American Journal of Epidemiology Advance Access originally published online on June 22, 2005
American Journal of Epidemiology 2005 162(2):101-114; doi:10.1093/aje/kwi174
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HUMAN GENOME EPIDEMIOLOGY (HuGE) REVIEW |
Genetics of Leptin and Obesity: A HuGE Review
From the Unit of Molecular and Genetic Epidemiology, Fondazione Policlinico IRCCS, Milano, Italy
Correspondence to Dr. Emanuela Taioli, Fondazione Policlinico IRCCS, Unit of Molecular and Genetic Epidemiology, Via Pace 9, Milano 20122, Italy (e-mail: taioli{at}policlinico.mi.it).
Received for publication November 30, 2004. Accepted for publication March 7, 2005.
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ABSTRACT |
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TOP
ABSTRACT
INTRODUCTIONLeptin is an important regulator of the mass of adipose tissue and of body weight; it operates by inhibiting food intake and stimulating energy expenditure. Some polymorphic genes involved in the regulation of leptin—the leptin gene (LEP A19G), the leptin receptor gene (LEPR Q223R, K109R, and K656N), and the peroxisome proliferator-activated receptor-gamma gene (PPARG P12A and C161T)—have been investigated as possible factors associated with obesity. Allelic frequencies of these polymorphisms show ethnic variation. The authors performed a meta-analysis of the available data on the association between these polymorphisms and obesity based on case-control studies. Odds ratios and 95% confidence intervals for obesity associated with leptin polymorphisms were calculated by using both fixed- and random-effects models. Results suggest no evidence of association between the genes under study and obesity. The lack of association could be due to the complex pathogenesis of obesity, which involves a number of genetic and environmental factors. Large studies including testing of multiple genes in both obese and lean subjects, with epidemiologic data on dietary habits in different ethnic groups, are necessary to better understand the role of leptin in regulating weight in human populations.
epidemiology; genetics; LEP; LEPR; leptin; meta-analysis; obesity; PPARG
Abbreviations: BMI, body mass index; CI, confidence interval; LEP, leptin gene; LEPR, leptin receptor gene; PPARG, peroxisome proliferator-activated receptor-gamma gene
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INTRODUCTION |
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Leptin is a 167-amino acid protein produced by the leptin gene (LEP), whose name is derived from the Greek word "leptos," which means "thin." Leptin, an important signal in the regulation of adipose-tissue mass and body weight, operates by inhibiting food intake and stimulating energy expenditure. Defects in leptin production cause severe obesity (http://www.ncbi.nlm.nih.gov/entrez/). Leptin is also known to play a role in different parts of the body, such as the male and female reproductive organs, the mammary gland, bone mineral density, the immune system, the gut, the kidney, and the lung (1
). Many of the genes involved in the regulation of leptin are polymorphic. This paper reviews polymorphisms in three genes—LEP, the leptin receptor gene (LEPR), and the peroxisome proliferator-activated receptor-gamma gene (PPARG)—and their association with obesity.
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BIOLOGY OF LEPTIN |
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The structure of leptin consists of a complex of four helices, similar to that of cytokines. Leptin is produced by the white adipose tissue, the most frequent form of adipose tissue in mammals. The white adipose tissue provides a long-term fuel reserve that can be mobilized during food deprivation with the release of fatty acids for oxidation in other organs; it also provides thermal insulation and has a mechanical role for vital organs (2
). Leptin is produced in many sites in addition to white adipose tissue, but the amount of body fat is the main determinant of the circulating levels of this hormone. After it is produced, leptin is secreted into the bloodstream, where it circulates attached to proteins, and is transported to the brain, where it stimulates or inhibits release of several neurotransmitters. It down-regulates some orexigenic neuropeptides, such as the neuropeptide Y, melanin-concentrating hormone, orexins, and agouti-related peptide. Leptin up-regulates anorexigenic neuropeptides such as alpha-melanocyte-stimulating hormone, which acts on the melanocortin-4 receptor, cocaine and amphetamine-regulated transcripts, and corticotropin-releasing-hormone (3). Leptin may also directly affect the metabolism and function of peripheral tissues such as the adipocytes, skeletal muscle, ovary, adrenal cortex, and pancreatic beta cells (4, 5).
Leptin is expressed in the adipocytes: both its expression and its secretion are highly correlated with body fat and adipocyte size (4). However, the study of serum leptin levels in relation to several measures of adiposity demonstrates that obesity is not characterized by leptin deficiency but rather by hyperleptinemia; in fact, leptin levels have been found to be elevated in obese patients (6, 7). The inability of such elevated leptin levels to alter the obese state of these persons may be related to "leptin resistance," an inability of leptin to enter the cerebral spinal fluid to reach the hypothalamus regions that regulate appetite, or it may simply reflect the large amount of fat tissue in these persons (4). Serum leptin levels follow a circadian rhythm, which seems to be predominantly related to an increase in insulin and cortisol rhythm. These two hormones may be among the major regulators of leptin production by the adipose tissue. Compared with males, females have higher leptin levels if leptin levels are expressed as a percentage of body adiposity (8). This difference may be related to the different distribution of adipose tissue in the two genders as well as to hormonal differences. Leptin levels have been shown to differ with medical conditions involving the endocrine system. For example, a comparison between diabetic and nondiabetic subjects shows that leptin levels are lower in the diabetic population (9).
The biologic activities of leptin on target tissues are carried out through selective binding to a specific receptor, LEPR. This gene is found in many tissues in several alternatively spliced forms.
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GENES |
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LEP
The LEP gene encodes for leptin. It has been localized in humans on the 7alpha31.3 chromosome and consists of three exons separated by two introns (10
).
It has been suggested that the "obese" promoter is a natural target of CCAAT/enhancer-binding protein-alpha, a transcription factor implicated in the development and metabolic regulation of adipocytes (11). Overexpression of the human LEP gene has been found in both subcutaneous and omental adipose tissue of massively obese persons (12).
LEP gene expression may be influenced by modulation of CCAAT/enhancer-binding protein-alpha levels or activity (13). Knowledge of the sequence elements and factors regulating LEP gene expression as well as the precise definition of the structure of the gene could be relevant when conducting further studies on mutations in this gene that may predispose to certain forms of obesity.
LEPR
LEPR maps in humans to the 1p31 chromosome and has at least five isoforms. The extracellular and transmembrane domains are identical between the short and the long isoforms; differences are due to changes in the length of the cytoplasmic domain. The long form (LEPR1) has 302 cytoplasmic residues compared with the short form (LEPRs), whose cytoplasmic residues range from 32 to 40 amino acids in length. Another form of the leptin receptor, the soluble form (LEPRe), is supposed to contain nonintracellular motifs or transmembrane residues, thus consisting entirely of the extracellular domain of the receptor (5).
Isoforms of the receptor have been identified in multiple tissues, such as the pituitary gland, male and female reproductive organs, mammary gland, immune system, gut, kidney, and lung (1). Studies performed on mice showed that the long form, thought to be the most important for transmitting the leptin signal to the cells, is located predominantly in the hypothalamus and not in most other tissues (14), whereas the short forms are expressed throughout the body, especially in the kidney, lungs, and choroid plexus (15).
The structure of the leptin receptor is similar to that of the helical cytokine receptor (class I). Leptin receptors form homodimers, which are capable of activating Janus kinases. The Janus kinase is then able to start activators of the transcription family. Leptin signaling via the Janus kinases–start activators of transcription system is associated largely with the LEPR1 form (16).
PPARG
The peroxisome proliferator-activated receptor genes (PPARs) are members of the nuclear hormone receptor subfamily of transcription factors that is expressed predominantly in the adipose tissue and the immune system. Such receptors control adipocyte differentiation and regulate glucose and lipid homeostasis (http://www.ncbi.nlm.nih.gov/entrez/). PPARs form heterodimers with retinoid X receptors (RXRs), which regulate the transcription of various genes implicated in the control of lipid metabolism, insulin synthesis, carcinogenesis, and inflammation (17, 18). There are three known subtypes of PPARs: PPARA, PPARD, and PPARG. PPARG is located on the 3p25 chromosome and is thought to be involved in adipocyte differentiation (19).
PPARG1 and PPARG2 are members of the family of orphan nuclear receptors that function as transactivators of fat-specific genes and thus are dominant activators of fat cell differentiation. The PPARG gene contains nine exons and spans more than 100 kb. PPARG1 is encoded by eight exons and PPARG2 by seven exons (20). Human PPARG is expressed at high levels in adipocytes and at a much lower level in the bone marrow, spleen, testis, brain, skeletal muscle, and liver (21).
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GENES VARIANTS |
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LEP
A mutation in the mouse LEP gene was first described in 1950 (22
): the ob/ob obese mouse shows a nonsense mutation in codon 105 of the original mouse strain (23) resulting in the absence of leptin production. This mutation causes obesity, hyperphagia, hypothermia, extreme insulin resistance, and infertility. Administration of leptin restores the normal condition. The homologous LEP mutation in humans has not been detected (24). The structure of the LEP gene is preserved in all mammalians: human leptin and mouse leptin share 84 percent sequence identity. In humans, a mutation in the LEP gene was reported in two children with the same consanguineous pedigree (25). The homozygous frameshift mutation was the result of deletion of a single guanine nucleotide in codon 133. These children produced a very small quantity of leptin and presented with early-onset obesity and hyperphagia but normal body temperatures and normal plasma cortisol and glucose concentrations. Other variants of the human LEP gene have been reported: a rare mutation at codon F17L, a rare mutation at codon V110M (26), and a polymorphism C(-188)A in the promoter region of the LEP gene (27) have been found. Different microsatellite markers flanking the LEP gene have been also identified, but the possible linkages with obesity are inconsistent. Other studies (28–31) reported a polymorphism in the promoter untranslated exon 1 of the LEP gene (A19G).
LEPR
The LEPR gene maps to chromosome 4 of the mouse in regions that contain the db/db and Zucker fa/fa mutations. These mutations cause severe obesity in mouse, not reversible by administration of leptin. Human LEPR and the mouse gene share 78 percent homology. Several variants commonly occur, which cause two nonconservative changes: glutamine to arginine at codon 223 (CAG to CGG) in exon 6 (Q223R) and lysine to asparagine at codon 656 (AAG to AAC) in exon 14 (K656N); a conservative change: lysine to arginine at codon 109 (AAG to AGG) in exon 4 (K109R); a silent TC change at codon 343; and a silent GA transition at codon 1019. One study found that the leptin receptor is expressed in the hypothalamus of human subjects (32). It has been suggested that leptin responsiveness to energy restriction is affected by the functionality of the leptin receptor. No effect of the Q223R, K109R, and K656N polymorphisms of the LEPR gene was observed on the acute decline in leptin after energy restriction (33).
PPARG
A screening of the PPARG gene for sequence variants has allowed identification of several genetic variants. P115Q is a very rare gain-of-function mutation associated with obesity (34); V290M and P467L are two loss-of-function mutations reported in three persons with severe insulin resistance but normal body weight (35). Two common polymorphisms are 1) a CG substitution in exon B, resulting in conversion of proline to alanine at residue 12 of the PPARG protein (P12A), which may modify susceptibility to type II diabetes mellitus and obesity (36); and 2) a synonymous CT substitution at nucleotide position 161 in exon 6 (C161T).
The Pro12Ala polymorphism has been shown to prevent insulin resistance and obesity induced by a high-fat diet (37). Expression of the P12A polymorphism is not significantly different in obese subjects carrying one or the other variant of the allele (38).
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META-ANALYSIS |
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To examine the frequencies of the polymorphisms in the general population and the association between the various genes involved in regulation of leptin and obesity, we performed a meta-analysis of published studies, following established guidelines (39
–41). To investigate the presence of publication bias, funnel plots were created, and their asymmetry was tested statistically: Begg's adjusted rank correlation (42) and Egger's regression asymmetry of the Ln(odds ratio) over the standard error (43) were calculated.
To estimate the heterogeneity of the allele frequencies and of the odds ratios, the Cochran Q-test was performed (44). For the meta-allele frequencies of each specific allele and the meta–odds ratios, a fixed-effects model was used if the assumption of homogeneity among studies could be accepted, while a random-effects model was used when heterogeneity across studies was statistically observed (45).
Population frequencies
A MEDLINE search was performed up to November 2004 by using different combinations of the keywords "leptin," "gene," "polymorphisms," "leptin gene receptor," "PPARG polymorphism," "obesity," and "BMI." We also searched for specific polymorphisms of the LEP, LEPR (Q223R, K109R, K656N), and PPARG (C161T, P12A) genes. The search was restricted to articles published in English on human subjects, although we checked the number of articles published in other languages and found that such articles represented 7 percent of the whole relevant literature. The computer search was supplemented by consulting the bibliographies of the articles found through the MEDLINE search. Case-control or cohort, genotype-based studies that reported allele frequency for polymorphisms of LEP, LEPR, and PPARG genes in healthy subjects (both lean and obese subjects and excluding clinically diagnosed diabetes) were selected, whereas studies including only diabetic or nonhealthy subjects and studies on families or twins were excluded. Allelic frequency of the different polymorphisms for each of the above-mentioned genes were evaluated. For each study and for each gene included in the present review, allele frequencies and 95 percent confidence intervals for healthy subjects were calculated. Pooled frequencies were calculated on the whole sample and according to ethnicity.
Associations
Case-control studies reporting allele frequency for lean (controls) and obese (cases) subjects were included in the meta-analysis. For each study and for each gene, we calculated crude odds ratios and 95 percent confidence intervals as a measure of the association between a gene polymorphism and obesity. The overall odds ratios and 95 percent confidence intervals for obesity associated with leptin polymorphisms were calculated after pooling the data from the single studies. Forests plots were used to convey the results of the meta-analysis.
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POPULATION FREQUENCIES |
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LEP A19G
Three studies conducted in Europe (18
–20) reported allele frequency in healthy subjects. Table 1 describes the studies. The allelic frequency of 19G for the Caucasian population (375 subjects) was 0.46 (95 percent confidence interval (CI): 0.29, 0.73), with comparable values in France and Italy and higher values in Finland. The Cochran Q-test indicated heterogeneity among studies (Q = 27.88; p < 0.0001).
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LEPR Q223R
Frequencies of this polymorphism were reported in 18 articles (46
–63), and the studies are described in table 2. Five of the studies were conducted in the United States (46, 59–62), three in Asia (56–58), eight in Europe (47–54), and two in Oceania (55, 63). The allelic frequency varied significantly across different countries and ethnic groups (p < 0.0001). In particular, the frequency of the 223R allele for Asians was significantly higher than for other ethnicities. The Cochran Q-test showed heterogeneity among only those studies performed among Caucasians (Q = 42.70; p < 0.0001).
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LEPR K109R
Eleven articles (table 2) were reviewed for this polymorphism (47
, 49–54, 56, 58, 60, 61); two studies were conducted in the United States (60, 61), two in Asia (56, 58), and seven in Europe (47, 49–54). The frequency of the 109R allele was significantly different among ethnic groups, being higher in Asians than in other populations (table 2). A significant asymmetry of the funnel plots of the studies performed among Caucasians (pEgger = 0.03) indicates the possible presence of publication bias.
LEPR K656N
Ten articles (46, 47, 49–54, 56, 61) were included in the present analysis (table 2); two studies were conducted in the United States (46, 61), one in Asia (56), and seven in Europe (47, 49–54). The frequency of the 656N allele showed differences among ethnic groups; the polymorphic allele was more frequent in Caucasians than in Asians (table 2).
PPARG C161T
Six articles, described in table 3, were reviewed for this polymorphism (64–69); one study was conducted in the United States on Pima Indians (68), one in Asia (69), three in Europe (64–66), and one in Oceania (67). The 161T allele showed similar frequencies in Caucasians and Asians, while the frequency was higher in Pima Indians (table 3).
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PPARG P12A
The frequency of this polymorphism in healthy populations was reported in 26 articles (64
, 68, 70–93). Table 4 describes the studies. Six were conducted in the United States (68, 70–73, 93), five in Asia (88–92), 14 in Europe (64, 74–86), and one in Oceania (87). The frequency of the 12Ala allele was statistically different among ethnic groups, with Caucasians showing the highest frequency of this variant allele (table 4).
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DISEASE |
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Obesity is a common condition in industrialized societies and is increasing rapidly; its etiology is complex and results from combined effects of genes, environment, lifestyle, and their interactions (94
–99). Obesity is defined as an increase in body fat, while overweight is an increase in weight relative to a standard. In most studies, obesity is defined on the basis of anthropometric measures, mainly height, weight, and waist circumference. Such measurements give information on the degree and distribution of obesity (100). On this basis, subjects are defined as overweight if their body mass index (BMI; weight in kilograms divided by height in meters squared) is equal to or greater than 25 kg/m2 and obese if their BMI is 30 kg/m2 or more (i.e., weight exceeding 20 percent of the ideal weight), according to World Health Organization indications (101).
Several other ways to define obesity have been mentioned in the literature. Some studies have reported waist-to-hip ratio as a rough approximation of body fat distribution (102). In the elderly, sarcopenic obesity has been described, which is defined as an excess of fat with loss of lean body mass (103). Some studies have also described a form of ectopic deposition, which consists of an excess deposition of fat in muscle, liver, and pancreas resulting in insulin resistance and beta-cell dysfunction. The central adipose tissue responds to this unbalance by releasing large quantities of free fatty acids (104).
Body composition can also be estimated by using a variety of technical methods. Included are densitometry methods, such as hydrostatic weighing and plethysmography, bioelectrical impedance analysis, dual energy x-ray absorptiometry, and near-infrared interactance.
Obesity affects 10–25 percent of the European population and nearly one third of the US population, and the number continues to increase (105–107). Each year, obesity causes at least 300,000 excess deaths in the United States (http://www.obesity.org/). Risk factors for obesity include a poor diet consisting of low-nutrient but high-calorie foods, lack of physical activity, medical conditions such as rare hereditary diseases and a hormonal imbalance (e.g., hypothyroid disease), age, genetic factors, ethnicity, and gender (108, 109). Overweight and obesity increase steadily with age in both men and women and occur at higher rates in ethnic minority populations in the United States, such as African Americans and Hispanic Americans compared with White Americans, while the prevalence in Asian Americans is relatively low (110). Women and persons of low socioeconomic status within minority populations appear to be particularly affected by overweight and obesity (111). Cultural factors that influence dietary and exercise behaviors are reported to play a major role in the development of excess weight in minority groups. In these ethnic minorities, rates of several obesity-related diseases (diabetes, hypertension, cancer, and heart disease) are higher than those among Whites (112–115). Obesity is associated with medical conditions that can cause poor health and premature death, among which are arthritis, birth defects, various forms of cancer, cardiovascular disease, diabetes, hypertension, infertility, chronic venous insufficiency, deep vein thrombosis, end-stage renal disease, gout, impaired immune response and impaired respiratory function, liver disease, pancreatitis, sleep apnea, and stroke (116–118).
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ASSOCIATIONS |
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LEP A19G
Only one case-control study, which was conducted in Finland (29
) and included 141 cases and 65 controls, was available on the association between this polymorphism and obesity. The observed odds ratio was 1.04 (95 percent CI: 0.67, 1.61).
LEPR Q223R
Ten studies satisfied the selection criteria and were included in the meta-analysis (46, 47, 49, 53, 54, 56, 57, 59, 61, 62) (table 5). The overall odds ratio was 1.13 (95 percent CI: 0.98, 1.30) (figure 1A), with no evidence of statistical heterogeneity nor of publication bias (figure 2A).
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LEPR K109R
Seven studies were considered for the meta-analysis (47
, 49, 53, 54, 56, 59, 61) (table 5). The overall association between LEPR K109R and obesity was 1.05 (95 percent CI: 0.89, 1.23) (figure 1B). The Cochran Q-test showed homogeneity among studies; the funnel plot showed no evidence of publication bias (figure 2B).
LEPR K656N
Seven studies were included in this meta-analysis (46, 47, 49, 53, 54, 56, 61) (table 5). The overall odds ratio was 1.02 (95 percent CI: 0.86, 1.21) (figure 1C), with no evidence of statistical heterogeneity nor of publication bias (figure 2C).
PPARG C161T
Of seven articles reviewed, none included data for both lean and obese subjects but instead reported information on one or the other of the two categories. Therefore, no formal statistical analysis was performed on these data.
PPARG P12A
Six studies were considered in this meta-analysis (70, 80, 88, 85–87) (table 5). The overall association between PPARG P12A and obesity was 1.13 (95 percent CI: 0.98, 1.29) (figure 1D). The Cochran Q-test showed that the results of the different studies were distributed homogeneously, with no statistical evidence of publication bias from the funnel plots (figure 2D).
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INTERACTIONS |
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Gene-environment interactions
Since leptin is involved in weight regulation, it is interesting to assess whether any interaction exists between leptin polymorphisms and diet or gender. Polymorphisms in the LEPR gene have been studied as possible modifying factors of the response to diet (28
) or of survival in cancer patients according to their BMI (119), but the associations, if present, represented secondary subgroup analyses of the data. A pooled analysis (120) and a meta-analysis (121) suggested an interaction between gender and the R109R genotype on BMI, although the reported effect was modest. A study in a Brazilian population indicated that the association between LEPR Q223R and BMI was stronger in nonsmokers than in the general population (62). The presence of a gene-diet interaction was studied in 592 nondiabetic subjects genotyped for the P12A variant of PPARG (122). Results showed that when the ratio of polyunsaturated to saturated fats in the diet was low, BMI was greater in Ala carriers than in Pro homozygous subjects. The opposite effect was seen when the ratio was high. An analysis of several genes involved in regulation of body weight suggested that the allelic variants of LEP and PPARG might affect diet-related obesity risk (123).
Gene-gene interactions
Interactions between polymorphisms involved in regulation of leptin have been reported. An interaction between polymorphisms in the LEP and LEPR genes on the risk of non-Hodgkin's lymphoma has been suggested (124) and on insulin levels in the population of Nauruans (63). An interaction between the 109R and 223R variants on blood pressure levels was suggested (52), as was one between the K109R and K656N polymorphisms on BMI (120, 121).
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DISCUSSION |
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Systematic screenings of the genome have allowed several polymorphisms in the genes involved in leptin regulation to be identified. In this review, we have reported data on the association between obesity and a polymorphism in the LEP gene (A19G), three polymorphisms in the LEPR gene (Q223R, K109R, and K656N), and two polymorphisms in the PPARG gene (C161T and P12A). A meta-analysis performed on the data suggests no evidence of an association between the genes involved in leptin regulation and obesity. The analysis stratified according to ethnicity did not show any variation across populations, in agreement with published literature on this topic (125
). Functional data on these genetic variants are very limited and are consistent with a lack of association between these polymorphisms and obesity. The results of our analysis are consistent with those observed in another meta-analysis of 20 studies on 3,263 subjects of different ethnic groups (62 percent of whom were family members of one or more subjects in the data set), which reported no significant effect of the polymorphisms of LEPR on obesity (121). In a meta-analysis by Masud and Ye (126), the P12A polymorphism was associated with BMI in markedly obese persons. It has been suggested that P12A is a functional polymorphism and that substitution of alanine for proline leads to a decrease in PPARG activity, thus reducing its ability to regulate expression of the gene (82). The P12A polymorphism has been associated with diabetes, although the reported effect is modest (126). Our data do not indicate an association between obesity and the P12A polymorphism. One strength of the present meta-analysis is that, to our knowledge, this is the first such study performed exclusively on unrelated, healthy subjects. A possible limitation is that we could evaluate only the allele frequency of the different polymorphisms, since very few studies reported the genotype frequencies. Another limitation is that the number of case-control studies conducted on healthy subjects is still small; several studies reported data on only lean or on only obese persons, but these studies could not be included. The cutoff for obesity, when specified, differed among studies; however, we had to use the definition given by each author, since this was a meta-analysis of published data.
The reported lack of association between leptin polymorphisms and obesity could be due to the complex pathogenesis of obesity, which involves a large number of both genetic and environmental factors. In addition, it should be taken into account that the results were based on studies that used BMI as a marker for the obesity phenotype, while several other methods of defining this condition are available. Therefore, studies including different measures of obesity could be useful in this field.
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LABORATORY TESTS |
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The detailed methods used for determining the different polymorphisms are described in each article. All studies included in the present analysis used genomic DNA extracted from blood. Thirty-one articles reported the use of polymerase chain reaction followed by restriction fragment length polymorphism, 10 used polymerase chain reaction followed by single strand conformation polymorphism; three studies used Southern blot, four studies sequencing, and one hybridization techniques in addition to polymerase chain reaction.
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POPULATION SCREENING |
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Attempts to relate DNA sequence variation in specific genes to obesity phenotypes continue to grow. The obesity gene map shows putative loci on all chromosomes except Y. Overall, more than 430 genes, markers, and chromosomal regions have been associated or linked with human obesity phenotypes (127
). However, neither the biologic nor the epidemiologic data on these genes are complete enough to make them candidates for screening in obese people. Before planning a screening program, the association between the gene and the disease should be established with some degree of certainty, and efficacious preventive intervention targeting at-risk subjects should be available. Considering these premises, there is insufficient evidence at present to justify population testing for the LEP, LEPR, or PPARG polymorphisms in an obesity screening program in the general population. |
CONCLUSION AND RESEARCH PRIORITIES |
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Obesity is a major public health concern given the association of this condition with several chronic diseases. Identification of genetic variants that increase a person's susceptibility to the common forms of obesity is a critical problem. Several recent studies have made an attempt in this direction (128
). The main summary of the literature indicates no association between the genes involved in leptin regulation and obesity. It is also evident from this review that the pathogenesis of obesity is complex and that the interaction between genetic and environmental factors is a crucial event.
Further areas of research include both gene-gene and gene-environment interaction as well as individual genetic and metabolic profiles using the developments occurring in genomics and proteomics (129). Larger studies on both obese and lean subjects are needed, with testing of multiple genes and detailed epidemiologic data on the dietary habits of different ethnic groups, including a better definition of the obesity phenotype.
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INTERNET SITES |
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Online Mendelian Inheritance in Man (OMIM). Center for Medical Genetics, Johns Hopkins University (Baltimore, Maryland) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, Maryland), 1999: http://www.ncbi.nlm.nih.gov/omim/
American Obesity Association (AOA): http://www.obesity.org/
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ACKNOWLEDGMENTS |
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Conflict of interest: none declared.
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NOTES |
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Editor's note: This paper is also available on the website of the Human Genome Epidemiology Network (http://www.cdc.gov/genomics/hugenet/).
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References |
|---|
- Baratta M. Leptin—from a signal of adiposity to a hormonal mediator in peripheral tissues. Med Sci Monit 2002;8:RA282–92.[Medline]
- Trayhurn P, Beattie JH. Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ. Proc Nutr Soc 2001;60:329–39.[Web of Science][Medline]
- Jequier E. Leptin signaling, adiposity, and energy balance. Ann N Y Acad Sci 2002;967:379–88.[Web of Science][Medline]
- Houseknecht KL, Baile CA, Matteri RL, et al. The biology of leptin: a review. J Anim Sci 1998;76:1405–20.
[Abstract/Free Full Text] - Houseknecht KL, Portocarrero CP. Leptin and its receptors: regulators of whole-body energy homeostasis. Domest Anim Endocrinol 1998;15:457–75.[CrossRef][Web of Science][Medline]
- Caro JF, Sinha MK, Kolaczynski JW, et al. Leptin: the tale of an obesity gene. Diabetes 1996;45:1455–62.[Web of Science][Medline]
- Spiegelman BM, Flier JS. Adipogenesis and obesity: rounding out the big picture. Cell 1996;87:377–89.[CrossRef][Web of Science][Medline]
- Martin LJ, Mahaney MC, Almasy L, et al. Leptin's sexual dimorphism results from genotype by sex interactions mediated by testosterone. Obes Res 2002;10:14–21.[Web of Science][Medline]
- Tatti P, Masselli L, Buonanno A, et al. Leptin levels in diabetic and nondiabetic subjects. Endocrine 2001;15:305–8.[CrossRef][Web of Science][Medline]
- Isse N, Ogawa Y, Tamura N, et al. Structural organization and chromosomal assignment of the human obese gene. J Biol Chem 1995;270:27728–33.
[Abstract/Free Full Text] - He Y, Chen H, Quon MJ, et al. The mouse ‘obese’ gene: genomic organization, promoter activity, and activation by CCAAT/enhancer-binding protein-alpha. J Biol Chem 1995;270:28887–91.
[Abstract/Free Full Text] - Lonnqvist F, Arner P, Nordfors L, et al. Overexpression of the obese (ob) gene in adipose tissue of human obese subjects. Nat Med 1995;1:950–3.[CrossRef][Web of Science][Medline]
- Miller SG, De Vos P, Guerre-Millo M, et al. The adipocyte specific transcription factor C/EBP-alpha modulates human ob gene expression. Proc Nat Acad Sci 1996;93:5507–11.
[Abstract/Free Full Text] - Schwartz MW, Seeley RJ, Campfield LA, et al. Identification of targets of leptin action in rat hypothalamus. J Clin Invest 1996;98:1101–6.[Web of Science][Medline]
- Tartaglia LA, Dembski M, Weng X, et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 1995;83:1263–71.[CrossRef][Web of Science][Medline]
- Watowich SS, Wu H, Socolovsky M, et al. Cytokine receptor signal transduction and the control of hematopoietic cell development. Annu Rev Cell Dev Biol 1996;12:91–128.[CrossRef][Web of Science][Medline]
- Dubuquoy L, Dharancy S, Nutten S, et al. Role of peroxisome proliferator-activated receptor gamma and retinoid X receptor heterodimer in hepatogastroenterological diseases. Lancet 2002;360:1410–18.[CrossRef][Web of Science][Medline]
- Mukherjee R, Jow L, Croston GE, et al. Identification, characterization, and tissue distribution of human peroxisome proliferator-activated receptor (PPAR) isoforms PPAR-gamma-2 versus PPAR-gamma-1 and activation with retinoid X receptor agonists and antagonists. J Biol Chem 1997;272:8071–6.
[Abstract/Free Full Text] - Greene ME, Blumberg B, McBride OW, et al. Isolation of the human peroxisome proliferator activated receptor gamma cDNA: expression in hematopoietic cells and chromosomal mapping. Gene Expr 1995;4:281–99.[Medline]
- Fajas L, Auboeuf D, Raspe E, et al. The organization, promoter analysis, and expression of the human PPAR-gamma gene. J Biol Chem 1997;272:18779–89.
[Abstract/Free Full Text] - Elbrecht A, Chen Y, Cullinan CA, et al. Molecular cloning, expression and characterization of human peroxisome proliferator activated receptors gamma-1 and gamma-2. Biochem Biophys Res Commun 1996;224:431–7.[CrossRef][Web of Science][Medline]
- Ingalls AM, Dickie MM, Snell GD. Obese, a new mutation in the house mouse. J Hered 1950;41:317–18.
[Free Full Text] - Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the mouse obese gene and its human homologue. Nature 1994;372:425–32.[CrossRef][Medline]
- Considine RV, Considine EL, Williams CJ, et al. Evidence against either a premature stop codon or the absence of obese gene mRNA in human obesity. J Clin Invest 1995;95:2986–8.[Web of Science][Medline]
- Montague CT, Farooqi IS, Whitehead JP, et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997;387:903–8.[CrossRef][Medline]
- Echwald SM, Rasmussen SB, Sorensen TI, et al. Identification of two novel missense mutations in the human OB gene. Int J Obes Relat Metab Disord 1997;21:321–6.[CrossRef][Web of Science][Medline]
- Oksanen L, Kainulainen K, Heiman M, et al. Novel polymorphism of the human ob gene promoter in lean and morbidly obese subjects. Int J Obes Relat Metab Disord 1997;21:489–94.[CrossRef][Web of Science][Medline]
- Mammès O, Betoulle D, Aubert R, et al. Novel polymorphisms in the 5' region of the LEP gene: association with leptin levels and response to low-calorie diet in human obesity. Diabetes 1998;47:487–9.[Web of Science][Medline]
- Karvonen MK, Pesonen U, Heinonen P, et al. Identification of new sequence variants in the leptin gene. J Clin Endocrinol Metab 1998;83:3239–42.
[Abstract/Free Full Text] - Hager J, Clement K, Francke S, et al. A polymorphism in the 5' untranslated region of the human ob gene is associated with low leptin levels. Int J Obes Relat Metab Disord 1998;22:200–5.[CrossRef][Web of Science][Medline]
- Lucantoni R, Ponti E, Berselli ME, et al. The A19G polymorphism in the 5' untranslated region of the human obese gene does not affect leptin levels in severely obese patients. J Clin Endocrinol Metab 2000;85:3589–91.
[Abstract/Free Full Text] - Considine RV, Considine EL, Williams CJ, et al. The hypothalamic leptin receptor in humans: identification of incidental sequence polymorphisms and absence of the db/db mouse and fa/fa rat mutations. Diabetes 1996;45:992–4.[Abstract]
- Mars M, van Rossum CT, de Graaf C, et al. Leptin responsiveness to energy restriction: genetic variation in the leptin receptor gene. Obes Res 2004;12:442–4.[Web of Science][Medline]
- Ristow M, Muller Wieland D, Pfeiffer A, et al. Obesity associated with a mutation in a genetic regulator of adipocyte differentiation. N Engl J Med 1998;339:953–9.
[Abstract/Free Full Text] - Barroso I, Gurnell M, Crowley VE, et al. Dominant negative mutations in human PPARG associated with severe insulin resistance, diabetes mellitus and hypertension. Nature 1999;402:880–3.[Medline]
- Yen CJ, Beamer BA, Negri C, et al. Molecular scanning of the human peroxisome proliferator activated receptor gamma (hPPAR-gamma) gene in diabetic Caucasians: identification of a pro12ala PPAR-gamma-2 missense mutation. Biochem Biophys Res Commun 1997;241:270–4.[CrossRef][Web of Science][Medline]
- Yamauchi T, Waki H, Kamon J, et al. Inhibition of RXR and PPARgamma ameliorates diet-induced obesity and type 2 diabetes. J Clin Invest 2001;108:1001–13.[CrossRef][Web of Science][Medline]
- Kolehmainen M, Uusitupa MI, Alhava E, et al. Effect of the Pro12Ala polymorphism in the peroxisome proliferator-activated receptor (PPAR) G2 gene on the expression of PPARG target genes in adipose tissue of massively obese subjects. J Clin Endocrinol Metab 2003;88:1717–22.
[Abstract/Free Full Text] - Sacks HS, Berrier J, Reitman D, et al. Meta-analyses of randomized controlled trials. N Engl J Med 1987;316:450–5.[Abstract]
- Oxman AD, Cook DJ, Guyatt GH. Users' guides to the medical literature. VI. How to use an overview. Evidence-Based Medicine Working Group. JAMA 1994;272:1367–71.
[Abstract/Free Full Text] - Cook DJ, Sackett DL, Spitzer WO. Methodologic guidelines for systematic reviews of randomized control trials in health care from the Potsdam Consultation on Meta-Analysis. J Clin Epidemiol 1995;48:167–71.[CrossRef][Web of Science][Medline]
- Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;50:1088–101.[CrossRef][Web of Science][Medline]
- Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629–34.
[Abstract/Free Full Text] - Cochran G. The combination of estimates from different experiments. Biometrics 1954;10:101–29.[CrossRef][Web of Science]
- Normand SL. Meta-analysis: formulating, evaluating, combining, and reporting. Stat Med 1999;18:321–59.[CrossRef][Web of Science][Medline]
- Silver K, Walston J, Chung WK, et al. The Gln223Arg and Lys656Asn polymorphisms in the human leptin receptor do not associate with traits related to obesity. Diabetes 1997;46:1898–900.[Web of Science][Medline]
- Gotoda T, Manning BS, Goldstone AP, et al. Leptin receptor gene variation and obesity: lack of association in a white British male population. Hum Mol Genet 1997;6:869–76.
[Abstract/Free Full Text] - Quinton ND, Lee AJ, Ross RJ, et al. A single nucleotide polymorphism (SNP) in the leptin receptor is associated with BMI, fat mass and leptin levels in postmenopausal Caucasian women. Hum Genet 2001;108:233–6.[CrossRef][Web of Science][Medline]
- Mammes O, Aubert R, Betoulle D, et al. LEPR gene polymorphisms: associations with overweight, fat mass and response to diet in women. Eur J Clin Invest 2001;31:398–404.[CrossRef][Web of Science][Medline]
- Wauters M, Mertens I, Chagnon M, et al. Polymorphisms in the leptin receptor gene, body composition and fat distribution in overweight and obese women. Int J Obes Relat Metab Disord 2001;25:714–20.[CrossRef][Web of Science][Medline]
- van Rossum CT, Hoebee B, Seidell JC, et al. Genetic factors as predictors of weight gain in young adult Dutch men and women. Int J Obes Relat Metab Disord 2002;26:517–28.[CrossRef][Web of Science][Medline]
- Rosmond R, Chagnon YC, Holm G, et al. Hypertension in obesity and the leptin receptor gene locus. J Clin Endocrinol Metab 2000;85:3126–31.
[Abstract/Free Full Text] - Echwald SM, Sorensen TD, Sorensen TI, et al. Amino acid variants in the human leptin receptor: lack of association to juvenile onset obesity. Biochem Biophys Res Commun 1997;233:248–52.[CrossRef][Web of Science][Medline]
- Yiannakouris N, Yannakoulia M, Melistas L, et al. The Q223R polymorphism of the leptin receptor gene is significantly associated with obesity and predicts a small percentage of body weight and body composition variability. J Clin Endocrinol Metab 2001;86:4434–9.
[Abstract/Free Full Text] - de Silva AM, Walder KR, Boyko EJ, et al. Genetic variation and obesity in Australian women: a prospective study. Obes Res 2001;9:733–40.[Web of Science][Medline]
- Matsuoka N, Ogawa Y, Hosoda K, et al. Human leptin receptor gene in obese Japanese subjects: evidence against either obesity-causing mutations or association of sequence variants with obesity. Diabetologia 1997;40:1204–10.[CrossRef][Web of Science][Medline]
- Endo K, Yanagi H, Hirano C, et al. 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. Int J Obes Relat Metab Disord 2000;24:443–9.[CrossRef][Web of Science][Medline]
- Koh JM, Kim DJ, Hong JS, et al. 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. Eur J Endocrinol 2002;147:777–83.[Abstract]
- Thompson DB, Ravussin E, Bennett PH, et al. Structure and sequence variation at the human leptin receptor gene in lean and obese Pima Indians. Hum Mol Genet 1997;6:675–9.
[Abstract/Free Full Text] - Stefan N, Vozarova B, Del Parigi A, et al. The Gln223Arg polymorphism of the leptin receptor in Pima Indians: influence on energy expenditure, physical activity and lipid metabolism. Int J Obes Relat Metab Disord 2002;26:1629–32.[CrossRef][Web of Science][Medline]
- Chung WK, Power-Kehoe L, Chua M, et al. Exonic and intronic sequence variation in the human leptin receptor gene (LEPR). Diabetes 1997;46:1509–11.[Web of Science][Medline]
- Mattevi VS, Zembrzuski VM, Hutz MH. Association analysis of genes involved in the leptin-signaling pathway with obesity in Brazil. Int J Obes Relat Metab Disord 2002;26:1179–85.[CrossRef][Web of Science][Medline]
- de Silva AM, Walder KR, Aitman TJ, et al. Combination of polymorphisms in OB-R and the OB gene associated with insulin resistance in Nauruan males. Int J Obes Relat Metab Disord 1999;23:816–22.[CrossRef][Web of Science][Medline]
- Valve R, Sivenius K, Miettinen R, et al. Two polymorphisms in the peroxisome proliferator-activated receptor-G gene are associated with severe overweight among obese women. J Clin Endocrinol Metab 1999;84:3708–12.
[Abstract/Free Full Text] - Meirhaeghe A, Fajas L, Helbecque N, et al. A genetic polymorphism of the peroxisome proliferator-activated receptor G gene influences plasma leptin levels in obese humans. Hum Mol Genet 1998;7:435–40.
[Abstract/Free Full Text] - Orio F Jr, Matarese G, Di Biase S, et al. Exon 6 and 2 peroxisome proliferator-activated receptor-G polymorphisms in polycystic ovary syndrome. J Clin Endocrinol Metab 2003;88:5887–92.
[Abstract/Free Full Text] - Wang XL, Oosterhof J, Duarte N. Peroxisome proliferator-activated receptor G C161
T polymorphism and coronary artery disease. Cardiovasc Res 1999;44:588–94.[Abstract/Free Full Text] - Muller YL, Bogardus C, Beamer BA, et al. A functional variant in the peroxisome proliferator-activated receptor G2 promoter is associated with predictors of obesity and type 2 diabetes in Pima Indians. Diabetes 2003;52:1864–71.
[Abstract/Free Full Text] - Ogawa S, Urano T, Hosoi T, et al. Association of bone mineral density with a polymorphism of the peroxisome proliferator-activated receptor G gene: PPARG expression in osteoblasts. Biochem Biophys Res Commun 1999;260:122–6.[CrossRef][Web of Science][Medline]
- Beamer BA, Yen CJ, Andersen RE, et al. Association of the Pro12Ala variant in the peroxisome proliferator-activated receptor-G2 gene with obesity in two Caucasian populations. Diabetes 1998;47:1806–8.[Web of Science][Medline]
- Memisoglu A, Hankinson SE, Manson JE, et al. Lack of association of the codon 12 polymorphism of the peroxisome proliferator-activated receptor G gene with breast cancer and body mass. Pharmacogenetics 2002;12:597–603.[CrossRef][Web of Science][Medline]
- Memisoglu A, Hu FB, Hankinson SE, et al. Prospective study of the association between the proline to alanine codon 12 polymorphism in the PPARG gene and type 2 diabetes. Diabetes Care 2003;26:2915–17.
[Abstract/Free Full Text] - Memisoglu A, Hu FB, Hankinson SE, et al. Interaction between a peroxisome proliferator-activated receptor G gene polymorphism and dietary fat intake in relation to body mass. Hum Mol Genet 2003;12:2923–9.
[Abstract/Free Full Text] - Franks PW, Luan J, Browne PO, et al. Does peroxisome proliferator-activated receptor G genotype (Pro12ala) modify the association of physical activity and dietary fat with fasting insulin level? Metabolism 2004;53:11–16.[CrossRef][Web of Science][Medline]
- Ringel J, Engeli S, Distler A, et al. Pro12Ala missense mutation of the peroxisome proliferator activated receptor G and diabetes mellitus. Biochem Biophys Res Commun 1999;254:450–3.[CrossRef][Web of Science][Medline]
- Koch M, Rett K, Maerker E, et al. The silent PPARG exon 6 CAC(His) CAT(His) polymorphism does not affect the plasma leptin levels in a collective of first degree relatives of type 2 diabetes patients from South West Germany. Exp Clin Endocrinol Diabetes 2000;108:341–6.[CrossRef][Web of Science][Medline]
- Evans D, Mann WA, Heer J, et al. Variation in the gene for human peroxisome proliferator activated receptor G (PPARG) does not play a major role in the development of morbid obesity. Int J Obes Relat Metab Disord 2000;24:647–51.[CrossRef][Web of Science][Medline]
- Evans D, Wolf AM, Nellessen U, et al. Association between polymorphisms in candidate genes and morbid obesity. Int J Obes 2001;25:S19–S21.[CrossRef]
- Vigouroux C, Fajas L, Khallouf E, et al. Human peroxisome proliferator-activated receptor-G2: genetic mapping, identification of a variant in the coding sequence, and exclusion as the gene responsible for lipoatrophic diabetes. Diabetes 1998;47:490–2.[Web of Science][Medline]
- Ek J, Urhammer SA, Sorensen TI, et al. Homozygosity of the Pro12Ala variant of the peroxisome proliferation-activated receptor-G2 (PPAR-G2): divergent modulating effects on body mass index in obese and lean Caucasian men. Diabetologia 1999;42:892–5.[CrossRef][Web of Science][Medline]
- Frederiksen L, Brodbaek K, Fenger M, et al. Comment: studies of the Pro12Ala polymorphism of the PPAR-G gene in the Danish MONICA cohort: homozygosity of the Ala allele confers a decreased risk of the insulin resistance syndrome. J Clin Endocrinol Metab 2002;87:3989–92.
[Abstract/Free Full Text] - Deeb SS, Fajas L, Nemoto M, et al. A Pro12Ala substitution in PPARG2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet 1998;20:284–7.[CrossRef][Web of Science][Medline]
- Niskanen L, Lindi V, Erkkila A, et al. Association of the PRO12ALA polymorphism of the PPAR-G2 gene with oxidized low-density lipoprotein and cardiolipin autoantibodies in nondiabetic and type 2 diabetic subjects. Metabolism 2003;52:213–17.[CrossRef][Web of Science][Medline]
- Mancini FP, Sabatino L, Colantuoni V, et al. Variants of uncoupling protein-2 gene and obesity: interaction with peroxisome proliferator-activated receptorG2. Clin Endocrinol (Oxf) 2003;59:817–22.[CrossRef][Medline]
- Vaccaro O, Mancini FP, Ruffa G, et al. Pro12Ala mutation in the peroxisome proliferator-activated receptor G2 (PPARG2) and severe obesity: a case-control study. Int J Obes Relat Metab Disord 2000;24:1195–9.[CrossRef][Web of Science][Medline]
- Gonzalez Sanchez JL, Serrano Rios M, Fernandez Perez C, et al. Effect of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor G-2 gene on adiposity, insulin sensitivity and lipid profile in the Spanish population. Eur J Endocrinol 2002;147:495–501.[Abstract]
- Swarbrick MM, Chapman CM, McQuillan BM, et al. A Pro12Ala polymorphism in the human peroxisome proliferator-activated receptor-G 2 is associated with combined hyperlipidaemia in obesity. Eur J Endocrinol 2001;144:277–82.[Abstract]
- Mori Y, Kim-Motoyama H, Katakura T, et al. Effect of the Pro12Ala variant of the human peroxisome proliferator-activated receptor G 2 gene on adiposity, fat distribution, and insulin sensitivity in Japanese men. Biochem Biophys Res Commun 1998;251:195–8.[CrossRef][Web of Science][Medline]
- Hara K, Okada T, Tobe K, et al. The Pro12Ala polymorphism in PPAR G2 may confer resistance to type 2 diabetes. Biochem Biophys Res Commun 2000;271:212–16.[CrossRef][Web of Science][Medline]
- Yamamoto Y, Hirose H, Miyashita K, et al. PPAR(G)2 gene Pro12Ala polymorphism may influence serum level of an adipocyte-derived protein, adiponectin, in the Japanese population. Metabolism 2002;51:1407–9.[CrossRef][Web of Science][Medline]
- Kahara T, Takamura T, Hayakawa T, et al. PPARG gene polymorphism is associated with exercise-mediated changes of insulin resistance in healthy men. Metabolism 2003;52:209–12.[CrossRef][Web of Science][Medline]
- Lei HH, Chen MH, Yang WS, et al. Peroxisome proliferator-activated receptor G 2 Pro12Ala gene variant is strongly associated with larger body mass in the Taiwanese. Metabolism 2000;49:1267–70.[CrossRef][Web of Science][Medline]
- Kao WH, Coresh J, Shuldiner AR, et al. Pro12Ala of the peroxisome proliferator-activated receptor-G2 gene is associated with lower serum insulin levels in nonobese African Americans: the Atherosclerosis Risk in Communities Study. Diabetes 2003;52:1568–72.
[Abstract/Free Full Text] - Clement K. Leptin and the genetics of obesity. Acta Paediatr Suppl 1999;88:51–7.[Medline]
- Lonnqvist F, Nordfors L, Schalling M. Leptin and its potential role in human obesity. J Intern Med 1999;245:643–52.[CrossRef][Web of Science][Medline]
- Arner P. Obesity—a genetic disease of adipose tissue? Br J Nutr 2000;83(suppl 1):S9–16.
- Hebebrand J, Sommerlad C, Geller F, et al. The genetics of obesity: practical implications. Int J Obes Relat Metab Disord 2001;25(suppl 1):S10–18.
- Trayhurn P. Biology of leptin—its implications and consequences for the treatment of obesity. Int J Obes Relat Metab Disord 2001;25(suppl 1):S26–8.
- Rosmond R. Association studies of genetic polymorphisms in central obesity: a critical review. Int J Obes Relat Metab Disord 2003;27:1141–51.[CrossRef][Web of Science][Medline]
- Bray GA. Evaluation of obesity. Who are the obese? Postgrad Med 2003;114:19–27, 38.[Medline]
- World Health Organization. Obesity: preventing and managing the global epidemic. Report of a WHO Consultation on Obesity, Geneva, 3–5 June, 1997. Geneva, Switzerland: World Health Organization, 1998. (WHO TRS 894).
- Moyad MA. Current methods used for defining, measuring, and treating obesity. Semin Urol Oncol 2001;19:247–56.[Medline]
- Sezginsoy B, Ross K, Wright JE, et al. Obesity in the elderly: survival of the fit or fat. J Okla State Med Assoc 2004;97:437–9.[Medline]
- Raz I, Eldor R, Cernea S, et al. Diabetes: insulin resistance and derangements in lipid metabolism. Cure through intervention in fat transport and storage. Diabetes Metab Res Rev 2005;21:3–14.[CrossRef][Web of Science][Medline]
- Pi-Sunyer FX. The obesity epidemic: pathophysiology and consequences of obesity. Obes Res 2002;10:97S–104S.[Web of Science][Medline]
- Pi-Sunyer FX. The medical risks of obesity. Obes Surg 2002;12(suppl 1):6S–11S.
- Speakman JR. Obesity: the integrated roles of environment and genetics. J Nutr 2004;134:2090S–2105S.
[Abstract/Free Full Text] - Swinburn BA, Caterson I, Seidell JC, et al. Diet, nutrition and the prevention of excess weight gain and obesity. Public Health Nutr 2004;7:123–46.[CrossRef][Web of Science][Medline]
- Blundell JE, Cooling J. Routes to obesity: phenotypes, food choices and activity. Br J Nutr 2000;83(suppl 1):S33–8.
- James PT. Obesity: the worldwide epidemic. Clin Dermatol 2004;22:276–80.[CrossRef][Web of Science][Medline]
- Ryan DH, Stewart TM. Medical management of obesity in women: office-based approaches to weight management. Clin Obstet Gynecol 2004;47:914–27.[Web of Science][Medline]
- Ribeiro R, Lopes C, Medeiros R. Leptin and prostate: implications for cancer prevention—overview of genetics and molecular interactions. Eur J Cancer Prev 2004;13:359–68.[CrossRef][Web of Science][Medline]
- Pi-Sunyer FX. The epidemiology of central fat distribution in relation to disease. Nutr Rev 2004;62:S120–6.[Web of Science][Medline]
- Clark DO. Physical activity efficacy and effectiveness among older adults and minorities. Diabetes Care 1997;20:1176–82.[Abstract]
- Savage PJ, Harlan WR. Racial and ethnic diversity in obesity and other risk factors for cardiovascular disease: implications for studies and treatment. Ethn Dis 1991;1:200–11.[Medline]
- Kenchaiah S, Gaziano JM, Vasan RS. Impact of obesity on the risk of heart failure and survival after the onset of heart failure. Med Clin North Am 2004;88:1273–94.[CrossRef][Web of Science][Medline]
- Calle EE, Thun MJ. Obesity and cancer. Oncogene 2004;23:6365–78.[CrossRef][Web of Science][Medline]
- Sowers KM, Sowers JR. Obesity, hypertension, and vascular disease. Curr Hypertens Rep 1999;1:140–4.[Medline]
- Ross JA, Oeffinger KC, Davies SM, et al. Genetic variation in the leptin receptor gene and obesity in survivors of childhood acute lymphoblastic leukemia: a report from the childhood cancer survivor study. J Clin Oncol 2004;22:3558–62.
[Abstract/Free Full Text] - Heo M, Leibel RL, Boyer BB, et al. Pooling analysis of genetic data: the association of leptin receptor (LEPR) polymorphisms with variables related to human adiposity. Genetics 2001;159:1163–78.
[Abstract/Free Full Text] - Heo M, Leibel RL, Fontaine KR, et al. A meta-analytic investigation of linkage and association of common leptin receptor (LEPR) polymorphisms with body mass index and waist circumference. Int J Obes Relat Metab Disord 2002;26:640–6.[CrossRef][Web of Science][Medline]
- Luan J, Browne PO, Harding AH, et al. Evidence for gene-nutrient interaction at the PPARG locus. Diabetes 2001;50:686–9.
[Abstract/Free Full Text] - Nieters A, Becker N, Linseisen J. Polymorphisms in candidate obesity genes and their interaction with dietary intake of n-6 polyunsaturated fatty acids affect obesity risk in a sub-sample of the EPIC-Heidelberg cohort. Eur J Nutr 2002;41:210–21.[CrossRef][Web of Science][Medline]
- Skibola CF, Holly EA, Forrest MS, et al. Body mass index, leptin and leptin receptor polymorphisms, and non-Hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev 2004;13:779–86.
[Abstract/Free Full Text] - Ioannidis JP, Ntzani EE, Trikalinos TA. ‘Racial’ differences in genetic effects for complex diseases. Nat Genet 2004;36:1312–18.[CrossRef][Web of Science][Medline]
- Masud S, Ye S. Effect of the peroxisome proliferator activated receptor-G gene Pro12Ala variant on body mass index: a meta-analysis. J Med Genet 2003;40:773–80.
[Free Full Text] - Snyder EE, Walts B, Perusse L, et al. The human obesity gene map: the 2003 update. Obes Res 2004;12:369–439.[Web of Science][Medline]
- Chagnon YC, Rankinene T, Snyder EE, et al. The human obesity gene map: the 2002 update. Obes Res 2003;11:313–67.[Web of Science][Medline]
- Steinbeck KS. The future of obesity management. Clin Obstet Gynecol 2004;47:942–56.[Web of Science][Medline]
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