CDH13 genotype-dependent association of high-molecular-weight adiponectin with all-cause mortality

INTRODUCTION:  Adiponectin is an adipocyte-derived secretory protein that has peripheral insulin-sensitizing activity. Despite its anti-inflammatory and anti-atherogenic 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.

METHODS:  This 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.

RESULTS:  Mean 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=1.92, p=0.006). The CDH13 rs4783244 genotype was strongly associated with baseline HMWA levels (per-allele effect size =1.65 μg/ml, p<0.001). In a separate analysis by the CDH13 genotype, the hazard ratio for all-cause mortality was linearly increased with the number of G-alleles (p-value for HMWA*CDH13 genotype interaction=0.023).

CONCLUSIONS:  Higher 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. The G-allele of the CDH13 genotype causes secondary hyper-adiponectinemina by altering the amount or functionality of T-cadherin. This genetically dependent adiponectin resistance and consequent reduction in adiponectin’s anti-inflammatory and anti-atherogenic effects may explain the increased mortality ratio in subjects with higher HMWA levels.