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J Am Coll Cardiol, 2004; 43:1195-1200, doi:10.1016/j.jacc.2003.10.049
© 2004 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: ATHEROSCLEROSIS

Adiponectin I164T mutation is associated with the metabolic syndrome and coronary artery disease

Koji Ohashi, MD*, Noriyuki Ouchi, MD, PhD*, Shinji Kihara, MD, PhD*,*, Tohru Funahashi, MD, PhD*, Tadashi Nakamura, MD, PhD*, Satoru Sumitsuji, MD{ddagger}, Toshiharu Kawamoto, MD, PhD§, Satoru Matsumoto, MD||, Hiroyuki Nagaretani, MD*, Masahiro Kumada, MD*, Yoshihisa Okamoto, MD*, Hitoshi Nishizawa, MD, PhD*, Ken Kishida, MD, PhD*, Norikazu Maeda, MD*, Hisatoyo Hiraoka, MD, PhD*, Yoshio Iwashima, MD{dagger}, Kazuhiko Ishikawa, MD, PhD{dagger}, Mitsuru Ohishi, MD, PhD{dagger}, Tomohiro Katsuya, MD, PhD{dagger}, Hiromi Rakugi, MD, PhD{dagger}, Toshio Ogihara, MD, PhD{dagger} and Yuji Matsuzawa, MD, PhD*

* Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Suita, Japan
{dagger} Department of Geriatric Medicine, Graduate School of Medicine, Osaka University, Izumisano, Japan
{ddagger} Department of Cardiology, Rinku General Medical Center, Rinku, Japan
§ Department of Cardiology, National Hospital Kure Medical Center, Kure, Japan
|| Department of Cardiology, Toyonaka Municipal Hospital, Toyonaka, Japan

Manuscript received April 21, 2003; revised manuscript received September 12, 2003, accepted October 20, 2003.

* Reprints requests and correspondence: Dr. Shinji Kihara, Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan.
kihara{at}imed2.med.osaka-u.ac.jp


   Abstract
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 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: This study examined the association of mutations in adiponectin gene with the prevalence of coronary artery disease (CAD).

BACKGROUND: Coronary artery disease is a major cause of mortality in the industrial countries. Adiponectin gene locus, chromosome 3q27, is the candidate site for CAD. We have reported that adiponectin has antiatherogenic and antidiabetic properties, and that the plasma levels negatively correlated with body mass index (BMI) are significantly low in patients with CAD or type 2 diabetes.

METHODS: The study subjects were 383 consecutive patients with angiographically confirmed CAD and 368 non-CAD subjects adjusted for age and BMI in the Japanese population. Single nucleotide polymorphisms (SNPs) in the adiponectin gene were determined by Taqman polymerase chain reaction (PCR) method or a PCR-based assay for the analysis of restriction fragment length polymorphism. The plasma adiponectin concentration was measured by enzyme-linked immunosorbent assay.

RESULTS: Among SNPs, the frequency of I164T mutation was significantly higher in CAD subjects (2.9%) than in the control (0.8%, p < 0.05). The plasma adiponectin levels in subjects carrying the I164T mutation were significantly lower than in those without the mutation, and were independent of BMI. In contrast, SNP94 and SNP276, which are reported to be associated with an increased risk of type 2 diabetes, were associated neither with CAD prevalence nor with plasma adiponectin level. Subjects with I164T mutation exhibited a clinical phenotype of the metabolic syndrome.

CONCLUSIONS: The I164T mutation in the adiponectin gene was a common genetic background associated with the metabolic syndrome and CAD in the Japanese population.

Abbreviations and Acronyms
  BMI = body mass index
  CAD = coronary artery disease
  HbA1C = hemoglobin A1C
  HDL-chol = high-density lipoprotein cholesterol
  HOMA = homeostasis model assessment
  PCR = polymerase chain reaction
  SNP = single nucleotide polymorphism
  T-chol = total cholesterol
  TG = triglyceride
  TNF = tumor necrosis factor

Cardiovascular disease is a major cause of morbidity and mortality in industrial countries. Both environmental and genetic factors contribute to the development of cardiovascular disease (1). Among various adipocyte-derived bioactive substances, adipocytokines, dysregulated production of leptin, tumor necrosis factor (TNF)-{alpha}, and plasminogen activator inhibitor type 1 is closely associated with increased cardiovascular mortality and morbidity (2–6). Adiponectin is an adipocyte-specific adipocytokine, which we identified in the human adipose tissue complementary DNA library (7). The mouse homologue of adiponectin was identified as ACRP30 and AdipoQ (8,9). Hypoadiponectinemia (low plasma adiponectin level) has been identified in patients with coronary artery disease (CAD) (10) and type 2 diabetes, and is a predictor of cardiovascular outcome in patients with end-stage renal failure (11). Plasma adiponectin rapidly accumulates in the subendothelial space of an injured human artery (12). We have reported that human recombinant adiponectin suppresses endothelial adhesion molecule expression, vascular smooth muscle cell proliferation, and macrophage-to-foam cell transformation as well as TNF-{alpha} production by macrophages in vitro (13,14). Recently, we reported that the adiponectin-knockout mice exhibited enhanced neointimal thickening after vascular injury (15). In addition, we and others demonstrated that adiponectin treatment improved insulin resistance and glucose metabolism in diabetic mice model (16–18). These findings suggest that adiponectin has both antiatherogenic and antidiabetic properties and acts as an endogenous mediator of vascular and metabolic diseases.

We have previously identified several mutations of the adiponectin gene, including missense mutations (R112C, I164T, R221S, and H241P) in the globular domain and the G/T single nucleotide polymorphism at nucleotide 94 (SNP94) in the Japanese population (19,20). Among these mutations, the I164T mutation correlated with type 2 diabetes (19); SNP94 was reported to be associated with type 2 diabetes and obesity (21,22). A weak association was observed between SNP94 and plasma adiponectin levels in French Caucasians, although no significant association was found in the Japanese population (23). Recently, SNP at position 276 (SNP276) was reported to be associated with type 2 diabetes (21); SNP276 was associated with plasma adiponectin levels in French Caucasians and only in obese Japanese subjects (21,23). In addition, the haplotype identified by SNP94 and SNP276 was related with obesity and other features of the insulin resistance syndrome in Caucasians (24). A susceptibility locus for type 2 diabetes was mapped on chromosome 3q27, which harbors the adiponectin gene (25). A genome-wide scan for CAD replicated linkage with the metabolic syndrome on the region 3q27, suggesting that adiponectin might be one of the candidate genes susceptible for the metabolic syndrome-linked CAD (26). Although the metabolic syndrome includes insulin resistance, it is very important to elucidate the genetic contribution of adiponectin in the development of CAD.

In the present study, we investigated the frequency and the clinical significance of I164T, SNP94, and SNP276 of adiponectin gene in consecutive CAD patients and age- and body mass index (BMI)-matched non-CAD subjects.


   Methods
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 Methods
Results
 Discussion
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Study subjects.   Consecutive 383 CAD patients were recruited from the inpatients who were admitted to Osaka University Hospital. The criteria for CAD were a 75% ≤ organic stenosis of at least one segment of a major coronary artery confirmed by coronary angiogram. The control subjects were selected from people who received medical check in Osaka University Hospital or our affiliated hospitals. In these latter subjects, it was unethical to perform coronary angiography to rule out the presence of asymptomatic CAD. Therefore, the following inclusion criteria were used: no history of angina or other atherosclerotic vascular diseases, and normal exercise electrocardiogram stress testing. They were matched with CAD patients for age and BMI. All patients and subjects enrolled in this study were Japanese and gave written informed consent. This study was approved by the Ethics Committee of Osaka University.

Laboratory methods.   Venous blood was drawn from all patients and control subjects after an overnight fast. Plasma samples were kept at –80° centigrade for subsequent assay. Plasma concentration of adiponectin was evaluated by a sandwich ELISA system (Adiponectin ELISA Kit, Otsuka Pharmaceutical Co. Ltd., Tokushima, Japan) as previously reported (27). Serum total cholesterol (T-chol) and triglyceride (TG) concentrations were determined by an enzymatic method. High-density lipoprotein cholesterol (HDL-chol) was also measured by an enzymatic method after heparin and calcium precipitation. Plasma glucose was measured by a glucose oxidase method. The value of hemoglobin A1c (HbA1c) was determined by high-performance liquid chromatography. Insulin resistance was assessed by homeostasis model assessment (HOMA) (insulin resistance index = [fasting glucose (mmol/l) x fasting insulin (U/ml)]/22.5 (28). Body mass index was calculated as weight/height2.

Definitions of risk factors.   Diabetes mellitus was defined according to World Health Organization criteria, and/or having received treatment for diabetes mellitus (29). Dyslipidemia was defined as a T-chol concentration >5.69 mmol/l, a TG concentration >1.69 mmol/l, an HDL-chol concentration <1.03 mmol/l, and/or having received treatment for dyslipidemia. Hypertension was defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or having received treatment for hypertension. We did not exclude the subjects under medical treatment for diabetes mellitus, dyslipidemia, and hypertension.

DNA extraction and genotyping.   Genomic DNA was prepared from frozen whole blood with the use of a QIAamp DNA Blood Mini Kit (QIAGEN, Valencia, California). We determined the missense mutation I164T and the SNP276 of adiponectin gene by the TaqMan (Roche Molecular Systems Inc., Pleasanton, California) polymerase chain reaction (PCR) chemistry method as previously described (30). The TaqMan probe is a fluorogenic probe that consists of an oligonucleotide labeled with both a fluorescent reporter dye and a quenched dye. The fluorescent reporter dye, such as VIC and FAM (Applied Biosystems Inc., Foster City, California), is covalently linked to the 5' end of the nucleotide. Each of the reporters is quenched by minor groove binder, typically located at the 3' end. The following primers were used for the missense mutation I164T: a forward primer, 5'-AACATTCCTGGGCTGTACTACTTTG-3'; a reverse primer, 5'- GGCTGACCTTCACATCCTTCATA-3'; a T-allele-specific probe, 5'-VIC-ACCACATCACAGTCTA-MGB-3'; a C-allele-specific probe, 5'-FAM-CCACACCACAGTCT-MGB-3'. The following primers were used for the G/T SNP at position 276: a forward primer, 5'-AGAATGTTTCTGGCCTCTTTCATC-3'; a reverse primer, 5'- TTCTCCCTGTGTCTAGGCCTTAGT-3'; a G-allele-specific probe, 5'-FAM-CTATATGAAGGCATTCATTA-MGB-3'; T-allele-specific probe, 5'-VIC-AAACTATATGAAGTCATTCATTA-MGB-3'. The fluorescence level of PCR products was measured with the ABI PRISM 7200 Sequence Detector (Applied Biosystems, Inc.). We determined the SNP94 in exon 2 of adiponectin gene by a PCR-based assay for the analysis of restriction fragment length polymorphism as previously described (20).

Statistical methods.   For continuous variables, results are presented as mean ± SE. Differences in continuous parameter, such as BMI, between two groups were calculated by the Student t test, and differences in continuous parameter, such as plasma adiponectin level, among more than three groups were evaluated by analysis of variance. Because plasma adiponectin level, HOMA, and TG were skewed, these three parameters were log-transformed before analysis, and the parameters presented were back-transformed. Categorical variables were presented using frequency counts, and intergroup comparisons were analyzed by chi-square test. A level of p < 0.05 was accepted as statistically significant. All calculations were performed using a standard statistical package (JMP for Macintosh, version 4.0, SAS Institute Inc., Cary, North Carolina).


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
The clinical characteristics of CAD patients and non-CAD control subjects are shown in Table 1. The mean plasma adiponectin level in CAD patients was significantly lower than the control (p < 0.001), as we described previously (10). Patients with CAD had significantly higher levels of fasting plasma glucose, HbA1c, TG, numbers of diabetes mellitus, dyslipidemia, and lower levels of HDL-chol and diastolic blood pressure than the control group. There were no significant differences in age, gender, BMI, number of family history for diabetes, T-chol, systolic blood pressure, and number of hypertension between the two groups.


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  		Table 1 Clinical Characteristics of Control Subjects and CAD Patients

 
The frequency of I164T mutation in CAD patients (11 [2.9%] of 383) was significantly higher than that in non-CAD subjects (3 [0.8%] of 368, p < 0.05) (Table 2). All subjects with the mutation were heterozygotes. In contrast to this mutation, no significant differences in the distribution of SNP94 and SNP276 genotypes were observed between the two groups. The plasma adiponectin levels in subjects carrying the I164T mutation (3.2 ± 0.5 µg/ml) were significantly lower than in subjects without the mutation (6.9 ± 0.2 µg/ml, p < 0.0001) (Fig. 1A), although no significant difference was observed in BMI between the subjects with and without I164T mutation (24.4 ± 1.2 vs. 24.0 ± 0.1 kg/m2). The plasma adiponectin levels in subjects with the mutation were markedly low in both CAD and control groups (2.9 ± 0.6 vs. 4.3 ± 1.2 µg/ml, respectively), and did not correlate with BMI. The negative correlation between plasma adiponectin levels and BMI was observed in subjects without the mutation (data not shown). These data indicated that hypoadiponectinemia in subjects with the mutation was independent of BMI. The plasma adiponectin levels of the subjects with G/G, G/T, and T/T allele at SNP94 were 6.2 ± 0.6, 6.6 ± 0.2, and 7.1 ± 0.2 µg/ml, respectively (Fig. 1B). The plasma adiponectin level in the subjects having G allele at SNP94 tended to be lower, but it was not statistically significant. On the other hand, no differences were observed in plasma adiponectin levels of the subjects with G/G, G/T, and T/T allele at SNP276 (6.6 ± 0.2, 7.2 ± 0.2, and 6.7 ± 0.5 µg/ml, respectively) (Fig. 1C).


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  		Table 2 Frequency of Mutation and Polymorphism in Adiponectin Gene

 


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  		Figure 1 Association of I164T mutation, SNP94, and SNP276 with plasma adiponectin concentrations. (A) Plasma adiponectin levels in the subjects with wild type (WT) or I164T mutation in adiponectin gene. (B) Relationship between SNP94 genotypes and plasma adiponectin levels. (C) Relationship between SNP276 genotypes and plasma adiponectin levels. Columns and vertical bars denote mean and SE of the indicated sample numbers. *p < 0.05 vs. WT.

 
As shown in Table 3, all subjects carrying I164T had at least one risk factor including diabetes mellitus, hypertension, and dyslipidemia. Six (case 4 to 8, and 11) of the 11 CAD patients with the I164T mutation and 75 of 372 wild type CAD patients had all three metabolic abnormalities, which is a key feature of the metabolic syndrome. The percentage of the subjects with all three metabolic abnormalities was significantly higher in I164T mutation (54.5%) than that in wild type (20.2%) (p < 0.01). Nine (case 4 to 8 and 11 to 14) of 14 subjects with I164T mutation had diabetes mellitus, and cases 13 and 14 had received insulin treatment. However, except three cases (3, 4, and 8), six diabetic I164T patients had no apparent insulin resistance assessed by HOMA-insulin resistance (IR) compared with CAD patients (n = 383, HOMA-IR; 2.4 ± 0.2). In addition, there were no differences in HOMA-IR levels between nondiabetic I164T subjects (case 1 to 3, 9, and 10) and control subjects (n = 368, HOMA-IR; 1.8 ± 0.1).


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  		Table 3 Clinical Profile of the Subjects With I164T Mutation

 

   Discussion
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 Abstract
 Methods
 Results
 Discussion
References
 
In the present study, we found that the I164T mutation of adiponectin gene was associated with CAD prevalence and hypoadiponectinemia in the Japanese population. In contrast, the genotypes of SNP94 and SNP276, which were reported to be present in type 2 diabetes, influenced neither the prevalence of CAD nor the plasma adiponectin level. Importantly, all subjects carrying I164T in the present study including CAD and non-CAD subjects had at least one or more metabolic disorders including diabetes mellitus, hypertension, and dyslipidemia. Among CAD patients, the prevalence of the metabolic syndrome was significantly higher in I164T mutation than that in wild type. These findings suggest that the I164T mutation of adiponectin gene is associated with the development of the metabolic syndrome-linked CAD. Importantly, the severe hypoadiponectinemia in subjects with the I164T mutation was independent of BMI. Recently, we have demonstrated that intimal thickening was accelerated in mechanically injured arteries of adiponectin knockout mice, and that adenovirus-mediated supplement of adiponectin completely abolished the enhanced neointimal formation (15). These results suggest that hypoadiponectinemia directly contributes to abnormal vascular remodeling. Therefore, the I164T mutation plays a pivotal role in the development of atherosclerosis.

We have reported that the plasma adiponectin levels were significantly low in subjects with obesity (27), diabetes mellitus (31), and hypertension (32). In addition, we reported that plasma adiponectin level was predictive of the development of type 2 diabetes in the Pima Indian population (33). These observations suggest that the plasma adiponectin levels might be closely associated with the development of the metabolic syndrome. In adiponectin knockout mice, glucose metabolism was normal under standard diet, and severe insulin resistance, hyperglycemia, and hypertension were developed after two weeks' feeding of atherogenic diet (18,34). In the present study, all subjects carrying I164T had at least one or more coronary risk factors. However, HOMA-IR levels of nondiabetic I164T mutation were no different than those of control subjects. These results suggest that the hypoadiponectinemia caused by I164T mutation might lead to diabetes mellitus, hypertension, and atherosclerosis only under overnutrition in the modern industrialized countries.

A recent study demonstrated that the I164T mutation was not found in the type 2 diabetic and obese French Caucasian subjects and that the genotypes of SNP94 and SNP276 affected plasma adiponectin levels (23). Higher plasma adiponectin levels were associated with the T allele of SNP94 and the G allele of SNP276 in Caucasians (23). We and others demonstrated that the I164T mutation was observed in the Japanese population (19,21). In the present study, the G allele of SNP94 tended to be associated with lower plasma adiponectin levels, and SNP276 did not correlate with plasma adiponectin levels in CAD and non-CAD Japanese subjects whose mean BMI were approximately 24 kg/m2. Recently, the genotypes of SNP276 were reported to be associated with plasma adiponectin levels only in the obese subgroup of Japanese subjects (21). These differences between the French and Japanese populations may be due to ethnic background, although a larger population study is required to elucidate the discrepancy.

In the current study, three of the 14 subjects with the I164T mutation did not suffer from CAD, although they had at least one coronary risk factor and markedly low plasma adiponectin level. The follow-up study will be necessary to clarify whether the non-CAD subjects with I164T mutation develop CAD in the future.

In summary, we demonstrated that the I164T mutation of adiponectin gene affects CAD prevalence and the clustering of multiple risk factors for atherosclerosis. Our results indicate that screening the common genetic background of hypoadiponectinemia is helpful in evaluating the risk of the metabolic syndrome and CAD.


   Acknowledgments
 
The authors gratefully acknowledge the technical assistance of Sachiyo Tanaka, Atsuko Ohya, and Chiaki Ikegami.


   Footnotes
 
Supported by grants from the Japanese Ministry of Education, the Japan Society for Promotion of Science-Research for the Future Program, the Takeda Medical Research Foundation, and the Fuji Foundation for Protein Research. Drs. Ohashi and Ouchi contributed equally to this work.


   References
Top
 Abstract
 Methods
 Results
 Discussion
 References
 

  1. Milewicz DM, Seidman CE. Genetics of cardiovascular disease. Circulation. 2000;102:103–111
  2. Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372:425–432[CrossRef][Medline]
  3. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: Direct role in obesity-linked insulin resistance. Science. 1993;259:87–91[Abstract/Free Full Text]
  4. Shimomura I, Funahashi T, Takahashi M, et al. Enhanced expression of PAI-1 in visceral fat: Possible contributor to vascular disease in obesity. Nat Med. 1996;2:800–803[CrossRef][Medline]
  5. Wallace AM, McMahon AD, Packard CJ, et al. Plasma leptin and the risk of cardiovascular disease in the west of Scotland coronary prevention study (WOSCOPS). Circulation. 2001;104:3052–3056[Abstract/Free Full Text]
  6. Ridker PM, Rifai N, Pfeffer M, et al. Elevation of tumor necrosis factor-alpha and increased risk of recurrent coronary events after myocardial infarction. Circulation. 2000;101:2149–2153[Abstract/Free Full Text]
  7. Maeda K, Okubo K, Shimomura I, et al. cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1). Biochem Biophys Res Commun. 1996;221:286–289[CrossRef][Medline]
  8. Scherer PE, Williams S, Fogliano M, et al. A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem. 1995;270:26746–26749[Abstract/Free Full Text]
  9. Hu E, Liang P, Spiegelman BM. AdipoQ is a novel adipose-specific gene dysregulated in obesity. J Biol Chem. 1996;271:10697–10703[Abstract/Free Full Text]
  10. Ouchi N, Kihara S, Arita Y, et al. Novel modulator for endothelial adhesion molecules; adipocyte-derived plasma protein adiponectin. Circulation. 1999;100:2473–2476[Abstract/Free Full Text]
  11. Zoccali C, Mallamaci F, Tripepi G, et al. Adiponectin, metabolic risk factors, and cardiovascular events among patients with end-stage renal disease. J Am Soc Nephrol. 2002;13:134–141[Abstract/Free Full Text]
  12. Okamoto Y, Arita Y, Nishida M, et al. An adipocyte-derived plasma protein, adiponectin, adheres to injured vascular walls. Horm Metab Res. 2000;32:47–50[Medline]
  13. Arita Y, Kihara S, Ouchi N, et al. Adipocyte-derived plasma protein adiponectin acts as a platelet-derived growth factor-BB-binding protein and regulates growth factor-induced common postreceptor signal in vascular smooth muscle cell. Circulation. 2002;105:2893–2898[Abstract/Free Full Text]
  14. Yokota T, Oritani K, Takahashi I, et al. Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood. 2000;96:1723–1732[Abstract/Free Full Text]
  15. Matsuda M, Shimomura I, Sata M, et al. Role of adiponectin in preventing vascular stenosis—the missing link of adipo-vascular axis. J Biol Chem. 2002;277:37487–37491[Abstract/Free Full Text]
  16. Yamauchi T, Kamon J, Waki H, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 2001;7:941–946[CrossRef][Medline]
  17. Berg AH, Combs TP, Du X, et al. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med. 2001;7:947–953[CrossRef][Medline]
  18. Maeda N, Shimomura I, Kishida K, et al. Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med. 2002;8:731–737[CrossRef][Medline]
  19. Kondo H, Shimomura I, Matsukawa Y, et al. Association of adiponectin mutation with type 2 diabetes: A candidate gene for the insulin resistance syndrome. Diabetes. 2002;51:2325–2328[Abstract/Free Full Text]
  20. Takahashi M, Arita Y, Yamagata K, et al. Genomic structure and mutations in adipose-specific gene, adiponectin. Int J Obes Relat Metab Disord. 2000;24:861–868[CrossRef][Medline]
  21. Hara K, Boutin P, Mori Y, et al. Genetic variation in the gene encoding adiponectin is associated with an increased risk of type 2 diabetes in the Japanese population. Diabetes. 2002;51:536–540[Abstract/Free Full Text]
  22. Stumvoll M, Tschritter O, Fritsche A, et al. Association of the T-G polymorphism in adiponectin (exon 2) with obesity and insulin sensitivity: Interaction with family history of type 2 diabetes. Diabetes. 2002;51:37–41[Abstract/Free Full Text]
  23. Vasseur F, Helbecque N, Dina C, et al. Single-nucleotide polymorphism haplotypes in the both proximal promoter and exon 3 of the APM1 gene modulate adipocyte-secreted adiponectin hormone levels and contribute to the genetic risk for type 2 diabetes in French Caucasians. Hum Mol Genetics. 2002;11:2607–2614[Abstract/Free Full Text]
  24. Menzaghi C, Ercolino T, Paola R, et al. A haplotype at the adiponectin locus is associated with obesity and other features of the insulin resistance syndrome. Diabetes. 2002;51:2306–2312[Abstract/Free Full Text]
  25. Kissebah AH, Sonnenberg GE, Myklebust J, et al. Quantitative trait loci on chromosomes 3 and 17 influence phenotypes of the metabolic syndrome. Proc Natl Acad Sci USA. 2000;97:14478–14483[Abstract/Free Full Text]
  26. Francke S, Manraj M, Lacquemant C, et al. A genome-wide scan for coronary heart disease suggests in Indo-Mauritians a susceptibility locus on chromosome 16p13 and replicates linkage with the metabolic syndrome on 3q27. Hum Mol Genetics. 2001;10:2751–2765[Abstract/Free Full Text]
  27. Arita Y, Kihara S, Ouchi N, et al. Paradoxical decrease of an adipose specific protein, adiponectin, in obesity. Biochem Biophys Res Commun. 1999;257:79–83[CrossRef][Medline]
  28. Matthews DR, Rudenski AS, Naylor BA, et al. Homeostasis model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412–419[CrossRef][Medline]
  29. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997;20:1183–1197[Medline]
  30. Ishikawa K, Baba S, Katsuya T, et al. T+31C polymorphism of angiotensinogen gene and essential hypertension. Hypertension. 2001;37:281–285[Abstract/Free Full Text]
  31. Hotta K, Funahashi T, Arita Y, et al. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol. 2000;20:1595–1599[Abstract/Free Full Text]
  32. Adamczak M, Wiecek A, Funahashi T, et al. Decreased plasma adiponectin concentration in patients with essential hypertension. Am J Hypertens. 2003;16:72–75[CrossRef][Medline]
  33. Lindsay RS, Funahashi T, Hanson RL, et al. Adiponectin and development of type 2 diabetes in the Pima Indian population. Lancet. 2002;360:57–58[CrossRef][Medline]
  34. Ouchi N, Ohishi M, Kihara S, et al. Association of hypoadiponectinemia with impaired vasoreactivity. Hypertension. 2003;42:231–234[Abstract/Free Full Text]



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Am J Physiol Heart Circ Physiol, April 1, 2007; 292(4): H1655 - H1663.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
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A Big Fat Wedding: Association of Adiponectin With Coronary Vascular Lesions
J. Am. Coll. Cardiol., September 19, 2006; 48(6): 1163 - 1165.
[Full Text] [PDF]

Home page
 DiabetesHome page
X. Guo, M. F. Saad, C. D. Langefeld, A. H. Williams, J. Cui, K. D. Taylor, J. M. Norris, S. Jinagouda, C. H. Darwin, B. D. Mitchell, et al.
Genome-Wide Linkage of Plasma Adiponectin Reveals a Major Locus on Chromosome 3q Distinct From the Adiponectin Structural Gene: The IRAS Family Study
Diabetes, June 1, 2006; 55(6): 1723 - 1730.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
K. Ohashi, S. Kihara, N. Ouchi, M. Kumada, K. Fujita, A. Hiuge, T. Hibuse, M. Ryo, H. Nishizawa, N. Maeda, et al.
Adiponectin Replenishment Ameliorates Obesity-Related Hypertension
Hypertension, June 1, 2006; 47(6): 1108 - 1116.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
I. M. Heid, S. A. Wagner, H. Gohlke, B. Iglseder, J. C. Mueller, P. Cip, G. Ladurner, R. Reiter, A. Stadlmayr, V. Mackevics, et al.
Genetic Architecture of the APM1 Gene and Its Influence on Adiponectin Plasma Levels and Parameters of the Metabolic Syndrome in 1,727 Healthy Caucasians
Diabetes, February 1, 2006; 55(2): 375 - 384.
[Abstract] [Full Text] [PDF]

Home page
 StrokeHome page
S. P. Efstathiou, D. I. Tsioulos, A. G. Tsiakou, Y. E. Gratsias, A. V. Pefanis, and T. D. Mountokalakis
Plasma Adiponectin Levels and Five-Year Survival After First-Ever Ischemic Stroke
Stroke, September 1, 2005; 36(9): 1915 - 1919.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
M. O. Goodarzi, K. D. Taylor, X. Guo, M. J. Quinones, J. Cui, Y. Li, M. F. Saad, H. Yang, W. A. Hsueh, H. N. Hodis, et al.
Association of the Diabetes Gene Calpain-10 With Subclinical Atherosclerosis: The Mexican-American Coronary Artery Disease Study
Diabetes, April 1, 2005; 54(4): 1228 - 1232.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Chem.Home page
D. C. Chan, G. F. Watts, T. W.K. Ng, Y. Uchida, N. Sakai, S. Yamashita, and P. H. R. Barrett
Adiponectin and other Adipocytokines as Predictors of Markers of Triglyceride-Rich Lipoprotein Metabolism
Clin. Chem., March 1, 2005; 51(3): 578 - 585.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
A. N. DeMaria, O. Ben-Yehuda, D. Berman, G. K. Feld, B. H. Greenberg, J. D. Knoke, K. U. Knowlton, W. Y.W. Lew, J. Narula, D. Sahn, et al.
Highlights of the year in JACC 2004
J. Am. Coll. Cardiol., January 4, 2005; 45(1): 137 - 153.
[Full Text] [PDF]

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