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Clinical Chemistry 52: 2021-2027, 2006. First published September 21, 2006; 10.1373/clinchem.2006.074476
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(Clinical Chemistry. 2006;52:2021-2027.)
© 2006 American Association for Clinical Chemistry, Inc.

Molecular Diagnostics and Genetics

Association of Adiponectin Gene Variations with Risk of Incident Myocardial Infarction and Ischemic Stroke: A Nested Case-Control Study

Hillary H. Hegener1,2,3,4, I-Min Lee4, Nancy R. Cook1,2,3,4, Paul M. Ridker1,2,3,4 and Robert Y.L. Zee1,2,3,4,a

1 Center for Cardiovascular Disease Prevention, 2 Donald W. Reynolds Center for Cardiovascular Research, 3 Leducq Center for Molecular and Genetic Epidemiology and the 4 Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.

aAddress correspondence to this author at: Laboratory of Genetic and Molecular Epidemiology, Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, Harvard Medical School, 900 Commonwealth Ave. East, Boston, MA 02215. Fax: 617-783-9212; e-mail: rzee{at}rics.bwh.harvard.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Adiponectin (ADIPOQ) gene variations are associated with risk of cardiovascular disease in patients with diabetes. No prospective data are available, however, on the risk of atherothrombotic disorders in persons with ADIPOQ variations who do not have diabetes.

Methods: From a group of DNA samples collected at baseline in a prospective cohort of 14 916 initially healthy American men, we assessed the presence of 5 ADIPOQ genetic variants (rs266729, rs182052, rs822396, rs2241766, and rs1501299) in samples from 600 Caucasian men who subsequently suffered an atherothrombotic event (incident myocardial infarction or ischemic stroke) and from 600 age- and smoking-matched Caucasian men who remained free of reported vascular disease during follow-up (controls).

Results: Genotype distributions for the variations tested were in Hardy-Weinberg equilibrium. Marker-by-marker conditional logistic regression analysis, adjusted for potential risk factors, showed an association of rs266729 [recessive: odds ratio (OR), 0.26; 95% confidence interval (CI), 0.10–0.64; P = 0.004] and rs182052 (recessive: OR, 0.40; 95% CI, 0.21–0.76; P = 0.006) with decreased risk of ischemic stroke. These findings remained significant after Bonferroni correction. Haplotype-based (constituted by rs266729, rs182052, and rs822396) conditional logistic regression analysis, adjusted for the same potential risk factors, showed an association of haplotype G-A-G (OR, 0.28; 95% CI, 0.09–0.87; P = 0.03) with decreased risk of ischemic stroke. Prespecified analysis limited to participants without baseline diabetes showed similar significant findings.

Conclusions: The present prospective investigation provides further evidence for a protective role of adiponectin gene variation in the risk of ischemic stroke that was independent of the presence of diabetes.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Adiponectin, an adipose tissue–specific plasma protein, is structurally homologous to collagens VIII and X and complement factor C1q (1) and plays an important role in regulating energy homeostasis, glucose and lipid metabolism, and antiinflammatory responses in the vascular system (2)(3)(4). Low plasma concentrations of adiponectin have been associated with type 2 diabetes (5), obesity(5), hypertension(6), myocardial infarction (MI)1 (7), and ischemic stroke(8). Potential mechanisms of adiponectin and its associations with these inflammatory-related diseases include its inhibition of smooth muscle cell proliferation, monocyte adhesion to endothelium, and macrophage uptake by LDL (8). Recent evidence from linkage studies has implicated a region encompassing the adiponectin, C1Q, and collagen domain–containing gene (ADIPOQ, 3q27, Gene ID 9370)2 with risk of coronary heart disease (9) and metabolic syndrome (10). ADIPOQ gene variations have also been shown to be associated with adiponectin plasma concentrations (11)(12)(13)(14)(15)(16)(17)(18). Furthermore, recent studies found an association of selected ADIPOQ gene variants (19), in particular the +276G>T (intron2, rs1501299) variation, with decreased cardiovascular risk in patients with (14)(20) and without(21) diabetes under a recessive mode of inheritance.

To validate and confirm these findings in a prospective setting, we conducted an extended investigation to examine the possible association of 5 variations [–11377C>G (rs266729), –10066G>A (rs182052), –3971A>G (rs822396), +45T>G (rs2241766), and +276G>T (rs1501299)] in ADIPOQ with risk of incident MI and ischemic stroke in participants drawn from the Physicians Health Study (PHS) cohort. These variations were selected on the basis of prior evidence of associations with cardiovascular risk, validated allele frequency and heterozygosity, and sequence-demonstrated allelic variation listed in the National Center for Biotechnology Information database (http://www.ncbi.nlm.nih.gov).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
study design
We used a prospective, nested case-control design within PHS, a completed randomized controlled trial of aspirin and beta-carotene initiated in 1982 among 22 071 male, predominantly white (>94%), US physicians, 40–84 years old at study entry (22). Before randomization, 14 916 participants provided an EDTA-anticoagulated blood sample that was stored for further analyses. All participants were free of prior MI, stroke, transient ischemic attacks, and cancer at study entry. History of cardiovascular risk factors, such as hypertension, diabetes, or hyperlipidemia, was defined by self-report at entry into the study. For all reported incident vascular events occurring after study enrollment, relevant hospital records, death certificates, and autopsy reports were requested and reviewed by an outcomes committee with standardized diagnostic criteria.

A diagnosis of MI was confirmed by evidence of symptoms in the presence of either diagnostic increases of cardiac enzymes or diagnostic changes on electrocardiograms. In the case of fatal events, the diagnosis of MI based on autopsy findings was also accepted. Stroke was defined by the presence of a new focal neurologic deficit with symptoms and signs persisting for >24 h and was ascertained from blinded review of medical records, autopsy results, and the judgment of a board-certified neurologist on the basis of clinical reports or computed tomographic or magnetic resonance image scanning.

For each case (MI or ischemic stroke), a control matched by age, smoking history, and length of follow-up was chosen. The control participants were selected from those who remained event-free up to the date that the dataset was closed for selection of study participants and were at risk for cardiovascular disease at the time the index event occurred in the case participant; 341 MI pairs and 259 ischemic stroke pairs were identified for the present investigation, all Caucasian men. The study was approved by the Brigham and Women’s Hospital Institutional Review Board for Human Subjects Research.

genotype determination
Genotype determination was performed with an ABI fluorescence-based allelic discrimination method (Applied BioSystems) (23). Each 5-µL amplification reaction volume contained 1x TaqMan Universal Master Mix (Applied BioSystems) and 10 ng of template DNA. Amplification reactions were carried out with an ABI 7900HT Sequence Detection System according to the manufacturer’s specifications.

To confirm genotype assignment, scoring was carried out by 2 independent observers. Discordant results (<1% of all scoring) were resolved by a joint reading and, if necessary, a repeat genotyping. Results were scored blinded as to case-control status.

statistical analysis
Allele and genotype frequencies among cases and controls were compared with values predicted by Hardy-Weinberg equilibrium by the {chi}2-test. Odds ratios (ORs) of any cardiovascular event, MI, or ischemic stroke associated with each genotype were calculated separately by logistic regression analysis conditioned on age, smoking status, and length of follow-up since randomization and further adjusted for randomized treatment assignment, history of hypertension (≥140/90 mmHg or on antihypertensive medication), presence of diabetes, and body mass index. To compare our findings with prior published data (14)(20)(21), we performed conditional logistic regression analysis with a recessive mode of inheritance. Pairwise linkage disequilibrium was examined as described by Devlin and Risch (24). Haplotype estimation and inference were determined with PHASE v2.1.1 (25). Haplotype blocks were defined with entropy blocker (EB) as described by Rinaldo et al. (26). EB, unlike most methods for discovering haplotype blocks, does not aim to discover haplotype tagging single-base variations [also known as single-nucleotide polymorphisms (SNPs)], but rather to differentiate between regions populated by weakly correlated single-base variations and regions populated by at least several single-base variations in strong linkage disequilibrium. Haplotype distributions (as defined by EB) between cases and controls were examined by permutation testing. In addition, the relationship between haplotypes and incident MI or ischemic stroke was examined by haplotype-based conditional logistic regression analysis with baseline parameterization (27), adjusting for the same potential confounders/risk factors. Furthermore, prespecified analysis limited to participants without baseline diabetes was performed. All analyses were carried out with the SAS v9.1 package (SAS Institute Inc). For each OR, we calculated 95% confidence intervals (CIs). A 2-tailed P value of 0.05 was considered a statistically significant result.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Baseline characteristics of the study population are shown in Table 1 . As expected, the case patients had a higher prevalence of traditional cardiovascular risk factors at baseline than the controls. The observed genotype distributions were in Hardy-Weinberg equilibrium in the control group. According to standard marker-by-marker {chi}2 analysis, the genotype distribution was significantly different between ischemic stroke cases and controls for rs266729 (P = 0.0009, Table 2 ) and rs182052 (P = 0.002, Table 2 ). Results from the conditional logistic regression analysis showed an association of decreased risk of ischemic stroke for rs266729 (recessive: adjusted, OR, 0.26; 95% CI, 0.10–0.64; P = 0.004; Table 3 ) and rs182052 (recessive: adjusted, OR, 0.40; 95% CI, 0.21–0.76; P = 0.006; Table 3 ). Similar significant findings with decreased risk of ischemic stroke were again observed for rs266729 (recessive: adjusted, OR, 0.18; 95% CI, 0.06–0.51; P = 0.001; Table 3 ) and rs182052 (recessive: adjusted, OR, 0.32; 95% CI, 0.16–0.65; P = 0.002; Table 3 ) in participants without baseline diabetes. Furthermore, these findings remained statistically significant for rs266729 (univariable: P = 0.004; multivariable: P = 0.02; without baseline diabetes; P = 0.005), and rs182052 (univariable: P = 0.01; multivariable: P = 0.03; without baseline diabetes; P = 0.01) with risk of ischemic stroke when Bonferroni correction was applied.


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  		Table 1. Baseline characteristics of study participants.1


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  		Table 2. Genotype and allele distribution.


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  		Table 3. ORs of cardiovascular disease from conditional logistic regression analysis in a recessive mode of inheritance.1

On the basis of the linkage disequilibrium patterns (see Table 1Up in the Data Supplement that accompanies the online version of this article at http://www.clinchem.org/content/vol52/issue11), a haplotype block (named as EB haplotype), constituted by rs266729-rs182052-rs822396, was identified and used for subsequent analyses. Overall, the EB haplotype frequencies were similar between cases and controls (see Table 2 in the online Data Supplement). Results from the haplotype-based conditional logistic regression analysis showed that compared with the referent C-G-A, haplotype G-A-G was associated with decreased risk of ischemic stroke (OR, 0.28; 95% CI, 0.09–0.87; P = 0.03; Table 4 ); in prespecified analysis, it was limited to participants without baseline diabetes (OR, 0.25; 95% CI, 0.08–0.83; P = 0.02; Table 4 ).


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  		Table 4. Conditional logistic regression with haplotype-based parameterization.1


   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present nested case-control investigation, we found no evidence for an association of the tested ADIPOQ gene variations/haplotypes with risk of incident MI. We also found no evidence for an association of –3971A>G, +45T>G, or +276G>T with risk of incident ischemic stroke. However, we found an association of –11377C>G and –11066G>A with decreased risk of incident ischemic stroke. Furthermore, a haplotype block (defined by EB and constituted by –11377C>G, –11066G>A, and –3971A>G) carrying a specific haplotype, G-A-G, was found to be associated with decreased risk of incident ischemic stroke. Similar significant findings were observed in analyses limited to participants without baseline diabetes.

Coronary artery disease (CAD) is a major cause of morbidity and mortality around the world, and inflammation is believed to play an important role in the pathogenesis of atherothrombotic events, including MI and ischemic stroke. Adiponectin, an inhibitor of smooth muscle cell proliferation, monocyte adhesion, and macrophage uptake, mediates vascular inflammation and has been associated with decreased risk of type 2 diabetes (5), obesity(5), hypertension (6), MI(7), and ischemic stroke (8). Hypoadiponectinemia [<4.0 mg/L, as suggested by Kumada et al. (28)] has been identified as a risk factor for CAD (28) and subclinical atherosclerosis (29), independent of well-known CAD risk factors. ADIPOQ gene variations have also been associated with differential plasma adiponectin concentrations (11)(12)(13)(14)(15)(16)(17)(18); in particular, the +45T>G and +276G>T gene variants and haplotypes carrying these specific variants were recently shown to be associated with decreased plasma adiponectin concentrations (30)(31), suggesting a functional involvement of the ADIPOQ gene in inflammatory responses via altered transcriptional activity.

Several studies have found associations of ADIPOQ variations with risk of cardiovascular disease in persons without (13) as well as with diabetes (14)(19)(20), but none have evaluated associations with actual atherothrombotic events in a nondiabetic population.

A recent study by Lacquemant et al. (19) demonstrated an association of the +45T>G variation with increased risk of CAD in diabetic patients (OR, 1.9; 95% CI, 1.2–2.9; P = 0.0036) in 189 French and 288 Swiss individuals in 2 population-based cohorts. By contrast, 2 other recent studies (14)(20) found no association of the same variation with CAD risk in their diabetic patients. Filippi et al. (13) also found no evidence for an association in patients without diabetes in a group of younger CAD patients (age ≤50 years).

As for the +276G>T variant, the same 2 studies (14)(20) both reported an association of this variation with decreased risk of CAD [Qi et al. (14): OR, 0.38; 95% CI, 0.18–0.79; P = 0.009; Bacci et al. (20): OR, 0.13; 95% CI, 0.04–0.46; P = 0.002) under a recessive mode of inheritance. Interestingly, Lacquemant et al. (19) reported no association between the +276G>T variant and CAD risk in diabetic patients, whereas Filippi et al. (13) reported an association of the variant with increased CAD risk in individuals without diabetes.

For the –11377C>G variant, Qi et al. (14) and Lacquemant et al. (19) independently found no evidence for an association with diabetic-CAD risk.

Compared with the above-mentioned previously published data, our present PHS investigation found (a) no evidence for an association of either the +45T>G or +276G>T variation with risk of incident MI and ischemic stroke, (b) evidence for an association of the –11377C>G variant and the –11066G>A variant (not tested by previous investigators) with decreased risk of incident ischemic stroke, and (c) an association of a specific haplotype carrying the promoter variants tested with decreased risk of incident ischemic stroke.

The apparent discrepancies in our results and those of previous studies could be partly attributable to allelic heterogeneity, case-control selection criteria, phenotype/trait definition, and different population backgrounds. Of note, the genotype frequencies in our control group were similar to those previously reported in other studies (13)(14)(19)(20)(21)(30)(31).

The prospective nature of the PHS cohort greatly reduces the possibility that our findings are attributable to bias and/or confounding, as does the use of a closed, prospective cohort in which the determination of case status was based solely on the subsequent development of disease rather than on any arbitrary selection criteria designed by the investigators. Nonetheless, our sample population consists of Caucasian males only, so the data cannot be generalized to other ethnic groups or to women. Association studies such as the present one examine only the possible association between phenotype and tested variation(s); such studies cannot exclude the possibility that the variations/haplotypes tested are in linkage disequilibrium with one or more yet-to-be-identified susceptibility genes/variations that are responsible for the observed significant associations. The –11377C>G (rs266729) variation maps to within 2 kb of an mRNA transcript for ADIPOQ, and the –11066G>A (rs182052) variation is located in the 5'-untranslated intron 1 region (http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?locusId=9370). However, to the best of our knowledge, we are not aware of reports/data regarding these gene variants containing any (putative) transcriptional factor binding site(s). Thus, the functionality of ADIPOQ gene variants and the pathophysiologic consequences of their altered transcriptional activity remain elusive. Because no data are available on the baseline plasma adiponectin concentrations in our sample population, the effect of this intermediate phenotype cannot be examined within the present investigation. Our present study aimed to replicate/validate previous association findings; therefore, uncorrected P values were presented. As stated in Results, our marker-by-marker findings for rs266729 and rs182052 remained statistically significant when Bonferroni correction was applied.

In conclusion, these prospective data from a large cohort of apparently healthy Caucasian US men provide evidence of an association between specific ADIPOQ promoter variations/haplotypes tested and decreased risk of incident ischemic stroke. If corroborated in other prospective studies, our data suggest a potential protective effect of ADIPOQ in the pathophysiology of ischemic stroke.


   Acknowledgments
 
This study was supported by grants from the National Heart Lung and Blood Institute (HL-58755 and HL-63293), the Doris Duke Charitable Foundation, the American Heart Association, and the Donald W. Reynolds Foundation (Las Vegas, NV).


   Footnotes
 
1 Nonstandard abbreviations: MI, myocardial infarction; PHS, Physicians Health Study; OR, odds ratio; EB, entropy blocker; CI, confidence interval; CAD, coronary artery disease.

2 Human gene: ADIPOQ, adiponectin, C1Q, and collagen domain–containing gene (ADIPOQ, 3q27, Gene ID 9370).


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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