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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 10 5110-5115
Copyright © 2004 by The Endocrine Society

Lack of an Association between Peroxisome Proliferator-Activated Receptor-{gamma} Gene Pro12Ala Polymorphism and Adiponectin Levels in the Polycystic Ovary Syndrome

Francesco Orio, Jr., Stefano Palomba, Teresa Cascella, Sebastiano Di Biase, Donato Labella, Tiziana Russo, Silvia Savastano, Fulvio Zullo, Annamaria Colao, Roberto Vettor and Gaetano Lombardi

Department of Molecular and Clinical Endocrinology and Oncology (F.O., T.C., A.C., G.L.), University "Federico II," 80131 Naples, Italy; Chair of Obstetrics and Gynecology (S.P., T.R., F.Z.), University of Catanzaro "Magna Graecia," 88100 Catanza, Italy; MeriGen Laboratory of Molecular Biology (S.D.B., D.L.), 80131 Naples, Italy; and Internal Medicine, Department of Medical and Surgical Sciences (R.V.), University of Padova, 35128 Padova, Italy

Address all correspondence and requests for reprints to: Francesco Orio, M.D., Department of Molecular and Clinical Endocrinology and Oncology, University "Federico II" of Naples, Via G. Santoro n.14-84100 Salerno, Italy. E-mail: francescoorio{at}virgilio.it.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Polycystic ovary syndrome (PCOS) is one of the most common endocrine metabolic diseases and is characterized by obesity in approximately 50% of those affected. Adiponectin is an adipocyte-derived protein that possesses an antiatherosclerotic action and improves insulin sensitivity. Peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}) regulates the transcription of several adipocyte-specific genes. The aim of this study was to investigate the putative influence of the PPAR-{gamma} gene Pro12Ala polymorphism on the adiponectin levels in PCOS and healthy women.

One hundred twenty women with PCOS and 120 healthy women whose ages and body mass indexes matched those of the PCOS patients were investigated. The genetic analysis of PPAR-{gamma} gene Pro12Ala polymorphism was performed by restriction fragment of polymorphisms. Serum adiponectin levels were evaluated, and the homeostasis model assessment score was also calculated. No subject was homozygous for the Ala12 allele of the PPAR-{gamma} gene. No significant differences in body mass index, plasma glucose and lipid levels, and homeostasis model assessment scores were observed between and within genotype groups in PCOS and control women. No significant differences in serum adiponectin concentrations were observed between and within genotype groups in PCOS and control women.

In conclusion, our results confirm that adiponectin concentrations are similar in PCOS and controls and demonstrate no effect of the PPAR-{gamma} gene Pro12Ala polymorphism on serum adiponectin levels.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
POLYCYSTIC OVARY SYNDROME (PCOS) is one of the most common endocrine metabolic diseases, affecting up to 10% of fertile women (1, 2). Obesity is present in approximately 50% of women with PCOS, and obesity renders the clinical aspect of this metabolic syndrome more serious (1, 3).

Adiponectin, a 244-amino-acid protein with high structural homology to collagen VIII, X, complement C1q, and TNF{alpha} (4, 5), is a plasma protein secreted specifically by adipose tissue and is increased by peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}) agonists (6, 7). PPAR-{gamma} is mainly expressed in adipocytes and regulates the transcription of many adipocyte-specific genes. Moreover, a Pro12Ala substitution has been detected in the exon 2 of PPAR-{gamma} gene (8).

Despite the fact that adiponectin is secreted only from adipose tissue, its plasma levels in obese subjects are, paradoxically, lower than in nonobese subjects (9). Thus, reductions of body weight increase adiponectin concentrations (10), suggesting that adiponectin expression is probably down-regulated by adipose tissue (11). In addition, serum adiponectin concentrations correlate inversely with the severity of insulin resistance (12, 13, 14) and with plasma low-density lipoprotein cholesterol (LDL-c) and triglyceride (Tg) levels (11, 15, 16).

Although the physiological role of this protein has yet to be clarified, we have recently demonstrated that PCOS subjects have serum adiponectin levels not significantly different in comparison with those of healthy women (17) and that exon 2 PPAR-{gamma} gene Pro12Ala polymorphism does not seem to affect obesity in PCOS (18). Furthermore, an association of this polymorphism with body mass index (BMI) (19, 20, 21), insulin sensitivity (22, 23), and diabetes mellitus (24, 25) has been reported.

Some authors (6, 26) found a marked increase in plasma adiponectin values in subjects treated with synthetic PPAR-{gamma} ligands, thiazolidinediones. It was reported that Pro12Ala polymorphism of PPAR-{gamma} was associated with a reduced transactivation activity (19), at lower adiponectin levels in the Japanese population of both sexes (27) and at normal values of adiponectin in the healthy general Caucasian population (28).

At present, no data are available on the relationships between the PPAR-{gamma} gene Pro12Ala polymorphism and adiponectin levels in women with PCOS. Given this lack of data, the aim of the present study was to investigate the effects of the PPAR-{gamma} gene Pro12Ala polymorphism on a metabolic parameter, such as serum adiponectin levels, in PCOS subjects.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

One hundred twenty overweight and obese women with PCOS and 120 healthy, young volunteer females, matched for age and BMI, were enrolled in this case-control study protocol. All the subjects were divided according to BMI as normal weight (BMI between 20 and 25 kg/m2); a BMI between 25 and 30 kg/m2 was considered as index of overweight, whereas a BMI greater than 30 kg/m2 was considered as the index of obesity (29).

The PCOS diagnosis was performed as previously described (18). All patients fulfilled the National Institute of Child Health and Human Development criteria for PCOS (30).

The state of the health of the controls was verified by medical history, physical and pelvic examination, and blood chemistry tests. Their normal ovulatory state was confirmed by transvaginal ultrasonography and plasma progesterone (P) levels during the luteal phase of the cycle. Women with clinical and/or biochemical hyperandrogenism were excluded from the control group. The controls were not genetically related to the PCOS group.

Exclusion criteria for both groups were pregnancy, hypothyroidism, hyperprolactinemia Cushing’s syndrome, nonclassical congenital adrenal hyperplasia, current or previous (within the last 6 months) use of oral contraceptives, glucocorticoids, antiandrogens, ovulation induction agents, antidiabetic and antiobesity drugs, and other hormonal drugs. Subjects with glucose intolerance, as evaluated according to World Health Organization criteria (31) with the oral glucose tolerance test, were excluded from the study. No patient had diabetes or renal, neoplastic, metabolic, hepatic, cardiovascular, or malabsorptive disorders. All subjects were nonsmokers, had a normal physical activity, and none drank alcoholic beverages.

Study protocol

The procedures used in this study were in accordance with the guidelines of the Helsinki Declaration on human experimentation. The Institutional Review Board of the University of Naples "Federico II" approved the study. The purpose of the protocol was explained both to patients and to the control women, and written consent was obtained from them before beginning the study.

At study entry, venous blood sample was taken from both groups for genetic study and for hormonal, lipid profile, glucose, and insulin assays. Blood samples were obtained between 0800 and 0900 h after an overnight fast with the individual resting in bed, during the early follicular phase (d 2–5) of the spontaneous or P-induced menstrual cycle. During the same visit, subjects underwent transvaginal ultrasonography, anthropometric measurements including BMI (kilograms per meter squared) and waist-to-hip ratio (WHR), measurement of systolic and diastolic blood pressure, adiponectin measurements, echocardiographic assessment, and echocolor-Doppler with evaluation of intima-media thickness.

Biochemical and hormonal analysis

Plasma LH, FSH, 17ß-estradiol, P, 17OH-progesterone (17OH-P), testosterone (T), androstenedione (A), dehydroepiandrosterone sulfate (DHEA-S), prolactin, SHBG, glucose, insulin, and adiponectin levels were evaluated in each subject in duplicate.

LH, FSH, 17ß-estradiol, P, T, A, DHEA-S, 17OH-P, and prolactin were measured by specific RIA as previously described (32, 33, 34). SHBG was measured using an immunoradiometric assay (32). Blood glucose levels were determined by the glucose oxidase method, and serum insulin was measured by a solid-phase chemiluminescent enzyme immunoassay (32). The serum total cholesterol (Tc), high-density lipoprotein cholesterol (HDL-c), LDL-c, and Tg levels were measured with an autoanalyzer (Monarch 1000; Instrumentation Laboratory, Milan, Italy) using commercial kits (IL TEST; Instrumentation Laboratory) (35). Adiponectin was measured in serum using a commercially available RIA kit (Linco Research, Inc., St. Charles, MO) in which 125I-labeled murine adiponectin and a multispecies adiponectin rabbit antiserum were used to determine the level of adiponectin in serum by the double-antibody/polyethylene glycol. Adiponectin standards were prepared using recombinant human adiponectin with a sensitivity of 1 ng/ml and intraassay and interassay coefficients of variation of 3.1 and 5%, respectively (17).

The ratio of T x 100/SHBG was used to calculate the free androgen index (FAI) (36). The estimate of insulin resistance by homeostasis model assessment (HOMA) score was also calculated in all subjects as described by Matthews et al. (37).

DNA analysis

Blood samples were collected in tubes containing disodium-EDTAate (EDTA) as anticoagulant and stored at 4 C until DNA extraction. DNA was extracted by the salt phenol chloroform method from the buffy coat cells (38). The extracted DNA was stored at –20 C until analysis. We used the restriction fragment of polymorphisms technique and PCR to examine the Pro12Ala polymorphism in exon 2 of the PPAR-{gamma} gene. Exon 2 of the PPAR-{gamma} gene was amplified by PCR using the primers G2F (5'-CTGATGTCTTGACTCATGGG-3') and G2R (5'-GGAAGACAAACTACAAGAGC-3'). The 295-bp PCR product was digested overnight with HgaI, which cleaves the G (Ala) allele so as to generate two DNA fragments of 178 and 117 bp, respectively (22). The DNA fragments and the PCR products were separated on 3% agarose gel electrophoresis and visualized under UV light after ethidium bromide staining. Genotypes were expressed in exon 2 as CC and CG for homozygous normal and heterozygous, respectively.

Statistical analysis

The clinical and biochemical data in PCOS and control group were analyzed using unpaired Student’s t test. Allelic and genotypic frequencies were determined from observed genotype counts, and the expectations of the Hardy-Weinberg equilibrium were evaluated by {chi}2 analysis. Differences in the genotype distribution between different groups were assessed by Fisher’s exact test. The data between the PPAR-{gamma} groups in PCOS and controls were compared by unpaired Student’s t test. Correlation analysis by Pearson and Spearman tests, when appropriate, was applied to analyze the relationships between adiponectin and patients’ hormonal and metabolic profile. The statistical analysis was performed by using the SPSS 12.0.1 package (SPSS, Inc., Chicago, IL). Data are presented as mean ± SD. Statistical significance was set at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Table 1Go shows anthropometric, biochemical, and endocrine data in PCOS and control women. As expected, LH, P, 17OH-P, T, A, DHEA-S, SHBG, insulin, HOMA, and FAI differ in PCOS compared with controls (Table 1Go). Serum Tc, Tg, HDL-c, and LDL-c concentrations resulted higher in PCOS than in controls (Table 1Go). No difference was observed in adiponectin levels between PCOS and controls even when they were stratified by BMI class (normal weight, overweight, obese) (Table 1Go).


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  		TABLE 1. Clinical, hormonal, and metabolic characteristics of women with PCOS and controls

 
Genotype frequencies were similar and conformed to the Hardy-Weinberg equilibrium. There were no homozygous subjects for the Ala12 allele of the PPAR-{gamma} gene.

In PCOS and controls, BMI, plasma glucose, serum insulin, lipids, HOMA score, and FAI were similar for women with or without the Pro12Ala polymorphism (Tables 2Go and 3Go). Serum adiponectin levels were also similar in women with or without the Pro12Ala polymorphism, in both the PCOS and the control groups (Tables 2Go and 3Go).


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  		TABLE 2. Relationships between the PPAR{gamma} Pro12Ala genotype and subject characteristics and metabolic variables in control women

 

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  		TABLE 3. Relationships between the PPAR{gamma} Pro12Ala genotype and subject characteristics and metabolic variables in PCOS women

 
In the PCOS and the control groups, serum adiponectin levels were significantly related to BMI (r = –0.51 and r = –0.45 in PCOS and controls, respectively) and to HOMA score (r = –0.39 and r = –0.35 in PCOS and controls, respectively). On the contrary, a significant (P < 0.05) relation was found between BMI and HOMA score in both the PCOS and the control groups (r = +0.51 and r = +0.61 for PCOS and control subjects, respectively). No significant correlation was found between adiponectin levels and the other clinical and biochemical variables.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Although PPAR-{gamma} gene Pro12Ala polymorphism has been reported to affect lipids (21, 39, 40), plasma glucose (41, 42), and insulin levels (22, 43), this is the first study to investigate the relationships between this polymorphism and serum adiponectin levels in PCOS patients.

No effect of the PPAR-{gamma} gene Pro12Ala polymorphism on serum adiponectin concentrations either in PCOS or in controls was detected in the present study, confirming the data showed by Thamer et al. (28). However, Yamamoto et al. (27), even if they did not find any homozygous subjects for the Ala12 allele of the exon 2 PPAR-{gamma} gene, reported reduced serum concentrations of the adiponectin in healthy Japanese carriers of the Pro12Ala polymorphism in the PPAR{gamma}2.

The discrepancy with the results of the Japanese group may be explained by the differences in genetic and ethnic background of the studied population. Environmental factors (e.g. food intake, fatty acid composition of the diet) or gene-environment/gene-nutrient interaction could be a putative explanation (44). In fact, in the Japanese population, the frequency of the Ala12 allele was much lower than that in Europeans (0.027 vs. 0.119, Japanese vs. European populations, respectively). It is possible that environmental factors may interact with the PPAR-{gamma} gene and/or the adiponectin gene, resulting in some difference in adiponectin levels that is not found in our PCOS population. In addition, it has been suggested that genetic variation in the PPAR-{gamma} gene, together with other genes, may influence the adiponectin serum level, which is considered to prevent atherosclerosis (27).

The present study, as in the previously described studies (27, 28), was not powered to detect difference in adiponectin levels between PCOS and healthy controls. Our data are experimental and not clinical. In fact, to perform a clinical trial with an adequate power (>80%), about 5,000 cases (PCOS women) would be required, and, considering the prevalence of PCOS in the South of Italy (~8–10%), we should have had screened at least 60,000 women.

Several studies on the relationship between Pro12Ala polymorphism and plasma lipids showed discrepant results (19, 24, 39, 40). In the present study, although all lipids were increased in PCOS compared with controls, we do not report any difference between women with or without the Ala12 allele either in PCOS or in controls.

As previously reported (21, 25, 39), no significant association was found between PPAR-{gamma} gene Pro12Ala polymorphism and fasting plasma glucose. There are conflicting data in the literature regarding the relationship between Pro12Ala polymorphism and fasting insulin levels. In fact, some studies (19, 22, 45), but not others (23, 25, 39, 46), have found a significant association between Pro12Ala polymorphism and fasting insulin concentrations. In the present study, no difference was observed between the PCOS and the control group in the HOMA index. Despite the fact that insulin levels were higher and insulin sensitivity, as assessed by HOMA, was increased in controls, serum adiponectin concentrations did not differ between the two groups. Therefore, the high degree of insulin resistance in women with PCOS (47) does not influence (is unlikely to modify) adiponectin levels, even though adiponectin levels have been widely recognized to be decreased in insulin resistance state (12). The link between adiponectin and insulin sensitivity was further enforced by the observation that this adipocytokine is able to stimulate glucose use (48) and to reduce the hepatic glucose production (49).

Although Hara et al. (22) showed an association between the Ala allele and increased insulin sensitivity only in Caucasian women with PCOS, we recently reported that exon 2 PPAR-{gamma} gene Pro12Ala polymorphism does not seem to affect obesity and insulin sensitivity in PCOS (18). Moreover, their two study populations were very different in terms of BMI (36.3 ± 0.8 vs. 30.3 ± 6.5). In fact, in our study (18), normal, overweight, and obese PCOS women were included, whereas Hara et al. (22) enrolled exclusively obese PCOS women.

Hyperinsulinemia causes a significant decrease of adiponectin plasma levels; therefore, hypoadiponectinemia might at least be partly a link between hyperinsulinemia and vascular disease in metabolic syndrome (50).

Furthermore, no difference in adiponectin levels was reported between PCOS patients and BMI-matched healthy women for adiponectin levels (17). Therefore, we hypothesize that some gene/environmental factors might interfere with the mechanism regulating adiponectin secretion in PCOS. In fact, Pro12Ala polymorphism might be considered as a protective factor in PCOS because, as is known, androgens decrease plasma adiponectin values. In addition, this last phenomenon is related to the high risks of insulin resistance (50) and atherosclerosis (51), but the presence of Ala12 allele could be responsible for normal values of adiponectin in PCOS, in contrast to the higher androgen and insulin levels that characterize this metabolic syndrome.

In conclusion, our results further confirm that in PCOS patients the adiponectin concentrations are similar to those observed in healthy women and demonstrate no association between exon 2 PPAR-{gamma} gene Pro12Ala polymorphism and serum adiponectin levels in women with and without PCOS.


   Acknowledgments
 
We thank Dr. Francesco Manguso (Department of Clinical and Experimental Medicine, Gastroenterology Unit, "Federico II" University, Naples, Italy) for his invaluable assistance in statistical support and Mr. Christian Siatka (Ecole de l’ADN, Nimes, France) for his great help in the analysis and the elaboration of the data.


   Footnotes
 
Abbreviations: A, Androstenedione; BMI, body mass index; DHEA-S, dehydroepiandrosterone sulfate; FAI, free androgen index; HDL-c, high-density lipoprotein cholesterol; HOMA, homeostasis model assessment; LDL-c, low-density lipoprotein cholesterol; 17OH-P, 17OH-progesterone; P, progesterone; PCOS, polycystic ovary syndrome; PPAR-{gamma}, peroxisome proliferator-activated receptor-{gamma}; T, testosterone; Tc, total cholesterol; WHR, waist-to-hip ratio.

Received January 22, 2004.

Accepted July 8, 2004.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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