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Spread Forex H K Oral Sex De 1 Ghrelin receptor gene polymorphisms are associated with female metabolic syndrome in Chinese population

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The ghrelin receptor, also named growth hormone secretagogue receptor (GHSR), is a G protein- coupled receptor that stimulates production of growth hormone.¹ GHSR is mainly expressed in the pituitary and hypothalamus, and also found in some peripheral tissues such as adipocyte, pancreatic islet and mononuclear cell. It has potent effects on several aspects of energy homeostasis, including its stimulation of food intake, carbohydrate utilization, and reducing the lipid metabolism.² Ghrelin, the endogenous ligand for GHSR, is generated predominantly in the stomach.³ Ghrelin levels are increased greatly in response to a fast decrease after meal. Chronic ghrelin administration causes weight gain.⁴ Ghrelin stimulates food intake through the activation of the orexigenic neuropeptide Y/agouti-related protein (NPY/AgRP) neurons in the arcuate nucleus of the hypothalamus (ARH).⁵ Ghrelin, released from pancreatic islets, is a physiological regulator of glucose-induced insulin release, antagonist of the ghrelin function has been proved to enhance insulin release in meeting the increased demand for insulin in high-fat diet-induced obesity and thereby normalize glycemic control.⁶ It was also shown that serum ghrelin levels are much lower in obesity and in type 2 diabetes than in normal individual.⁷ These results demonstrate that GHSR system plays a significant role in regulating the process of obesity and type 2 diabetes that are important components of metabolic syndrome.⁸

Evidence from recent population studies shows that polymorphisms in GHSR gene increase the risk of obesity, myocardial hypertrophy or coronary heart disease. However, these results were only demonstrated in Caucasians population.^9-11 The objectives of our study were to investigate whether polymorphisms in GHSR are associated with metabolic syndrome in Chinese population.

Ethical approval
The Fuwai Hospital ethical committee and other relevant regulatory bodies in China approved the study, and all subjects provided their informed consent in writing to participate in the study.

Subjects
A total of 698 unrelated patients, including 232 men (mean age 57.57±8.35 years) and 466 women (mean age 57.48±7.45 years) diagnosed as metabolic syndrome using International Diabetes Federation (IDF) 2005 criteria¹² were recruited from two local hypertension clinic services in Xinyang County, Henan Province, China from March to May in 2005. A total of 762 age and gender matched controls were selected from the same region and during the same period as the patients were. All participants were of Chinese Han ethnic group and have not been treated with medicine for hypertension, diabetes and dyslipidemia. The patients with the following diseases were excluded: chronic lung diseases, cardiac insufficiency, renal inadequacy, valvular heart disease, chronic liver ailment and tumors. A standard questionnaire about demographic information and medical history were accomplished through in-person interview by trained research staff.

IDF definition of metabolic syndrome
Central obesity: waist circumference ≥90 cm for men, ≥80 cm for women, together with at least two of the following components: (1) triglycerides level: ≥1.7 mmol/L; (2) HDL-C: <1.29 mmol/L for women or <1.03 mmol/L for men; (3) hypertension: arterial blood pressure ≥130/85 mmHg; (4) fasting plasma glucose: ≥5.6 mmol/L or previously diagnosed type 2 diabetes.

Physical examination and laboratory test
Each participant was required not smoking, drinking alcohol or coffee and engaging heavy exercise for 2 hours before examination. Two blood pressures were recorded at 5-minute intervals according to JNC7.¹³ The average of two measurements was used for analysis. Body weight with light clothing and height were measured. Body mass index was calculated as weight in kilograms divided by height in meters squared. Waist circumference was measured at the midpoint between the bottom of rib cage and the top of lateral border of iliac crest during minimal respiration.

Blood samples were collected after a 12-hour overnight fast. Peripheral blood (10 ml) was collected into tubes containing trisodium citrate (final concentration in blood, 0.026 mol/L), and centrifuged at 3000 ×g for 10 minutes at room temperature, and plasma and “buffy-coat” were separated and stored in 1.5 ml EP tube at –70°C. Serum total cholesterol, HDL-C, triglycerides, glucose and potassium concentration were analyzed using an automatic analyzer (Hitachi 7060, Hitachi, Tokyo, Japan).

SNPs selection in GHSR gene
According to SNP database of National Center for Biotechnology Information (NCBI) (SNP/) and HapMap (cgi- perl/gbrowse/hapmap20_B35), only two SNPs (rs2922126 and rs572169) within the promoter met the criteria of minor allele frequency (MAF) >10% and resulted in the binding change of transcription factors. SNPs rs509035 in intron has been reported to be associated with obesity.⁹ Therefore, these three polymorphisms were selected for the investigation of their association with either metabolic syndrome or its components.

Genotype
Genomic DNA was extracted from “buffy-coat” as described previously.¹⁴ All three SNPs were genotyped by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) technique. PCR was carried out in 10 µl of reaction mixture containing 50 ng of genomic DNA (2 µl), 5 µl 2×Taq PCR Master MIX (TIANWEI-biotech com, Beijing, China), 1 µl (5 pmol/L) of each primer, 1 µl ddH₂O. The primers were designed using Oligo6.0 software. All assays were performed in duplicate. The length of PCR products and restriction fragments is list in Table 1.

Characteristics of the subjects
Demographic and clinical characteristics of all the subjects are shown in Table 2. Male patients were slightly older than male controls. The average age of female patients and controls were statistically equivalent. As expected, all five components of the metabolic syndrome were more prevalent in patients with metabolic syndrome than in controls. The prevalence of smoking status and alcohol consumption was higher in men with metabolic syndrome than those in the corresponding controls.

No significant difference was identified for the genotypes rs572169 between the patients and the controls. We further categorized the subjects by components of the metabolic syndrome and did not find any association between genotypes and these clinical components.

In the present study, we demonstrated that the SNP rs2922126 within GHSR was associated with obesity, high fast blood glucose and metabolic syndrome in women. The rs509030 A/A genotype variant contributed to a low level of high density lipoprotein in women. No association with metabolic syndrome was found in men. Our results are consistent with the previous study,⁹ which revealed that genotype variant rs 509030A/A was a risk factor for obesity in Caucasian population.

Two major etiological factors (insulin resistance and obesity) underlying the metabolic syndrome are influenced by gender^15,16 and the diagnostic criteria of metabolic syndrome for men and women are different, so we conducted our analyses separately by sex. GHSR was identified to have two transcripts, one encoding the full-length G-protein-coupled receptor (GHSR1a) and the other encoding a truncated receptor (GHSR1b). Only GHSR1a can be activated by ghrelin, and the function of GHSR1b remains unknown.¹⁷

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