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Variants in the CDH13 gene have been identified as determinants of blood levels of adiponectin, an insulin-sensitizing adipokine. However, their association with other metabolic risk factors remains unclear. We examined variants at CDH13 in relation to total and high-molecular-weight (HMW) adiponectin using data from a genome-wide association study performed in 2,434 Singaporean Chinese with replication in up to 3,290 Japanese and 1,610 Koreans. The top signal rs4783244 in CDH13 showed strong associations with total adiponectin (standardized β [β] = -0.34, 95% CI -0.38 to -0.30, P = 2.0 x [10.sup.-70]), HMW adiponectin (β = HMW-to-total adiponectin ratio (β = -0.44, 95% CI -0.49 to -0.40, P = 3.2 x [10.sup.-83]). In the replication study, this single nucleotide polymorphism explained 4.1% of total and 6.5% of HMW adiponectin levels. No association was observed between rs4783244 and metabolic traits associated with insulin resistance before adjustment for HMW adiponectin levels. After adjustment for HMW adiponectin levels, the minor allele was associated with lower BMI (β = -0.15, 95% CI -0.19 to -0.11, P = 3.5 x [10.sup.-14]), homeostasis model assessment-insulin resistance index (β = -0.16, 95% CI -0.20 to -0.12, P = 9.2 x [10.sup.-16]), and triglycerides (β = -0.16, 95% CI -0.19 to -0.12, P = 1.3 x [10.sup.-16]) and with higher HDL (β = 0.16, 95% CI 0.12 to 0.19, P = 2.1 x [10.sup.-17]). CDH13 variants strongly influence plasma total and HMW adiponectin levels in East Asian populations but appear to alter adiponectin sensitivity, resulting in better metabolic health than expected based on circulating adiponectin levels., Adiponectin is a protein abundantly secreted by adipose tissue with anti-inflammatory (1) and insulin-sensitizing properties (2). Blood levels of diponectin are inversely associated with obesity (3), insulin resistance (4), and [...]

The adipocyte-secreted protein adiponectin is associated with insulin sensitivity in observational studies. We aimed to evaluate whether this relationship is causal using a Mendelian randomization approach. In a sample of Swedish men aged 71 years (n = 942) from the Uppsala Longitudinal Study of Adult Men (ULSAM), insulin sensitivity (M/I ratio) was measured by the euglycemic insulin clamp. We used three genetic variants in the ADIPOQ locus as instrumental variables (IVs) to estimate the potential causal effect of adiponectin on insulin sensitivity and compared these with results from conventional linear regression. The three ADIPOQ variants, rs17300539, rs3774261, and rs6444175, were strongly associated with serum adiponectin levels (all P ≤ 5.3 x [10.sup.-9]) and were also significantly associated with M/I ratio in the expected direction (all P ≤ 0.022). IV analysis confirmed that genetically determined adiponectin increased insulin sensitivity (β = 0.47-0.81, all P ≤ 0.014) comparable with observational estimates (β = 0.50, all [P.sub.difference] ≥ 0.136). Adjustment for BMI and waist circumference partly explained the association of both genetically determined and observed adiponectin levels with insulin sensitivity. The observed association between higher adiponectin levels and increased insulin sensitivity is likely to represent a causal relationship partly mediated by reduced adiposity., Adiponectin is the most abundantly secreted protein by white adipose tissue. Unlike most other adipokines, it has a well-known inverse relationship with adiposity and risk of type 2 diabetes (1-3). [...]