RESUMEN
The putative protein tyrosine kinase (PTK) inhibitor tyrphostin AG126 has proven beneficial in various models of inflammatory disease. Yet molecular targets and cellular mechanisms remained enigmatic. We demonstrate here that AG126 treatment has beneficial effects in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. AG126 alleviates the clinical symptoms, diminishes encephalitogenic Th17 differentiation, reduces inflammatory CNS infiltration as well as microglia activation and attenuates myelin damage. We show that AG126 directly inhibits Bruton's tyrosine kinase (BTK), a PTK associated with B cell receptor and Toll-like receptor (TLR) signaling. However, BTK inhibition cannot account for the entire activity spectrum. Effects on TLR-induced proinflammatory cytokine expression in microglia involve AG126 hydrolysis and conversion of its dinitrile side chain to malononitrile (MN). Notably, while liberated MN can subsequently mediate critical AG126 features, full protection in EAE still requires delivery of intact AG126. Its anti-inflammatory potential and especially interference with TLR signaling thus rely on a dual mechanism encompassing BTK and a novel MN-sensitive target. Both principles bear great potential for the therapeutic management of disturbed innate and adaptive immune functions.
Asunto(s)
Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Tirfostinos/farmacología , Agammaglobulinemia Tirosina Quinasa , Animales , Células Cultivadas , Citocinas/metabolismo , Encefalomielitis Autoinmune Experimental/patología , Encefalomielitis Autoinmune Experimental/fisiopatología , Femenino , Hidrólisis , Factores Inmunológicos/química , Factores Inmunológicos/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microglía/efectos de los fármacos , Microglía/fisiología , Factor 88 de Diferenciación Mieloide/metabolismo , Fármacos Neuroprotectores/química , Nitrilos/química , Nitrilos/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Bazo/citología , Bazo/efectos de los fármacos , Bazo/fisiopatología , Células Th17/efectos de los fármacos , Células Th17/patología , Células Th17/fisiología , Tirfostinos/químicaRESUMEN
We identified a locus on chromosome 6q16.3-q24.2 (ref. 1) associated with childhood obesity that includes 2.4 Mb common to eight genome scans for type 2 diabetes (T2D) or obesity. Analysis of the gene ENPP1 (also called PC-1), a candidate for insulin resistance, in 6,147 subjects showed association between a three-allele risk haplotype (K121Q, IVS20delT-11 and A-->G+1044TGA; QdelTG) and childhood obesity (odds ratio (OR) = 1.69, P = 0.0006), morbid or moderate obesity in adults (OR = 1.50, P = 0.006 or OR = 1.37, P = 0.02, respectively) and T2D (OR = 1.56, P = 0.00002). The Genotype IBD Sharing Test suggested that this obesity-associated ENPP1 risk haplotype contributes to the observed chromosome 6q linkage with childhood obesity. The haplotype confers a higher risk of glucose intolerance and T2D to obese children and their parents and associates with increased serum levels of soluble ENPP1 protein in children. Expression of a long ENPP1 mRNA isoform, which includes the obesity-associated A-->G+1044TGA SNP, was specific for pancreatic islet beta cells, adipocytes and liver. These findings suggest that several variants of ENPP1 have a primary role in mediating insulin resistance and in the development of both obesity and T2D, suggesting that an underlying molecular mechanism is common to both conditions.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad , Prueba de Tolerancia a la Glucosa , Obesidad/genética , Hidrolasas Diéster Fosfóricas/genética , Pirofosfatasas/genética , Adulto , Estudios de Casos y Controles , Niño , Haplotipos , Humanos , ARN Mensajero/genéticaRESUMEN
Type 2 diabetes mellitus results from the interaction of environmental factors with a combination of genetic variants, most of which were hitherto unknown. A systematic search for these variants was recently made possible by the development of high-density arrays that permit the genotyping of hundreds of thousands of polymorphisms. We tested 392,935 single-nucleotide polymorphisms in a French case-control cohort. Markers with the most significant difference in genotype frequencies between cases of type 2 diabetes and controls were fast-tracked for testing in a second cohort. This identified four loci containing variants that confer type 2 diabetes risk, in addition to confirming the known association with the TCF7L2 gene. These loci include a non-synonymous polymorphism in the zinc transporter SLC30A8, which is expressed exclusively in insulin-producing beta-cells, and two linkage disequilibrium blocks that contain genes potentially involved in beta-cell development or function (IDE-KIF11-HHEX and EXT2-ALX4). These associations explain a substantial portion of disease risk and constitute proof of principle for the genome-wide approach to the elucidation of complex genetic traits.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad/genética , Genoma Humano , Estudios de Casos y Controles , Proteínas de Transporte de Catión/genética , Cromosomas Humanos Par 10/genética , Cromosomas Humanos Par 8/genética , Francia , Humanos , Desequilibrio de Ligamiento , Transportador 8 de ZincRESUMEN
Background: The French Universal Health Cover (CMU) aims to compensate for inequalities between precarious and non-precarious populations, enabling the former to access to free healthcare. These measures rely on the principle that precarious populations' health improves if healthcare is free. We designed a study to examine whether CMU fails to compensate for inequalities in reimbursed drugs prescriptions in precarious populations. Material and method: This retrospective pharmaco-epidemiological study compared the Defined Daily Dose relative to different reimbursed drugs prescribed by general practitioners (GPs) to precarious and non-precarious patients in France in 2015. Data were analysed using Mann-Whitney tests. Findings: 6 out of 20 molecules were significantly under-reimbursed in precarious populations. 2 were over-reimbursed. The 12 remaining molecules did not differ between groups. Interpretation: The under-reimbursement of atorvastatin, rosuvastatin, tamsulosine and timolol reflects well-documented epidemiological differences between these populations. In contrast, the equal reimbursement of amoxicillin, pyostacine, ivermectin, salbutamol and tiopropium is likely an effect of lack of compensation for inequalities. Precarious patients are more affected by diseases that these molecules target (e.g., chronic bronchitis, bacterial pneumonia, cutaneous infections). This could also be the case for the equal and under-reimbursement of insulin glargine and metformin (targeting diabetes), respectively, although this has to be considered with caution. In conclusion, the French free healthcare cover does not fail to compensate for all but only for some selective inequalities in access to reimbursed drugs prescriptions. These results are discussed with respect to the interaction of the doctor-patient relationship and the holistic nature of primary care, potentially triggering burnout and empathy decrease and negatively impacting the quality of care in precarious populations.
Asunto(s)
Médicos Generales , Relaciones Médico-Paciente , Cobertura Universal del Seguro de Salud , Poblaciones Vulnerables , Atención a la Salud , Prescripciones de Medicamentos , Francia , Humanos , Estudios RetrospectivosRESUMEN
Adiponectin is a metabolic link between adipose tissue and insulin action, mediating part of obesity-associated insulin resistance and type 2 diabetes. Two adiponectin receptors have been identified, and we investigated whether sequence variations in adiponectin receptor 1 (ADIPOR1) and adiponectin receptor 2 (ADIPOR2) genes could contribute to the genetic risk for type 2 diabetes in a case-control study of 1,498 Caucasian subjects. We sequenced the putative functional regions of the two genes in 48 subjects and selected single nucleotide polymorphisms (SNPs) from the public database. Five SNPs in ADIPOR1 and 12 in ADIPOR2 were tested for association with type 2 diabetes. No SNP of ADIPOR1 showed association in any of the samples from the French population. In contrast, three SNPs of ADIPOR2 showed nominal evidence for association with type 2 diabetes before correction for multiple testing (odds ratio [OR] 1.29-1.37, P = 0.034-0.014); only rs767870, located in intron 6, was replicated in an additional diabetes dataset (n = 636, OR 1.29, P = 0.020) with significant allelic association from the overall meta-analysis of 2,876 subjects (adjusted OR 1.25 [95% CI 1.07-1.45], P = 0.0051). In conclusion, our data suggest a modest contribution of ADIPOR2 variants in diabetes risk in the French population.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Polimorfismo de Nucleótido Simple , Receptores de Superficie Celular/genética , Población Blanca/genética , Adulto , Anciano , Femenino , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Receptores de AdiponectinaRESUMEN
The gene GAD2 encoding the glutamic acid decarboxylase enzyme (GAD65) is a positional candidate gene for obesity on Chromosome 10p11-12, a susceptibility locus for morbid obesity in four independent ethnic populations. GAD65 catalyzes the formation of gamma-aminobutyric acid (GABA), which interacts with neuropeptide Y in the paraventricular nucleus to contribute to stimulate food intake. A case-control study (575 morbidly obese and 646 control subjects) analyzing GAD2 variants identified both a protective haplotype, including the most frequent alleles of single nucleotide polymorphisms (SNPs) +61450 C>A and +83897 T>A (OR = 0.81, 95% CI [0.681-0.972], p = 0.0049) and an at-risk SNP (-243 A>G) for morbid obesity (OR = 1.3, 95% CI [1.053-1.585], p = 0.014). Furthermore, familial-based analyses confirmed the association with the obesity of SNP +61450 C>A and +83897 T>A haplotype (chi(2) = 7.637, p = 0.02). In the murine insulinoma cell line betaTC3, the G at-risk allele of SNP -243 A>G increased six times GAD2 promoter activity (p < 0.0001) and induced a 6-fold higher affinity for nuclear extracts. The -243 A>G SNP was associated with higher hunger scores (p = 0.007) and disinhibition scores (p = 0.028), as assessed by the Stunkard Three-Factor Eating Questionnaire. As GAD2 is highly expressed in pancreatic beta cells, we analyzed GAD65 antibody level as a marker of beta-cell activity and of insulin secretion. In the control group, -243 A>G, +61450 C>A, and +83897 T>A SNPs were associated with lower GAD65 autoantibody levels (p values of 0.003, 0.047, and 0.006, respectively). SNP +83897 T>A was associated with lower fasting insulin and insulin secretion, as assessed by the HOMA-B% homeostasis model of beta-cell function (p = 0.009 and 0.01, respectively). These data support the hypothesis of the orexigenic effect of GABA in humans and of a contribution of genes involved in GABA metabolism in the modulation of food intake and in the development of morbid obesity.
Asunto(s)
Cromosomas Humanos Par 10/genética , Cromosomas Humanos Par 10/ultraestructura , Glutamato Descarboxilasa/genética , Glutamato Descarboxilasa/fisiología , Isoenzimas/genética , Isoenzimas/fisiología , Obesidad Mórbida/genética , Obesidad/genética , Adulto , Anciano , Alelos , Autoanticuerpos/química , Estudios de Casos y Controles , Catálisis , Línea Celular , Mapeo Cromosómico , Ingestión de Alimentos , Salud de la Familia , Conducta Alimentaria , Femenino , Ligamiento Genético , Genotipo , Glutamato Descarboxilasa/química , Haplotipos , Humanos , Hambre , Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/metabolismo , Isoenzimas/química , Escala de Lod , Luciferasas/metabolismo , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Neuropéptido Y/metabolismo , Oportunidad Relativa , Núcleo Hipotalámico Paraventricular/metabolismo , Plásmidos/metabolismo , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Riesgo , Encuestas y Cuestionarios , Ácido gamma-Aminobutírico/metabolismoRESUMEN
CONTEXT: Both adverse intrauterine events and genetic background have been suggested to promote insulin resistance in subjects born small for gestational age (SGA). Among candidate genes that potentially influence both fetal growth and glucose metabolism is insulin. The potential effect of the insulin gene VNTR (INS) on birth weight has been controversial so far. OBJECTIVE: The present association study aimed at testing for the contribution of the INS VNTR locus on birth weight and on the metabolic profile of young adults born SGA (mean age, 22 yr). Two groups of subjects were selected on birth data: SGA (birth weight < 10th percentile; n = 735), and appropriate for gestational age (AGA; birth weight between 25th and 75th percentiles; n = 886). All subjects were genotyped for rs689 A/T single nucleotide polymorphism, in complete linkage disequilibrium with the INS VNTR classes I and III, respectively. RESULTS: Class I INS frequencies were similar in the two groups (70% in AGA; 72% in SGA; P = 0.42). There was significant effect on mean birth weight in neither SGA (P = 0.99) nor AGA (P = 0.18). Although the INS VNTR locus did not associate with anomalies of insulin resistance indices in the AGA group, in the SGA group, INS VNTR class III allele was associated with higher insulin resistance (quantitative insulin sensitivity check index = 0.38 vs. 0.39; P = 0.05). Furthermore, there was evidence of an interaction between the SGA/AGA status and INS VNTR locus on insulin resistance indices (P = 0.01) in a multivariate analysis. CONCLUSION: The INS VNTR locus does not associate in a major way with SGA in the French population. However, our data support an interaction between severe fetal growth restriction and INS VNTR locus, which were associated with insulin resistance in young adults born SGA.
Asunto(s)
Recién Nacido Pequeño para la Edad Gestacional , Resistencia a la Insulina , Insulina/genética , Repeticiones de Minisatélite , Adulto , Genotipo , Humanos , Recién NacidoRESUMEN
Low birth weight is a risk factor for obesity and type 2 diabetes. The fetal insulin hypothesis proposes that low birth weight might be mediated partly by genetic factors that impair insulin secretion/sensitivity during the fetal stage, as shown for glucokinase, the ATP-sensitive K+ channel subunit Kir6.2, and the small heterodimer partner genes. Glutamic acid decarboxylase 2 gene (GAD2) overexpression impairs insulin secretion in animals. Recently, polymorphisms in the GAD2 gene were associated with adult morbid obesity. In the present study, we investigated potential effects of the functional -243 A-->G polymorphism in the 5' promoter region of the GAD2 gene on fetal growth, insulin secretion, food intake, and risk of obesity in 635 French Caucasian severely obese children from three different medical centers. The case/control study confirmed the association between the GAD2 single-nucleotide polymorphism (SNP) -243 A-->G and obesity (odds ratio, 1.25; P = 0.04). In addition, SNP -243 GG children carriers showed a 270 g lower birth weight and a 1.5 cm lower birth height compared with AA carriers (P = 0.009 and P = 0.013, respectively). The relation between birth weight and Z score of BMI was linear in AA carrier children (P = 0.00001) and quadratic (U-shaped curve) in AG/GG carrier children (P = 0.0009). G allele children carriers presented a trend toward lower insulinogenic index with 25% reduction of insulin secretion in response to glucose load compared with A carriers (P = 0.09). Eighteen percent of GG obese carriers vs. 5.7% of AA carriers reported binge eating phenotype (P = 0.04). These results confirm the association between GAD2-243 promoter SNP and the risk for obesity and suggest that GAD2 may be a polygenic component of the complex mechanisms linking birth weight to further risk for metabolic diseases, possibly involving the pleiotropic effect of insulin on fetal growth and later on feeding behavior.
Asunto(s)
Peso al Nacer , Glutamato Descarboxilasa/genética , Obesidad/genética , Polimorfismo de Nucleótido Simple , Adolescente , Estatura , Índice de Masa Corporal , Niño , Conducta Alimentaria , Femenino , Humanos , Recién Nacido de Bajo Peso , Recién Nacido , Insulina/metabolismo , Secreción de Insulina , MasculinoRESUMEN
Positional candidate gene analysis of the obesity-linked chromosome Xq24 locus identified two obesity-associated single nucleotide polymorphisms (SNPs) in the membrane amino acid transporter encoding the SLC6A14 (solute carrier family 6 [neurotransmitter transporter], member 14) gene in the Finnish population. Since we previously reported a modest evidence of linkage for this region in French obese families, we analyzed these SNPs in 1,267 obese adult case and 649 lean control subjects. SNPs 20649 C>T (odds ratio 1.23, 95% CI 1.04-1.45; P = 0.013) and 22510 C>G (1.36, 1.16-1.59; P = 0.0001) were shown to be associated with obesity in the French population. In addition, pedigree disequilibrium test results showed a modest excess of both at-risk SNP alleles in affected offspring (P = 0.05 and P = 0.08 for SNPs 20649 C>T and 22510 C>G, respectively). The SNP 22510 C>G at-risk G allele was associated, both in adult women with moderate obesity and in 234 obese girls, with higher body fat and modified perception of hunger and satiety (0.003 < P < 0.06). In conclusion, these data confirm an association of the SLC6A14 gene locus with obesity.
Asunto(s)
Proteínas de Transporte de Membrana/genética , Obesidad/genética , Polimorfismo de Nucleótido Simple , Adulto , Femenino , Francia , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Proteínas de Transporte de Membrana/metabolismo , Persona de Mediana Edad , Neurotransmisores/metabolismo , Población Blanca/genéticaRESUMEN
The genetic background that predisposes the Japanese population to type 2 diabetes is largely unknown. Therefore, we conducted a 10-cM genome-wide scan for type 2 diabetes traits in the 359 affected individuals from 159 families, yielding 224 affected sib-pairs of Japanese origin. Nonparametric multipoint linkage analyses performed in the whole population showed one suggestive linked region on 11p13-p12 (maximum logarithm of odds score [MLS] 3.08, near Pax6) and seven potentially linked regions (MLS >1.17) at 1p36-p32, 2q34, 3q26-q28, 6p23, 7p22-p21, 15q13-q21, and 20q12-q13 (near the gene for hepatocyte nuclear factor-4alpha [HNF-4alpha]). Subset analyses according to maximal BMI and early age at diagnosis added suggestive evidence of linkage with type 2 diabetes at 7p22-p21 (MLS 3.51), 15q13-q21 (MLS 3.91), and 20q12-q13 (MLS 2.32). These results support previous indication for linkage found on chromosome 3q, 15q, and 20q in other populations and identifies two new potential loci on 7p and 11p that may confer genetic risk for type 2 diabetes in the Japanese population.
Asunto(s)
Cromosomas Humanos Par 15 , Cromosomas Humanos Par 20 , Cromosomas Humanos Par 3 , Proteínas de Unión al ADN , Diabetes Mellitus Tipo 2/genética , Genoma Humano , Adulto , Edad de Inicio , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice , Mapeo Cromosómico , Cromosomas Humanos Par 1 , Cromosomas Humanos Par 7 , Diabetes Mellitus Tipo 2/clasificación , Ligamiento Genético , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Factor Nuclear 4 del Hepatocito , Humanos , Japón , Persona de Mediana Edad , Núcleo Familiar , Fosfoproteínas/genética , Factores de Transcripción/genéticaRESUMEN
An adipocyte-derived peptide, adiponectin (also known as GBP28), is decreased in subjects with type 2 diabetes. Recent genome-wide scans have mapped a diabetes susceptibility locus to chromosome 3q27, where the adiponectin gene (APM1) is located. Herein, we present evidence of an association between frequent single nucleotide polymorphisms at positions 45 and 276 in the adiponectin gene and type 2 diabetes (P = 0.003 and P = 0.002, respectively). Subjects with the G/G genotype at position 45 or the G/G genotype at position 276 had a significantly increased risk of type 2 diabetes (odds ratio 1.70 [95% CI 1.09-2.65] and 2.16 [1.22-3.95], respectively) compared with those having the T/T genotype at positions 45 and 276, respectively. In addition, the subjects with the G/G genotype at position 276 had a higher insulin resistance index than those with the T/T genotype (1.61 +/- 0.05 vs. 1.19 +/- 0.12, P = 0.001). The G allele at position 276 was linearly associated with lower plasma adiponectin levels (G/G: 10.4 +/- 0.85 microg/ml, G/T: 13.7 +/- 0.87 microg/ml, T/T: 16.6 +/- 2.24 microg/ml, P = 0.01) in subjects with higher BMIs. Based on these findings together with the observation that adiponectin improves insulin sensitivity in animal models, we conclude that the adiponectin gene may be a susceptibility gene for type 2 diabetes.
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Pueblo Asiatico/genética , Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad , Variación Genética , Péptidos y Proteínas de Señalización Intercelular , Proteínas/genética , Adiponectina , Anciano , Secuencia de Bases/genética , Índice de Masa Corporal , Diabetes Mellitus Tipo 2/patología , Diabetes Mellitus Tipo 2/fisiopatología , Femenino , Humanos , Resistencia a la Insulina/genética , Japón , Masculino , Persona de Mediana Edad , Polimorfismo Genético , RiesgoRESUMEN
BACKGROUND: Cocaine and amphetamine regulated transcript (CART) is an anorectic neuropeptide located principally in hypothalamus. CART has been shown to be involved in control of feeding behavior, but a direct relationship with obesity has not been established. The aim of this study was to evaluate the effect of polymorphisms within the CART gene with regards to a possible association with obesity in a Caucasian population. RESULTS: Screening of the entire gene as well as a 3.7 kb region of 5' upstream sequence revealed 31 SNPs and 3 rare variants; 14 of which were subsequently genotyped in 292 French morbidly obese subjects and 368 controls. Haplotype analysis suggested an association with obesity which was found to be mainly due to SNP-3608T>C (rs7379701) (p = 0.009). Genotyping additional cases and controls also of European Caucasian origin supported further this possible association between the CART SNP -3608T>C T allele and obesity (global p-value = 0.0005). Functional studies also suggested that the SNP -3608T>C could modulate nuclear protein binding. CONCLUSION: CART SNP -3608T>C may possibly contribute to the genetic risk for obesity in the Caucasian population. However confirmation of the importance of the role of the CART gene in energy homeostasis and obesity will require investigation and replication in further populations.
Asunto(s)
Proteínas del Tejido Nervioso/genética , Obesidad/genética , Polimorfismo Genético , Población Blanca/genética , Secuencia de Bases , Estudios de Casos y Controles , Genotipo , Humanos , Polimorfismo de Nucleótido Simple , Factores de RiesgoRESUMEN
Obesity is a typical common multifactorial disease in which environmental and genetic factors interact. In rare cases of severe obesity with childhood onset, a single gene has a major effect in determining the occurrence of obesity, with the environment having only a permissive role in the severity of the phenotype. Exceptional mutations of the leptin gene and its receptor, pro-opiomelanocortine (POMC), prohormone convertase 1 (PC1) and more frequently, mutations in the melanocortin receptor 4 (1 to 4% of very obese cases) have been described. All these obesity genes encode proteins that are strongly connected as part of the same loop of the regulation of food intake. They all involve the leptin axis and one of its hypothalamic targets; the melanocortin pathway. Pathways of bodyweight regulation involved in monogenic forms of obesity might represent targets for future drug development. Successful leptin protein replacement in a leptin-deficient child has contributed to the validation of the usefulness of gene screening in humans. However, the individual variability in response to leptin treatment might be related to genetic variability. The efficiency of leptin itself or of small-molecule agonists of the leptin receptor should be studied in relation with genetic variations in the leptin gene promoter. The most common forms of obesity are polygenic. Two general approaches have been used to date in the search for genes underlying common polygenic obesity in humans. The first approach focuses on selected genes having some plausible role in obesity on the basis of their known or presumed biological role. This approach yielded putative susceptibility genes with only small or uncertain effects. The second approach attempts to map genes purely by position and requires no presumptions on the function of genes. Genome-wide scans identify chromosomal regions showing linkage with obesity in large collections of nuclear families. Genome-wide scans in different ethnic populations have localized major obesity loci on chromosomes 2, 5, 10, 11 and 20. Susceptibility gene(s) for obesity may be positionally cloned in the intervals of linkage. The candidate gene and positional cloning of major obesity-linked regions approaches are discussed in this paper.
Asunto(s)
Obesidad/genética , Ligamiento Genético/genética , Humanos , Mutación/genética , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Farmacogenética/métodosRESUMEN
OBJECTIVE: The endocannabinoid pathway is involved in eating behavior and body weight regulation in both animals and humans. The association of a missense polymorphism (Pro129Thr) in FAAH gene with overweight/obesity has been recently questioned. SUBJECTS AND METHODS: To evaluate the contribution of the FAAH gene variation in polygenic obesity and type 2 diabetes mellitus (T2DM) in the French population, we investigated the entire FAAH locus. We selected and genotyped ten tagged single nucleotide polymorphisms (SNPs) in 635 obese children, 896 morbidly obese adults, 2,238 T2DM subjects and 1,340 control subjects, all of French European origin. Case control association tests were performed using logistic regression models. RESULTS: Nominal evidences of association were observed for rs6429600, rs324419, rs324418, rs2295633, rs7520850 and risk for class III adult obesity (0,001 < p < 0.04). The rs324420 (Pro129Thr) was nominally associated with class III adult obesity (ORadditive = 0.79 (95% CI 0.67-0.93), p = 0.005; ORdominant = 0.76 (95% CI 0.63-0.92), p = 0.005), Pro129 being the obesity risk allele. These associations did not remain significant after Bonferroni correction for multiple testing. There was no significant association between FAAH SNPs and risk for childhood obesity or T2DM. CONCLUSION: Our results in 5,109 subjects suggest that FAAH Pro129Thr polymorphism may modestly contribute to class III adult obesity in the French population. Further validation is needed to precise the role of this gene variant in obesity susceptibility background.
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Amidohidrolasas/genética , Diabetes Mellitus Tipo 2/genética , Obesidad/genética , Adolescente , Adulto , Anciano , Niño , Femenino , Francia , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
Mutations in PCSK1 cause monogenic obesity. To assess the contribution of PCSK1 to polygenic obesity risk, we genotyped tag SNPs in a total of 13,659 individuals of European ancestry from eight independent case-control or family-based cohorts. The nonsynonymous variants rs6232, encoding N221D, and rs6234-rs6235, encoding the Q665E-S690T pair, were consistently associated with obesity in adults and children (P = 7.27 x 10(-8) and P = 2.31 x 10(-12), respectively). Functional analysis showed a significant impairment of the N221D-mutant PC1/3 protein catalytic activity.
Asunto(s)
Predisposición Genética a la Enfermedad , Obesidad/genética , Polimorfismo de Nucleótido Simple , Proproteína Convertasa 1/genética , Adulto , Estudios de Casos y Controles , Niño , Humanos , Obesidad/metabolismo , Proproteína Convertasa 1/metabolismo , Población BlancaRESUMEN
Animal studies have illustrated the importance of the expression in adipose tissue of the leptin receptor (OB-R), and of SOCS3 an inhibitor of the leptin signaling pathway, in body weight regulation. The aim of the present study was to investigate in human adipose tissues of the same patients the OB-R isoforms and SOCS3 expression. Subcutaneous and omental adipose tissues were obtained from 6 lean and 18 morbidly obese women. The long isoform OB-Rb mRNA mediating leptin signaling, and SOCS3 mRNA are abundantly present in the subcutaneous fat of lean women, but are 90% and 70% decreased (P<0.0001) in obese women. In visceral fat from lean and obese women, both OB-Rb and SOCS3 mRNA are detected at very low levels. Subcutaneous/visceral ratios for OB-Ra the short OB-R isoform, OB-Rb, and SOCS3 mRNA abundance strongly correlate with the insulin sensitivity index, HOMA-% S, (r=0.49, P<0.0001, r=0.42, P=0.0002 and r=0.38, P=0.0002, respectively) in both lean and obese patients without type 2 diabetes. The near absence of OB-Rb mRNA and the similarly decreased SOCS3 expression in obese adipose tissue may reflect a defective leptin signaling pathway that could play a role in the impairment of insulin sensitivity associated with excess adiposity.
Asunto(s)
Grasa Intraabdominal/metabolismo , Obesidad/metabolismo , Receptores de Superficie Celular/metabolismo , Grasa Subcutánea/metabolismo , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Adulto , Femenino , Regulación de la Expresión Génica , Humanos , Insulina/análisis , Persona de Mediana Edad , Obesidad/diagnóstico , Obesidad/genética , Epiplón/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , ARN Mensajero/metabolismo , Receptores de Superficie Celular/genética , Receptores de Leptina , Proteína 3 Supresora de la Señalización de Citocinas , Proteínas Supresoras de la Señalización de Citocinas/genética , Delgadez/diagnóstico , Delgadez/genética , Delgadez/metabolismoRESUMEN
OBJECTIVES: To study if genes with common single nucleotide polymorphisms (SNPs) associated with obesity-related phenotypes influence weight loss (WL) in obese individuals treated by a hypo-energetic low-fat or high-fat diet. DESIGN: Randomised, parallel, two-arm, open-label multi-centre trial. SETTING: Eight clinical centres in seven European countries. PARTICIPANTS: 771 obese adult individuals. INTERVENTIONS: 10-wk dietary intervention to hypo-energetic (-600 kcal/d) diets with a targeted fat energy of 20%-25% or 40%-45%, completed in 648 participants. OUTCOME MEASURES: WL during the 10 wk in relation to genotypes of 42 SNPs in 26 candidate genes, probably associated with hypothalamic regulation of appetite, efficiency of energy expenditure, regulation of adipocyte differentiation and function, lipid and glucose metabolism, or production of adipocytokines, determined in 642 participants. RESULTS: Compared with the noncarriers of each of the SNPs, and after adjusting for gender, age, baseline weight and centre, heterozygotes showed WL differences that ranged from -0.6 to 0.8 kg, and homozygotes, from -0.7 to 3.1 kg. Genotype-dependent additional WL on low-fat diet ranged from 1.9 to -1.6 kg in heterozygotes, and from 3.8 kg to -2.1 kg in homozygotes relative to the noncarriers. Considering the multiple testing conducted, none of the associations was statistically significant. CONCLUSIONS: Polymorphisms in a panel of obesity-related candidate genes play a minor role, if any, in modulating weight changes induced by a moderate hypo-energetic low-fat or high-fat diet.
RESUMEN
BACKGROUND: The development of obesity is influenced by both genetic and environmental risk factors. Whereas changes in the environment appear to be responsible for the increasing prevalence of obesity, genetic factors interacting with environmental factors would contribute to explain obesity onset and severity. AIM: To explore epidemiologic genotype-by-nutrient interactions in obesity. METHODS: A total of 42 polymorphisms of 26 candidate genes for obesity were genotyped in 549 adult obese women recruited from eight European centres in a case-only study. The nutritional variables assessed in this study were the dietary fibre intake (grams per day), the ratio of dietary polyunsaturated fat to saturated fat (P:S ratio) and the percentage of energy derived from fat in the diet as calculated from a weighed three-day food record (%E). Under the assumption of genotype-nutrient independence in the population, the odds ratio calculated in a sample of obese women would indicate the existence of genotype-by-nutrient interactions, measured as deviations from the multiplicative effects of the genetic and the nutrient factors separately. RESULTS: No new but confirmaty evidences for genotype-by-nutrient interactions in obesity were detected in this case-only study. The test of interaction between fibre intake and the -514 C > T polymorphism of the hepatic lipase gene (LIPC) yielded P-values of 0.01 across different statistical models. Likewise, the -11377G > C polymorphism of the adiponectin gene (ADIPOQ) and the -681 C > G polymorphism of the PPARG3 gene might interact with the percentage of energy derived from fat in the diet for the development of obesity (P-values in the range of 0.01-0.05 across different statistical models). The P-values were not adjusted for multiple testing, so these results should be considered with caution. CONCLUSIONS: Although the use of obese-only samples is theoretically a useful approach to detect interactions, few genotype-by-nutrient interactions have been suggested in obese European women after the analysis of candidate polymorphisms and the selected nutrient variables. The most remarkable multiplicative interaction found in this study refers to the combination of the hepatic lipase gene polymorphism -514 C > T and fibre intake.
Asunto(s)
Adiponectina/genética , Ambiente , Lipasa/genética , Obesidad/genética , PPAR gamma/genética , Polimorfismo de Nucleótido Simple , Adulto , Grasas de la Dieta/administración & dosificación , Fibras de la Dieta/administración & dosificación , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Hígado/enzimología , Persona de Mediana Edad , Obesidad/etiología , Factores de RiesgoRESUMEN
Adiponectin (ACRP30), an adipocyte-secreted protein encoded by the APM1 gene, is known to modulate insulin sensitivity and glucose homeostasis, those effects protecting obese mice from diabetes. Plasma adiponectin levels correlate well with insulin sensitivity in humans, and are decreased in both type 2 diabetes (T2D) and obesity. We screened for single-nucleotide polymorphisms (SNPs) the APM1 gene coding and 5' sequences in 40 French Caucasians: 12 SNPs and 4 rare non-synonymous mutations of exon 3 were detected. The 10 most frequent SNPs were genotyped in 1373 T2D and obese French Caucasian subjects and in all subjects available from 148 T2D multiplex families. The screening for rare mutations of exon 3 was extended to 1246 T2D and obese French subjects and to the members of the 148 T2D multiplex families. A haplotype including SNPs -11391 and -11377, both located in the 5' sequences, was associated with adiponectin levels (P<0.0001) and with T2D (P=0.004). The presence of at least one non-synonymous mutation in exon 3 showed evidence of association with adiponectin levels (P=0.0009) and with T2D (P=0.005). We failed to detect an association with insulin resistance indexes. Although family-based association analysis with T2D did not reach significance, our results suggest that an at-risk haplotype of common variants located in the promoter and rare mutations in exon 3 contribute to the variation of the adipocyte-secreted adiponectin hormone level, and may be part of the genetic determinants for T2D in the French Caucasian population.