Causal Relationship between Adiponectin and Metabolic Traits: A Mendelian Randomization Study in a Multiethnic Population

Background
Adiponectin, a secretagogue exclusively produced by adipocytes, has been associated with metabolic features, but its role in the development of the metabolic syndrome remains unclear.
Objectives
We investigated the association between serum adiponectin level and metabolic traits, using both observational and genetic epidemiologic approaches in a multiethnic population assembled in Canada.
Methods
Clinical data and serum adiponectin level were collected in 1,157 participants of the SHARE/SHARE-AP studies. Participants were genotyped for the functional rs266729 and rs1260326 SNPs in ADIPOQ and GCKR genes.
Results
Adiponectin level was positively associated with HDL cholesterol and negatively associated with body mass index, waist-to-hip ratio, triglycerides, fasting glucose, fasting insulin, systolic and diastolic pressure (all P<0.002). The rs266729 minor G allele was associated with lower adiponectin and higher HOMA-IR (P = 0.004 and 0.003, respectively). The association between rs266729 SNP and HOMA-IR was no longer significant after adjustment for adiponectin concentration (P = 0.10). The rs266729 SNP was associated with HOMA-IR to an extent that exceeded its effect on adiponectin level (0.15 SD 95% C.I. [0.06, 0.24], P<0.001). There was no significant interaction between rs266729 SNP and ethnicity on adiponectin or HOMA-IR. In contrast, the SNP rs1260326 in GCKR was associated with HOMA-IR (P<0.001), but not with adiponectin level (P = 0.67).
Conclusion
The association of the functional promoter polymorphism rs266729 with lower serum adiponectin and increased insulin resistance in diverse ethnic groups may suggest a causal relationship between adiponectin level and insulin resistance.

背景：脂联素是一种仅由脂肪细胞产生的分泌性激素，其与多种代谢表型存在关联，但在代谢综合征发生发展中的具体作用仍未明确。
研究目的：本研究针对加拿大招募的多族裔人群，采用观察性与遗传流行病学相结合的研究方法，探讨血清脂联素水平与代谢性状之间的关联。
研究方法：本研究纳入SHARE/SHARE-AP研究的1157名参与者，收集其临床资料与血清脂联素水平；对参与者ADIPOQ基因的功能性位点rs266729及GCKR基因的rs1260326单核苷酸多态性（Single Nucleotide Polymorphism, SNP）进行基因分型。
研究结果：血清脂联素水平与高密度脂蛋白胆固醇（High-Density Lipoprotein, HDL）呈正相关，与体质量指数、腰臀比、甘油三酯、空腹血糖、空腹胰岛素、收缩压及舒张压均呈负相关（所有P值均<0.002）。rs266729的次要等位基因G与较低的脂联素水平及升高的稳态模型评估胰岛素抵抗指数（Homeostasis Model Assessment of Insulin Resistance, HOMA-IR）相关（分别对应P=0.004与P=0.003）。在校正血清脂联素浓度后，rs266729 SNP与HOMA-IR之间的关联不再具有统计学意义（P=0.10）。rs266729 SNP对HOMA-IR的影响程度超过其对脂联素水平的影响（标准化回归系数0.15，95%置信区间（95% Confidence Interval, 95% CI）[0.06, 0.24]，P<0.001）。rs266729 SNP与种族在脂联素水平或HOMA-IR方面未存在显著交互作用。与之相反，GCKR基因的rs1260326 SNP与HOMA-IR相关（P<0.001），但与脂联素水平无显著关联（P=0.67）。
结论：功能性启动子多态性rs266729与不同族裔人群较低的血清脂联素水平及升高的胰岛素抵抗相关，这一发现提示脂联素水平与胰岛素抵抗之间可能存在因果关联。