Genetic Variation in the Leptin Receptor Gene,Leptin, and Weight Gain in Young Dutch Adults

Objective: To investigate the association between leptin levels, polymorphisms in the leptin receptor (LEPR) gene, and weight gain. Research Methods and Procedures: From two large prospective cohorts in The Netherlands (n = 17, 500), we compared the baseline leptin of 259 subjects who had gained an average of 12.6 kg (range 5.5 to 33 kg) with 277 subjects who kept stable weight (range ?2.6 to 3.1 kg) after a mean follow‐up of 6.8 years. Three polymorphisms in the LEPR gene (Lys109Arg, Gln223Arg, and Lys656Asn) were determined. Results: Weight gainers had significantly higher baseline leptin levels than those who kept stable weight (odds ratio = 1.27, 95% confidence interval 1.1 to 1.5, per SD increase in log_e‐transformed leptin). Weight gainers with the Arg109 or the Arg223 alleles had higher leptin levels compared with the noncarriers of these alleles. Only among men, the association between leptin and weight gain tended to be stronger among those with an Arg223 allele compared with those without this mutation. Discussion: Relatively high leptin levels predict weight gain, suggesting that leptin resistance plays a role in the development of obesity in the general population. Higher leptin levels for those with a Lys109Arg or Gln223Arg mutation (or a linked other marker) may imply that these subjects have a modified functional leptin receptor. However, the role of these mutations on weight gain is limited.     

Leptin Levels,Leptin Receptor Gene Polymorphisms,and Energy Metabolism in Women

Objective: Resting metabolic rate (RMR) is mainly determined by fat‐free mass and additionally by age, sex, hormones, and possibly genetic differences. We evaluated whether leptin levels and polymorphisms in the leptin receptor (LEPR) gene were associated with energy expenditure phenotypes. Methods: RMR, body composition, and leptin levels were measured in 125 overweight and obese women. Three LEPR polymorphisms, Lys109Arg, Gln223Arg, and Lys656Asn, were typed on genomic DNA of another group of 192 women in whom RMR was measured. Fat, protein, and carbohydrate oxidation were calculated for 103 of these subjects. In 38 subjects, glucose‐induced thermogenesis was measured over 3 hours. Results: In the first study group, a negative correlation between RMR and leptin levels was found after controlling for fat and fat‐free mass. In multiple regression analysis, leptin contributed significantly to RMR, independent of body composition. In the second study group, RMR was not associated with LEPR polymorphisms. Differences in substrate oxidation rates were found among genotypes at the Lys656Asn site. In fasting conditions, Lys656Lys showed a trend to oxidize more carbohydrates and less fat than Asn656 carriers, a trend which became significant after the glucose load when carbohydrate oxidation rate in Lys656Lys was 15% higher than in Asn656 carriers (p = 0.04), and fat oxidation rate was 44% lower (p = 0.02). Discussion: These results suggest that DNA sequence variations in the LEPR gene could affect substrate oxidation. We hypothesize that this might be caused by differences in glucose levels, leading to differences in glucose oxidation rates.     

Associations among Lipids, Leptin, and Leptin Receptor Gene Gin223Arg Polymorphisms and Breast Cancer in China

We evaluated the relationship among the leptin receptor (LEPR) gene Gln223Arg polymorphism, body mass index (BMI), waist and hip circumference ratio (WHR), dietary structure, lifestyle, and other biomarkers with breast cancer and determined whether they could be effective for the prevention and treatment of breast cancer. The Gln223Arg polymorphisms in the LEPR gene were investigated in blood deoxyribonucleic acid (DNA) available for 240 breast cancer cases and 500 controls. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism. Leptin, insulin were determined by enzyme-linked immunosorbent assays. We found that the serum levels of leptin, insulin, triglyceride (TG), free cholesterol (FCH), apolipoprotain (APO) A1, and BMI were significantly higher in breast cancer cases than the controls, while physical activity was clearly less in breast cancer cases (P < 0.02 approximately P < 0.001, respectively). Moreover, there were significant association between the Gln223Arg genotype and breast cancer risk; homozygotes for AA and heterozygotes for AG,AG + GG genotypes had been proved to increase the risk of breast cancer, and their corresponding odds ratio were 7.14 (95% confidence interval [CI] = 1.92-25.64), 1.33(95% CI = 1.03-2.70), and 2.04 (95% CI = 1.09-3.82). Interestingly, logistic regression analysis showed that LEPR gene Gln223Arg polymorphism and elevated leptin, insulin, TG, FCH, APOA1, WHR, and reduced APOB increased the risk of developing breast cancer, respectively. And, it also suggested that LEPR gene Gln223Arg polymorphisms, elevated leptin, insulin, TG, FCH, APOA1, WHR, and reduced APOB should play a major role in the development of breast cancer.     

Relationship between leptin receptor and polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders, which is involved in the multi-system disease, and its etiology is still not clearly understood. It is currently considered that not only the genetic factors but also the environment factors play a crucial role in the pathogenesis of PCOS. Obesity plays an important role through the insulin, leptin and endocannabinoid system in the pathological process of PCOS, leading to more severe clinical manifestations. The aim of our present study is to investigate whether there is association between single nucleotide polymorphisms (SNPs) of Gln223Arg and Pro1019Pro in the leptin receptor gene (LEPR) and PCOS in a Korean population. Interestingly, a significant association was found between the Pro1019Pro in LEPR gene and PCOS, and a highly significant association was found between the Gln223Arg in LEPR gene and PCOS (P = 0.033, OR = 1.523, 95% confidence interval and P < 0.0001, OR = 0.446, 95% confidence interval). Moreover, genotype combination and haplotype analyses indicate that Gln223Arg and Pro1019Pro polymorphisms of LEPR are significantly associated with the risk of PCOS.     

Effect of LEPR Gln223Arg polymorphism on breast cancer risk in different ethnic populations: a meta-analysis

Leptin and leptin receptor have been implicated in processes leading to breast cancer initiation and progression. An A to G transition mutation in codon 223, in exon 6 of the leptin receptor gene (LEPR) can result in glutamine to arginine substitution (Gln223Arg). A variety of case–control studies have been published evaluating the association between LEPR Gln223Arg polymorphism and breast cancer. However, published studies have yielded contradictory conclusions. This meta-analysis enrolled eight studies to estimate the overall risk of LEPR Gln223Arg polymorphism associated with breast cancer. The pooled ORs were performed for codominant model (Arg/Arg versus Gln/Gln; Arg/Gln versus Gln/Gln), dominant model (Arg/Arg + Arg/Gln versus Gln/Gln), recessive model (Arg/Arg versus Arg/Gln + Gln/Gln). Overall significantly elevated breast cancer risk was found for recessive model (OR 1.32, 95% CI 1.03–1.69) and for genotype Arg/Gln versus Gln/Gln (OR 1.16, 95% CI 1.01–1.34). In the stratified analysis by ethnicity, significantly increased risks were also found among Africans for genotype Arg/Arg versus Gln/Gln: OR 1.86, 95% CI 1.28–2.71, Arg/Gln versus Gln/Gln: OR 1.48, 95% CI 1.10–1.99, dominant model: OR 1.60, 95% CI 1.21–2.11 and recessive model: OR 1.48, 95% CI 1.07–2.05; for Asians, Arg/Arg versus Gln/Gln: OR 6.79, 95% CI 3.42–13.47 and dominant model: OR 2.03, 95% CI 1.42–2.90. However, no significantly increased risk was found among Europeans for all genetic models. In conclusion, the LEPR 223Arg is a low-penetrant risk for developing breast cancer, especially for black African women.     

Leptin receptor Arg109 homozygotes display decreased total mortality as well as lower incidence of cardiovascular disease and related death

Two leptin receptor single nucleotide polymorphisms, Lys109Arg and Gln223Arg, have been shown to associate with several risk factors for cardiovascular disease. In addition, we have previously shown that Arg109 and Arg223 homozygotes displayed lower intima-media thickness in our well-defined OPERA (Oulu Project Elucidating Risk of Atherosclerosis) study. This current research investigated the impact of these LEPR polymorphisms on cardiovascular events and related death as well as to total mortality in the 19-year follow-up of OPERA. Subjects were randomly selected, middle-aged drug-treated hypertensives and their age- and sex-matched control subjects recruited to the OPERA study between 1990 and 1993. Mortality and hospital events of 1045 subjects were followed up until 2009. A total of 151 coronary heart disease (CHD) and 211 cardiovascular disease (CVD) events or deaths including 58 CHD and 69 CVD deaths occurred. Furthermore, during this follow-up, a total of 165 subjects died. Logistic regression analysis was performed to assess the impact of Lys109Arg and Gln223Arg on the events and death. Further modeling was performed with Cox regression for Lys109Arg. The logistic regression analysis revealed a significant protective impact of Arg109Arg genotype on CHD (OR 0.433; CI 95% 0.217–0.863) and CVD (OR 0.540; CI 95% 0.309–0.942) events or death as well as on total mortality (OR 0.390; CI 95% 0.196–0.775) when adjusted with age, sex and study group. Even after further adjustment with BMI, smoking status, systolic blood pressure and low-density lipoprotein cholesterol, the protective effect of Arg109Arg on CHD events or death and total mortality still remained statistically significant (OR 0.463; CI 95% 0.230–0.931 and OR 0.442; CI 95% 0.218–0.896, respectively). Arg109Arg was also shown to confer protection against CHD mortality (HR 0.224; CI95% 0.055–0.919) and overall mortality (HR 0.413; CI95% 0.218–0.783) also in Cox regression analysis. In conclusion, the Arg109Arg genotype of LEPR seems to be protective from cardiovascular events and death and this phenomenon seems to be independent of the traditional risk factors for atherosclerosis.     

Polymorphic markers associated with genes responsible for lipid and carbohydrate metabolism disorders and insulin resistance in cancer patients

Glucose intolerance and insulin resistance are among the leading risk factors for breast (BC) and endometrial cancer (EC). Differences in the degree of association of these endocrine disorders with BC and EC can at least partly be explained by the diverse polygenic nature of the aforementioned metabolic shifts as well as of oncological diseases themselves. In 105 healthy postmenopausal women and 301 female cancer patients (110 BC and 191 EC) without overt diabetes mellitus, we compared the frequencies of the following genetic polymorphisms: insulin receptor substrate-1, IRS Gly972Arg; leptin receptor, LEPR Lys109Arg and Gln223Arg; mitochondrial uncoupling protein-2, UCP2_866G/A; and the ND3 gene of mitochondrial DNA, mtDNA 10398A/G. Genotyping was performed by allele-specific real-time PCR. The heterozygous genotype Gln/Arg of the Gln223Arg polymorphism in LEPR and the combination of the Gln/Arg and Gln/Gln genotypes proved to be associated with elevated risks of both BC (OR _Gln/Arg = 2.03 (CI = 1.08–3.81), p = 0.027; OR _{Gln/Arg+Gln/Gln} = 1.87 (CI = 1.02–3.43), p = 0.042) and EC ( OR _Gln/Gln = 2.05 (CI = 1.00–4.17), p = 0.046, OR _Gln/Arg = 1.88 (CI = 1.07–3.28), p = 0.026). Other markers (genotype UCP2_866AA and mtDNA polymorphism 10398A) appeared to be relatively more frequent in EC than in BC, which may account for lower insulin sensitivity and higher incidence of carbohydrate metabolism disorders in EC cases.     

G-2548A polymorphism of the leptin gene is correlated with extreme obesity in Taiwanese aborigines

We examined the genetic associations of the G-2548A polymorphism in the promoter of the leptin (LEP) gene and the Gln223Arg (Q223R) polymorphism of the leptin receptor (LEPR) gene with obesity. Two hundred twenty-six obese aboriginal subjects (BMI > or = 27 kg/m2) and 182 aboriginal subjects with normal weight (BMI < 25 kg/m2) participated in this study. The polymorphisms of LEP G-2548A and LEPR Q223R were genotyped by polymerase chain reaction/restriction fragment length polymorphism, and their anthropometric characteristics were measured. Levels of leptin, triglycerides, and cholesterol were measured after overnight fasting. We found that the frequencies of the LEP G/G homozygote (22.6%) with Mendelian recessive (chi2 = 7.89, p = 0.005) and codominant (chi2 = 7.93, p = 0.02) models to be higher in the extremely obese subjects (BMI > or = 35 kg/m2) than in normal weight subjects (6.9%) but not in moderately obese subjects (35 > BMI > or = 27 kg/m2). There was no difference in genotypic frequency of the LEPR Q223R polymorphism between the extreme obese and control groups. We suggest that the LEP -2548 G/G homozygote plays a genetic recessive role in the development of extreme obesity in Taiwanese aborigines.     

Leptin G-2548A and leptin receptor Q223R gene polymorphisms are not associated with obesity in Romanian subjects

We aimed to investigate whether polymorphisms LEP G-2548A and LEPR Q223R in the human leptin (LEP), and leptin receptor (LEPR) genes are associated with obesity and metabolic traits in a sample of Romanian population. Two hundred and two subjects divided in obese (body mass index, BMI ? 30 kg/m²), and non-obese were included in this study. The polymorphisms were genotyped using polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP) analysis. The results showed no significant differences in LEP and LEPR genotype and allele frequencies between obese and non-obese subjects. Logistic regression analysis showed that LEP -2548GG genotype presented an increased risk of obesity (p = 0.013, OR = 1.003, 95% CI = 1.000-1.007), after adjusting for age and gender. The association analysis with metabolic syndrome quantitative traits showed that homozygous for LEP -2548G allele had significantly higher leptin levels (17.2 ± 6.6 ng/ml vs. 13.2 ± 4.9 ng/ml, p = 0.011), and carriers of R allele had higher levels of triglycerides (p = 0.017) and glucose (p = 0.040), and enhanced systolic (p = 0.015) and diastolic blood pressure (p = 0.026), after adjustment for age, gender, and BMI. These results indicate that LEP G-2548A and LEPR Q223R SNPs may not be considered as genetic risk factors for obesity in a sample of Romanian population. However, LEP -2548GG genotype appear to be important in regulating leptin levels, whereas the LEPR 223R allele might predispose healthy subjects to develop metabolic disturbances.     

Leptin Does Not Play a Major Role in Platelet Aggregation in Obesity and Leptin Deficiency

Objective: A recent study suggested that high concentrations of leptin enhance platelet aggregations. Therefore, the aim of this study was to investigate whether platelet aggregation is altered in patients with leptin gene mutations compared with obese subjects or controls. Research Methods and Procedures: Four men (one homozygous man and his three heterozygous brothers) carrying a leptin gene mutation; 20 age‐matched, healthy, unrelated men; and 18 age‐matched obese men were enrolled in the study. Adenosine diphosphate (ADP)‐, collagen‐, and epinephrine‐induced platelet aggregation were evaluated in all individuals. Results: Our results show that patients with the leptin gene mutation (both the homozygous and heterozygous patients) had significantly higher ADP‐induced (78.3 ± 3.4% vs. 57.9 ± 9.3%, p = 0.001), collagen‐induced (78.1 ± 2.9% vs. 56.7 ± 9.3%, p = 0.007), and epinephrine‐induced (76.5 ± 9.2% vs. 59.5 ± 7.70%, p = 0.003) platelet aggregation compared with controls. However, ADP‐, collagen‐, or epinephrine‐induced platelet aggregations were similar to those in obese patients. Platelet aggregation responses to a combination of pretreatment with leptin at concentrations of 20, 50, 100, or 500 ng/mL for 5 minutes and ADP at concentrations of 2 μmol/liter also were evaluated. However, we did not find significant increases in platelet aggregation even at high concentrations of leptin (100 or 500 ng/mL) in leptin‐deficient patients, obese subjects, or controls. Discussion: Our data show that similar to findings in obese humans, homozygous or heterozygous leptin deficiency is associated with increased platelet aggregation compared with controls, and that higher concentrations of leptin do not increase platelet aggregation.     

Leptin and the Development of Obesity and Diabetes in Psammomys obesus

COLLIER, GREG R, KEN WALDER, PAUL LEWAN DOWSJCI, ANDREW SANIGORSKI, PAUL ZIMMET. Leptin and the development of obesity and diabetes in Psammomys obesus. The recently discovered ob gene and its circulating product, leptin, may be critical factors in the control of energy balance. Recent studies in ob/ob mice, which lack circulating leptin, have shown dramatic reductions in food intake and bodyweight after leptin treatment. In addition, studies in both humans with obesity and animal models of obesity have demonstrated hyperleptinemia. Here, we report a longitudinal study examining changes in circulating leptin during the development of obesity and diabetes in Psammomys obesus. Over the 8 weeks of the study, lean animals increased their bodyweight by 154% and leptin levels remained essentially unchanged. In contrast, animals that developed obesity (223 % increase in bodyweight), hyperglycemia, and hyperinsulinemia also developed hyperleptinemia between 4 weeks and 8 weeks of age. These results demonstrate that the development of hyperleptinemia is associated with the development of obesity and subsequent metabolic abnormalities.     

Association between variants of the leptin receptor gene (LEPR) and overweight: a systematic review and an analysis of the CoLaus study

Background

Three non-synonymous single nucleotide polymorphisms (Q223R, K109R and K656N) of the leptin receptor gene (LEPR) have been tested for association with obesity-related outcomes in multiple studies, showing inconclusive results. We performed a systematic review and meta-analysis on the association of the three LEPR variants with BMI. In addition, we analysed 15 SNPs within the LEPR gene in the CoLaus study, assessing the interaction of the variants with sex.

Methodology/Principal Findings

We searched electronic databases, including population-based studies that investigated the association between LEPR variants Q223R, K109R and K656N and obesity- related phenotypes in healthy, unrelated subjects. We furthermore performed meta-analyses of the genotype and allele frequencies in case-control studies. Results were stratified by SNP and by potential effect modifiers. CoLaus data were analysed by logistic and linear regressions and tested for interaction with sex. The meta-analysis of published data did not show an overall association between any of the tested LEPR variants and overweight. However, the choice of a BMI cut-off value to distinguish cases from controls was crucial to explain heterogeneity in Q223R. Differences in allele frequencies across ethnic groups are compatible with natural selection of derived alleles in Q223R and K109R and of the ancient allele in K656N in Asians. In CoLaus, the rs10128072, rs3790438 and rs3790437 variants showed interaction with sex for their association with overweight, waist circumference and fat mass in linear regressions.

Conclusions

Our systematic review and analysis of primary data from the CoLaus study did not show an overall association between LEPR SNPs and overweight. Most studies were underpowered to detect small effect sizes. A potential effect modification by sex, population stratification, as well as the role of natural selection should be addressed in future genetic association studies.     

LEP (−2548G>A LEP) and LEPR (223Gln>Arg, 109Lys>Arg) polymorphisms as breast cancer risk factors in the Polish female population

On a global scale, breast cancer is the most common type of cancer in women, and it is still a growing problem. Therefore, new prognostic or diagnostic markers are required that would facilitate the assessment of patients or provide more efficient therapy, respectively. In these studies, we analyzed the contribution of LEP (2548G>A) and LEPR (109 Lys>Arg and 223Gln>Arg) genes polymorphisms to the risk of breast cancer development. The study involved 209 women aged 59.6?±?11 years diagnosed with breast cancer and 202 healthy women aged 57.8?±?8.2 years, who were blood donors. Polymorphism were evaluated by PCR–RFLP reaction followed by the verification of part of the samples by sequencing. The results of the study confirmed obesity as a significant breast cancer development risk factor in Polish women. However, no significant association between the studied polymorphisms and breast cancer risk or severity of the neoplastic disease was found. Interestingly, it was shown that wild type 223Gln>Gln leptin receptor (LEPR) was statistically more common in women with human epidermal growth factor receptor 2 negative (HER2?) than human epidermal groth factor receptor 2 positive (HER2+) breast cancer and wild type form of 2548G>A LEP was more common in women with progesterone receptor positive (PR+) than progesterone receptor negative (PR?) breast cancer. Studied polymorphisms of the LEP and LEPR genes do not increase breast cancer risk in the population of Polish women. However, they can affect PR an HER receptors expression and thus the severity of the disease. Noteworthy, this interesting correlation is being reported for the first time and might constitute an essential contribution to the identification of molecular mechanisms of carcinogenesis.

     

Percent Body Fat and Lean Mass Explain the Gender Difference in Leptin: Analysis and Interpretation of Leptin in Hispanic and Non‐Hispanic White Adults

Objective: To reassess the relationship between body fat and fasting leptin concentrations comparing plasma vs. serum assessments of leptin; ratios vs. regression adjustment for body composition; fat and lean mass vs. percent body fat; and gender‐, ethnic‐, and age‐related variations. Research Methods and Procedures: Subjects included 766 adults from the nondiabetic cohort of the San Luis Valley Diabetes Study examined at follow up (1997 to 1998). Body composition was determined by dual energy X‐ray absorptiometry. Leptin concentrations were determined after an overnight fast. Results: Fasting serum and plasma assessments of leptin were correlated with percent body fat to the same degree. Women had significantly higher serum leptin concentrations than men when leptin concentrations were divided by body mass index, fat mass in kilograms or percent body fat. The methodological problem inherent in interpreting these ratio measures is pictorially demonstrated. In regression analysis, fat mass alone did not explain the gender difference. However, lean body mass was inversely related to leptin concentrations (p < 0.0001) and explained 71% of the gender difference at a given fat mass. Percent body fat explained all of the gender difference in leptin concentrations in both Hispanics and non‐Hispanic whites. Similar to findings about gender differences, ethnic‐ and age‐related variations in the leptin‐body fat association were minimized when percent body fat was employed as the body fat measure. Discussion: Regression analysis and percent body fat measured with dual energy X‐ray absorptiometry are recommended when assessing the relationship between leptin and body fat. Gender differences in leptin concentrations were accounted for by percent body fat in free living (no diet control), Hispanic and non‐Hispanic white adults.     

Plasma Leptin Response to an Epinephrine Infusion in Lean and Obese Women

Objective: Because leptin production by adipose tissue is under hormonal control, we examined the impact of epinephrine administration on plasma leptin concentrations. Research Methods and Procedures: We measured plasma leptin, insulin, and free fatty acid (FFA) responses after a 60-minute epinephrine infusion (0.010 μg/kg fat free mass/min) followed by a 30-minute recovery period (no infusion) in a group of 11 lean (mean body mass index ± SD: 22.6 ± 1.1 kg/m²) and 15 obese (30.0 ± 1.3 kg/m²) premenopausal women. Leptin, insulin, and FFA levels were measured in plasma before (−15 and 0 minutes) and at every 30 minutes over the 90-minute period. Results: In both lean and obese individuals, plasma leptin was significantly reduced by epinephrine (p < 0.0001). Body fat mass was associated with fasting leptin levels (r = 0.64, p < 0.0005) as well as with the decrease in leptinemia (r = −0.51, p < 0.01) produced by epinephrine administration. Furthermore, we noted a large range of leptin response to epinephrine among our subjects, especially in obese women (from −12 to −570 ng/mL per 60 minutes). However, there was no association between postepinephrine leptin and FFA levels (r = −0.14, p = 0.55). Discussion: Results of this study indicate that leptin levels decrease after epinephrine administration in both lean and obese premenopausal women. However, the heterogeneity in the response of leptin to catecholamines suggests potential alterations of the leptin axis that may contribute to generate a positive energy balance and, thus, may favor weight gain in some obese individuals.     

Leptin receptor is a key gene involved in the immunopathogenesis of thyroid-associated ophthalmopathy

Thyroid-associated ophthalmopathy (TAO), the most common and severe manifestation of Graves' disease (GD), is a disfiguring and potentially blinding autoimmune disease. The high relapse rate (up to 20%) and substantial side effects of glucocorticoid treatment further decrease the life quality of TAO patients. To develop novel therapies, we amid to explore the immunopathogenesis of TAO. To identify the key immune-related genes (IRGs) in TAO, we integrated the IRG expression profiles in thyrocytes from a GD patient set (GD vs healthy control) and a TAO patient set (TAO vs GD). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), protein-protein interaction (PPI) and receiver operating characteristic (ROC) curve analyses identified the leptin receptor (LEPR) gene as the key IRG in TAO immunopathogenesis. Gene set enrichment analysis (GSEA) suggested enrichment of the antigen presentation pathway in TAO patients with higher LEPR. Increased LEPR expression was validated in TAO orbital tissues, and weighted gene co-expression network analysis (WGCNA) showed that cell adhesion processes were positively correlated with LEPR. Our study revealed that LEPR is a key gene in TAO immunopathogenesis and plays different roles in thyrocytes and orbital tissues. Our findings provide new insights into diagnostic and therapeutic biomarkers for TAO.     

Leptin and leptin receptor gene polymorphisms and their association with plasma leptin levels and obesity in a multi-ethnic Malaysian suburban population

Background

This study was to investigate the prevalence of single nucleotide polymorphisms (SNPs) in leptin gene LEP (A19G and G2548A) and leptin receptor gene LEPR (K109R and Q223R) and their association with fasting plasma leptin level (PLL) and obesity in a Malaysian suburban population in Kampar, Perak.

Methods

Convenience sampling was performed with informed consents, and the study sample was drawn from patients who were patrons of the Kampar Health Clinic. A total of 408 subjects (mean age, 52.4 ± 13.7 years; 169 men, 239 women; 190 obese, 218 non-obese; 148 Malays, 177 ethnic Chinese, 83 ethnic Indians) participated. Socio-demographic data and anthropometric measurements were taken, and genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).

Results

The LEP A19G, G2548A and LEPR K109R, Q223R variant allele frequencies were 0.74, 0.67 and 0.61, 0.79, respectively. The genotype and allele distributions of these gene variants were significantly different among ethnic groups, but not among body mass index (BMI) classes. Subjects with LEPR K109 and Q223 allele had significantly higher systolic blood pressure and adiposity indices after adjustment for ethnicity (higher BMI, total body and subcutaneous fat; lower skeletal muscle percentage). Subjects with LEPR 109R allele had lower PLL than their wild-type allele counterparts. The influence of LEP A19G and G2548A SNPs on blood pressures, anthropometrics, and PLL was not evident. Interestingly, synergistic effect of the LEP and LEPR SNPs was observed as subjects homozygous for all four SNPs studied exhibited significantly higher subcutaneous fat and PLL than those with other genotype combinations.

Conclusions

The LEP and LEPR SNPs in this study may not be an obesity marker among Malaysians in this population, but were associated with ethnicity. Our findings suggest that each of these SNPs contributes to minor but significant variation in obesity-related traits and in combination they display synergistic effects on subcutaneous fat and PLL.     

Leptin −2548 G/A polymorphisms are associated to clinical progression of oral cancer and sensitive to oral tumorization in nonsmoking population

Oral cancer is causally associated with environmental carcinogens, and the susceptibility to carcinogen-mediated tumorigenesis is proposed to be genotype-dependent. Leptin (LEP) and leptin receptor (LEPR) both play a crucial role in the mediation of physiological reactions and carcinogenesis and may serve as a candidate biomarker of oral cancer. The current case-control study aimed to examine the effects of LEP −2548 G/A (rs7799039), LEPR K109R (rs1137100), and LEPR Q223R (rs1137101) single-nucleotide polymorphisms (SNPs) with or without interacting to environmental carcinogens on the risk for oral squamous cell carcinoma. The SNPs of three genetic allele, from 567 patients with oral cancer and 560 healthy controls in Taiwan were analyzed. The results shown that the patients with polymorphic allele of LEP −2548 have a significant low risk for the development of clinical stage (A/G: adjusted odds ratio [AOR] = 0.670, 95% confidence interval [CI] = 0.454-0.988, P < 0.05; A/G + G/G: AOR = 0.676, 95% CI = 0.467-0.978, P < 0.05) compared to patients with ancestral homozygous A/A genotype. In addition, an interesting result was found that the impact of LEP −2548 G/A SNP on oral carcinogenesis in subjects without tobacco consumption is higher than subjects with tobacco consumption. These results suggest that the genetic polymorphism of LEP −2548 G/A (rs7799039), LEPR K109R (rs1137100), and LEPR Q223R (rs1137101) were not associated to the susceptibility of oral cancer; SNP in LEP −2548 G/A showed a poor clinicopathological development of oral cancer; population without tobacco consumption and with polymorphic LEP −2548 G/A gene may significantly increase the risk to have oral cancer.     

Leptin and Altitude in the Cardiovascular Diseases

Objective: The lower mortality from coronary ischemic disease in populations living at high altitude has been related to an increase of high‐density lipoprotein (HDL)‐cholesterol at altitude. Leptin has been proposed as a cardiovascular risk factor. We investigated whether leptin varies according to the altitude at which people live. Research Methods and Procedures: This was a cross‐sectional study of the first 889 people enrolled in a cohort study in the Canary Islands, Spain. The relationship among serum leptin, altitude, obesity, and other cardiovascular risk factors was analyzed by bivariate and multivariate tests. Results: Leptin levels showed an inverse correlation to altitude expressed in meters (r = ?0.10). Obese subjects had this leptin‐altitude association (r = ?0.19), but they also had a direct correlation of leptin to HDL‐cholesterol (r = 0.27) and an inverse correlation of leptin to the total cholesterol‐to‐HDL‐cholesterol ratio (r = ?0.34), triglycerides (r = ?0.29), apolipoprotein B (r = ?0.21), and glycemia (r = ?0.19). Nonobese subjects had only the leptin‐altitude association (r = ?0.11). The final regression model included altitude as predictor. Other associated variables were gender, physical activity, BMI, age, smoking (reducing leptin independently of BMI), alcohol, heart rate, and income. Discussion: Serum leptin level decreases when altitude increases, and this association could help to explain the lower cardiovascular mortality rate at high altitude. However, because in obese subjects there is a direct association of leptin with HDL‐cholesterol and an inverse association with the lipid atherogenic fractions, we suggest the hypothesis of different roles for bound and free leptin, with free leptin being a cardiovascular protective factor in obese people.     

Low serum leptin predicts mortality in patients with chronic kidney disease stage 5

Objective: Leptin, secreted from adipose tissue, regulates food intake, energy expenditure, and immune function. It is unknown whether leptin predicts mortality in patients with chronic kidney disease stage 5 on hemodialysis therapy. Research Methods and Procedures: We performed a prospective cohort study of 71 patients with chronic kidney disease stage 5 in an outpatient hemodialysis center. Subjects were recruited in June 1998 and followed for 83 months. Survival was compared by the Kaplan‐Meier method. Results: After 83 months of follow‐up, 48 patients (68%) had died. Serum leptin concentrations at study entry were lower among all deceased patients compared with those patients who survived (5.2 ± 9.0 μg/L; n = 48; vs. 7.7 ± 7.8 μg/L; n = 23; p = 0.005). Baseline serum leptin concentrations were significantly lower in patients who died from cardiovascular diseases (4.7 ± 9.4 μg/L, n = 32) or infections (4.0 ± 2.7 μg/L; n = 10; each p < 0.05), but not cancer (9.4 ± 7.9 μg/L; n = 6), than in survivors (7.7 ± 7.8 μg/L; n = 23; p = 0.003). The relative risk for mortality in patients with serum leptin concentrations below the median (<2.6 μg/L) compared with patients above the median was 1.96 (95% confidence interval, 1.01 to 3.79; p = 0.04). Survival was shorter in patients with leptin concentrations below the median compared with those whose leptin concentrations were above the median (all‐cause mortality, χ² = 5.05; p = 0.02). Discussion: Low serum leptin concentration is an independent predictor of mortality in patients with chronic kidney disease stage 5 on hemodialysis therapy.