Association of <i>CDH13</i> Genotypes/Haplotypes with Circulating Adiponectin Levels, Metabolic Syndrome, and Related Metabolic Phenotypes: The Role of the Suppression Effect

<div><p>Objective</p><p>Previous genome-wide association studies have indicated an association between <i>CDH13</i> genotypes and adiponectin levels. In this study, we used mediation analysis to assess the statistical association between <i>CDH13</i> locus variants and adiponectin levels, metabolic syndrome, and related metabolic phenotypes.</p><p>Methods and results</p><p>A sample population of 530 Taiwanese participants was enrolled. Four <i>CDH13</i> gene variants in the promoter and intron 1 regions were genotyped. After adjustment for clinical covariates, the <i>CDH13</i> genotypes/haplotypes exhibited an association with the adiponectin levels (lowest <i>P</i> = 1.95 × 10⁻¹¹ for rs4783244 and lowest <i>P</i> = 3.78 × 10⁻¹³ for haplotype <i>ATTT</i>). Significant correlations were observed between the adiponectin levels and the various metabolic syndrome-related phenotypes (all <i>P</i> ≤ 0.005). After further adjustment for the adiponectin levels, participants with a minor allele of rs12051272 revealed a considerable association with a more favorable metabolic profile, including higher insulin sensitivity, high-density lipoprotein cholesterol levels, lower diastolic blood pressure, circulating levels of fasting plasma glucose, and triglycerides, and as a lower risk of metabolic syndrome (all <i>P</i> < 0.05). The mediation analysis further revealed a suppression effect of the adiponectin levels on the association between <i>CDH13</i> genotypes and metabolic syndrome and its related phenotypes (Sobel test; all <i>P <</i> 0.001).</p><p>Conclusion</p><p>The genetic polymorphisms at the <i>CDH13</i> locus independently affect the adiponectin levels, whereas the adiponectin levels exhibit a suppressive effect on the association between <i>CDH13</i> locus variants and various metabolic phenotypes and metabolic syndrome. In addition, these results provide further evidence of the association between the <i>CDH13</i> gene variants and the risks of metabolic syndrome and atherosclerotic cardiovascular disease.</p>