A Comprehensive Study of the Association between LEPR Gene rs1137101 Variant and Risk of Digestive System Cancers.

Objective: The leptin receptor, encoded by the LEPR gene, is involved in tumorigenesis. A potential functional variant of LEPR, rs1137101 (Gln223Arg), has been extensively investigated for its contribution to the risk of digestive system (DS) cancers, but results remain conflicting rather than conclusive. Here, we performed a case-control study and subsequent meta-analysis to examine the association between rs1137101 and DS cancer risk. Methods: A total of 1,727 patients with cancer (gastric/liver/colorectal: 460/480/787) and 800 healthy controls were recruited. Genotyping of rs1137101 was conducted using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay and confirmed using Sanger sequencing. Twenty-four eligible studies were included in the meta-analysis. Results: After Bonferroni correction, the case-control study revealed that rs1137101 was significantly associated with the risk of liver cancer in the Hubei Chinese population. The meta-analysis suggested that rs1137101 is significantly associated with the risk of overall DS, gastric, and liver cancer in the Chinese population. Conclusion: The LEPR rs1137101 variant may be a genetic biomarker for susceptibility to DS cancers (especially liver and gastric cancer) in the Chinese population.

The Arg/Arg genotype of leptin receptor gene Gln223Arg polymorphism may be an independent risk factor for nonalcoholic fatty liver disease.

BACKGROUND: Given that obesity and insulin resistance play key roles in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and the connection between leptin and these metabolic diseases, the association between NAFLD and a leptin receptor gene (LEPR) polymorphism was examined. METHODS: In this genetic case-control association study, 144 biopsy-proven NAFLD patients and 144 controls were genotyped for the LEPR gene Gln223Arg (rs1137101) polymorphism using the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: The distributions of genotypes and alleles of Gln223Arg variant were in accordance with the Hardy-Weinberg equilibrium in the study groups (P > .05). Multivariate logistic regression analysis showed that the LEPR Gln223Arg Arg/Arg genotype was an independent risk factor for NAFLD; the Arg/Arg genotype, compared with the Gln/Gln genotype, was associated with a 2.09-fold increased risk for NAFLD (P = .036, odds ratio = 2.09 [95% CI = 1.31-5.95]). CONCLUSIONS: We found that the LEPR Gln223Arg Arg/Arg genotype was independently associated with a more than 2-fold rise in biopsy-proven NAFLD risk. Our findings, however, need to be corroborated by further studies.

Serum Leptin Receptor and the rs1137101 Variant of the LEPR Gene Are Associated with Bladder Cancer.

Globally, bladder cancer (BC) is one of the ten most common tumors. Obesity is a worldwide problem associated with an increased BC risk. Considering that levels of leptin and/or its receptor are often deregulated in obese individuals, we hypothesized that they could contribute to BC. To test this hypothesis, we utilized a case-control study in which 116 patients with a confirmed diagnosis of BC and 116 controls were recruited. The serum levels of leptin and leptin receptor were measured. Patients and controls were also genotyped for SNPs in the LEP (rs7799039, rs791620, and rs2167270) and LEPR genes (rs1137100, rs1137101, and rs1805094). The univariate analysis indicated that BC patients had significantly higher levels of leptin and lower levels of leptin receptor (p < 0.05). Moreover, rs7799039 of LEP and rs1137101 of LEPR were associated with BC (p < 0.05). In the multivariate analysis, leptin receptor levels were protective (OR: 0.98, 95% CI = 0.97-0.99, p = 0.002) while the GG genotype of rs1137101 of LEPR increased BC risk (OR: 3.42, 95% CI = 1.27-9.20, p = 0.02). These findings highlight that lifestyle changes could be useful in preventing BC and that disturbances in energy metabolism could play a role in the pathobiology of BC.

Association of rs1137101 with hypertension and type 2 diabetes mellitus of Mongolian and Han Chinese.

BACKGROUND: Hypertension (HTN) and type 2 diabetes mellitus (T2DM) are often coincident, and each condition is considered a risk factor for the other. Both occur frequently in the Inner Mongolia region of China. The reasons for differences in risk between Han and Mongolian ethnic groups are not known. The LEPR gene and its polymorphism, rs1137101 (Gln223Arg), are both considered risk factors for HTN and T2DM, but any role of rs1137101 in the occurrence of HTN + T2DM remains unclear for Mongolian and Han populations in the Inner Mongolia region. AIM: To investigate the relationship between rs1137101 and the occurrence of HTN with T2DM in Mongolian and Han populations in Inner Mongolia. METHODS: A total of 2652 subjects of Han and Mongolian ethnic origins were enrolled in the current study, including 908 healthy controls, 1061 HTN patients and 683 HTN patients with T2DM. RESULTS: The association between the rs1137101 polymorphism and HTN with T2DM was analyzed, and differences between Han and Mongolian individuals assessed. There was a significant correlation between rs1137101 and HTN (co-dominant, dominant, over-dominant and log-additive models) and HTN + T2DM (co-dominant, dominant, over-dominant and log-additive models) after adjustment for sex and age in individuals of Mongolian origin. rs1137101 was significantly associated with HTN (co-dominant, recessive and log-additive models) and HTN + T2DM (co-dominant, dominant, over-dominant and log-additive models) in the Han Chinese population. CONCLUSION: Mongolian and Han subjects from Inner Mongolia with HTN who had rs1137101 were protected against the development of T2DM. Allele A has the opposite impact on the occurrence of HTN in Mongolian and Han Chinese populations.

Association of Single Nucleotide Polymorphism LEP-R c.668A>G (p.Gln223Arg, rs1137101) of leptin receptor gene with endometrial cancer.

BACKGROUND: The aim of this study was to analyze the frequencies of genotypes and alleles of Single Nucleotide Polymorphism (SNP) LEP-R c.668A>G (p.Gln223Arg, rs1137101) of leptin receptor gene and to assess the influence this DNA marker has on endometrial cancer (EC) with respect to total body fat content. METHODS: The study comprised 120 patients treated for endometrial cancer and 90 controls treated for uterine fibroids. In total, 210 patients were included in this research. DNA was isolated from archival post-operative specimens. Polymerase Chain Reaction - Restriction Fragment Length Polymorphism was employed to analyze the SNP. RESULTS: In this paper we have demonstrated that heterozygous genotype AG of SNP LEP-R c.668A>G (p.Gln223Arg, rs1137101) is statistically less frequent in women with endometrial cancer (EC) than in controls: 33 versus 57%, respectively. Similarly, this heterozygous genotype is statistically significantly less frequent in obese (BMI > 30) women with EC than in lean controls (BMI < 25): 30 versus 63%, respectively. CONCLUSIONS: AG polymorphic variant of SNP LEP-R c.668A>G (p.Gln223Arg, rs1137101) in LEP-R may be considered a protective factor in the development of endometrial cancer.

The impact of CPT1B rs470117, LEPR rs1137101 and BDNF rs6265 polymorphisms on the risk of developing obesity in an Italian population.

OBJECTIVE: This study aimed to analyze 11 single nucleotide polymorphisms (SNPs) belonging to 9 genes involved in metabolic pathways (BDNF rs6265; PNPLA3 rs2294918 and rs2076212; CIDEA rs11545881; NTRK2 rs2289658; ALOX12 rs1126667; ALOX12B rs2304908; LEPR rs1137101; CPT1B rs470117 and rs8142477; rs2305507 CPT1A) in obese patients and controls. METHODS: Polymorphisms were analyzed in 300 severe obese patients undergoing bariatric surgery (body mass index >30 kg/m2) and 404 control subjects in order to evaluate their association with obesity and clinical variables. RESULTS: Our findings showed significant differences for the allelic distributions of CPT1B rs470117 and LEPR rs11371010 in obese subjects compared to controls. The BDNF rs6265 correlates with obesity only when associated with the other two SNPs. In particular, for CPT1B rs470117 and LEPR rs1137101, the rare allele was associated with a reduced risk of developing the obese phenotype, whereas the simultaneous presence of the common C allele for rs470117 and A allele for rs1137101 was more frequent in obese patients (p = 0.002, OR = 1.417). A significant association between CPT1B rs470117 and steatosis was found. Moreover, we observed that by associating the rare allele T of the BDNF rs6265 with the most common alleles of the SNPs CPT1B rs470117 and LEPR rs1137101, the combination of T-C-A alleles was associated with a higher risk of developing an obese phenotype (p = 0.001, OR = 1.6679). CONCLUSIONS: Our results suggest that SNPs CPT1B rs470117 and LEPR rs1137101 taken individually and in association with BDNF rs6265 may be involved in an increased risk of developing obese phenotype in an Italian cohort.

Association study of rs7799039, rs1137101 and rs8192678 gene variants with disease susceptibility/severity and corresponding LEP, LEPR and PGC1A gene expression in multiple sclerosis.

BACKGROUND: Leptin (LEP), leptin receptor (LEPR) and peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC1A) are involved in the pathogenesis of multiple sclerosis (MS) by affecting the inflammatory response and reactive oxygen species production. LEP rs7799039 and LEPR rs1137101 genetic variants modify the serum LEP levels and PGC1A rs8192678 alters the PGC1A activity. The study objective was to explore the associations of these variants with susceptibility to MS, disease course/clinical parameters and also with peripheral blood mononuclear cell expression of the target genes and plasma LEP concentrations, in the study subjects. METHODS: The study groups included 528 patients with MS and 429 controls. TaqMan® assays were used for genotyping and gene expression quantification. The Chi-square, parametric and nonparametric tests and simple/multiple logistic regression were performed for the statistical analysis of data. RESULTS: A multiple logistic regression model including all three investigated variants, applied to patients (RRMS + SPMS) and controls, showed that PGC1A rs8192678 minor allele had an increased risk for the occurrence of disease, with OR (95%CI) = 1,32 (1,01-1,73), P = 0,04. Between-effect of gender and LEPR variant on the multiple sclerosis severity score (MSSS) was identified (P = 0,005). In male patients (relapsing-remitting and secondary progressive), LEPR minor allele carriers had increased MSSS (GG + AG vs AA, median (minimum-maximum) = 5,38 (0,64-9,88) vs 4,27 (0,78-9,63); P = 0,01, Padj = 0,03). In relapsing-remitting patients LEP rs7799039 affected the LEP gene expression (P = 0,006; Padj = 0,04). CONCLUSION: The current findings implicate an impact of investigated genetic variants on the pathogenesis of MS.

Fat mass and obesity-associated (FTO) and leptin receptor (LEPR) gene polymorphisms in Egyptian obese subjects.

BACKGROUND: Several studies addressed the contribution of fat mass and obesity-associated (FTO) and leptin receptor (LEPR) polymorphisms for the susceptibility to obesity among different ethnic subjects. The main purpose of this work is to evaluate the association of these polymorph\isms with obesity among Egyptian subjects. SUBJECTS AND METHODS: This case-control study was carried out on 110 unrelated obese Egyptian subjects who were compared with 122 controls. Their genomic DNA was genotyped using the PCR technique. RESULTS: The allelic frequencies of FTO rs9939609 (A) and LEPR rs1137101 (223R) were significantly higher in obese subjects compared with non-obese controls (p < .001). Comparing different phenotype frequencies including clinical, anthropometric, and biochemical parameters in obese subjects revealed no significant difference in relation to their genotype frequencies (p> .05). CONCLUSIONS: This study designates a strong association for FTO and LEPR variants with the risk of obesity among Egyptian subjects.

Study of rs1137101 polymorphism of leptin receptor gene with serum levels of selenium and copper in the patients of non-ST-segment elevation myocardial infarction (NSTEMI) in an Iranian population.

OBJECTIVE: NSTEMI is a type of myocardial infarction (MI) causing partial but progressive occlusion of cardiac coronary vessels. The aim of this study was to investigate rs1137101 polymorphism of soluble leptin receptor (sLEPR) as well as circulatory selenium and copper levels in NSTEMI patients and their usefulness in analyzing susceptibility to NSTEMI. METHODS: We collected sera and whole blood of 80 NSTEMI patients and 80 healthy individuals using cTnI levels plus electrocardiography as the "gold standard". Polymorphism analysis was done after DNA extraction by high-resolution melt PCR, selenium and copper levels by atomic absorption spectrophotometry, and sLEPR by ELISA. RESULTS AND DISCUTION: There was Hardy-Weinberg (HWE) equilibrium for both patient and control loci (χ2 = 0.368434509 and 0.341447368, respectively). The frequencies of A/A, A/G, and G/G genotypes were 18 (22%), 37 (46%), and 25 (31%) for patients, and 30 (38%), 36 (45%), and 14 (18%) for healthy controls, respectively. The frequencies of A and G alleles were 73 (46%) and 87 (54%) for patients and 96 (60%) and 64 (40%) for control groups. There was correlation between allele G and sLEPR level and Body Mass Index (BMI). Selenium levels were lower in patient group than control group (66.307 ±â€¯11.013 against 87.488 ±â€¯11.839 µg/L; p < 0.001) but copper concentrations were higher (1.8105 ±â€¯0.358 against 1.366 ±â€¯0.454 mg/L; p < 0.001). sLEPR levels were also higher in patient than control group (30.568 ±â€¯3.290 against 23.740 ±â€¯5.457 ng/dL; p < .001). Low selenium and high copper concentration had positive diagnostic value for disease. CONCLUSION: We find for the first time that there is a significant association between rs1137101 polymorphism and susceptibility to NSTEMI. There is also statistically meaningful association between decrease in serum selenium and increase in serum copper levels with susceptibility to NSTEMI.

characterization of lepr gene Q223R (RS1137101) genotypes in patients with knee joint osteoarthritis of different radiographic stages.

OBJECTIVE: Introduction: Osteoarthritis is a multifactorial joint disease with a significant role of the genetic factor. The numerous studies have demonstrated that genetic dependence is specific for individual hand, hip and knee regions with a genetic contribution to the pathogenesis of osteoarthrosis varying from 40% to 65%. To assess the role of leptin gene receptor functional activity disturbance in the pathogenesis of osteoarthrosis, it is important to study the relationship between the LEPR gene polymorphism and a number of clinical and laboratory parameters. The study objective was to determine the relationship between the LEPR gene Q223R (rs1137101) polymorphism and the radiographic stage of osteoarthrosis of the knee in female patients of the Ukrainian population. PATIENTS AND METHODS: Materials and methods: The rs1137101 polymorphism was genotyped in 99 female patients diagnosed with osteoarthrosis of the knee using polymerase chain reaction in a real-time mode. RESULTS: Results: It was a tendency of lower prevalence of AA homozygotes and higher prevalence of AG heterozygotes with growing the severity of the disease. The high prevalence of homozygous carriers of the variant allele G in radiographic Stage I patients preconditioned the absence of statistically significant differences in the distribution of genotypes between the groups. CONCLUSION: Conclusion: No statistically significant differences in the distribution of prevalence of alleles and LEPR gene Q223R (rs1137101) genotypes in the groups of patients with the knee OA of different radiographic stages have been revealed.

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.

BACKGROUND: We 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). METHODS: Five 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. RESULTS: Six 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. CONCLUSION: The Gln223Arg polymorphisms in the Caucasian population and the Pro1019Pro polymorphisms in the Chinese population are risk factors for OSAS.