Gln223Arg Polymorphism Research Articles

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.

The Gln223Arg polymorphism in the leptin receptor is associated with familial combined hyperlipidemia

Familial combined hyperlipidemia (FCH) is characterized by elevated levels of total cholesterol (TC), triglycerides (TG) and apolipoprotein B (apo B) and is associated with premature cardiovascular disease (CVD). Other features of FCH are obesity and insulin resistance. Serum leptin levels have also been associated with obesity, insulin resistance and atherosclerosis. Leptin exerts its effect through the leptin receptor (LEPR). The aim of this study is to determine whether the Gln223Arg polymorphism in the LEPR gene contributes to FCH and its associated phenotypes. The study population consists of 37 families, comprising 644 subjects, of whom 158 subjects were diagnosed as FCH. The FCH diagnosis was based on plasma TC and TG levels, adjusted for age and gender, and absolute apo B levels, according to our recently published nomogram. The Gln223Arg polymorphism was studied by restriction fragment length polymorphism-PCR. Carriers of one or two Arg alleles had an increased risk of FCH, compared to subjects homozygous for the Gln allele (OR=1.6 [95% CI 1.0-2.4]). A difference in high-density lipoprotein cholesterol (HDL-c) levels was present between carriers and non-carriers of an Arg allele, 1.21 vs 1.28 mmol/l, respectively (P=0.04), but no differences in obesity, insulin resistance and other lipid parameters were found. The Gln223Arg polymorphism in the LEPR gene is associated with FCH, which is supported by a significant association between HDL-c levels and the LEPR gene.

Association analysis of the Gln223Arg polymorphism in the human leptin receptor gene, and traits related to obesity in Mexican adolescents

Polymorphisms of leptin receptor (LEPR) may contribute to a common form of obesity and, as a consequence, obesity-related diseases. We evaluated the potential role of genetic variation at the LEPR gene in heart sympathetic activity and other traits related to obesity in Mexican adolescents. Adolescents aged between 12 and 17 years, with steady body weight for the last 3 months were included. We evaluated anthropometric measurements, blood pressure, seric glucose, insulin, leptin levels, heart sympathetic activity (by electrocardiograph monitoring at rest), and the Gln223Arg and Pro1019Pro LEPR polymorphisms in each subject. In total, 103 adolescents (55 obese and 48 nonobese) were included. The group of obese adolescents showed higher sympathetic activity, blood pressure, glucose, insulin, and leptin levels. The genotype frequencies for the two polymorphisms were found to be in Hardy-Weinberg equilibrium. There was no difference in the genotype frequencies for Gln223Arg or Pro1019Pro polymorphisms between obese and nonobese adolescents. However, there was a higher prevalence of Gln223 allele among subjects with higher insulin levels (0.72 vs 0.57; P = 0.04 for adolescents with insulin levels higher and lower than 100 pmol/l, respectively). According to Gln223Arg polymorphism, those with Gln allele (Gln/Gln and Gln/Arg) had higher heart sympathetic activity, body fat percentage, and leptin levels. To conclude, our results support the hypothesis that Gln223Arg polymorphism of LEPR in Mexican adolescents is associated with haemodynamic and metabolic disturbances related to obesity.

Relationships between serum soluble leptin receptor level and serum leptin and adiponectin levels, insulin resistance index, lipid profile, and leptin receptor gene polymorphisms in the Japanese population

Leptin plays an important role in the regulation of body weight and is known to circulate in both free and bound forms. One of the leptin receptor isoforms exists in a circulating soluble form that can bind leptin. Clinical studies have shown that soluble leptin receptor (sOB-R) levels are lower in obese individuals. In the present study, we measured the serum sOB-R level in 419 healthy Japanese subjects (198 men and 221 women, aged 30 to 65 years, body mass index [BMI] 21.7 ± 2.6 [SD] kg/m 2) and in 150 type 2 diabetic patients (96 men and 54 women, BMI 24.3 ± 3.8 kg/m 2). We investigated the relationships between serum sOB-R level and BMI, blood pressure, homeostasis model assessment-insulin resistance index (HOMA-IR), serum leptin and adiponectin levels, lipid profile, and leptin receptor (LEPR) gene Lys109Arg and Gln223Arg polymorphisms. Serum leptin and sOB-R levels were measured by radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA), respectively. The serum sOB-R level in men was significantly higher than that in women. The serum sOB-R level was negatively correlated with BMI, fasting insulin, HOMA-IR, and serum leptin level and positively correlated with high-density lipoprotein (HDL)-cholesterol and serum adiponectin levels. The correlations between serum sOB-R level and fasting insulin, HOMA-IR, serum leptin, adiponectin, and HDL-cholesterol levels were significant even after adjustment for age, sex, and BMI in healthy subjects. There was no association between serum sOB-R level and the LEPR polymorphisms examined. These findings suggest that the serum sOB-R level is negatively correlated with HOMA-IR and serum leptin level and positively correlated with HDL-cholesterol level and serum adiponectin level, independent of age, sex, and BMI, in the Japanese population.

Association between leptin receptor gene polymorphisms and early‐onset prostate cancer

To report a case-control study examining the relationship between polymorphisms in the leptin receptor (OBR) gene and the development of young-onset prostate cancer, because epidemiological studies report that prostate cancer risk is associated with animal fat intake, and thus we investigated if this association occurs via this genetic mechanism. The Lys109Arg (OBR1) and Gln223Arg (OBR2) polymorphisms in the coding region of OBR were studied in blood DNA from 271 patients with prostate cancer aged < 56 years at diagnosis and 277 geographically matched control subjects. Cases were collected through the Cancer Research UK/British Prostate Group Familial Prostate Cancer Study. Blood DNA was genotyped using the polymerase chain reaction and a restriction enzyme digest. There was no statistically significant association between the OBR genotype and prostate cancer risk; men homozygous for 109Arg genotype had a slightly increased risk for prostate cancer, with a relative risk (95% confidence interval) of 1.36 (0.65-2.85), and those homozygous for the 223Arg allele had some reduction in prostate cancer risk, at 0.82 (0.58-1.26), but neither was statistically significant. This case-control study showed no significant association between leptin receptor gene polymorphisms and the risk of young-onset prostate cancer, suggesting that genetic variations in OBR are unlikely to have a major role in the development of early-onset prostate cancer in the UK.

The Gln223Arg polymorphism of the leptin receptor in Pima Indians: influence on energy expenditure, physical activity and lipid metabolism.

Leptin regulates body weight by its receptor-mediated anorectic, thermogenic and antisteatotic effects. Recently, lower leptin binding to the soluble form of the leptin receptor (LEPR) was shown in carriers of the Arg223-encoding allele of the Gln223Arg polymorphism of the LEPR. To investigate whether this variant influences energy metabolism and adiposity in Pima Indians, we genotyped non-diabetic Pima Indians in whom we had measured body composition and 24 h energy expenditure (24 h EE), physical activity level (PAL) and 24 h respiratory quotient (24 h RQ) in a respiratory chamber (n=268) and who had undergone percutaneous fat biopsies from the periumbilical region (n=184). Genotype was not associated with percent body fat (P>0.39), but was associated with 24 h EE, PAL and mean subcutaneous abdominal adipocyte size (SAAS all P<0.05). Homozygotes for the Arg223-encoding allele had lower 24 h EE (P=0.04) and PAL (P=0.007), but larger SAAS (P=0.01) than Gln homozygotes. These findings are consistent with a role of the Gln223Arg polymorphism in reducing peripheral and central leptin binding to the LEPR in humans. However, these effects do not seem to have a major impact on adiposity in this population.

Estrogen receptor alpha gene polymorphisms Pvu II and Xba I influence association between leptin receptor gene polymorphism (Gln223Arg) and bone mineral density in young men.

The peak bone mass is recognized as an important determinant in the development of osteoporosis. We investigated associations between bone mineral density (BMD) and polymorphisms of the leptin receptor (LEPR) and estrogen receptor alpha (ERalpha) genes in young men. BMD, anthropometric characteristics, and serum leptin concentrations were measured in young men and compared with regard to the LEPR and ERalpha genotype. From 219 healthy volunteers aged 20-34 Years, we genotyped the Lys109Arg, Gln223Arg, Ser492Thr, Ala976Asp, and Pro1019Pro variants of LEPR and the PvuII and XbaI variants of ERalpha using the polymerase chain reaction-restriction fragment length polymorphism method. We determined serum leptin concentrations by radioimmunoassay (RIA) and BMD by dual energy X-ray absorptiometry. The subjects carrying the Gln223 allele of LEPR had higher BMD at the lumbar spine compared with the subjects without this allele. There were no significant differences in BMD among PvuII and XbaI genotypes of ERalpha. However, an association between LEPR and BMD was noted in the subjects carrying the PP homozygotes of PvuII or the X alleles of XbaI, but this was not significant in those without these genotypes. This study indicates that the Gln223Arg polymorphism of LEPR is important for determination of the peak bone mass in men and that it is influenced by ERalpha gene polymorphisms.

Association analysis of genes involved in the leptin-signaling pathway with obesity in Brazil.

To investigate associations of polymorphisms in the LEP, LEPR and NPY genes with obesity-related traits in a Brazilian population of European descent. A total of 183 women and 153 men (mean body mass index (BMI), 26.1+/-4.8 kg/m(2)) were genotyped using the PCR-RFLP procedure for the LEP A19G, LEPR Gln223Arg, LEPR PRO1019pro and NPY Leu7Pro polymorphisms. Frequencies were compared among normal-weight and overweight plus obese groups with chi-square tests, mean BMI and waist circumference were compared among genotypes by t-tests and analysis of variance. The genotype and allele frequencies of the LEPR Gln223Arg polymorphism were significantly different between normal-weight and overweight plus obese groups (P=0.013 and 0.009, respectively). Although there was no difference in the mean adjusted BMI among the three LEPRGln223Arg genotypes, a trend was observed for Arg/Arg individuals to have a higher mean BMI compared to Gln/Gln homozygotes, with heterozygote individuals presenting intermediate mean BMI between the two homozygote groups (ANOVA, P=0.063). However, in non-smokers, the LEPR Gln223Arg polymorphism showed a highly significant effect over BMI (P=0.009). When the analysis was restricted to premenopausal women, a highly significant effect of NPY was observed. Women bearing the Pro variant presented a lower BMI than wild-type homozygotes (P=0.001). Our findings suggest that genetic variability in the leptin receptor and neuropeptide Y genes is implicated in body weight regulation, the LEPR Gln223Arg variant being associated with a BMI increase in this Caucasian population, especially in non-smokers, while the NPY Leu7Pro polymorphism was associated with BMI reduction in premenopausal women.

Leptin receptor Gln223Arg variant is associated with a cluster of metabolic abnormalities in response to long-term overfeeding.

The role of the leptin receptor (LEPR) gene Gln223Arg polymorphism on the metabolic and body composition changes in response to overfeeding was studied. Twelve pairs of male monozygotic twins ate a 4.2 MJ day-1 energy surplus, 6 days week-1, during a period of 100 days. Overfeeding induced a significantly greater increase in glucose (P = 0.001 for percentage change) and insulin (P = 0.038) areas under the curve during oral glucose tolerance tests (OGTTs) in the GlnGln (n = 10) than in the GlnArg/ArgArg (n = 14) subjects. In addition, the GlnGln genotype was associated with a greater increase in plasma levels of leptin (P = 0.037) and total triglycerides (P = 0.003), as well as a greater decrease in high-density lipoprotein cholesterol (P = 0.010), than for the combined GlnArg/ArgArg genotypes. Body composition changes were not different between the genotypes. We conclude that the GlnGln subjects of the LEPR gene polymorphism are more susceptible to metabolic abnormalities when they are exposed to long-term positive energy balance. These findings provide new information on the genetic basis of individual differences in response to chronically elevated food intake.

Association of Trp64Arg polymorphism of the beta3-adrenergic receptor gene and no association of Gln223Arg polymorphism of the leptin receptor gene in Japanese schoolchildren with obesity.

To investigate whether Trp64Arg polymorphism of the beta3-adrenergic receptor (beta3-AR) gene and Gln223Arg polymorphism of the leptin receptor (Ob-R) gene are associated with obesity in Japanese schoolchildren. Population study of participants from a rural town located within 50 km northeast of Tokyo based on school medical examinations. 553 Japanese schoolchildren (291 boys and 262 girls) who were 9-15 y old with a mean age of 11.9 +/- 1.8 y. DNA was extracted from whole blood and genotyped by PCR-RFLP. Height, weight and blood pressure were measured in school medical examinations. Total cholesterol, triglyceride and HDL-cholesterol concentrations were measured by an autoanalyzer. Obesity index, body mass index (BMI) and LDL-cholesterol concentration were calculated by the respective formulae. In Trp64Arg polymorphism of the beta3-AR gene, the number of obese subjects with Trp/Arg or Arg/Arg genotypes was significantly higher than that of the non-obese subjects (chi2=5.79, P=0.02). The obesity index of subjects with the Arg/Arg or Arg/Trp genotype was significantly higher than that of those with the Trp/Trp genotype (8.2 +/- 18.7% vs 4.5 +/- 15.8%, P=0.04). Moreover, after adjustments for age and gender, BMI of subjects with the Trp/Arg or Arg/Arg genotype was significantly higher than that of those with the Trp/Trp genotype (19.4 +/- 3.6 kg/m2 vs 18.9 +/- 3.2 kg/m2, P= 0.02). However, no significant differences were observed in the clinical characteristics among the genotype groups of the Ob-R gene. Trp64Arg polymorphism of the beta3-AR gene appears to be a genetic risk factor for obesity in Japanese children, but Gln223Arg polymorphism of the Ob-R gene does not appear to be associated with obesity.

Combination of polymorphisms in OB-R and the OB gene associated with insulin resistance in Nauruan males.

To investigate the relationship between polymorphisms in the OB-R and OB genes and metabolic markers for obesity and glucose intolerance in a population of Nauruan men. In addition, we examined the effect of the simultaneous presence of the three polymorphisms on the phenotype of individuals in this population. This study was conducted in a population from the Pacific Island of Nauru. Populations in this region have some of the highest recorded rates of obesity and type 2 diabetes and are therefore of great interest in the genetic analysis of these diseases. Two hundred and thirty-two male subjects were examined in this cross-sectional study. All subjects were non-diabetic and the group had a mean age of 31 y and a mean body weight of 104 kg. Several phenotypic measures of body fatness and fat distribution (anthropometry), fasting plasma insulin, glucose and leptin concentrations, blood pressure and 2 h plasma glucose concentration, genotypes of subjects for the Gln223Arg, PRO1019pro (OB-R gene) and OB gene polymorphisms. Individually, the OB gene and Gln223Arg OB-R polymorphisms were not associated with the obese or glucose-intolerant phenotype in this population. Individuals with the PRO1019pro polymorphism were found to have elevated insulin concentrations and diastolic blood pressure (Pc = 0.04). In addition, individuals found to simultaneously exhibit homozygosity of the common allele of all three polymorphisms (genotypes: Arg/Arg, pro/pro and II/II) exhibited significantly elevated fasting insulin levels (Pc = 0.03). Pacific Island populations exhibit a remarkably high prevalence rate of obesity and type 2 diabetes and represent a unique population for genetic studies of obesity. In the present study we have revealed that a specific combination of alleles in OB and OB-R, two candidate genes for obesity, may confer an increased risk for the development of insulin resistance in Nauruan males.