Leptin Receptor Polymorphisms Research Articles

Leptin receptor gene polymorphisms and morbid obesity in Mexican patients.

BackgroundHuman obesity is due to a complex interaction among environmental, behavioral, developmental and genetic factors, including the interaction of leptin (LEP) and leptin receptor (LEPR). Several LEPR mutations and polymorphisms have been described in patients with early onset severe obesity and hyperphagic eating behavior; however, some contradictory findings have also been reported. In the present study we explored the association of six LEPR gene polymorphisms in patients with morbid obesity.FindingsTwenty eight patients with morbid obesity and 56 non-obese Mexican Mestizo individuals were included. Typing of rs1137100, rs1137101, rs1805134, Ser492Thr, rs1805094 and rs1805096 LEPR polymorphisms was performed by PCR and allele specific hybridization. The LEPR Ser492Thr polymorphism was monomorphic with the presence of only the Ser492Thr-G allele. Allele C and genotype T/C for rs1805134 polymorphism were associated with susceptibility to morbid obesity (p = 0.02 and p = 0.03, respectively). No association was observed with any haplotype. Linkage disequilibrium (LD) showed that five polymorphisms (rs1137100, rs1137101, rs1805134, rs1805094 and rs1805096) were in absolute (D’ = 1) but none in perfect (r2 = 1) LD.ConclusionsOur results suggest that rs1805134 polymorphism could be involved in the development of morbid obesity, whilst none of the alleles of the LEPR gene, rs1137100, rs1137101, rs1805094 and rs1805096 were associated as risk factors. However, more studies are necessary to confirm or reject this hypothesis.

Hyperprolactinemia in Children and Adolescents with Use of Risperidone: Clinical and Molecular Genetics Aspects.

In children and adolescents treated with risperidone, hyperprolactinemia is a frequent complication that may have clinical repercussions. Several genes have been associated with this occurrence. The aim of this study was to evaluate the frequency of hyperprolactinemia in children and adolescents treated with risperidone, and its associations with clinical and pharmacological data and certain polymorphisms of the following genes: Dopamine receptor D2 (DRD2), 5-hydroxytryptamine (serotonin) receptor 2C (HTR2C), cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6), leptin (LEP), leptin receptor (LEPR), melanocortin 4 receptor (MC4R), and scavenger receptor class B, member 2 (SCARB2). The study included patients using risperidone (8-20 years old) and healthy subjects not exposed to the medication. Psychopathological symptoms, doses, and duration of treatment with risperidone, sex, skin color, body mass index (BMI), use of other psychotropic drugs, and polymorphisms of DRD2, HTR2C, CYP2D6, LEP, LEPR, MC4R, and SCARB2 genes were evaluated. There were 120 patients and 197 individuals not exposed to risperidone who were evaluated. Among patients, hyperprolactinemia was found in 79 (65.8%) cases, with no differences regarding sex, skin color, or being in monotherapy with risperidone (26.7% of total patients) or not. The level of prolactin was not correlated, either in case or control groups, with chronological age, bone age, prescribed dose of risperidone, weight-adjusted dose of risperidone, or BMI (p > 0.05), but was negatively correlated with the treatment duration (r = -0.352, p = 0.001 among cases; and r = -0.324, p = 0.039 among controls). There were significant differences in use of risperidone between patients and healthy subjects without the medication in the frequency of the polymorphisms of the DRD2, HTR2C, and LEP genes. Considering both sexes together and also specifically among females, the occurrence of hyperprolactinemia was higher in the presence of the C allele of the rs6318 single nucleotide polymorphisms (SNP) of the HTR2C gene. This group of children and adolescents with or without isolated use of risperidone presented with a high frequency of hyperprolactinemia, although asymptomatic, and associated, when considering only females or both sexes together, with being a carrier of the C allele of the rs6318 SNP of the HTR2C gene.

Association of LEPR and ANKK1 Gene Polymorphisms with Weight Gain in Epilepsy Patients Receiving Valproic Acid.

Background:Weight gain is the most frequent adverse effect of valproic acid (VPA) treatment, resulting in poor compliance and many endocrine disturbances. Similarities in the weight change of monozygotic twins receiving VPA strongly suggests that genetic factors are involved in this effect. However, few studies have been conducted to identify the relevant genetic polymorphisms. Additionally, the causal relationship between the VPA concentration and weight gain has been controversial. Thus, we investigated the effects of single nucleotide polymorphisms (SNPs) in several appetite stimulation and energy homeostasis genes and the steady state plasma concentrations (Css) of VPA on the occurrence of weight gain in patients.Methods:A total of 212 epilepsy patients receiving VPA were enrolled. Nineteen SNPs in 11 genes were detected using the Sequenom MassArray iPlex platform, and VPA Css was determined by high-performance liquid chromatography (HPLC).Results:After 6 months of treatment, 20.28% of patients were found to gain a significant amount of weight (weight gained ≥7%). Three SNPs in the leptin receptor (LEPR), ankyrin repeat kinase domain containing 1 (ANKK1), and α catalytic subunit of adenosine monophosphate-activated protein kinase (AMPK) showed significant associations with VPA-induced weight gain (p < 0.001, p = 0.017 and p = 0.020, respectively). After Bonferroni correction for multiple tests, the genotypic association of LEPR rs1137101, the allelic association of LEPR rs1137101, and ANKK1 rs1800497 with weight gain remained significant. However, the VPA Css in patents who gained weight were not significantly different from those who did not gain weight (p = 0.121).Conclusions: LEPR and ANKK1 genetic polymorphisms may have value in predicting VPA-induced weight gain.

Polymorphisms of Leptin (-2548 G/A) and Leptin Receptor (Q223R) Genes in Iranian Women with Breast Cancer.

Recent studies have shown that polymorphisms in leptin and leptin receptor genes are associated with increased risk for breast cancer. This study aimed at investigating -2548 G/A polymorphism in leptin gene and Q223R polymorphism in leptin receptor gene in patients with breast cancer. The study included 45 women with breast cancer and 41 healthy women. PCR-RFLP was used to determine the genotype of the subjects in terms of -2548 G/A polymorphism in leptin gene and Q223R polymorphism in leptin receptor gene. Serum levels of leptin were also measured by ELISA. For -2548 G/A polymorphism, the genotypes were homozygous AA (OR = 1.13; p = 0.8) and heterozygous GA (OR = 0.41; p = 0.2) and for Q223R polymorphism, the genotypes were homozygous RR (OR = 6.7; p = 0.09) and heterozygous QR (OR = 8.3; p = 0.06). The mean serum level of leptin was 33.22 ± 21.35 ng/mL in patients and 29.49 ± 23.27 ng/mL in the normal participants (p = 0.3). Although, despite the magnitude of the associations, the results suggested no statistically significant contribution of -2548 G/A polymorphism (in leptin gene), Q223R polymorphism (in leptin receptor gene), and serum leptin levels in predicting the risk of breast cancer, further studies with larger sample size are suggested.

The Impact ofLEPG-2548A andLEPRGln223Arg Polymorphisms on Adiposity, Leptin, and Leptin-Receptor Serum Levels in a Mexican Mestizo Population

The polymorphisms in leptin (LEP G-2548A) and leptin-receptor (LEPR Gln223Arg) seem to influence obesity and lipid metabolism among others. The aim of this study was to investigate the effect of these polymorphisms on adiposity, leptin (sLeptin), and leptin-receptor (sLeptin-receptor) serum concentrations as well as inflammation markers. We included 382 adults originally from Western Mexico. They were genotyped by PCR-RFLP. Obese individuals showed higher sLeptin (58.2 ± 31.35 ng/mL) but lower sLeptin-receptor (12.6 ± 3.74 ng/mL) levels than normal weight ones (17.6 ± 14.62 ng/mL, 17.4 ± 4.62 ng/mL, resp.), P < 0.001. Obese subjects carriers of Arg/Arg genotype had more (P = 0.016) sLeptin-receptor (14.7 ± 4.96 ng/mL) and less (P = 0.004) sLeptin (44.0 ± 28.12 ng/mL) levels than Gln/Gln genotype (11.0 ± 2.92 ng/mL, 80.3 ± 33.24 ng/mL, resp.). Body fat mass was lower (P from 0.003 to 0.045) for A/A (36.5% ± 6.80) or Arg/Arg (36.8% ± 6.82) genotypes with respect to G/G (41.3% ± 5.52) and G/A (41.6% ± 5.61) or Gln/Gln (43.7% ± 4.74) and Gln/Arg (41.0% ± 5.52) genotypes carriers. Our results suggest that LEP -2548A and LEPR 223Arg could be genetic markers of less body fat mass accumulation in obese subjects from Western Mexico.

Leptin receptor polymorphism Gln223Arg (rs1137101) in oral squamous cell carcinoma and potentially malignant oral lesions.

The purpose of this study was to assess the LEPR gene Gln223Arg polymorphism (rs1137101) in oral squamous cell carcinoma (OSCC) and in potentially malignant oral lesions (PMOL) in comparison to normal oral mucosa in a Brazilian population. Smokers (n = 89) were selected from a representative sample of 471 individuals from the general population of Montes Claros, Brazil. Participants were age and gender matched to patients with OSCC (n = 25) and oral epithelial dysplasia (n = 25). We investigated the LEPR Gln223Arg polymorphism (A>G; rs1137101) in these groups. Genotype variants were assessed by RFLP-PCR, using MspI (HPAII) restriction endonuclease. The institutional review board of the Universidade Estadual de Montes Claros approved the study (process number 2667/2011). Written informed consent for this study was obtained from all participants. The GG genotype (Arg223Arg) appears to be the more relevant polymorphic variant in OSCC. It occurred, approximately, twice as frequently in OSCC patients than in the general population. In contrast, the A allele in its homozygosis form (Gln223Gln) is significantly associated with the development of PMOL; 80% of the samples from the PMOL group exhibit AA genotype. Our findings suggest new insights regarding LEPR gene variations in the development of OSCC and PMOL.

Association of Genetic Polymorphisms of Leptin Receptor (LEPR) With New Onset Diabetes After Transplantation in Renal Transplantation.

BACKGROUND: Posttransplantation diabetes mellitus (PTDM) is a serious metabolic complication after renal transplantation. Leptin has an important role in the regulation of fat metabolism and glucose uptake. Although the links of insulin resistance and genetic variants at leptin (LEP) and leptin receptor gene (LEPR) were reported, relatively no studies have investigated the associations of PTDM. In this study, we investigated whether single nucleotide polymorphisms in LEP and LEPR have any association with PTDM in renal transplant recipients. METNODS: A total of 301 patients who had received kidney transplants without previously diagnosed diabetes were included. We analyzed the association between the PTDM development and the 5 SNPs within LEP and LEPR. RESULTS: Of 301 subjects, PTDM developed in 48 patients (15.9%). Patients in the PTDM group were older than those in the non-PTDM group. The sex ratio and BMI between two groups were similar. The percentage of steroid-treated acute rejection episodes and using tacrolimus were no significant different between the two groups. The patients with PTDM had significantly higher allele frequency of the LEPR rs1137100*G allele. We also observed significant higher distribution of A/A plus G/A genotypes of LEPR rs1137100 in PTDM subjects than in control subjects under a dominant model. Of four SNPs, the rs2167270 and rs13228377 of the LEP gene and the rs1327118 and rs3806318 of the LEPR were not significantly associated with the development of PTDM. CONCLUSION: Our data suggests that genetic variants of LEPR might have an essential role in the pathogenesis of PTDM.

Association of leptin receptor Lys109Arg and Gln223Arg polymorphisms with increased risk of clear cell renal cell carcinoma.

Although roles of genetic polymorphisms of leptin receptor (LEPR) gene in several cancers have been documented, the association between polymorphisms of LEPR and clear cell renal cell carcinoma (CC-RCC) remains unknown. The aim of this study was to explore any relation. The study population consisted of 77 patients with CC-RCC and 161 healthy control subjects. Polymorphism analyses of Lys109Arg and Gln223Arg were performed by direct DNA sequencing and PCR-restriction fragment length polymorphism approaches respectively. Comparisons of allelic and genotypic frequencies in Lys109Arg and Gln223Arg showed no significant difference between the cases and controls. However, when evaluating the combined genotype of Lys109Arg and Gln223Arg, risk with GG/GG was increased (OR=1.85, 95%CI=1.04-3.30) and with GA/GG or GG/GA was decreased (OR=0.07, 95%CI=0.01-0.54; OR and 95%CI of the latter could not be calculated for a value of zero) . Furthermore, the G-G haplotype frequency of Lys109Arg and Gln223Arg in the cases was higher (OR=1.68; 95%CI=1.02-2.76). In contrast, the A-G and G-A haplotype frequencies in the cases were lower than those in the controls (OR=0.06; 95%CI=0.01 to 0.47; OR and 95%CI of the latter could not be calculated for a value of zero). In addition, the Lys109Arg A allele was in LD with the Gln223Arg A allele (d'=0.9399) in the CC-RCC subjects, but not in the controls. Our data suggest that the GG/GG combined genotype and G-G haplotype of Lys109Arg and Gln223Arg can act as evaluating factors for CC-RCC risk.

Advances of the relationship between leptin system and non-small cell lung cancer

瘦素系统在肺部炎症反应、癌症发生发展等过程中发挥重要作用，但是其在肿瘤微环境中的作用机理、对肺癌的诊断价值仍不明晰。本文就瘦素系统与非小细胞肺癌之间的关系，从瘦素及其受体在循环和肿瘤组织中的表达变化、瘦素信号转导通路、瘦素与调节性T细胞的相互作用和瘦素及其受体的基因多态性等方面进行叙述，以期为非小细胞肺癌的诊治提供新方法。

Association between polymorphisms in leptin, leptin receptor, and β-adrenergic receptor genes and bone mineral density in postmenopausal Korean women

Association between polymorphisms in leptin, leptin receptor, and β-adrenergic receptor genes and bone mineral density in postmenopausal Korean women

Funkcjonalne polimorfizmy genów leptyny i receptora leptyny korelują z długowiecznością oraz z ryzykiem zawału mięśnia serca i cukrzycy 2 typu

Longevity is commonly associated with good health and with delayed onset of age-related diseases with usually benign course. Leptin (LEP) significantly affects metabolism and numerous functions of the organism. To find out if extreme longevity and its phenotype are associated with genetic variants of leptin and leptin receptor (LEPR) genes, we analysed the frequencies of the -2548 G/A and +19 G/A LEP, as well as the K109R, Q223R, and K656N LEPR polymorphisms in centenarians and in control groups. The frequencies of the LEP and LEPR polymorphisms were tested by restriction fragment length polymorphism in 128 centenarians, 414 young controls (Y), 226 myocardial infarction (MI) patients, and 190 type 2 diabetes mellitus (DM2) patients. The GG genotype of the -2548 G/A LEP polymorphism was significantly more common in centenarians than in the Y, MI and DM2 groups (p = 0.048, p = 0.003, p = 0.049, respectively). In addition, the AA genotype of the K109R LEPR polymorphism was significantly less frequent in centenarians than in the Y, MI, and DM2 groups (p = 0.026, p = 0.013, and p = 0.001, respectively). We suggest that the leptin pathway plays a role in the regulation of longevity, possibly by modulating the risk of development of MI and of DM2.

Leptin and leptin receptor polymorphisms are related to body mass index in a Turkish population

Leptin is a hormone that is known to be related to weight gain and obesity. The soluble leptin receptor has been found in plasma as an important determinant of leptin sensitivity. In this study, our goal was to investigate the association between leptin levels and leptin receptor polymorphisms in a Turkish population. The sample pool of this study consisted of 202 subjects. G2548A variant in the promoter region of the leptin gene and Q223R polymorphism of the leptin receptor gene were evaluated by using PCR-RFLP. Leptin levels were determined by ELISA. Leptin levels were significantly higher in subjects with the A allele than in subjects without the A allele. Leptin receptor levels were lower in subjects with the AA genotype than in those with the AG genotype. There was a higher prevalence of the leptin-2548 AA genotype among subjects with a BMI ≥ 25 kg/m2 than in those with a BMI < 25 kg/m2. The leptin-2548A allele might be a predisposing factor for obesity.

Association between polymorphisms in leptin, leptin receptor, and β-adrenergic receptor genes and bone mineral density in postmenopausal Korean women

The purpose of this study was to investigate the association between single nucleotide polymorphisms in leptin (LEP), leptin receptor (LEPR), and β-adrenergic receptor (ADRB) genes and bone mineral density (BMD) in postmenopausal Korean women. LEP c.280G>A, LEPR c.326A>G, LEPR c.668A>G, LEPR c.1968G>C, LEPR c.2096C>T, ADRB2 c.46A>G, ADRB2 c.79C>G, ADRB2 c.718T>C, ADRB2 c.741G>T, ADRB2 c.769G>A, and ADRB3 c.190T>C polymorphisms were analyzed in 592 postmenopausal Korean women. Serum levels of leptin, soluble leptin receptor, osteoprotegerin, soluble receptor activator of the nuclear factor-κB ligand, bone alkaline phosphatase, and carboxy-terminal telopeptide of type I collagen were measured, and BMDs at the lumbar spine and femoral neck were also examined. Among the polymorphisms measured, only the LEPR c.1968G>C polymorphism was found to be associated with BMD at the femoral neck, and higher BMD was observed with increasing number of G alleles (P = 0.04). Osteoporosis at the femoral neck was 3.27 and 3.89 times more frequently observed in the AG and GG genotypes than in the AA genotype in the ADRB2 c.46A>G polymorphism (P = 0.024 and P = 0.015, respectively). However, no significant differences in serum levels of leptin, soluble leptin receptor, free leptin index, osteoprotegerin, soluble receptor activator of the nuclear factor-κB ligand, and bone turnover markers were detected among single and haplotype genotypes. These results suggest that the LEPR c.1968G>C polymorphism may be one of the genetic factors affecting femoral neck BMD in postmenopausal Korean women and that an analysis of the ADRB2 c.46A>G polymorphism may be useful in identifying women at risk for osteoporosis at the femoral neck.

Leptin receptor gene polymorphisms are associated with adiposity and metabolic alterations in Brazilian individuals

The aim of the study was to investigate whether adiposity and metabolic markers, such as leptin, glucose, and lipids, are influenced by leptin (LEP) and leptin receptor (LEPR) gene polymorphisms in a sample of our population. A group of 326 individuals of Caucasian-European descent, aged 30 to 80 years, 87 men and 239 women, 148 obese and 178 non-obese, was randomly selected at two clinical hospitals in the city of Sao Paulo, Brazil. All individuals declared their ethnic group as white during the initial interview. Anthropometric measurements, body mass index (BMI), and fat mass were evaluated. Blood samples were drawn for DNA extraction and measurements of leptin, soluble leptin receptor, glucose, and lipids. LEP -2548G>A and LEPR Lys109Arg (c.326A>G), Gln233Arg (c.668A>G) and Lys656Asn (c.1968G>C) polymorphisms were detected by PCR-RFLP. Increased leptin and serum lipids, and LEPR Arg223Arg (GG genotype) were associated with higher risk for obesity (p < 0.05), while reduced risk was found in LEPR Arg109Arg (GG genotype) carriers (OR: 0.38, 95%CI: 0.19-0.77, p = 0.007). Multiple linear regression analysis showed a relationship between LEPR 223Arg, increased waist circumference, and leptinemia (p < 0.05), while LEPR 109Arg was associated with high total cholesterol and triglycerides (p < 0.05). LEPR haplotype 3 (AGG: 109Lys/233Arg/656Lys) carriers have increased risk for obesity (OR: 2.56, 95% CI: 1.19-5.49, p = 0.017). Moreover, this haplotype was associated with increased BMI, waist circumference, and leptinemia (p < 0.05). LEPR polymorphisms are associated with obesity, hyperleptinemia, and atherogenic lipid profile, suggesting their potential role for leptin resistance and cardiovascular risk. Moreover, LEPR haplotype 3 confers susceptibility to adiposity and hyperleptinemia in our population.

Leptin Signaling and Hyperparathyroidism: Clinical and Genetic Associations

The role of leptin in mediating calcium-related metabolic processes is not well understood. We enrolled patients with hyperparathyroidism undergoing parathyroidectomy in a prospective study to assess postoperative changes to serum leptin and parathyroid hormone levels and to determine the presence of LEPR (leptin receptor) polymorphisms. Patients undergoing hemithyroidectomy under identical surgical conditions were enrolled as controls. Wilcoxon signed-rank test was used to analyze changes in leptin. Pearson correlations and Bland-Altman methods were used to examine the between-subject and within-subject correlations in changes in leptin and parathyroid hormone levels. Five single-nucleotide polymorphisms in the LEPR gene were genotyped, and linear regression analysis was performed for each polymorphism. Among the 71 patients included in the clinical study, after-surgery leptin levels decreased significantly in the parathyroid adenoma (p < 0.001) and parathyroid hyperplasia subgroups (p= 0.002) and increased in the control group (p= 0.007). On multivariate analysis, parathyroid disease subtype, baseline leptin levels, age, body mass index, and calcium at diagnosis was associated with changes in leptin. Among the 132 patients included in the genotyping analysis, under a recessive model of inheritance, single-nucleotide polymorphism rs1137101 had a significant association with the largest parathyroid gland and total mass of parathyroid tissue removed (p= 0.045 and p= 0.040, respectively). When analyzing obese patients only, rs1137100 and rs1137101 were significantly associated with total parathyroid size (p= 0.0343 and p= 0.0259, respectively). Our results suggest a role for the parathyroid gland in regulating leptin production. Genetic contributions from the leptin pathway might predispose to hyperparathyroidism.

Association of the 223A/G LEPR polymorphism with serum leptin levels in Iranian subjects with type 2 diabetes.

Leptin, an adipocyte-derived hormone, has a pivotal role in the regulation of body weight through acting on its specific leptin receptor (LEPR). The 223A/G polymorphism of the LEPR gene is one of the most common polymorphism in all populations. In this study, we aimed to investigate the impact of the 223A/G polymorphism of the LEPR gene on serum levels of leptin in type 2 diabetes mellitus (T2DM) in a sample of Iranian population. One hundred and forty-four T2DM patients were screened and compared to 147 healthy controls. The 223A/G LEPR polymorphism was genotyped using polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP). The serum levels of leptin were measured. The mean serum levels of leptin in T2DM patients were significantly higher than that of healthy control subjects; 22.90 ng/ml (95 % confidence interval [CI] = 20.79 - 25.23) vs. 8.70 ng/ml (95 % CI = 7.87 - 9.63). The genotypes (AA, AG, and GG) distributions of the 223A/G polymorphism were 55.5 %, 41 %, and 3.5 % in T2DM and 54.4 %, 42.2 %, and 3.4 % in healthy controls. The results showed no significant differences in the 223A/G LEPR genotype and allele frequencies between T2DM and control subjects (χ2 = 0.043, P = 0.979 and χ2 = 0.003, P = 0.957), respectively. In addition, the serum leptin levels were markedly higher in subjects with GG genotype than those with AG or GG genotype only in T2DM CONCLUSION: The 223A/G LEPR gene polymorphism is associated with markedly increased serum leptin levels in T2DM. However, no differences were determined in genotype and allele frequencies between T2DM patients and control subjects.

Polymorphisms in LEPR, PPARG and APM1 genes: associations with energy intake and metabolic traits in young children

To assess the association of single nucleotide polymorphisms (SNPs) in five genes - leptin, leptin receptor (LEPR), adiponectin (APM1), peroxisome proliferator-activated receptor gamma (PPARG) and uncoupling protein 1 - with anthropometric, metabolic, and dietary parameters in a Southern Brazilian cohort of 325 children followed up from birth to 4 years old. SNPs were analyzed using polymerase chain reaction-based procedures, and their association with phenotypes was evaluated by t-test, analysis of variance, and general linear models. LEPR223Arg allele (rs1137101) was associated with higher daily energy intake at 4 years of age (P = 0.002; Pcorrected = 0.024). PPARG 12Ala-carriers (rs1801282) presented higher glucose levels than Pro/Pro homozygotes (P = 0.007; Pcorrected = 0.042). Two of the six studied SNPs presented consistent associations, showing that it is already possible to detect the influences of genetic variants on susceptibility to overweight in 4-year-old children.

Effect of the Leptin Receptor Q223R Polymorphism on the Host Transcriptome following Infection with Entamoeba histolytica

Resistance to amebiasis is associated with a polymorphism in the leptin receptor. Previous studies demonstrated that humans with the ancestral Q223 leptin receptor allele were nearly four times less likely to be infected with Entamoeba histolytica than those carrying the mutant R223 allele. We hypothesized that the Q223 allele protected against E. histolytica via STAT3-mediated transcription of genes required for mucosal immunity. To test this, mice containing the humanized LEPR Q or R allele at codon 223 were intracecally infected with E. histolytica. Susceptibility to amebiasis was assessed, and cecal tissues were analyzed for changes in gene expression. By 72 h postchallenge, all Q223 mice had cleared E. histolytica, whereas 39% of 223R mice were infected. Thirty-seven genes were differentially expressed in response to infection at 72 h, including proinflammatory genes (CXCL2, S100A8/9, PLA2G7, ITBG2, and MMP9) and functions pertaining to the movement and activity of immune cells. A comparison at 12 h postchallenge of infected Q223 versus R223 mice identified a subset of differentially expressed genes, many of which were closely linked to leptin signaling. Further analyses indicated that the Q223 gene expression pattern was consistent with a suppressed apoptotic response to infection, while 223R showed increased cellular proliferation and recruitment. These studies are the first to illuminate the downstream effects of leptin receptor polymorphisms on intestinal infection by E. histolytica. As such, they are important for the insight that they provide into this previously uncharacterized mechanism of mucosal immunity.

The leptin gene family and colorectal cancer: interaction with smoking behavior and family history of cancer.

BackgroundPathologic condition associated with metabolic syndrome traits seems to increase the risk of colorectal cancer. One mechanism underlying this relationship may involve the growth-promoting effects of the circulation hormones associated with obesity and insulin resistance, such as leptin.Methodology/Principal FindingsA two-stage case-control study was used to explore the role of polymorphisms of Leptin (LEP) and Leptin receptor (LEPR), either alone or in combination with environmental factors in colorectal carcinogenesis. In stage 1, 20 single nucleotide polymorphisms (SNPs) that tag common SNPs in these two genes were genotyped among 470 cases and 458 controls. In stage 2, another population with 314 cases and 355 controls were genotyped for the two most promising SNPs from stage 1. LEPR rs12037879 only presented modestly increased colorectal cancer risk, with odds ratios of 1.41 (95% confidence interval [CI] 1.13–1.76) and 1.74 (95%CI 1.08–2.81) for GA and AA genotype when compared with GG genotype in combined population. Smokers carrying LEPR rs12037879 A allele presented 1.67-fold (95%CI 1.39-fold to 2.01-fold) increased colorectal cancer risk when compared with non-smokers carrying GG genotype in combined analysis. Individuals with family history of cancer harboring LEPR rs12037879 A allele showed 1.52-fold (95%CI: 1.24-fold to 1.86-fold) increased colorectal cancer risk, compared with individuals without family history of cancer harboring GG genotype. Multifactor gene-environment interaction analysis revealed significant interactions among LEPR rs12037879, LEPR rs6690625, smoking status and family history of cancer, exhibiting a gradient of increased colorectal cancer risk along with the increasing number of risk factors (P = 9.82×10−10).Conclusions/SignificanceOur research supports that polymorphisms in LEPR may be associated with marginal increase in the risk for colorectal cancer. Moreover, this association could be strengthened by cigarette smoking and family history of cancer.

Leptin and leptin receptor polymorphisms and recurrent pregnancy loss

Leptin signaling is important in the establishment of pregnancy. We sought to determine if single nucleotide polymorphisms (SNPs) in the leptin and leptin receptor genes are associated with idiopathic recurrent pregnancy loss (RPL). We conducted a case-control study with cases defined as women with idiopathic RPL and controls as parous women without pregnancy losses. A total of 99 cases and 108 controls were genotyped for the leptin (-2548 G/A) SNP and the leptin receptor A223G SNP. Genotype and allele frequencies were compared between cases and controls using χ(2) test. In this population, there was no significant difference in the genotype or allele frequencies for the leptin (-2548 G/A) or leptin receptor A223G SNPs between women with idiopathic RPL and controls. Although leptin signaling is critical to many aspects of reproduction, the maternal leptin and leptin receptor SNPs evaluated in this study are unlikely to have a clinically meaningful role in RPL.