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Adiponectin and Risk of Congestive Heart Failure
To the Editor: We recently reported that insulin resistance is an independent predictor of congestive heart failure (CHF).1 In a subsequent Letter to the Editor, Stefan et al2 proposed adiponectin as a mediator of that association. Low adiponectin concentration has been associated with risk of myocardial infarction.3 We therefore investigated in our cohort (Uppsala Longitudinal Study of Adult Men) whether circulating adiponectin (primary hypothesis) or single nucleotide polymorphisms (SNPs) in the adiponectin gene ADIPOQ (secondary hypothesis) predict incident CHF.
Methods
Frozen serum samples that had been collected during 1991 through 1995 from participants1 were used to analyze circulating adiponectin and to genotype for SNPs in the ADIPOQ gene. Serum adiponectin was analyzed using an immunofluorometric assay.4 Genotyping was performed at the WCN (Wallenberg Consortium North, Stockholm, Sweden) SNP technology platform (Uppsala University, Uppsala, Sweden). The overall sample success rate was 95.9%, with an accuracy of 99.9% according to duplicate analysis of 31% (3508/11 196) of the genotypes.
The genotype distribution conformed to Hardy-Weinberg equilibrium for all SNPs except rs1648707, for which approximately 100 heterozygote samples failed due to technical reasons. Haplotypes were estimated using the PHASE program.5 Data were collected on baseline CHF risk factors (body mass index, diabetes, acute myocardial infarction, hypertension, left ventricular hypertrophy, smoking, and serum cholesterol level, as previously defined1).
A total of 946 men aged 70 years, who were free of CHF at baseline, were followed up until December 2002 (median follow-up, 9.1 years; range, 0.10-11.4 years). New cases of CHF were identified in the hospital discharge register and validated.1 All participants provided written informed consent and the ethics committee of Uppsala University approved the study.
Univariable and multivariable Cox proportional hazards analyses (including the baseline CHF risk factors) were used to examine the relationships between CHF and adiponectin concentrations, each SNP,6 and haplotypes, each in separate models. The statistical power was 87% to detect a hazard ratio (HR) of 0.7 for a 1-SD increase of adiponectin and approximately 80% to detect a HR of 2.0 for each of the SNPs. Interaction terms between adiponectin concentrations, SNPs, and CHF risk factors were fitted but were nonsignificant. The proportionality assumption was met and there was no evidence of colinearity. Because this was a subset of the original cohort that had demonstrated the association between insulin sensitivity and CHF, we also repeated all comparisons from the previous study for validation.1 Statistical significance was set at P<.05. PASS 2002 statistical software (NCSS, Kaysville, Utah) was used for power calculations and STATA version 8.2 (STATA Corp, College Station, Tex) was used for the other analyses.
Results
During follow-up, 76 men developed CHF. In unadjusted analyses, adiponectin concentration (1 SD increase) was not significantly associated with incident CHF (HR, 0.90; 95% confidence interval, 0.72-1.13; P = .35). There was no significant association after adjusting for all baseline CHF risk factors (HR, 1.09; 95% confidence interval, 0.86-1.38; P = .47). No significant associations were found between any of the 10 SNPs in the ADIPOQ gene and CHF or between any haplotype and CHF in unadjusted or adjusted models (Table). Adiponectin concentrations were highly correlated with body mass index (r = –0.31; P<.001) and insulin sensitivity (euglycemic clamp; r = 0.42; P<.001). The validating analyses showed similar results as the previous study.1
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Table. Congestive Heart Failure (CHF) Incidence in Relation to Different Single Nucleotide Polymorphisms (SNPs) in the Adiponectin Gene (ADIPOQ)
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Comment
Contrary to our hypotheses, neither circulating adiponectin nor ADIPOQ gene polymorphisms predicted CHF in this longitudinal, community-based cohort of men without CHF at baseline. These hypotheses had considered animal studies in which adiponectin knockout mice had increased insulin resistance, cardiac mass, left ventricular dimensions, and pulmonary congestion compared with controls.7 In addition, adiponectin has predicted mortality in patients with manifest CHF.4 Circulating adiponectin could play an important role in the pathophysiology of cardiovascular disease,3 possibly due to anti-atherogenic, anti-inflammatory, and insulin-sensitizing effects. Polymorphisms in the ADIPOQ gene have been associated with serum adiponectin concentrations and cardiovascular risk.8
Limitations of this study are that there may not have been adequate power to detect weak associations and that it is a post-hoc study of a hypothesis that was not prespecified. In addition, we did not assess high-molecular-weight adiponectin, which may be the most relevant form in humans.9 Finally, the 10 SNPs examined in this study may not capture all possible genetic variation (such as the common +45T>G SNP8) in the ADIPOQ gene.
While further studies may be needed to explore other SNPs of ADIPOQ and CHF risk, our observational data do not support a major role of adiponectin in the development of CHF.
Author Contributions: Dr Ingelsson had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Ingelsson, Axelsson, Lundmark, Zethelius.
Acquisition of data: Ingelsson, Risérus, Frystyk, Flyvbjerg, Axelsson, Lundmark, Zethelius.
Analysis and interpretation of data: Ingelsson, Risérus, Berne, Flyvbjerg, Axelsson, Lundmark, Zethelius.
Drafting of the manuscript: Ingelsson, Risérus, Flyvbjerg, Axelsson, Lundmark.
Critical revision of the manuscript for important intellectual content: Ingelsson, Risérus, Berne, Frystyk, Flyvbjerg, Axelsson, Lundmark, Zethelius.
Statistical analysis: Ingelsson, Axelsson, Lundmark.
Obtained funding: Ingelsson, Berne, Zethelius.
Administrative, technical, or material support: Frystyk, Flyvbjerg, Axelsson, Lundmark, Zethelius.
Study supervision: Risérus, Berne, Flyvbjerg, Zethelius.
Financial Disclosures: None reported.
Funding/Support: This study was supported by the Uppsala University, the Uppsala County, the Wallenberg Consortium North, the Family Ernfors Fund for Diabetes, the Swedish Society for Medical Research, and the Danish Diabetes Association.
Role of the Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript.
Erik Ingelsson, MD, PhD
erik.ingelsson{at}pubcare.uu.se
Ulf Risérus, MMed, PhD
Department of Public Health and Caring Sciences/Geriatrics
Uppsala University
Uppsala, Sweden
Christian Berne, MD, PhD
Department of Medical Sciences
Uppsala University
Uppsala, Sweden
Jan Frystyk, MD, PhD;
Allan Flyvbjerg, MD, PhD
Medical Research Laboratories
Aarhus University Hospital
Aarhus, Denmark
Tomas Axelsson, PhD;
Per Lundmark, MSc
Department of Medical Sciences
Uppsala University
Uppsala, Sweden
Björn Zethelius, MD, PhD
Department of Public Health and Caring Sciences/Geriatrics
Uppsala University
Uppsala, Sweden
1. Ingelsson E, Sundström J, Ärnlöv J, Zethelius B, Lind L. Insulin resistance and risk of congestive heart failure. JAMA. 2005;294:334-341.
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2. Stefan N, Fritsche A, Häring H-U. Insulin resistance and congestive heart failure. JAMA. 2005;294:2578.
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3. Pischon T, Girman CJ, Hotamisligil GS, Rifai N, Hu FB, Rimm EB. Plasma adiponectin levels and risk of myocardial infarction in men. JAMA. 2004;291:1730-1737.
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4. Kistorp C, Faber J, Galatius S, et al. Plasma adiponectin, body mass index, and mortality in patients with chronic heart failure. Circulation. 2005;112:1756-1762.
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5. Stephens M, Smith NJ, Donnelly P. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet. 2001;68:978-989.
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6. dbSNP Home Page. NCBI single nucleotide polymorphism. Available at: http://www.ncbi.nih.gov/SNP. Accessed February 15, 2006.7. Liao Y, Takashima S, Maeda N, et al. Exacerbation of heart failure in adiponectin-deficient mice due to impaired regulation of AMPK and glucose metabolism. Cardiovasc Res. 2005;67:705-713.
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8. Qi L, Li T, Rimm E, et al. The +276 polymorphism of the APM1 gene, plasma adiponectin concentration, and cardiovascular risk in diabetic men. Diabetes. 2005;54:1607-1610.
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9. Pajvani UB, Hawkins M, Combs TP, et al. Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity. J Biol Chem. 2004;279:12152-12162.
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Letters Section Editor: Robert M. Golub, MD, Senior Editor.
JAMA. 2006;295:1772-1774.
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