Role of Adiponectin in Coronary Heart Disease Risk: A Mendelian Randomization Study

Abstract

Rationale: Hypoadiponectinemia correlates with several coronary heart disease (CHD) risk factors. However, it is unknown whether adiponectin is causally implicated in CHD pathogenesis.

Objective: We aimed to investigate the causal effect of adiponectin on CHD risk.

Methods and results: We undertook a Mendelian randomization study using data from genome-wide association studies consortia. We used the ADIPOGen consortium to identify genetic variants that could be used as instrumental variables for the effect of adiponectin. Data on the association of these genetic variants with CHD risk were obtained from CARDIoGRAM (22 233 CHD cases and 64 762 controls of European ancestry) and from CARDIoGRAMplusC4D Metabochip (63 746 cases and 130 681 controls; ≈ 91% of European ancestry) consortia. Data on the association of genetic variants with adiponectin levels and with CHD were combined to estimate the influence of blood adiponectin on CHD risk. In the conservative approach (restricted to using variants within the adiponectin gene as instrumental variables), each 1 U increase in log blood adiponectin concentration was associated with an odds ratio for CHD of 0.83 (95% confidence interval, 0.68-1.01) in CARDIoGRAM and 0.97 (95% confidence interval, 0.84-1.12) in CARDIoGRAMplusC4D Metabochip. Findings from the liberal approach (including variants in any locus across the genome) indicated a protective effect of adiponectin that was attenuated to the null after adjustment for known CHD predictors.

Conclusions: Overall, our findings do not support a causal role of adiponectin levels in CHD pathogenesis.

Keywords: adiponectin; cardiovascular disease; coronary artery disease; mendelian randomization analysis obesity.

Figure 1.

Analysis plan. Summary data from the association of single-nucleotide polymorphism (SNP) with phenotypes were extracted from genome-wide association study (GWAS) consortia data sets (ADIPOGen, CARDIoGRAM, C4D, MAGIC, GLGC, and GIANT). The effect of adiponectin on CHD was estimated using a conservative Mendelian randomization approach (instrumental variable: SNPs within ADIPOQ locus [±50 kb]) and a liberal approach (instrumental variable: SNPs in any locus). For the conservative approach, inverse-variance weighted (IVW) method was used. For the liberal approach, IVW method was used in both crude and adjusted analysis for known pleiotropic factors and MR-Egger regression in the analysis accounting for hidden pleiotropy (sensitivity analysis). BMI indicates body mass index; CARDIoGRAM, Coronary Artery Disease Genome-wide Replication and Meta-analysis; CARDIoGRAMplusC4D Metabochip, CARDIoGRAMplusC4D Metabochip meta-analysis; GIANT, genetic investigation of anthropometric traits; GLGC, Global Lipids Genetics Consortium; Hb_A1c: glycohemoglobin; HDL, high-density lipoprotein; IV, instrumental variable; LDL, low-density lipoprotein; MAGIC, Meta-Analyses of Glucose and Insulin-related traits Consortium; MR, Mendelian randomization; SNP, single-nucleotide polymorphism; TAG, triacylglycerol; and WC, waist circumference.

Figure 2.

Forest plots of mean difference in log adiponectin levels and odds ratio of coronary heart disease per allele of single-nucleotide polymorphism (SNP) according to the conservative (A) and liberal (B) approaches. A, Conservative approach including 4 SNPs within ADIPOQ gene associated with adiponectin at genome-wide significant levels (P<5×10⁻⁸; C4). B, Liberal approach including 17 SNPs across the genome associated with adiponectin at genome-wide significant levels (P<5×10⁻⁸; L17). CHD indicates coronary heart disease; Chr, chromosome; and OR, odds ratio. Results for log adiponectin included 29 347 individuals from ADIPOGen consortium and for CHD risk included 86 995 individuals (22 233 CHD cases) from CARDIoGRAM and 194 427 individuals (63 746 CHD cases) from CARDIoGRAMplusC4D Metabochip consortium.

Figure 3.

Standardized mean difference (and 95% confidence interval [CI]) in cardiovascular risk biomarkers per 1 U increase in genetically instrumented log adiponectin levels. A, Conservative approach including 4 SNPs within ADIPOQ gene associated with adiponectin at genome-wide significant levels (P<5×10⁻⁸; C4). B, Liberal approach including 17 SNPs across the genome associated with adiponectin at genome-wide significant levels (P<5×10⁻⁸; L17). BMI indicates body mass index; Hb_A1c, glycohemoglobin; HDL-c, high-density lipoprotein cholesterol; LDL-c, low-density lipoprotein cholesterol; SNP, single-nucleotide polymorphism; TAG, triacylglicerols; and WC, waist circumference.

Figure 4.

Mendelian randomization estimates of odds ratio (and 95% confidence interval [CI]) of coronary heart disease risk per 1 U increase in genetically instrumented log adiponectin levels. CHD indicates coronary heart disease; IVW, inverse-variance weighted; MR-Egger, Mendelian randomization-Egger method; OR, odds ratio; and SNP, single-nucleotide polymorphism.