production, secretion, and function that regulate the function of insulin-target tissues. The current review demonstrates the candidate genes and the related miRNAs involved in molecular pathogenesis of insulin resistance in type 2 diabetes mellitus. In doing so, it provides an opportunity for more focused investigations that may identify the genes and miRNAs with a role in the pathogenesis of type 2 diabetes mellitus and its treatment.
    Applied Biochemistry and Biotechnology 07/2014; 174(1). DOI:10.1007/s12010-014-1014-z · 1.69 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Obesity is a major health problem strongly increasing the risk for various severe related complications such as metabolic syndrome, cardiovascular diseases, respiratory disorders, diabetic retinopathy, and cancer. Adipose tissue is an endocrine organ that produces biologically active molecules defined "adipocytokines," protein hormones with pleiotropic functions involved in the regulation of energy metabolism as well as in appetite, insulin sensitivity, inflammation, atherosclerosis, cell proliferation, and so forth. In obesity, fat accumulation causes dysregulation of adipokine production that strongly contributes to the onset of obesity-related diseases. Several advances have been made in the treatment and prevention of obesity but current medical therapies are often unsuccessful even in compliant patients. Among the adipokines, adiponectin shows protective activity in various processes such as energy metabolism, inflammation, and cell proliferation. In this review, we will focus on the current knowledge regarding the protective properties of adiponectin and its receptors, AdipoRs ("adiponectin system"), on metabolic complications in obesity and obesity-related diseases. Adiponectin, exhibiting antihyperglycemic, antiatherogenic, and anti-inflammatory properties, could have important clinical benefits in terms of development of therapies for the prevention and/or for the treatment of obesity and obesity-related diseases.
    BioMed Research International 07/2014; 2014:658913. DOI:10.1155/2014/658913 · 2.71 Impact Factor
    This article is viewable in ResearchGate's enriched format
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pioglitazone is the most widely used thiazolidinedione and acts as an insulin-sensitizer through activation of the Peroxisome Proliferator-Activated Receptor-γ (PPARγ). Pioglitazone is approved for use in the management of type 2 diabetes mellitus (T2DM), but its use in other therapeutic areas is increasing due to pleiotropic effects. In this hypothesis article, the current clinical evidence on pioglitazone pharmacogenomics is summarized and related to variability in pioglitazone response. How genetic variation in the human genome affects the pharmacokinetics and pharmacodynamics of pioglitazone was examined. For pharmacodynamic effects, hypoglycemic and anti-atherosclerotic effects, risks of fracture or edema, and the increase in body mass index in response to pioglitazone based on genotype were examined. The genes CYP2C8 and PPARG are the most extensively studied to date and selected polymorphisms contribute to respective variability in pioglitazone pharmacokinetics and pharmacodynamics. We hypothesized that genetic variation in pioglitazone pathway genes contributes meaningfully to the clinically observed variability in drug response. To test the hypothesis that genetic variation in PPARG associates with variability in pioglitazone response, we conducted a meta-analysis to synthesize the currently available data on the PPARG p.Pro12Ala polymorphism. The results showed that PPARG 12Ala carriers had a more favorable change in fasting blood glucose from baseline as compared to patients with the wild-type Pro12Pro genotype (p = 0.018). Unfortunately, findings for many other genes lack replication in independent cohorts to confirm association; further studies are needed. Also, the biological functionality of these polymorphisms is unknown. Based on current evidence, we propose that pharmacogenomics may provide an important tool to individualize pioglitazone therapy and better optimize therapy in patients with T2DM or other conditions for which pioglitazone is being used.
    Frontiers in Pharmacology 01/2013; 4:147. DOI:10.3389/fphar.2013.00147