CDH13 Genotype–Dependent Association of High–Molecular Weight Adiponectin With All-Cause Mortality: The J-SHIPP Study

Abstract

OBJECTIVEDespite its anti-inflammatory and antiatherogenic effects, adiponectin is potentially associated with adverse clinical outcomes, such as all-cause mortality. As plasma adiponectin levels are strongly influenced by single nucleotide polymorphisms in the gene encoding T-cadherin (CDH13), we conducted a longitudinal study to investigate the possible link between the CDH13 genotype, plasma adiponectin levels, and all-cause mortality. RESEARCH DESIGN AND METHODSThis longitudinal study evaluated 2,020 Japanese subjects. Baseline clinical parameters were obtained from subjects' personal health records as evaluated at annual medical check-ups. Plasma high-molecular weight adiponectin (HMWA) levels were measured by an ELISA assay, and genotyping was performed by a TaqMan probe assay. RESULTSMean follow-up duration was 6.5 years. Kaplan-Meier analysis showed that HMWA levels were positively associated with mortality (P < 0.001). HMWA levels were associated with older age, lower body weight, lower plasma triglyceride and glucose levels, and higher plasma HDL cholesterol. However, the Cox regression analysis showed that the positive association between HMWA and all-cause mortality was independent of these covariates (hazard ratio [HR] 1.92, P = 0.006). The CDH13 rs4783244 genotype was strongly associated with baseline HMWA levels (per-allele effect size 1.65 mg/mL, P < 0.001). In a separate analysis by the CDH13 genotype, the HR for all-cause mortality was linearly increased with the number of G alleles (P value for HMWA-CDH13 genotype interaction = 0.023). CONCLUSIONSHigher plasma HMWA level was an independent prognostic factor for all-cause mortality in a general population. The CDH13 genotype may be a factor that affects not only the plasma level of HMWA but also the prognostic significance of HMWA.

Gender-Specific Associations between Circulating T-Cadherin and High Molecular Weight-Adiponectin in Patients with Stable Coronary Artery Disease

“…T-cad-deficient mice exhibited elevated levels of circulating HMW-APN [11,12] and genome-wide association studies have linked variants in T-cad gene to elevated [33] or decreased [34] circulating levels of APN in humans, supporting that circulating APN is influenced by the presence and/or functionality of T-cad. Conversely, APN-deficient mice exhibited a reduced tissue level of T-cad protein that was restorable in vivo by delivery of exogenous APN [11,12].…”

“…total APN or HMW-total ratio) [49–51] have been demonstrated, and in the context of cardiovascular protective actions HMW-APN is regarded as the active form of this adipokine [49,51,52]. Additionally, in the context of associations between T-cad and APN a number of genome-wide studies revealed that association of SNPs in CDH13 gene were much stronger with levels of HMW-APN as compared total APN levels [33,53]. Fourth, and with regard to gender-issues, levels of testosterone and estradiol were not measured.…”

CDH13 promoter SNPs with pleiotropic effect on cardiometabolic parameters represent methylation QTLs

“…CAD coronary artery disease, LDL low-density lipoprotein, SBP systolic blood pressure. a Wallace et al ( 2008 ); b Org et al ( 2009 ), Fava et al ( 2011 ), Wan et al ( 2013 ); c Jee et al ( 2010 ); d Jee et al ( 2010 ), Wu et al ( 2010 ), Jo et al ( 2012 ); e Jee et al ( 2010 ), Chung et al ( 2011 ); f Lee et al ( 2013 ); g Chung et al ( 2011 ), Morisaki et al ( 2012 ), Gao et al ( 2013 ), Uetani et al ( 2014 ); h Morisaki et al ( 2012 ), Dastani et al ( 2012 ); i Dastani et al ( 2012 ); j Lee et al ( 2013 ); k Wellcome Trust Case Control Consortium ( 2007 ); l Ling et al ( 2009 ); m Levy et al ( 2007 ) …”

Mechanical Stresses, Arterial Stiffness, and Brain Small Vessel Diseases

“…The subjects attended a voluntary medical check-up program, Anti-Aging Doc, a program provided to residents of Ehime Prefecture, Japan, specifically designed to evaluate aging-related disorders, including atherosclerosis, cardiovascular disease, physical function, and cognitive impairment. 6,[18][19][20][21] Of the 1526 consecutive patients initially approached, 1296 (mean age, 65.4±9.1 years) gave written consent to all procedures and had no history of symptomatic cardiovascular events including peripheral arterial disease, stroke, coronary heart disease, or congestive heart failure. All participants were functionally independent in their daily lives.…”