LEPR Rs1137101 Research Articles

Contrasting association of Leptin receptor polymorphisms and haplotypes with polycystic ovary syndrome in Bahraini and Tunisian women: a case–control study

Background: The present study examined the contribution of ethnicity to the association of leptin receptor gene (LEPR) gene variants with polycystic ovary syndrome (PCOS) in Tunisian and Bahraini Arabic-speaking women.Methods: Subjects consisted of 320 women with PCOS, and 446 eumenorrhic women from Tunisia, and 242 women with PCOS and 238 controls from Bahrain. Genotyping of (exonic) rs1137100 and rs1137101 and (intronic) rs2025804 LEPR variants was done by allelic exclusion.Results: The minor allele frequencies (MAFs) of rs1137100 and rs1137101 were significantly different between PCOS cases and control women from Bahrain but not Tunisia, and LEPR rs1137101 was associated with increased PCOS susceptibility only in Bahraini subjects. Furthermore, rs1137100 was associated with decreased PCOS risk among Bahrainis under codominant and recessive models; rs1137100 was negatively associated with PCOS in Tunisians after controlling for testosterone. In addition, rs2025804 was associated with increased PCOS risk among Tunisian but not Bahraini women, after adjusting for key covariates. Negative correlation was seen between rs1137101 and triglycerides in Tunisians, while homeostasis model assessment of insulin resistance (HOMA-IR) and insulin correlated with rs2025804 and rs1137101 among Bahraini subjects, and rs1137101 correlated with estradiol and prolactin. Taking TAG haplotype as common, positive association of TAA and negative association of TGG haplotype with PCOS was seen among Bahraini women; no three-locus PCOS-associated haplotypes were found in Tunisians.Conclusions: The present study is the first to demonstrate the contribution of ethnicity to the association of LEPR gene variants with PCOS, thereby highlighting the significance of controlling for ethnicity in gene association investigations.

EFFECT OF LEPR AND GR GENE POLYMORPHISMS ON HEALTH STATUS OF MOTHERS WITH METABOLIC DISORDERS AND THEIR NEWBORNS

The high prevalence of obesity and metabolic syndrome throughout the world over the past two decades provided the grounds to the WHO to consider overweight as a non-infectious pandemic. Among the factors that negatively affect the metabolism, result in metabolic disorders and obesity there are genetic, prenatal, diet-related, somatic, psychogenic and others. Analysis of LEPR and GR gene polymorphisms among mothers and their newborns can be an important component in the prediction of metabolic disorders and obesity. The aim of this study was to analyze the presence of clinical and genetic determinants of metabolic syndrome in mothers and their newborns. Materials and methods. A cross-sectional study of 42 pairs of mothers and newborns was performed; we analyzed their anthropometric, clinical and laboratory parameters and, in particular, 2 types of genetic polymorphisms (LEPR rs1137101 and GR, BClI polymorphism). The main group consisted of 15 mother-child pairs, where the woman was clinically obese (body mass index more than 30), the comparison group included 27 mother-child pairs, where the women were overweight (body mass index more than 25). Results. Obese mothers were significantly more likely to have a miscarriage (p = 0.01). Children from obese mothers had significantly higher percentiles of birth weight compared to the control group (60.9 ± 7.7 and 49.75 ± 4.5, respectively, p = 0.05). The GG genotype of the GR gene was associated with more common indications for hospitalization (p = 0.012), rapid delivery (p = 0.01), umbilical cord entanglement around the neck of the foetus (p = 0.012). Among the children- carriers of the GG BclI genotype GR, cardio-metabolic disorders detected by the auscultation of the heart (arrhythmia, functional noise) were found out as significantly more frequent (p = 0.003). Conclusion. The study did not find the associations between LEPR and GR gene polymorphism in obese mothers and the development of overweight in their children, but the study revealed an adverse effect of polymorphic variants on obstetric and gynaecological status of mothers, labour and adaptation of infants in the early neonatal period.

Polymorphisms of leptin-melanocortin system genes associated with obesity in an adult population from Barranquilla

ResumenIntroducción. La obesidad se considera un grave problema de salud pública y por ello se hacen esfuerzos en la búsqueda de genes como el LEP, el LEPR y el MC4R del sistema leptina-melanocortina, el cual opera en la regulación neuroendocrina de la ingestión y el equilibrio energético e influye en la patogenia de la enfermedad. Los resultados contradictorios en torno a la asociación de estos genes con la obesidad plantean la necesidad de nuevas investigaciones.Objetivo. Analizar los polimorfismos rs2167270 del gen LEP, rs1137101 del gen LEPR y rs17782313 del gen MC4R asociados con la obesidad y sus variables clínicas y bioquímicas en una muestra de pacientes adultos de Barranquilla.Materiales y métodos. Se estudiaron 111 personas obesas y 155 no obesas como controles. Los polimorfismos se determinaron mediante reacción en cadena de la polimerasa (PCR) en tiempo real. Se tomaron las medidas antropométricas, se evaluó la presión arterial y se hicieron pruebas bioquímicas.Resultados. No se encontraron diferencias estadísticas en la frecuencia alélica y genotípica de los polimorfismos en los grupos estudiados. En cuanto a las variables clínicas y bioquímicas, el genotipo CC del polimorfismo rs17782313 del gen MC4R, se asoció con un aumento de la presión arterial sistólica y, el alelo T y su genotipo homocigoto, con una disminución del colesterol HDL en los obesos. No se evidenció ningún efecto de los otros polimorfismos en estas variables.Conclusiones. Los polimorfismos rs2167270 del gen LEP, rs1137101 del gen LEPR y rs17782313 del gen MC4R, no se asociaron con obesidad en la población analizada. Se encontró que el polimorfismo rs17782313 del gen MC4R influyó en el aumento de la presión arterial sistólica y la disminución del colesterol HDL en las personas obesas.

Association analysis of polymorphisms in LEP (rs7799039 and rs2167270) and LEPR (rs1137101) gene towards the development of type 2 diabetes in North Indian Punjabi population.

Obesity is a major risk factor in aetiology of type 2 diabetes mellitus (T2DM). Leptin (LEP) is an anti-obesity hormone which regulates food intake, energy expenditure and glucose metabolism. The genetic variants in leptin and leptin receptor gene (LEPR) may play major role in the pathogenesis of T2DM and obesity. The current study aimed to investigate the association of polymorphisms in LEP (rs7799039, -2548G/A and rs2167270, 19G/A) and LEPR (rs1137101, 668A/G) gene with type 2 diabetes in North Indian Punjabi population. A total of 817 subjects were included for the present case-control study, consisting of 417 T2DM patients and 400 healthy controls. The anthropometric, physiometric and biochemical measurements were taken from all the subjects. The genotyping of LEP and LEPR gene variants were carried out by polymerase chain reaction based restriction fragment length polymorphism method (PCR-RFLP), followed by genotyping of 10% of the samples for each polymorphism by Sanger sequencing method for quality control measurement. The risk genotype frequencies were found to be significantly higher in T2DM cases than control subjects (rs7799039, p=0.001; rs2167270, p=0.019 and rs1137101, p=0.003). Under recessive genetic model LEPrs7799039 and LEPRrs1137101 polymorphism conferred 3.4 and 2.1 fold risk towards the development of T2DM after adjustment of various covariates (OR=3.44, 95%CI: 1.768-6.681, p=0.001 and OR: 2.12, 95%CI: 1.256-3.569, p=0.005, respectively). In the stratified analysis of LEP variant rs7799039 by age, gender, BMI and alcohol use, a significantly increased risk of T2DM was found in female, BMI≥23 and never drinking subgroups. However, in the LEPR variant rs1137101, significantly increased risk of T2DM was observed in age <50, male, BMI≥23 and never drinking subgroup. The A-G haplotype combination of rs7799039A and rs2167270G conferred significant 2 fold risk towards T2DM (OR=2.35, 95%CI: 1.34-4.12, p=0.002). In control group, the genetic variants rs7799039 and rs1137101 were significantly associated with levels of random blood sugar and low density lipoprotein cholesterol levels. The present study revealed the association of LEP rs7799039 and LEPR rs1137101 with type 2 diabetes mellitus, which suggest its predominant role in the estimation of type 2 diabetes mellitus in North Indian Punjabi population.

P4479The association of LEPR rs1137101 polymorphism with the incidence of left ventricular hypertrophy in patients with obstructive sleep apnea and hypertension

Abstract Background/Introduction Obstructive sleep apnea (OSA) is one of the most common respiratory disease which is considered as a risk factor for cardiovascular disease and death. Although coexistence of OSA and arterial hypertension may be attributed to well-known common environmental risk factors for both diseases, a genetic background should be considered. LEPR rs1137101 polymorphism was reported to be associated with coronary artery disease and heart failure. Left ventricular hypertrophy is a part of hypertension-mediated organ damage assessment and an independent risk factor for adverse outcome in patients with hypertension. Purpose This study is aimed to establish the relationship between LEPR rs1137101 polymorphism and left ventricular hypertrophy in patients with OSA and arterial hypertension. Methods Consecutive patients with newly diagnosed OSA confirmed by polysomnography underwent genotyping for the single nucleotide polymorphisms of LEPR (rs1137101). LVH was diagnosed using standard 12-lead electrocardiogram according to the current European Society of Cardiology guidelines. Logistic regression was used to assess the relationship between LEPR rs1137101 polymorphisms and LVH. Results From 600 subjects diagnosed with OSA, 427 subjects with hypertension were included for further analysis (25.1% women, 74.9% men). In analyzed subpopulation mean age was 58.5±9.4 years, body mass index 33.7±6.6 kg/m2, apnea-hypopnea index 43.1±23.6/hour. In 34 (8.0%) subjects LVH was diagnosed. Genotyping revealed, that 123 (28.8%) subjects were LEPR rs1137101 AA homozygotes, 202 (47.3%) LEPR rs1137101 A/G heterozygotes and 102 (23.9) LEPR rs1137101 G/G homozygotes. Logistic regression showed, that LEPR rs1137101 A/A polymorphism vs A/G and G/G was associated with increased risk of LVH (odds ratio: 2.08, 95% confidence interval: 1.02–4.25, p=0.03). The relationship was significant also after adjustment for age, sex, apnea-hypopnea index and current smoking status (odds ratio: 2.28, 95% confidence interval: 1.08–4.83, p=0.03). Conclusions Our study shows a possible link between the polymorphism of the LEPR rs1137101 polymorphism and LVH in patients with OSA and arterial hypertension. Acknowledgement/Funding The study received financial support from the Polish National Science Centre (710/N-COST/2010/0)

Associations of polymorphisms of the FTO, ADRB3, LEPR genes with obesity and the impact on Them of a complex of recreational activities among residents of the North Caucasus

Annotation Objective To study the effect of a comprehensive health program on the effectiveness of reducing overweight depending on the carriage of allelic variants and FTO (rs9939609), ADRB3 (rs4994) and LepR (rs1137101) genotypes among residents of the North Caucasus. Materials and methods Gene polymorphisms were analyzed by the SNP-method with allele-specific primers on the test systems of ‘Litex’ Research and Production Company (RPC). The frequencies rs9939609, rs4994 and rs1137101 were studied in individuals with overweight, I-III degrees of obesity (n = 120) compared with the control group (n = 42). Experimental data were processed in the program SPSS Statistics 22.0. A comprehensive wellness program (CWP), along with health improving measures, limits caloric intake to 800–1200 kcal per day and excludes animal fats and proteins. The body mass index (BMI) of the examined individuals was calculated by the Ketle method as the ratio of body weight (kg) to height (m2). In accordance with WHO criteria (1997), the severity of overweight varies in the ranges of values: normal weight – 18–24.9 kg/m2; overweight – 25–29.9 kg/m2; I degree obesity – 30–34.9 kg/m2; II degree obesity – 35–39.9 kg/m2; III degree obesity – 40 and more kg/m2. Results A significant increase in rs9939609 (p = 0.003), rs4994 (p = 0.0001) was found in the group of patients when compared with the control. The 64Arg allele (р = 5.0E-6) and the Arg64Arg genotype (p = 0.0001) of the ADRB3 gene have the greatest prognostic significance for the diagnosis of obesity, increasing the risk by 10 and 17 times, respectively. Significant differences in the distribution of FTO gene polymorphism were established to a lesser extent and only by the T23525T genotype (χ2 = 7.20; р = 0.03). However, the correlation analysis revealed a number of strong positive connections for the T23525T FTO genotype between the ratio of visceral fat (r = +0.541; p = 0.01), fat (r = +0.548; p = 0.01) and muscle mass (r = +0.587; p = 0.01). It should be noted that with SNP-typing of three polymorphic variants of the FTO, ADRB3 and LepR genes, the transversion phenomenon was established by rs9939609 in 26 out of 120 participants (21.6%). Conclusion According to the obtained data, we confirmed the promising use of rs9939609, rs4994 as genetic markers of obesity. The discovered phenomenon of transversion of polymorphisms in the FTO gene under the influence of the complex health program does not exclude a multi-level regulation of reparation processes and epigenetic activation of genes, which requires further study.

Population pharmacokinetics of valproic acid in epileptic children: Effects of clinical and genetic factors

Valproic acid (VPA) is a first-line anti-epileptic drug that is used in the treatment of generalized and partial seizures. Gene variants had been proved to influence the pharmacokinetics (PK) of VPA and contribute to its inter-individual variability (IIV). The aim of this study was to systematically investigate the effects of candidate gene variants (CYPs, UGTs, ABC transporters, and nuclear receptors) on VPA PK in Chinese children with epilepsy. A total of 1065 VPA serum trough concentrations at steady state were collected from 264 epileptic pediatric patients aged 3 months to 16 years. The population pharmacokinetic (PPK) model was developed using a nonlinear mixed effects modelling (NONMEM) approach.For the final PPK model, the oral clearance (CL/F) of VPA was estimated to be 0.259 L/h with IIV of 13.3%. The estimates generated by NONMEM indicated that the VPA CL/F was significantly influenced by patient body weight (increased by an exponent of 0.662), co-administration with carbamazepine (increased CL/F by 22%), and daily dose of VPA (increased by an exponent of 0.22). CL/F in patients with the LEPR rs1137101 variant (668 AG and GG genotypes) was much lower than in patients with the AA genotype (17.8% and 22.6% lower, respectively). However, none of the CYPs or UGTs gene variants was found to influence the PK of VPA in this study. Evaluation by bootstrap and normalized prediction distribution error (NPDE) showed that the final model was stable. The predictive performance was evaluated by goodness-of-fit (GOF) plots and visual predictive checks (VPC), and the results indicated satisfactory precision. Our model suggests a correlation between VPA CL/F and LEPR rs1137101 variants, which might be beneficial in the context of individual dose optimization.

The combined effect of dietary supplement “Leptin Manager” and power fitness exercises on weight loss in women with different LEPR (rs1137101) genotypes

The combined effect of dietary supplement “Leptin Manager” and power fitness exercises on weight loss in women with different LEPR (rs1137101) genotypes

Polymorphisms in Genes Involved in the Leptin-Melanocortin Pathway are Associated with Obesity-Related Cardiometabolic Alterations in a Southern Chilean Population.

Polymorphisms in genes encoding proteins of the leptin-melanocortin pathway have been associated with obesity. The involvement of these polymorphisms with changes in body mass index (BMI) and anthropometric measures could also imply a contribution to the risk of metabolic syndrome (MetS) and metabolic alterations. We evaluated the relationship of leptin-melanocortin system polymorphisms with obesity, MetS, and other metabolic alterations in Southern Chilean individuals. Two-hundred individuals were grouped as normoweight (BMI 18.0-24.9kg/m2), overweight (BMI 25.0-29.9kg/m2), and obese (BMI≥30kg/m2) or according to MetS status. Anthropometric measures (BMI, abdominal circumference, waist-to-hip ratio [WHR]) and biochemical parameters (glycemia and lipid profile) were evaluated. Polymorphisms LEP rs7799039, LEPR rs1137101, MC3R rs3746619 and rs3827103, and MC4R rs17782313 were evaluated by real-time PCR using allelic discrimination assays. LEPR rs1137101 GG genotype was related to reduced risk of obesity (odds ratio [OR] 0.26, 95% confidence interval [CI] 0.08-0.79; p=0.018) and MetS (OR 0.36, 95% CI 0.15-0.88; p=0.024), but it was not significant after Bonferroni correction for multiple tests as compared to the AA genotype (p>0.01). Moreover, LEPR rs1137101 allele G (AG+GG) was related to lower BMI and WHR (p<0.01). Further multiple linear regression analysis demonstrated that this genotype was also responsible for reduced BMI in 2.44kg/m2 and WHR in 0.033 units. MC4R rs17782313 allele C (TC+CC) was slightly associated with diminished risk of MetS (OR 0.48, 95% CI 0.23-0.98; p=0.040) and reduced BMI values in 1.95kg/m2 (p<0.05). Regarding lipid profile, LEPR rs1137101 allele G carriers had lower triglycerides and very-low-density lipoprotein (VLDL) cholesterol, whereas individuals carrying the MC4R rs17782313 allele C had higher high-density lipoprotein (HDL) cholesterol (p<0.01). LEP rs7799039 allele A (GA+AA) was slightly associated with reduced total and low-density lipoprotein (LDL) cholesterol (p<0.05). These results suggest that polymorphisms at LEP, LEPR, and MC4R may be useful biomarkers of obesity-related cardiometabolic alterations in our population.

Study of the association between polymorphism of persistent obesity, human leptin gene/leptin receptor gene and molecular subtypes of breast cancer

Objectives: To explore the association between the polymorphism of persistent obesity and genetic variations in the LEP (human leptin gene, LEP) and LEPR (leptin receptor gene, LEPR) genes and different molecular subtypes of breast cancer. Methods: All 703 female patients of breast cancer diagnosed by histopathology in the Sichuan Cancer Hospital or the West China Hospital, excluding patients with metastatic breast cancer or mental disease, were selected as cases from April 2014 to May 2015. At the same time, 805 healthy women received physical examination in medical examination center of Sichuan People Hospital or Shuangliu maternal and child health care hospital, excluding those with therioma, breast disease, and mental disease, were enrolled in control group. A uniform questionnaire was used to collect general information including demographic characteristic, reproductive history height, weight, and so on. And the obesity status in recent 10 years was judged. Time of Flight Mass Spectrometer was used to determine the genotypes of LEP rs7799039, LEPR rs1137100 and LEPR rs1137101, while the multinomial logistic regression analysis was conducted to estimate the effect of risk factors related to breast cancer in different molecular subtypes; and then, the association between polymorphism of persistent obesity, the LEP, LEPR genes and breast cancer of different molecular subtypes was analyzed by binary logistic regression models. Results: The average age of controls was (48.98±8.83) years old, while the age of cases of TNBC, Luminal A, Luminal B, and HER-2+ were (51.43±11.33), (49.94±10.10), (49.73±9.38), (50.50±9.04) years old, respectively. The frequency of genotype LEP rs7799039, LEPR rs1137100 and LEPR rs1137101 in control group was separately 74.8%(1 157/1 546), 83.6%(1 339/1 602) and 88.4%(1 416/1 602); while 77.6% (1 074/1 384), 82.4% (1 155/1 402) and 87.9% (1 232/1 402) respectively in case group. Compared with non-persistent obesity subjects, the persistent obesity ones showed an increased risk in TNBC (OR=3.58, 95%CI: 1.90-6.72), Luminal A (OR=2.65, 95%CI: 1.35-5.21) and Luminal B (OR=1.90, 95%CI: 1.26-2.89) breast cancer. LEP rs7799039-AA was relevant with the upward risk of Luminal B independently (OR=1.30, 95%CI: 1.00-1.69). Besides, persistent obesity was found to have a combined effect on Luminal B (β=3.34, 95% CI: 1.00-11.12) with LEPR rs1137101-GG. Conclusion: Persistent obesity could increase the potential risk of TNBC, Luminal A and Luminal B breast cancer. Women who were suffered from persistent obesity with a genotype of LEPR rs1137101-GG were more susceptible to Luminal B breast cancer.

LEP rs7799039, LEPR rs1137101, and ADIPOQ rs2241766 and 1501299 Polymorphisms Are Associated With Obesity and Chemotherapy Response in Mexican Women With Breast Cancer

BackgroundObesity plays a major role in the pathogenesis of breast cancer. Leptin (LEP) and adiponectin (ADIPOQ) are important in the regulation of adipose tissue. The response to cancer treatment depends on the histological and molecular tumor type, clinical stage, and genetic variability that might promote carcinogenic development. The aim of this study was to investigate the association between overweight/obesity and polymorphisms in the LEP (rs7799039), LEP receptor (LEPR; rs1137101), and ADIPOQ genes (rs2241766, rs1501299) with the response to breast cancer treatment in Mexican women. Patients and MethodsA sample of 177 patients with primary breast cancer (stage I-III) and who received neoadjuvant therapy were included. Polymorphisms were genotyped and their serum LEP concentrations (n = 59) were quantified. ResultsThe patients' median age was 53.1 years, the frequency of overweight and obesity was 57 and 84 patients, respectively, 117 were postmenopausal, and 64 of the patients did not respond to chemotherapy. An association of the LEP rs7799039, LEPR rs1137101, and ADIPOQ rs1501299 polymorphisms with overweight/obesity was found. The patients who did not respond to treatment were more frequently obese, at clinical stage III, had metastases, and high levels of glucose. Moreover, in samples that were positive for estrogen receptor, higher levels of LEP were found, and in wild type genotypes for LEP rs7799039 and LEPR rs1137101. ConclusionThere was a direct association between the polymorphisms in LEP rs7799039 and ADIPOQ rs1501299 with overweight/obesity, and these genotypes affected the response to chemotherapeutic treatment, suggesting that an obesogenic microenvironment is more favorable for tumoral progression.

Relationship between polymorphisms in the CRP, LEP and LEPR genes and high sensitivity C-reactive protein levels in Spanish children.

We investigated the association of single nucleotide polymorphisms (SNPs) in the C-reactive protein (CRP), leptin (LEP) and leptin receptor (LEPR) genes with high sensitivity CRP (hs-CRP) levels in two independent cohorts of healthy Spanish children. We measured hs-CRP levels in 646 6-8-year-old and 707 12-16-year-old children using a high-sensitivity C-Reactive Protein ELISA kit. Four SNPs in the CRP gene (rs1205, rs1130864, rs2794521 and rs1800947), one SNP in the LEP gene (rs7799039) and two SNPs in the LEPR (rs1137100 and rs1137101) gene were determined by TaqMan® allelic discrimination assays. The four CRP SNPs studied were significantly (p<0.05) associated with hs-CRP levels in both cohorts. Furthermore, two common CRP haplotypes (constructed using the SNPs in order: rs1205, rs1130864, rs1800947, rs2794521) ACGA and GCGG were associated with significantly lower CRP levels (p<0.05) at both ages. The LEPR SNPs rs1137100 (K109R) and rs1137101 (Q223R), and LEP SNP rs7799039 (G2548A) were also associated to hs-CRP levels (p<0.05) in both cohorts. hs-CRP levels in healthy Spanish children, besides being associated to common polymorphisms in the CRP gene, are associated to polymorphisms in the LEP and LEPR genes, which suggests that other loci, in addition the CRP gene, may have a role determining CRP levels in children.

Genetic polymorphisms in leptin, adiponectin and their receptors affect risk and aggressiveness of prostate cancer: evidence from a meta-analysis and pooled-review.

Leptin and adiponectin signaling was associated with development and progression of various cancers. The present study aimed to clarify the role of genetic variants in leptin, adiponectin and their receptors in prostate cancer. After comprehensive search and manuscript scanning, a total of 49 genetic variants were enrolled and examined for their relations to cancer risk and aggressiveness. In the meta-analysis, LEP rs7799039 (allele contrast: OR 1.133, 95%CI 1.024-1.254), ADIPOQ rs2241766 (allele contrast: OR 1.201, 95%CI 1.015-1.422) and ADIPOR1 rs10920531 (allele contrast: OR 1.184, 95%CI 1.075-1.305) variants were identified to be correlated with increased risk of prostate cancer. On the contrary, LEPR rs1137101 (allele contrast: OR 0.843, 95%CI 0.730-0.973) and ADIPOR1 rs2232853 (allele contrast: OR 0.638, 95%CI 0.535-0.760) variants were associated with decreased risk of prostate cancer. From the pooled-review, we additionally recognized eight variants associated with cancer risk and another eight variants associated with cancer aggressiveness, respectively. These observations indicated important roles of leptin, adiponectin and their receptors in the development and progression of prostate cancer. The identified polymorphisms might assist in developing better risk-assessment tools, as well as generating novel targeted therapies, especially for obese cancer patients with impaired leptin and adiponectin signaling.

Association Between Gene Polymorphisms on Chromosome 1 and Susceptibility to Pre-Eclampsia: An Updated Meta-Analysis.

BackgroundThis meta-analysis enabled us to obtain a precise estimation of the association between gene polymorphisms on chromosome 1 (MTHFR, AGT, F5, IL-10, LEPR) and the susceptibility to pre-eclampsia (PE) in order to reach a uniform conclusion.Material/MethodsWeb of Science, PubMed, EMBASE, Cochran Library (CENTRAL), and Chinese databases (Chinese National Knowledge Infrastructure-CNKI and Wan Fang) were electronically searched to select relevant studies for this meta-analysis. We selected 95 case-control studies investigating 5 genes (MTHFR, AGT, F5, IL-10, and LEPR) with 8 SNPs. Odds ratios (OR) with their 95% confidence intervals (CI) were used for estimating the association.ResultsA total of 16 646 PE patients and 28 901 normal-pregnancy patients were included in this meta-analysis. The overall results suggested that rs1801133 of MTHFR (OR=1.17, 95% CI: 1.05–1.13) and rs6025 of F5 (OR=1.53, 95%CI: 1.07–2.20) are significantly associated with PE, whereas rs1801131 of MTHFR, rs699 and rs4762 of AGT, rs1800896 and rs1800871 of IL-10, and rs1137101 of LEPR have no significant association with PE. Subgroup analysis by ethnicity revealed that, except for MTHFR rs1801133 and F5 rs6025 in Caucasians, which were significantly associated with an increased risk of PE, none of these SNPs were significantly associated with PE. As suggested by a symmetric funnel plot in conjunction with the Egger’s test, there was no significant publication bias in MTHFR rs1801133 (P=0.318) and rs1801131 (P=0.204), F5 rs6025 (P=0.511), LEPR rs1137101 (P=0.511), AGT rs4762 (P=0.215) and rs699 (P=0.482), IL-10 rs1800871 (P=0.955), and rs1800896 (P=0.144).ConclusionsThis meta-analysis provides evidence that MTHFR rs1801133 and F5 rs6025 are associated with an increased risk of PE, especially in Caucasians. However, we do not have sufficient evidence to conclude there is a significant association between other gene polymorphisms and PE.

Genetic polymorphisms associated with overweight and obesity in uncontrolled Type 2 diabetes mellitus.

Generally, obese and overweight individuals display higher free fatty acid levels, which stimulate insulin resistance. The combination of overweight or obesity with insulin resistance can trigger Type 2 diabetes mellitus (T2DM) and are primary contributing factors to the development of uncontrolled T2DM. Genetic polymorphisms also play an important role as they can impact a population's susceptibility to becoming overweight or obese and developing related chronic complications, such as uncontrolled T2DM. This review specifically examines the genetic polymorphisms associated with overweight and obesity in patients with uncontrolled T2DM. Particularly, gene polymorphisms in ADIPOQ (rs1501299 and rs17300539), LepR (rs1137101 and rs1045895), IRS2 (rs1805092), GRB14 (rs10195252 and rs3923113) and PPARG (rs1801282) have been associated with overweight and obesity in uncontrolled T2DM.

Interaction of dietary fat intake with APOA2, APOA5 and LEPR polymorphisms and its relationship with obesity and dyslipidemia in young subjects.

BackgroundDiet is an important environmental factor that interacts with genes to modulate the likelihood of developing disorders in lipid metabolism and the relationship between diet and genes in the presence of other chronic diseases such as obesity. The objective of this study was to analyze the interaction of a high fat diet with the APOA2 (rs3813627 and rs5082), APOA5 (rs662799 and rs3135506) and LEPR (rs8179183 and rs1137101) polymorphisms and its relationship with obesity and dyslipidemia in young subjects.MethodsThe study included 200 young subjects aged 18 to 25 years (100 normal-weight and 100 obese subjects). Dietary fat intake was measured using the frequency food consumption questionnaire. Genotyping of polymorphisms was performed by PCR-RFLP.ResultsIndividuals carrying the APOA5 56 G/G genotype with a high saturated fatty acid consumption (OR = 2.7, p = 0.006) and/or total fat (OR = 2.4, p = 0.018), associated with an increased risk of obesity. We also found that A/G + G/G genotypes of the 668 A/G polymorphism in the LEPR gene with an intake ≥12 g/d of saturated fatty acids, have 2.9 times higher risk of obesity (p = 0.002), 3.8 times higher risk of hypercholesterolemia (p = 0.002) and 2.4 times higher risk of hypertriglyceridemia (p = 0.02), than those with an intake <12 g/d of saturated fatty acids. Similarly, LEPR 668 A/G + G/G carriers with a high fat total intake had 3.0 times higher risk of obesity (p = 0.002) and 4.1 times higher risk of hypercholesterolemia (p = 0.001).ConclusionOur results suggest that dietary fat intake modifies the effect of APOA5 and LEPR polymorphisms on serum triglycerides, cholesterol levels and obesity in young subjects.

Abstract P156: A Novel Gene-based Tool to Predict the Risk of Essential Hypertension and Initial Validation

Background: According to the CDC, 70 million American adults suffer from high blood pressure. With hypertension costing the United States $46 billion annually, efforts to screen, prevent, and treat hypertension are warranted. Objective: To create and evaluate the ability of a novel scoring algorithm derived from genotypic and phenotypic factors to predict the risk of essential hypertension. Subjects: For this multi-center, observational, retrospective study, 462 subjects were chosen from 14 clinical research sites across the U.S from the period of September 30, 2014 to December 17, 2014. The first study group of 126 subjects had a diagnosis of essential hypertension (ICD-9 codes 401, 401.1, and 401.9); and the first study set of 131 controls had no diagnosis of essential hypertension. The second study consisted of 95 subjects with a diagnosis of essential hypertension and 110 controls were used. Methods: Subjects were genotyped using TaqMan® SNP genotyping assays (Life Technologies, Carlsbad, CA). A scoring algorithm was developed using a logistic regression model with age as a phenotypic factor and 6 single nucleotide polymorphisms (COMT rs4680; PTGS1 rs1330344; SHMT1 rs1979277; LEPR rs1137101; and VKORC1 rs8050894). A second study was conducted to independently apply the algorithm and validate results. Results: For the first study group, the receiver operating characteristic (ROC) for the algorithm was statistically significant (AUC 0.917, p=0.000). From a scoring range of 0 - 17, 8.5 was determined to be the best cut-off score indicating a high risk of essential hypertension with a sensitivity of 83.17% (84 of 101); specificity 91.45% (107 of 117); PPV 89.36% (84 of 94); and NPV 86.29% (107 of 124). For the second study group, the ROC was also statistically significant (AUC 0.969, p=0.000). As in the first study group, a score of 8.5 was the best cut-off score for essential hypertension risk with a sensitivity of 91.58% (87 of 95); specificity 95.45% (105 of 110); PPV 94.57% (87 of 92); and NPV 92.92% (105 of 113). Conclusion: This scoring algorithm can reliably predict the risk of essential hypertension in two separate study groups. Implementing such a tool in clinical practice may guide treatment decisions for patients at risk of essential hypertension.

IGF2, LEPR, POMC, PPARG, and PPARGC1 gene variants are associated with obesity-related risk phenotypes in Brazilian children and adolescents.

Association studies of genetic variants and obesity and/or obesity-related risk factors have yielded contradictory results. The aim of the present study was to determine the possible association of five single-nucleotide polymorphisms (SNPs) located in the IGF2, LEPR, POMC, PPARG, and PPARGC1genes with obesity or obesity-related risk phenotypes. This case-control study assessed overweight (n=192) and normal-weight (n=211) children and adolescents. The SNPs were analyzed using minisequencing assays, and variables and genotype distributions between the groups were compared using one-way analysis of variance and Pearson's chi-square or Fisher's exact tests. Logistic regression analysis adjusted for age and gender was used to calculate the odds ratios (ORs) for selected phenotype risks in each group. No difference in SNP distribution was observed between groups. In children, POMC rs28932472(C) was associated with lower diastolic blood pressure (P=0.001), higher low-density lipoprotein (LDL) cholesterol (P=0.014), and higher risk in overweight children of altered total cholesterol (OR=7.35, P=0.006). In adolescents, IGF2 rs680(A) was associated with higher glucose (P=0.012) and higher risk in overweight adolescents for altered insulin (OR=10.08, P=0.005) and homeostasis model of insulin resistance (HOMA-IR) (OR=6.34, P=0.010). PPARG rs1801282(G) conferred a higher risk of altered insulin (OR=12.31, P=0.003), and HOMA-IR (OR=7.47, P=0.005) in overweight adolescents. PARGC1 rs8192678(A) was associated with higher triacylglycerols (P=0.005), and LEPR rs1137101(A) was marginally associated with higher LDL cholesterol (P=0.017). LEPR rs1137101(A) conferred higher risk for altered insulin, and HOMA-IR in overweight adolescents. The associations observed in this population suggested increased risk for cardiovascular diseases and/or type 2 diabetes later in life for individuals carrying these alleles.

Gene polymorphisms and increased DNA damage in morbidly obese women

Obesity is characterized by increased adipose tissue mass resulting from a chronic imbalance between energy intake and expenditure. Furthermore, there is a clearly defined relationship among fat mass expansion, chronic low-grade systemic inflammation and reactive oxygen species (ROS) generation; leading to ROS-related pathological events. In the past years, genome-wide association studies have generated convincing evidence associating genetic variation at multiple regions of the genome with traits that reflect obesity. Therefore, the present study aimed to evaluate the relationships among the gene polymorphisms ghrelin (GHRL–rs26802), ghrelin receptor (GHSR–rs572169), leptin (LEP–rs7799039), leptin receptor (LEPR–rs1137101) and fat mass and obesity-associated (FTO–rs9939609) and obesity. The relationships among these gene variants and the amount of DNA damage were also investigated. Three hundred Caucasian morbidly obese and 300 eutrophic (controls) women were recruited. In summary, the results demonstrated that the frequencies of the GHRL, GHSR, LEP and LEPR polymorphisms were not different between Brazilian white morbidly obese and eutrophic women. Exceptions were the AA-FTO genotype and allele A, which were significantly more frequent in obese women than in the controls (0.23% vs. 0.10%; 0.46 vs. 0.36, respectively), and the TT-FTO genotype and the T allele, which were less frequent in morbidly obese women (p<0.01). Furthermore, significant differences in the amount of genetic lesions associated with FTO variants were observed only in obese women. In conclusion, this study demonstrated that the analyzed SNPs were not closely associated with morbid obesity, suggesting they are not the major contributors to obesity. Therefore, our data indicated that these gene variants are not good biomarkers for predicting risk susceptibility for obesity, whereas ROS generated by the inflammatory status might be one of the causes of DNA damage in obese women, favoring genetically related diseases as obesity comorbidities.

Polymorphism in LEP and LEPR May Modify Leptin Levels and Represent Risk Factors for Thyroid Cancer.

Purpose. To understand the role of polymorphisms in the LEP (rs7799039 and rs2167270) and LEPR (rs1137101 and rs1137100) genes in DTC susceptibility and their effect on leptin levels. Methods. We studied 153 patients with DTC and 234 controls through TaqMan SNP Genotyping and ELISA, comparing these data to the clinicopathological data of patients with DTC. Results. Patients with AA genotype of rs7799039 had higher levels of serum leptin (9.22 ± 0.98 ng/mL) than those with AG genotype (10.07 ± 0.60 ng/mL; P = 0.005). Individuals with AG genotype of rs2167270 also produced higher serum leptin levels (10.05 ± 0.59 ng/mL) than the subjects with GG genotype (9.52 ± 0.79 ng/mL; P < 0.05). A multivariate logistic regression adjusted for gender, age, and BMI showed that the AG genotype of rs7799039 was an independent risk for DTC (OR, 11.689; P = 0.0183; 95% CI, 1.516–90.119). Similarly, AG and GG genotypes of rs1137101 increased the susceptibility to DTC (OR, 3.747; P = 0.027; 95% CI, 1.161–12.092 and OR, 5.437; P = 0.013; 95% CI, 1.426–20.729). Conclusions. We demonstrated that rs7799039 and rs2167270 polymorphisms modify the serum leptin concentrations in patients with DTC. Furthermore, polymorphisms rs7799039 and rs1137101 increase the risk of DTC development, although they do not correlate with tumor aggressiveness.