Relationship between variants of the leptin gene and obesity and metabolic biomarkers in Brazilian individuals

Associação entre variantes do gene de leptina e obesidade e biomarcadores metabólicos em indivíduos brasileiros

Abstracts

OBJECTIVE: The relationship between variants of the leptin gene (LEP) and obesity and metabolic biomarkers was investigated in Brazilian individuals. SUBJECTS AND METHODS: One-hundred-ten obese (BMI > 30 kg/m²) and 100 non-obese individuals (145 women and 65 men, aged 49 ± 14 years) were randomly selected. Plasma leptin, glycemia, serum lipid measurements and LEP -2548G>A and 3'HVR polymorphisms were analyzed. RESULTS: The LEP -2548GG genotype was associated with a 2.2% and 2.0% increase in BMI (p = 0.009) and plasma leptin (p = 0.031), respectively. 3'HVR I/II (classes I/I+I/II) genotypes contributed with 1.8% of BMI values (p = 0.046). LEP I/G combined genotypes (I/IGG, I/IGA and I/IIGG) were associated with obesity, and increased BMI, waist circumference, leptin and triglycerides (p < 0.05). These relationships were found in women (p < 0.05) but not in men. LEP I/G combined genotypes were not associated with hypertension, hyperglycemia, dyslipidemia and coronary artery disease. CONCLUSIONS: LEP I/G combined genotypes are associated with obesity-related metabolic biomarkers and phenotype in a gender-dependent manner.

Leptin; gene polymorphism; obesity; metabolic biomarkers; plasma leptin

OBJETIVO: A relação entre as variantes do gene da leptina (LEP) e obesidade e biomarcadores metabólicos foi investigada em indivíduos brasileiros. SUJEITOS E MÉTOODS: Cento e dez indivíduos obesos (IMC > 30 kg/m²) e 100 não obesos (145 mulheres e 65 homens, idade 49 ± 14 anos) foram selecionados aleatoriamente. Leptina plasmática, glicemia, lípides séricos e polimorfismos LEP -2548G>A e 3'HVR foram analisados. RESULTADOS: O genótipo -2548GG foi associado com aumento de 2,2% e 2,0% no IMC (p = 0,009) e leptina plasmática (p = 0,031), respectivamente, enquanto os genótipos 3´HVR I/II (classes I/I+I/II) contribuíram com 1,8% dos valores de IMC (p = 0,046). Os genótipos combinados LEP I/G (I/IGG, I/IGA e I/IIGG) foram associados com obesidade e IMC aumentado, circunferência abdominal, leptina e triglicérides aumentados (p < 0,05). Essas relações foram encontradas em mulheres (p < 0,05), mas não em homens. Os genótipos LEP I/G combinados não foram associados com hipertensão, hiperglicemia, dislipidemia e doença arterial coronariana. CONCLUSÕES: Genótipos combinados LEP I/G são associados com biomarcadores metabólicos e fenótipo de obesidade de forma gênero-dependente.

Leptina; polimorfismo genético; obesidade; biomarcadores metabólicos; leptina plasmática

ORIGINAL ARTCLE

Relationship between variants of the leptin gene and obesity and metabolic biomarkers in Brazilian individuals

Associação entre variantes do gene de leptina e obesidade e biomarcadores metabólicos em indivíduos brasileiros

Hamilton M. Hinuy^I; Mario H. Hirata^I; Marcelo F. Sampaio^II; Dikran Armaganijan^II; Simone Sorkin Arazi^I; Luis A. Salazar^III; Rosario D. C. Hirata^I

^IFaculdade de Ciências Farmacêuticas, Universidade de São Paulo (USP), São Paulo, SP, Brasil

^IIInstituto Dante Pazzanese de Cardiologia (IDPC), São Paulo, SP, Brasil

^IIIFacultad de Medicina, Universidad de La Frontera, Temuco, Chile

^{Correspondence to}

ABSTRACT

OBJECTIVE: The relationship between variants of the leptin gene (LEP) and obesity and metabolic biomarkers was investigated in Brazilian individuals.

SUBJECTS AND METHODS: One-hundred-ten obese (BMI > 30 kg/m²) and 100 non-obese individuals (145 women and 65 men, aged 49 ± 14 years) were randomly selected. Plasma leptin, glycemia, serum lipid measurements and LEP -2548G>A and 3'HVR polymorphisms were analyzed.

RESULTS: The LEP -2548GG genotype was associated with a 2.2% and 2.0% increase in BMI (p = 0.009) and plasma leptin (p = 0.031), respectively. 3'HVR I/II (classes I/I+I/II) genotypes contributed with 1.8% of BMI values (p = 0.046). LEP I/G combined genotypes (I/IGG, I/IGA and I/IIGG) were associated with obesity, and increased BMI, waist circumference, leptin and triglycerides (p < 0.05). These relationships were found in women (p < 0.05) but not in men. LEP I/G combined genotypes were not associated with hypertension, hyperglycemia, dyslipidemia and coronary artery disease.

CONCLUSIONS: LEP I/G combined genotypes are associated with obesity-related metabolic biomarkers and phenotype in a gender-dependent manner.

Keywords: Leptin; gene polymorphism; obesity; metabolic biomarkers; plasma leptin

RESUMO

OBJETIVO: A relação entre as variantes do gene da leptina (LEP) e obesidade e biomarcadores metabólicos foi investigada em indivíduos brasileiros.

SUJEITOS E MÉTOODS: Cento e dez indivíduos obesos (IMC > 30 kg/m²) e 100 não obesos (145 mulheres e 65 homens, idade 49 ± 14 anos) foram selecionados aleatoriamente. Leptina plasmática, glicemia, lípides séricos e polimorfismos LEP -2548G>A e 3'HVR foram analisados.

RESULTADOS: O genótipo -2548GG foi associado com aumento de 2,2% e 2,0% no IMC (p = 0,009) e leptina plasmática (p = 0,031), respectivamente, enquanto os genótipos 3´HVR I/II (classes I/I+I/II) contribuíram com 1,8% dos valores de IMC (p = 0,046). Os genótipos combinados LEP I/G (I/IGG, I/IGA e I/IIGG) foram associados com obesidade e IMC aumentado, circunferência abdominal, leptina e triglicérides aumentados (p < 0,05). Essas relações foram encontradas em mulheres (p < 0,05), mas não em homens. Os genótipos LEP I/G combinados não foram associados com hipertensão, hiperglicemia, dislipidemia e doença arterial coronariana.

CONCLUSÕES: Genótipos combinados LEP I/G são associados com biomarcadores metabólicos e fenótipo de obesidade de forma gênero-dependente.

Descritores: Leptina; polimorfismo genético; obesidade; biomarcadores metabólicos; leptina plasmática

INTRODUCTION

Leptin is a metabolic and neuroendocrine hormone produced and released mainly by adipocytes (1). Several systemic effects are attributed to leptin such as body mass control, lipid and glucose metabolism, thermogenesis, angiogenesis, immunity, reproductive, endocrine and cardiovascular functions, among other (2). Increased leptin is associated with adiposity and it is expected to reduce food intake and increase energy expenditure by binding to leptin receptors that further activate the hypothalamic melanocortin pathway and control body fat stores (3).

Several studies have suggested that variants in the leptin gene (LEP) may be important in the pathophysiology of human obesity (4-6). A common single nucleotide polymorphism (SNP) within the 5' promoter region (-2548G>A) of the LEP has been associated with variations in plasma leptin and body mass index (BMI) in obese individuals (6-9).

Microsatellite markers such as the highly variable tetranucleotide repeat (TTTC)_n located in the 3'-flanking region of the LEP (3'HVR) has also been associated with obesity-related traits and leptin plasma levels (6,10,11). However, the relation of this variant with other polymorphisms in the LEP gene on metabolic and obesity-related characteristics remains to be investigated.

In this study, the relationship between LEP 3´HVR and -2548G>A variants and obesity-related phenotype and metabolic biomarkers was investigated in a sample of the Brazilian population.

SUBJECTS AND METHODS

Study population

Two-hundred-ten unrelated individuals were randomly selected from Instituto Dante Pazzanese de Cardiologia (IDPC), Sao Paulo, Brazil. These individuals were declared to have European ancestry (non-African) by physical examination, however lack of relationship between color and genomic ancestry have been found in Brazilian samples (12). Sample size was estimated as 267 individuals considering 50% the frequency of LEP alleles related with obesity (95% confidence level, 5% confidence interval, and over 20,000 population size). Individuals with thyroid, liver or kidney diseases, evaluated by clinical and laboratory analyses, and pregnant women were not included in this sample.

Anthropometric measurements, such as BMI, waist circumference (WC) and waist-to-hip ratio (WHR) were taken from each participant. Individuals with BMI > 30 kg/m² were classified as obese and those with systolic/diastolic blood pressure over 140/90 mmHg or under lowering-pressure therapy were considered hypertensive. Individuals with fasting glycemia > 100 mg/dL were considered hyperglycemic. Cigarette smoking was considered when individuals smoked 3 or more cigarettes/day. Sedentary life style was considered when individuals practiced less than a 30 min walk 3 times a week. The presence of coronary artery disease (CAD) was investigated by coronary angiography. The study protocol was approved by the Local Ethics Committees (Institute of Cardiology Dante Pazzanese and School of Pharmaceutical Sciences, University of Sao Paulo).

Biomarker analysis

Blood samples were collected from each participant after a 12-hour fasting for serum chemistry tests. Glucose, triglycerides, and total cholesterol and high-density lipoprotein (HDL) cholesterol were measured by enzymatic-colorimetric assays using a Roche-Hitachi 912 automated analyzer (Hitachi, Nakakojo, Japan). Low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) cholesterol were calculated. Apolipoproteins AI (apoAI) and B (apoB) were determined in serum by nephelometry. Plasma leptin was determined by an ELISA method (Alexis Biochemical/Vendor BioAgency, Sao Paulo, Brazil). The atherogenic index of plasma (AIP) calculated as log (triglycerides/ HDL cholesterol), and ApoB/ApoAI ratio were used for evaluation of thecardiovascular risk.

DNA genotyping

Genomic DNA was extracted from 1 mL EDTA-anticoagulated whole blood by a salting-out method (13). LEP -2548G>A and 3´HVR polymorphisms were genotyped by polymerase chain reaction (PCR) and fragment analysis as previously described (8,11). The accuracy of the genotyping was evaluated by performing duplicate analysis of 20% samples randomly selected. Moreover, heterozygous LEP -2458G>A and 3´HVR samples were included as genotype controls in each run.

Statistical analysis

LEP 3´HVR alleles were grouped in class I (short) and class II (long) as previously described (11). LEP combined genotypes were formed by grouping 3´HVR and -2548G>A genotypes. The agreement of genotype frequencies with Hardy-Weinberg equilibrium (HWE) expectations was tested by the chi-square test. The linkage disequilibrium between LEP variants was estimated using the SNPAnalyzer software (D' index) (14). Relationships between the genotypes and categorical variables were evaluated by the chi-square test or Exact Fisher test.

Continuous variables without normal distribution (BMI, WC, leptin, glucose and lipid profile) were log transformed prior to the statistical analysis. Anthropometric and blood chemistry parameters were compared between LEP variants by One-way ANOVA and t-test. Pearson's correlation coefficients were used to estimate the association between continuous variables.

Logistic and linear regression analyses were used to verify the relationships between obesity, LEP variants and other variables such as BMI, WC, WHR and leptin. The models were adjusted by the covariates of age, gender, hypertension, hyperglycemia, CAD, cigarette smoking and sedentary life style. Statistical tests were performed by SAS System for Windows software version 8.02 (SAS Institute Inc, 1999-2001, Cary, NC, USA). The level of significance was considered p < 0.05.

RESULTS

Anthropometric, demographic and biochemical data of the studied group are shown in table 1. Four women refused to inform their ages. One woman and one man did not have their waist and hip measured. Obese individuals (BMI > 30 kg/m²) had higher means of age and anthropometric data (BMI, WC and WHR) as well as higher frequencies of hypertension, hyperglycemia, cigarette smoking, sedentary life style and CAD when compared with the non-obese group (p < 0.05). Plasma leptin was also higher in obese than in the non-obese group (p < 0.05).

LEP 3´HVR class I/I and I/II genotypes were more frequent in obese (I/I: 24%, I/II: 56%) than in non-obese individuals (I/I: 21%, I/II: 44%, p = 0.043) (Table 1). For -2548G>A polymorphism, the frequency of the GG genotype in obese (41%) was similar to that found in non-obese (28%) (p = 0.090) individuals. Both LEP 3´HVR and -2548G>A variants were under HWE in this sample (Table 1). A linkage disequilibrium was found between these polymorphisms (D' index = 0.7113). We found nine LEP combined genotypes that were grouped as: I/G (I/IGG + I/IGA+ I/ IIGG); II/A (I/IIAA + II/IIAA + II/IIGA); and others (I/IAA + I/IIGA + II/IIGG). Obese individuals had higher frequencies of I/G combined genotypes (45%) than non-obese subjects (27%, p = 0.018).

Results from univariate logistic regression analysis are shown in table 2. Variables were adjusted by the covariates of age, hypertension, hyperglycemia, cigarette smoking, sedentary life style and CAD due to their association with obesity previously demonstrated (13). Individuals carrying 3´HVR class I/II genotype had 3 times higher risk for obesity (OR: 3.12, 95% CI: 1.21 - 8.08) compared to those with class II/II genotype (p = 0.019). The carriers of -2548GA and GG genotypes had, respectively, 4 times (OR: 4.75, 95% CI: 1.30 - 17.36) and 8 times (OR: 8.695, 95% CI: 2.22 -34.05) more risk for obesity than the -2548AA genotype carriers (p < 0.05). In addition, the risk for obesity was 4 times higher in I/G carriers (OR: 3.97, 95% CI: 1.30 - 5.55) than in those carrying II/A (p = 0.012).

Multivariate logistic regression analysis using stepwise criteria for selection of the genetic variables related with obesity was also tested. After adjustment for covariates (age, hypertension, hyperglycemia, cigarette smoking, sedentary life style and CAD), only the LEP -2548GG genotype was associated with an increased risk for obesity (OR: 9.43, 95% CI: 1.84 - 48.31; p = 0.007) (data not shown).

The relationship between LEP variants and anthropometric and blood chemistry variables were also investigated in this study (Table 3). Individuals carrying I/G genotypes had higher serum triglycerides when compared to the II/A carriers (p < 0.05). AIP values were also higher in I/G carriers than in those carrying other genotypes (p < 0.05). We investigated whether the relationship between LEP variants and these variables were influenced by gender, considering that leptin and obesity-related traits (BMI, WC, WHR) were higher in women than in men (p < 0.05) (data not shown). I/G genotypes were associated with higher WC, BMI and leptin values in women but not in men (Figure 1).

Univariate linear regression analysis showed that the variations in log-transformed values of the BMI were partially explained by LEP 3´HVR class I/II genotype (1.80%, p = 0.046) and -2548GG genotype (2.20%, p = 0.009), as indicated by the determinant coefficient (R2) (Table 4). Moreover, only 2% of variation in log-transformed plasma leptin is explained by LEP -2548GG genotype (p = 0.031). Regression coefficients (estimates) indicate that the carriers of the 3´HVR class I/II genotype had log-transformed BMI 0.03 more than the non-carriers. Moreover, log plasma leptin was 0.11 higher in 3´HVR class I/II genotype and 0.20 higher in -2548GG genotype in comparison with those carrying other genotypes (Table 4).

We also investigated whether the LEP variants were associated with hypertension, hyperglycemia, dyslipidemia and CAD but no relationship was found between these clinical conditions and LEP variants in this sample (data not shown).

DISCUSSION

The LEP variants evaluated in this sample were associated with obesity. Individuals carrying the -2548GG genotype have higher risk for increased BMI than carriers of the -2548GA+AA genotypes. Moreover, the -2548GG genotype carriers have 8 times more risk for obesity than the non-carriers suggesting that LEP -2458G>A polymorphism maybe a good predictor for obesity.

The association between LEP -2548G>A polymorphism and increased BMI was also found in overweight Europeans and Taiwanese Aborigines with extreme obesity (15,16). We have also found a relationship between the -2548G>A variant and increased plasma leptin and BMI in Brazilian women (8). It is important to mention that the relationship between -2548GG genotype and obesity was found in recessive and codominant models, but not in the dominant model (16). In addition, common variants located in the 5´region of the LEP, including -2548G>A, were associated with increased BMI in men (17). The presence of the GG genotype was also associated with increase in BMI and weight gain in persons treated with olanzapine (18-20). However, no association was found between this polymorphism and obesity in a population-based case control study in Spain (21).

In this study, LEP -2458GG genotype was also shown to be a predictor for increased plasma leptin. This result confirms the findings from other investigations that showed an association between -2458AA (-/-) genotype and lower leptin levels in Caucasian obese girls and diabetic individuals from China (22,23). Conversely, as commented previously, -2458AA genotype was associated with increased plasma leptin in obese individuals (15). Moreover, carriers of this genotype had lesser decrease in circulating leptin after gastric banding surgery (24). The results from these studies are suggestive that the relationship between LEP -2548G>A and obesity-related phenotypes may be influenced by sample characteristics such as gender, sample size, population and other.

The variant -2548G>A has been implicated in the regulation of LEP mRNA expression and consequently leptin plasma levels (25). Gong and cols. (26) have described two repetitive sequences MER11 and Alu located at the LEP promoter (-2514 to 1545) that may regulate LEP expression (26). In addition, the 3-kb 5´-flanking region contains several putative binding sites for known transcription factors, including CREB, GRE, Sp1, LP1, C/EBP and TATA motifs (26,27). A Sp1 functional placental enhancer was found within the MER11 repetitive element suggesting that expression of leptin is the result of insertion of this element (28). Recently, Moreno-Aliaga and cols. (29) reported that the Sp1 binding site has a key role in the transcriptional activation of the LEP promoter by insulin-mediated glucose metabolism (29). Whether the -2548G>A variant located close to a Sp1 binding site (-2539) also modulates the transcription of the LEP remains to be investigated.

The role of leptin in body fat control is mediated by leptin receptors (LEPR) in specific hypothalamic centers that stimulate the production of anorectic peptides and inhibit the orexigenic molecules (30). LEPR gene (LEPR) polymorphisms have also been associated with increased BMI and other obesity-related characteristics in several populations (4,31-33). The combination of LEP -2548G>A and LEPR Q223R variants was related to a 58% increase in obesity risk in another sample of our population (34). Therefore, the relationship between LEP -2548G>A and increased BMI found in this study may be due to its linkage to Q223R or other LEPR polymorphisms.

The LEP 3´HVR is a (TTTC)_n tetranucleotide repeat located at the 3' end of the LEP that has been associated with increased risk for obesity and high plasma leptin levels as well (10-11). These effects may be due to the linkage of the 3'HVR with -2548G>A variant.

The presence of the LEP I/G genotypes was associated with an increased risk for obesity-related phenotype (BMI and WC) and the biomarker of plasma leptin. The influence of I/G variant was further demonstrated to be related to gender, even though this variable did not affect the distribution of the LEP I/G genotypes. Accordingly, it has been shown that the association between a LEP variant (A19G) and risk for obesity was restricted to females from the Atherosclerosis Risk in Communities (ARIC) Study (35).

Differences in plasma glucose were not related to LEP I/G genotypes, confirming the lack of association between these variants and hyperglycemia. This result suggests that LEP variants may not be implicated in glucose homeostasis. Accordingly, insulin responses to glucose and insulin sensitivity were similar among Japanese carriers of LEP 3´HVR genotypes (36). Serum triglycerides and AIP values were found to be higher in LEP I/G carriers suggesting a possible role of LEP combined genotypes in lipid metabolism and cardiovascular risk. However, association analyses did not show relationship of the LEP variants with dyslipidemia and CAD evaluated by coronary angiography. Therefore, further investigations are necessary to evaluate these data in larger populations.

The lack of association between hypertension or cardiovascular disease and LEP 3´HVR has been also shown in other populations (37-39). Therefore, the association between obesity and hypertension and other risk factors for CAD previously found in our sample (8) seems to be independent of the LEP I/G genotypes.

It is noteworthy that the results from this study may be influenced by the limited sample size, which reduced the power of the statistical tests. Therefore studies with larger samples from the Brazilian population are necessary to confirm our findings.

In conclusion, -2548G>A and 3´HVR variants of the LEP gene are in linkage disequilibrium, and I/G combined genotypes are associated with obesity-related biomarkers and phenotype and it is likely that they contribute to the regulation of circulating leptin and triglycerides in a gender-dependent manner.

Acknowledgements: This study was supported by Fapesp (Grants no. 01/10708-3 and 06/04994-7), Sao Paulo, SP, Brazil. We thank Dr. F. D. V. Genvigir for her assistance in linkage disequilibrium analysis. H. M. Hinuy and S. S. Arazi were recipients of fellowships from Fapesp. M. H. Hirata and R. D. C. Hirata were granted fellowships from CNPq, Brasilia, DF, Brazil.

Disclosure: no potential conflict of interest relevant to this article was reported.

Received on Jul/10/2009

Accepted on Nov/5/2009

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Publication Dates

• Publication in this collection
  26 May 2010
• Date of issue
  Mar 2010

History

• Received
  10 July 2009
• Accepted
  05 Nov 2009