Leptin Receptor Gln223Arg Polymorphism Research Articles

The Relationship of Leptin (+19) AG, Leptin (2548) GA, and Leptin Receptor Gln223Arg Gene Polymorphisms with Obesity and Metabolic Syndrome in Obese Children and Adolescents.

PurposeObesity is defined as the abnormal or excessive accumulation of fat over acceptable limits. Leptin is a metabolic hormone present in the circulation in amounts proportional to fat mass. Leptin reduces food intake and increases energy expenditure, thus regulating body weight and homeostasis. Various polymorphisms are present in the leptin gene and its receptor. These polymorphisms may be associated with obesity. This study aimed to show the association of leptin (+19) AG, leptin (2548) GA, and Gln223Arg leptin receptor polymorphisms with obesity and metabolic syndrome in Turkish children aged 6–17 years, and to conduct further investigations regarding the genetic etiology of obesity.MethodsA total of 174 patients diagnosed with obesity and 150 healthy children who were treated at Tokat Gaziosmanpaşa Medical School Hospital between September 2014 and March 2015 were included in this study. The ages of the children were between 6 and 17 years, and anthropometric and laboratory results were recorded. Genotyping of leptin (+19) AG, leptin (2548) GA, and leptin receptor Gln223Arg polymorphisms was performed by polymerase chain reaction.ResultsAn association between leptin receptor Gln223Arg gene polymorphism and obesity was detected.ConclusionFurther studies are needed to determine the role of genetic etiologies and to indicate the role of leptin signal transmission impairment in the pathogenesis of obesity. We hope that gene therapy can soon provide a solution for obesity.

Association of LEPRGln223ArgPolymorphism with Obstructive Sleep Apnea Syndrome: A Meta-Analysis.

Previous studies examining the association of leptin receptor (LEPR) Gln223Arg polymorphism with obstructive sleep apnea-hypopnea syndrome (OSAHS) risk have yielded controversial outcomes. We aimed to clarify whether LEPR Gln223Arg polymorphism was critically involved in the development of OSAHS. We thoroughly searched PubMed as well as CNKI datasets for collection of relevant studies, followed by analysis of odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Of the seven case-control studies we enrolled, there was insignificant correlation ofthe LEPR Gln223Arg polymorphism with OSAHSrisk. However, subgroup analysis by Newcastle-Ottawa scale (NOS) scores revealed that, LEPR Gln223Arg polymorphism was significantly related to OSAHS risk in high-quality studies. In addition, we found no publication bias. Our findings suggest that LEPR Gln223Arg polymorphism might contribute to the risk of OSAHS. Well-designed studies with more subjects are needed for further validation of these results.

Relationships between plasma leptin levels, leptin receptor Gln223Arg polymorphism and insulin resistance in Kyrgyz native subjects

Relationships between plasma leptin levels, leptin receptor Gln223Arg polymorphism and insulin resistance in Kyrgyz native subjects

Gln223Arg polymorphism in the Caucasian population and Pro1019Pro polymorphism in the Chinese population are risk factors for OSAS: An updated meta-analysis of 1159 subjects

BackgroundWe conducted a meta-analysis of published literature to identify the correlation between leptin receptor gene polymorphisms and the risk of obstructive sleep apnea syndrome (OSAS). MethodsFive different single nucleotide polymorphisms (SNPs) were studied. Only Gln223Arg and Pro1019Pro had multiple studies. Nine studies focused on the correlation between Gln223Arg and Pro1019Pro polymorphisms and OSAS risk. Fixed-effects model or random-effects model was used to calculate the pooled odds ratio (ORs) and its corresponding 95% confidence interval (95% CI). The Begg's, Egger's, Perter's and Harbord tests were used to measure publication bias. Sensitivity analysis was also performed to ensure the robustness of the findings. ResultsSix studies on Gln223Arg polymorphisms (661 cases and 498 controls) and three studies on Pro1019Pro polymorphisms (561 cases and 561 controls) were extracted. There was no correlation between the leptin receptor Gln223Arg polymorphism and the risk of OSAS (odd ratio=0.86, 95% CI=0.68–1.10, P=0.23). However, Caucasian OSAS patients had a higher Arg allele frequency; whereas Chinese population with G genotype were more susceptible to OSAS (odd ratio=1.28, 95% CI=1.04–1.57, P=0.02) in the studies on Pro1019Pro polymorphisms. ConclusionThe Gln223Arg polymorphisms in the Caucasian population and the Pro1019Pro polymorphisms in the Chinese population are risk factors for OSAS.

Leptin and leptin-receptor polymorphisms in fertile and infertile men

ABSTRACTThe association of leptin (LEP) -2548G/A and/or leptin receptor (LEPR) Gln223Arg polymorphisms with male infertility and plasma FSH, LH, and testosterone (T) levels was examined. The genotypes and allele frequency distributions of LEP -2548G/A and LEPR Gln223Arg polymorphisms were investigated in 150 fertile and 150 infertile men by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Also, plasma levels of FSH, LH, and T were measured using commercial ELISA kits. Frequencies of AA, AG and GG genotypes of LEP-2548G/A polymorphism were statistically different in fertile and infertile men (p=0.012). The AG genotype showed a protective effect which could decrease risk of male infertility about 3 fold (p = 0.004). We did not observe any differences in frequencies of LEPR Gln223Arg alleles and genotypes between groups (p > 0.05). Sperm counts from infertile men with the AG and GG genotypes of the LEP polymorphism were significantly higher than AA genotype (p<0.05). Moreover, infertile men who carried the RR genotype of LEPR showed a statistically higher percentage of sperm with progressive motility than individuals with other genotypes (p = 0.004). There was no correlation between different combinations of LEP and LEPR genotypes and LH, FSH, and T levels (p > 0.05). Our study suggests that the LEP -2548G/A polymorphism may play a role in male fertility and the AG genotype may have a protective effect through increasing sperm counts. The distribution of genotypes of LEP -2548G/A polymorphism are different in fertile and infertile males and may be a useful tool in evaluation of male infertility.Abbreviations: LEP: leptin; LEPR: leptin receptor; T: testosterone; FSH: follicle-stimulating hormone; LH: luteinizing hormone

Relationships between plasma leptin levels, leptin G2548A, leptin receptor Gln223Arg polymorphisms and gestational diabetes mellitus in Chinese population.

The purposes of this study were to examine concentrations of leptin and biochemical parameters in gestational diabetes mellitus (GDM) patients and normal glucose tolerance (NGT) individuals, and also to explore the links of leptin (LEP) G2548A and leptin receptor (LEPR) Gln223Arg polymorphisms with leptin levels and GDM risk among Chinese. Our study included 357 GDM and 355 NGT individuals who were at 24~30 gestational weeks. Plasma leptin and insulin levels were analyzed by ELISA. Gene polymorphisms were genotyped using TaqMan real-time polymerase chain reaction assay. The results showed that plasma leptin levels were significantly higher in the impaired fasting glucose (IFG) group than NGT group (34.35 (26.54, 56.48) ng/mL vs 26.31 (17.99, 37.87) ng/mL, P < 0.05). Plasma leptin levels correlated with plasma fasting insulin levels, pre-pregnant body mass index, homeostasis model assessment-insulin resistance and quantitative insulin sensitivity check index both in GDM and NGT group (P < 0.05). However, neither LEP G2548A nor LEPR Gln223Arg polymorphisms were significantly associated with GDM risk and plasma leptin levels (P > 0.05). Our findings showed that high leptin level was associated with GDM. And larger and more rigorous researches were needed to further explore the association of LEP and LEPR gene polymorphisms and GDM among Chinese population.

Association of expressions and gene polymorphisms of leptin receptor with breast cancer

Objective To evaluate the association of expressions and gene polymorphism of leptin receptor (LEPR) in breast cancer with tumorigenesis, development and clinicopathologic factors. Methods The immunohistochemical method and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) were used to evaluate LEPR expressions and LEPR Gln223Arg polymorphism in 150 cases with breast cancer, 80 cases with benign breast lesions, 50 cases with corresponding normal breast tissue and 128 healthy controls. Results The expression rate of LEPR genes in breast cancer tissues was significantly higher than that in benign breast lesions and that in corresponding normal breast tissues [70.67 % (106/150) vs 56.25 % (45/80) vs 44.00 % (22/50), P 0.05). The frequencies of alleles genes in breast cancer patients (G and A) were 78.33 % (235 cases) and 21.67 % (65 cases), and the differences were statistically significant compared with those in the benign disease group or in healthy control group (χ2 = 12.52, P= 0.001). The positive expression rate of LEPR gene in patients with lymph node metastasis was 87.8 %, which was higher than that in patients with no lymph node metastasis (60.2 %) (P= 0.02). According to the results of multivariable analyses, high expression of LEPR gene, LEPR Gin223Arg gene polymorphisms and increased waist-hip ratio (WHR) were risk factors for breast cancer (all OR > 1). Conclusion High expression of LEPR, LEPR Gln233Arg polymorphism and the elevated WHR may be correlated with breast cancer. Key words: Breast neoplasms; Leptin receptor; Genes; Polymorphism, single nucleotide

Association of Leptin Receptor Gene Polymorphisms with Genetic Susceptibility to Ischemic Stroke

Ischemic stroke is a multifactorial disease that is influenced by both genetic and environmental factors. Identification of the genetic factors that are underlining this disease is important. Leptin receptor (LEPR) mediates the leptin-regulated human energy homeostasis, and mutations of LEPR can increase cardiovascular risks and may predispose an individual to ischemic stroke. We analyzed distribution of 3 single nucleotide polymorphisms (SNPs) of LEPR gene (Lys109Arg, Gln223Arg, and Lys656Asn) in 101 patients with ischemic stroke and 105 controls by polymerase chain reaction-restriction fragment length polymorphism strategy. Our results showed that there were significant differences in the genotype and allele distribution of Lys109Arg and Gln223Arg polymorphisms of the LEPR gene between case and control. The 109GG and 223GG genotype were associated with a significantly increased risk of ischemic stroke (odds ratio [OR], 3.23; P = .001 and OR, 2.87; P = .008, respectively). The 109G and 223G alleles carriers were correlated with an increased incidence of ischemic stroke (OR, 2.72; P = .001; OR, 2.94; P = .004). By haplotype analyses, we found that 109A/223G/656G haplotype was associated with an increased risk of ischemic stroke although this was not observed in the control group (OR, 3.86; P = .029). LEPR 109GG and 223GG genotypes and the 109G and 223G alleles are associated with the risk of ischemic stroke. Our data suggest that LEPR Lys109Arg and Gln223Arg polymorphisms could be used as genetic predictive factor for ischemic stroke.

Association of the leptin receptor Gln223 Arg polymorphism with lipid profile in obese Pakistani subjects

ObjectiveLeptin receptor gene (LEPR) encodes a receptor for leptin hormone expressed in hypothalamus and single nucleotide polymorphisms in LEPR may have a considerable effect on obesity phenotype. The aim of this study was to investigate an extensively studied LEPR polymorphism Gln223 Arg in a Pakistani study group and its association patterns with different serum biochemical parameters. MethodsThe study included 250 obese and 225 nonobese subjects. Gln223 Arg polymorphism was genotyped by polymerase chain reaction restriction fragment-length polymorphism. Anthropometric parameters and plasma glucose, total cholesterol, triacylglycerols, high density lipoprotein cholesterol, low density lipoprotein cholesterol, leptin, and insulin were measured. ResultsThe Gln223 Arg polymorphism was found to be significantly associated with body mass index, systolic and diastolic blood pressure, and weight only in obese subjects, and with all lipid parameters in both obese and nonobese subjects when Gln/Gln or Gln/Arg genotypes were compared with Arg/Arg genotype. ConclusionsThe LEPR Gln223 is associated with obesity, lipid parameters, and plasma glucose in all subjects, with weight, body mass index, and systolic and diastolic blood pressure only in obese subjects, but showed no association with leptin, insulin, and HOMA-IR in a Pakistani study group.

Leptin receptor expression and Gln223Arg polymorphism as prognostic markers in oral and oropharyngeal cancer

The leptin gene product is released into the blood stream, passes through the blood-brain barrier, and finds the leptin receptor (LEPR) in the central nervous system. This hormone regulates food intake, hematopoiesis, inflammation, immunity, differentiation, and cell proliferation. The LEPR Gln223Arg polymorphism has been reported to alter receptor function and expression, both of which have been related with prognostics in several tumor types. Furthermore, several studies have shown a relationship between the Gln223Arg polymorphism and tumor development, and its role in oral and oropharyngeal squamous cell carcinoma is now well understood. In this study, 315 DNA samples were used for LEPR Gln223Arg genotyping and 87 primary oral and oropharyngeal squamous cell carcinomas were used for immunohistochemical expression analysis, such that a relationship between these and tumor development and prognosis could be established. Homozygous LEPR Arg223 was found to be associated with a 2-fold reduction in oral and oropharyngeal cancer risk. In contrast, the presence of the Arg223 allele in tumors was associated with worse disease-free and disease-specific survival. Low LEPR expression was found to be an independent risk factor, increasing the risk for lymph node metastasis 4-fold. In conclusion, the Gln223Arg polymorphism and LEPR expression might be valuable markers for oral and oropharyngeal cancer, suggesting that LEPR might serve as a potential target for future therapies.

Role of leptin receptor gene polymorphisms in susceptibility to the development of essential hypertension: a case–control association study in a Northern Han Chinese population

In order to explore the potential association between the leptin receptor (LEPR) gene polymorphisms and essential hypertension (EH) risk in the Northern Han Chinese population, we recruited 823 hypertensive subjects and 491 healthy control subjects from the Northern Han Chinese. Genotyping was performed to identify the Lys109Arg, Gln223Arg and Lys656Asn polymorphisms of the LEPR gene. Significant associations were found in a dominant genetic model ([GG+AG] vs AA), P=0.007, odds ratio (OR)=3.697, 95% confidence interval (CI) 1.442–9.482), and in homozygote comparison (GG vs AA, P=0.005, OR=3.890, 95% CI 1.501–10.077) for the Gln223Arg polymorphism. No significant association could be found between Lys109Arg or Lys656Asn polymorphism and EH risk. Linkage disequilibrium was detected between the Lys109Arg and Gln223Arg polymorphisms, and haplotype analyses identified that the G-A haplotype was a protective haplotype for EH. Our studies demonstrated that the LEPR Gln223Arg polymorphism had an important role in a patient's susceptibility to EH in the Northern Han Chinese population.

Association of Gln223Arg Polymorphism of the Leptin Receptor with Hypertensive Left Ventricular Hypertrophy

This study was aimed to determine whether the leptin receptor Gln223Arg polymorphism has an effect on plasma leptin levels and left ventricular hypertrophy in hypertension. The genotypes and allelic frequencies of the leptin receptor Gln223Arg were examined using the polymerase chain reaction and restriction fragment length polymorphism in 190 hypertensive patients and 88 healthy controls. Logarithmic (log) transformation of the plasma leptin level was carried out before performing comparison and regression analysis. The values of log(plasma leptin levels) in the hypertensive patients were higher than those of controls and they were higher in hypertensive patients with left ventricular hypertrophy than those without it (P &lt; 0.05). The genotype (AA, AG, and GG) distribution of Gln223Arg polymorphism was 6.8, 33.8, and 59.4% in hypertensive patients with left ventricular hypertrophy, 4.3, 27.6, and 68.1% in patients without left ventricular hypertrophy, and 2.3, 26.1, and 71.6% in the controls, respectively. A significant difference was found among these three groups (P &lt; 0.05). The frequency of allele A was higher in patients with left ventricular hypertrophy than in patients without it (23.6 vs. 18.1%; P &lt; 0.05). Log(plasma leptin levels) and left ventricular mass index were higher in patients with the AA genotype than those with the AG or GG genotype in hypertensive patients (P &lt; 0.05). In multivariate regression analysis, the AA genotype as an independent predictor had statistically significant effects on the left ventricular mass index. Our results suggest that the Gln223Arg polymorphism of the leptin receptor is significantly associated with plasma leptin levels and left ventricular hypertrophy in hypertension.

Association of leptin receptor gene Gln223Arg polymorphism with susceptibility to colorectal cancer.

Leptin is a 16 kDa polypeptide hormone which secreted by adipose tissue and has an important role in energy balance, insulin pathway and inflammation, because of that it may play an important role in colorectal cancer (CRC). Leptin exerts its effect through the leptin receptor (LEPR) a member of the class I cytokine receptor family. We have investigated whether glutamine to arginine substitution (Gln223Arg) in exon 6 of the leptin receptor gene, has implications for susceptibility to CRC. Polymerase chain reaction (PCR) and restriction enzyme digestion (RFLP) was performed to evaluate the association between the Gln223Arg polymorphism of the LEPR and CRC risk in a case-control study in 346 subjects involving 173 cases with CRC and 173 controls. There was no statistically evidence of significant difference in genotype and allele frequencies between the cases with CRC and controls for the Gln223Arg polymorphism of LEPR, before or after adjusting for confounders (age, BMI, sex, and smoking status). Furthermore, no significant difference was observed between the CRC cases and controls by BMI, sex and smoking status. Our findings suggest that the LEPR Gln223Arg polymorphism is not associated with the risk of CRC in Iranian population.

LEPTIN A19G POLYMORPHISM AND LEPTIN RECEPTOR Gln223Arg AND Lys109Arg POLYMORPHISMSIN POSTMENOPAUSAL OSTEOPOROSIS

Objective: to study an association of leptin (LEP) A19G polymorphism and leptin receptor (LEPR) Gln223Arg AND Lys109Arg polymorphisms with the predilection for postmenopausal osteoporosis (OP). Subjects and methods. PCR analysis was used to examine the polymorphisms among 428 women (254 patients with OP and 174 healthy women). The anthropometric, densitometric, and biochemical markers of bone remodeling and standard clinical and biochemical parameters were studied. Results. Statistically significant differences were found in the distribution of the genotypes of LEP A19G polymorphism between the women with OP and the controls (χ2 = 9.41; p = 0.009). In the patients with OP, the 19GG genotype frequency was significantly higher than that in the controls [OR = 2.0; 95% confidence interval (CI) 1.13-3.52 (p = 0.011)]. LEP 19GG genotype carriers were found to have lower mineral bone density (MBD) of the femoral neck than heterozygotes (p = 0.06). In LEPR 223GlnArg heterozygotes, the mean MBD of the trochanter and whole hip was statistically significantly lower than that in patients with the genotype 223ArgArg (p = 0.013). 223GlnGln carriers were taller than 223GlnArg ones (p = 0.04). There were no associations of the clinical and biochemical parameters with the polymorphisms studied. Conclusion. Our study confirmed the role of LEP A19G and LEPR Gln223Arg polymorphisms as important candidate genes involved in the formation of a predilection for OP.

Genotype × nutrient association of common polymorphisms in obesity-related genes with food preferences and time structure of energy intake

Personal food preferences can either enhance or suppress the development of obesity and the selection and proportion of macronutrients in the diet seem to have a heritable component. In the present study, we therefore focused on dietary composition as a specific trait related to obesity and we determined whether genetic variations in leptin (LEP), LEP receptor (LEPR), adiponectin (ADIPOQ), IL-6 and pro-opiomelanocortin (POMC) underlie specific native food preferences and obesity-related anthropometric parameters. The total of 409 individuals of Czech Caucasian origin were enrolled into the present study and 7 d food records were obtained from the study subjects along with selected anthropometric measurements. In a subset of study subjects, plasma levels of ADIPOQ, LEP and soluble LEPR were measured. Independently of the BMI of the individuals, common variations in LEP and LEPR genes were associated with specific eating patterns, mainly with respect to timing of eating. The LEP + 19A/G polymorphism served as an independent predictor for BMI, percentage of body fat and skinfold thickness and significantly affected the time structure of the daily energy intake. The POMC RsaI polymorphism was associated with percentage of body fat. The ADIPOQ 45 T/G polymorphism was associated with the thickness of the subscapular skinfold. The LEPR Gln223Arg polymorphism was associated with multiple parameters, including diastolic blood pressure, meal sizes during the day and plasma ADIPOQ levels. In a separate analysis, soluble leptin receptor (sObR) plasma levels and LEP:sObR ratio were significantly correlated with systolic blood pressure (beta = - 0.66, P = 0.002; beta = - 1.23, P = 0.02) and sObR plasma levels also served as an independent predictor for diastolic blood pressure (beta = - 0.50; P = 0.04). To conclude, we report common allelic variants associated with specific feeding behaviour and obesity-related anthropometric traits. Moreover, we identified allelic variants that significantly influence the time structure of food intake during the day.

Association between variants in the genes for leptin, leptin receptor, and proopiomelanocortin with chronic heart failure in the Czech population

Patients with chronic heart failure (CHF) express enhanced catabolic metabolism finally resulting in overall weight loss, whereas adipokines might play a crucial role in signaling among tissues. The aim of this study was to investigate the possible associations of defined variability in leptin (dbSNP ID rs7799039), proopiomelanocortin (dbSNP ID rs3754860 and dbSNP ID rs1009388), and leptin receptor gene (dbSNP rs1137101) with CHF and evaluate their potential as the CHF susceptibility genes. The case-control study comprised a total of 372 patients of Caucasian origin with chronic heart failure (New York Heart Association [NYHA] functional classes II-IV, ejection fraction (EF) <40%) and 407 healthy controls. They were genotyped for the leptin (LEP) -2548 G/A, leptin receptor (LEPR) Gln223Arg, and proopiomelanocortin (POMC) RsaI (5'-untranslated region) and C1032G variants (intron 1) using PCR-based methodology. No case-control differences in genotype as well as allele frequencies were observed between CHF patients and controls. We constructed POMC RsaI/C1032G haplotypes, having found no significant association with body mass index (BMI), left ventricle ejection fraction (LVEF), left ventricle hypertrophy (LVH) and diabetes mellitus (DM). Multivariate regression analyses revealed an approximately 2-fold risk for NYHA class IV associated with the LEPR Gln223Arg (P = 0.0000001, odds ratio [OR] = 2.10, 95% confidence interval [CI] = 1.56-2.84); it also displayed an independent prediction role for LVEF in heart failure cases of all etiologies (P = 0.002, OR = 4.05, 95% CI = 1.36-10.06). In subanalyses according to CHF etiology the LEPR Gln223Arg showed an independent prediction role for NYHA IV in IHD patients (P = 0.0001, OR = 2.50, 95% CI = 1.69-3.82) and both for NYHA IV(P = 0.007, OR = 2.04, 95% CI = 1.20-3.84) and LVEF (P = 0.004, OR = 11.87, 95% CI = 2.08-55.6) in DCMP patients. The role of the polymorphic variants in the genes encoding for adipokines as potential CHF susceptibility genes is unclear. Based on our findings, the LEPR Gln223Arg polymorphism could be considered a disease susceptibility modulating factor both in ischemic heart disease or dilated cardiomyopathy patients.

Leptin receptor Gln223Arg polymorphism and breast cancer risk in Nigerian women: A case control study

BackgroundLeptin, a 16 kDa polypeptide hormone, implicated in various physiological processes, exerts its action through the leptin receptor, a member of the class I cytokine receptor family. Both leptin and leptin receptor have recently been implicated in processes leading to breast cancer initiation and progression in animal models and humans. An A to G transition mutation in codon 223 in exon 6 of the leptin receptor gene, resulting in glutamine to arginine substitution (Gln223Arg), lies within the first of two putative leptin-binding regions and may be associated with impaired signaling capacity of the leptin receptor. This study was designed to assess the role of this polymorphism in breast cancer susceptibility in Nigerian women.MethodsWe utilized a polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) assay to evaluate the association between the Gln223Arg polymorphism of the leptin receptor gene and breast risk in Nigeria in a case control study involving 209 women with breast cancer and 209 controls without the disease. Study participants were recruited from surgical outpatient clinics and surgical wards of four University Teaching Hospitals located in Midwestern and southeastern Nigeria between September 2002 and April 2004.ResultsPremenopausal women carrying at least one LEPR 223Arg allele were at a modestly increased risk of breast cancer after adjusting for confounders (OR = 1.8, 95% confidence interval [CI] 1.0–3.2, p = 0.07). There was no association with postmenopausal breast cancer risk (OR = 0.9, 95% CI 0.4–1.8, p = 0.68).ConclusionOur results suggest that the LEPR Gln223Arg polymorphism in the extracellular domain of the LEPR receptor gene is associated with a modestly increased risk of premenopausal breast cancer in Nigerian women.