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1.
PLoS Genet ; 10(4): e1004235, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24699409

RESUMEN

Variants in the growth factor receptor-bound protein 10 (GRB10) gene were in a GWAS meta-analysis associated with reduced glucose-stimulated insulin secretion and increased risk of type 2 diabetes (T2D) if inherited from the father, but inexplicably reduced fasting glucose when inherited from the mother. GRB10 is a negative regulator of insulin signaling and imprinted in a parent-of-origin fashion in different tissues. GRB10 knock-down in human pancreatic islets showed reduced insulin and glucagon secretion, which together with changes in insulin sensitivity may explain the paradoxical reduction of glucose despite a decrease in insulin secretion. Together, these findings suggest that tissue-specific methylation and possibly imprinting of GRB10 can influence glucose metabolism and contribute to T2D pathogenesis. The data also emphasize the need in genetic studies to consider whether risk alleles are inherited from the mother or the father.


Asunto(s)
Proteína Adaptadora GRB10/genética , Proteína Adaptadora GRB10/metabolismo , Islotes Pancreáticos/metabolismo , Alelos , Diabetes Mellitus Tipo 2 , Ayuno/metabolismo , Estudio de Asociación del Genoma Completo/métodos , Glucosa/genética , Glucosa/metabolismo , Humanos , Insulina/genética , Insulina/metabolismo , Resistencia a la Insulina/genética , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Transducción de Señal/genética
2.
Nat Genet ; 39(6): 724-6, 2007 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-17496892

RESUMEN

We identified a set of SNPs in the first intron of the FTO (fat mass and obesity associated) gene on chromosome 16q12.2 that is consistently strongly associated with early-onset and severe obesity in both adults and children of European ancestry with an experiment-wise P value of 1.67 x 10(-26) in 2,900 affected individuals and 5,100 controls. The at-risk haplotype yields a proportion of attributable risk of 22% for common obesity. We conclude that FTO contributes to human obesity and hence may be a target for subsequent functional analyses.


Asunto(s)
Adiposidad , Índice de Masa Corporal , Cromosomas Humanos Par 16/genética , Predisposición Genética a la Enfermedad , Obesidad/genética , Polimorfismo de Nucleótido Simple/genética , Adulto , Edad de Inicio , Composición Corporal , Estudios de Casos y Controles , Niño , Estudios de Cohortes , Europa (Continente) , Femenino , Variación Genética/genética , Humanos , Intrones/genética , Masculino , Persona de Mediana Edad
3.
Nat Genet ; 37(8): 863-7, 2005 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16025115

RESUMEN

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/genética
4.
PLoS Genet ; 6(4): e1000916, 2010 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-20421936

RESUMEN

Meta-analyses of population-based genome-wide association studies (GWAS) in adults have recently led to the detection of new genetic loci for obesity. Here we aimed to discover additional obesity loci in extremely obese children and adolescents. We also investigated if these results generalize by estimating the effects of these obesity loci in adults and in population-based samples including both children and adults. We jointly analysed two GWAS of 2,258 individuals and followed-up the best, according to lowest p-values, 44 single nucleotide polymorphisms (SNP) from 21 genomic regions in 3,141 individuals. After this DISCOVERY step, we explored if the findings derived from the extremely obese children and adolescents (10 SNPs from 5 genomic regions) generalized to (i) the population level and (ii) to adults by genotyping another 31,182 individuals (GENERALIZATION step). Apart from previously identified FTO, MC4R, and TMEM18, we detected two new loci for obesity: one in SDCCAG8 (serologically defined colon cancer antigen 8 gene; p = 1.85x10(-8) in the DISCOVERY step) and one between TNKS (tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase gene) and MSRA (methionine sulfoxide reductase A gene; p = 4.84x10(-7)), the latter finding being limited to children and adolescents as demonstrated in the GENERALIZATION step. The odds ratios for early-onset obesity were estimated at approximately 1.10 per risk allele for both loci. Interestingly, the TNKS/MSRA locus has recently been found to be associated with adult waist circumference. In summary, we have completed a meta-analysis of two GWAS which both focus on extremely obese children and adolescents and replicated our findings in a large followed-up data set. We observed that genetic variants in or near FTO, MC4R, TMEM18, SDCCAG8, and TNKS/MSRA were robustly associated with early-onset obesity. We conclude that the currently known major common variants related to obesity overlap to a substantial degree between children and adults.


Asunto(s)
Peso Corporal/genética , Sitios Genéticos , Genoma Humano , Obesidad/genética , Adolescente , Adulto , Edad de Inicio , Alelos , Índice de Masa Corporal , Niño , Francia/epidemiología , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Alemania/epidemiología , Humanos , Obesidad/epidemiología , Polimorfismo de Nucleótido Simple
5.
Cell Metab ; 3(2): 135-40, 2006 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-16459314

RESUMEN

The melanocortin-4 receptor (MC4R) plays a critical role in the control of energy balance. Of its two pro-opiomelanocortin (POMC)-derived ligands, alpha- and beta-MSH, the majority of attention has focused on alpha-MSH, partly reflecting the absence of beta-MSH in rodents. We screened the POMC gene in 538 patients with severe, early-onset obesity and identified five unrelated probands who were heterozygous for a rare missense variant in the region encoding beta-MSH, Tyr221Cys. This frequency was significantly increased (p < 0.001) compared to the general UK Caucasian population and the variant cosegregated with obesity/overweight in affected family members. Compared to wild-type beta-MSH, the variant peptide was impaired in its ability to bind to and activate signaling from the MC4R. Obese children carrying the Tyr221Cys variant were hyperphagic and showed increased linear growth, both of which are features of MC4R deficiency. These studies support a role for beta-MSH in the control of human energy homeostasis.


Asunto(s)
Metabolismo Energético/genética , Homeostasis/genética , Obesidad/genética , beta-MSH/genética , Preescolar , Cromatografía Líquida de Alta Presión , Femenino , Tamización de Portadores Genéticos , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Mutación Missense/genética , Receptor de Melanocortina Tipo 4/metabolismo , Análisis de Secuencia de ADN , Reino Unido , Población Blanca , beta-MSH/metabolismo
6.
Sci Rep ; 9(1): 17123, 2019 11 20.
Artículo en Inglés | MEDLINE | ID: mdl-31748580

RESUMEN

We sequenced coding regions of the cluster of differentiation 36 (CD36) gene in 184 French individuals of European ancestry presenting simultaneously with type 2 diabetes (T2D), arterial hypertension, dyslipidemia, and coronary heart disease. We identified rare missense mutations (p.Pro191Leu/rs143150225 and p.Ala252Val/rs147624636) in two heterozygous cases. The two CD36 mutation carriers had no family history of T2D and no clustering of cardio-metabolic complications. While the p.Pro191Leu mutation was found in 84 heterozygous carriers from five ethnic groups from the genome aggregation database (global frequency: 0.0297%, N = 141,321), only one European carrier of the p.Ala252Val mutation was identified (global frequency: 0.00040%, N = 125,523). The Pro191 and Ala252 amino acids were not conserved (74.8% and 68.9% across 131 animal species, respectively). In vitro experiments showed that the two CD36 mutant proteins are expressed and trafficked to the plasma membrane where they bind modified low-density-lipoprotein (LDL) cholesterol as normal. However, molecular modelling of the recent CD36 crystal structure showed that Pro191 was located at the exit/entrance gate of the lipid binding chamber and Ala252 was in line with the chamber. Overall, our data do not support a major contribution of CD36 rare coding mutations to T2D and its cardio-metabolic complications in the French population.


Asunto(s)
Antígenos CD36/genética , Enfermedad Coronaria/genética , Diabetes Mellitus Tipo 2/genética , Dislipidemias/genética , Enfermedades Metabólicas/genética , Mutación Missense/genética , Hipertensión Arterial Pulmonar/genética , Membrana Celular/genética , Genotipo , Heterocigoto , Humanos , Lipoproteínas LDL/genética
7.
J Clin Endocrinol Metab ; 92(11): 4403-9, 2007 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17698913

RESUMEN

CONTEXT: The melanin-concentrating hormone receptor 2 (MCHR2) is a G protein-coupled receptor for melanin-concentrating hormone, a neuropeptide that plays an important role in feeding behaviors. MCHR2 maps on chromosome 6q16.3, in a susceptibility locus for childhood obesity. OBJECTIVE: The aim of this study was to investigate the association between MCHR2 variation and human obesity. DESIGN: Case control and family-based studies were performed. PARTICIPANTS: A total of 141 obese children and 24 nonobese adult subjects was sequenced, and case-control analyses were conducted using 628 severely obese children and 1,401 controls. RESULTS: There were 11 single nucleotide polymorphisms (SNPs) identified. We showed nominal association among -38,245 ATG A/G SNP (P = 0.03; 95% confidence interval 1.02-1.34; odds ratio 1.17), A76A T/C SNP (P = 0.03; 95% confidence interval 0.58-0.97; odds ratio 0.75), and childhood obesity. Analysis of 645 trios with childhood obesity supported further the A76A T/C association, showing an overtransmission to obese children of the at risk T allele (59.0%; P = 0.01), especially in children with most severe forms of obesity (Z score of body mass index > 4) (67.0%; P = 0.003). The A76A at risk T allele was also associated with overeating during meals (P = 0.02) in an additional group of 102 nonobese children. None of the MCHR2 variants, including the A76A SNP, showed association with adult severe obesity, although a trend for association of the T allele of this variant with food disinhibition (P = 0.06) and higher hunger (P = 0.09) was found. This variant was not associated with childhood obesity in an independent case-control study, including 1,573 subjects (P = 0.98). Moreover, the A76A SNP did not explain the linkage on the 6q locus. CONCLUSION: Our results altogether suggest that MCHR2 is not a major contributor to polygenic obesity and support a modest effect of the A76A SNP on food intake abnormalities in childhood.


Asunto(s)
Obesidad/genética , Receptores Acoplados a Proteínas G/genética , Receptores de la Hormona Hipofisaria/genética , Adulto , Alelos , Secuencia de Aminoácidos , Apetito/fisiología , Índice de Masa Corporal , Niño , Estudios de Cohortes , Replicación del ADN/fisiología , Exones/genética , Conducta Alimentaria , Trastornos de Alimentación y de la Ingestión de Alimentos/genética , Femenino , Ligamiento Genético/genética , Haplotipos , Humanos , Masculino , Datos de Secuencia Molecular , Obesidad/psicología
8.
Diabetes ; 55(3): 856-61, 2006 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-16505255

RESUMEN

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 Adiponectina
9.
BMC Med Genet ; 8: 44, 2007 Jul 07.
Artículo en Inglés | MEDLINE | ID: mdl-17617923

RESUMEN

BACKGROUND: 7B2 is a regulator/activator of the prohormone convertase 2 which is involved in the processing of numerous neuropeptides, including insulin, glucagon and pro-opiomelanocortin. We have previously described a suggestive genetic linkage peak with childhood obesity on chr15q12-q14, where the 7B2 encoding gene, SGNE1 is located. The aim of this study is to analyze associations of SGNE1 genetic variation with obesity and metabolism related quantitative traits. METHODS: We screened SGNE1 for genetic variants in obese children and genotyped 12 frequent single nucleotide polymorphisms (SNPs). Case control analyses were performed in 1,229 obese (534 children and 695 adults), 1,535 individuals with type 2 diabetes and 1,363 controls, all French Caucasians. We also studied 4,922 participants from the D.E.S.I.R prospective population-based cohort. RESULTS: We did not find any association between SGNE1 SNPs and childhood or adult obesity. However, the 5' region SNP -1,701A>G associated with higher area under glucose curve after oral glucose tolerance test (p = 0.0005), higher HOMA-IR (p = 0.005) and lower insulinogenic index (p = 0.0003) in obese children. Similar trends were found in obese adults. SNP -1,701A>G did not associate with risk of T2D but tends to associate with incidence of type 2 diabetes (HR = 0.75 95%CI [0.55-1.01]; p = 0.06) in the prospective cohort. CONCLUSION: SGNE1 genetic variation does not contribute to obesity and common forms of T2D but may worsen glucose intolerance and insulin resistance, especially in the background of severe and early onset obesity. Further molecular studies are required to understand the molecular bases involved in this process.


Asunto(s)
Variación Genética , Intolerancia a la Glucosa/genética , Proteína 7B2 Secretora Neuroendocrina/genética , Obesidad/genética , Adolescente , Adulto , Estudios de Casos y Controles , Niño , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Femenino , Francia , Genotipo , Humanos , Resistencia a la Insulina/genética , Masculino , Persona de Mediana Edad , Obesidad/complicaciones , Polimorfismo de Nucleótido Simple
10.
Diabetes ; 51(5): 1640-3, 2002 May.
Artículo en Inglés | MEDLINE | ID: mdl-11978668

RESUMEN

The Lim domain homeobox gene (Isl-1) is a positional candidate gene for obesity that maps on chromosome 5q11-q13, a locus linked to BMI and leptin levels in French Caucasians. Isl-1 might be involved in body weight regulation and glucose homeostasis via the activation of proglucagon gene expression, which encodes for glucagon and glucagon-like peptides. By mutation screening of 72 obese subjects, we identified three single-nucleotide polymorphisms (SNPs) in the Isl1 gene. The allele frequencies in the morbidly obese group did not differ from that of the control group. In the obese group, the -47G allele was associated with a decreased risk of type 2 diabetes (odds ratio 0.41, P = 0.019). The AG bearers displayed a higher maximal BMI than the AA bearers in the whole obese group (P = 0.026) as well as in the type 2 diabetic obese subgroup (P = 0.014). In obese families, this allele was not preferentially transmitted from heterozygous parents to their obese siblings, indicating that Isl-1 does not contribute to the linkage with obesity on 5cen-q. However, in French Caucasian morbidly obese subjects, the Isl1-47A-->G SNP may modulate the risk for type 2 diabetes and may increase body weight in diabetic morbidly obese subjects.


Asunto(s)
Cromosomas Humanos Par 5 , Diabetes Mellitus Tipo 2/genética , Proteínas de Homeodominio/genética , Proteínas del Tejido Nervioso , Obesidad Mórbida/genética , Adulto , Anciano , Diabetes Mellitus/epidemiología , Diabetes Mellitus/genética , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Francia/epidemiología , Ligamiento Genético , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Proteínas con Homeodominio LIM , Masculino , Persona de Mediana Edad , Obesidad , Obesidad Mórbida/epidemiología , Factores de Riesgo , Factores de Transcripción
11.
Diabetes ; 53(3): 803-11, 2004 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-14988267

RESUMEN

We conducted a genome-wide search for childhood obesity-associated traits, including BMI >/==" BORDER="0">95th percentile (PCT95), 97th percentile (PCT97), and 99th percentile (PCT99) as well as age of adiposity rebound (AAR), which corresponds to the beginning of the second rise in childhood adiposity. A set of 431 microsatellite markers was genotyped in 506 subjects from 115 multiplex French Caucasian families, with at least one child with a BMI >/==" BORDER="0">95th percentile. Among these 115 pedigrees, 97 had at least two sibs with a BMI >/==" BORDER="0">95th percentile. Fine-mapping was performed in the seven most positive loci. Nonparametric multipoint analyses revealed six regions of significant or suggestive linkage on chromosomes 2q33.2-q36.3, 6q22.31-q23.2, and 17p13 for PCT95, PCT97, or PCT99 and 15q12-q15.1, 16q22.1-q24.1, and 19p13.3-p13.11 for AAR. The strongest evidence of linkage was detected on chromosome 6q22.31 for PCT97 (maximum likelihood score: 4.06) at the marker D6S287. This logarithm of odds score meets genome-wide significance tested through simulation (empirical genome-wide P = 0.01 [0.0027-0.0254]). Six independent ge-nome scans in adults have reported quantitative trait loci on 6q linked to energy or glucose homeostasis-associated phenotypes. Possible candidate genes in this region include SIM1, MCHR2, and PC-1.


Asunto(s)
Mapeo Cromosómico , Cromosomas Humanos Par 6/genética , Genoma Humano , Obesidad/genética , Índice de Masa Corporal , Niño , Preescolar , Familia , Francia , Humanos , Lactante , Hermanos , Estadísticas no Paramétricas
12.
Diabetes ; 51(4): 1247-55, 2002 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-11916952

RESUMEN

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/genética
13.
BMC Genet ; 6: 19, 2005 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-15823203

RESUMEN

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 Riesgo
14.
J Clin Invest ; 123(7): 3037-41, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23778136

RESUMEN

Sim1 haploinsufficiency in mice induces hyperphagic obesity and developmental abnormalities of the brain. In humans, abnormalities in chromosome 6q16, a region that includes SIM1, were reported in obese children with a Prader-Willi-like syndrome; however, SIM1 involvement in obesity has never been conclusively demonstrated. Here, SIM1 was sequenced in 44 children with Prader-Willi-like syndrome features, 198 children with severe early-onset obesity, 568 morbidly obese adults, and 383 controls. We identified 4 rare variants (p.I128T, p.Q152E, p.R581G, and p.T714A) in 4 children with Prader-Willi-like syndrome features (including severe obesity) and 4 other rare variants (p.T46R, p.E62K, p.H323Y, and p.D740H) in 7 morbidly obese adults. By assessing the carriers' relatives, we found a significant contribution of SIM1 rare variants to intra-family risk for obesity. We then assessed functional effects of the 8 substitutions on SIM1 transcriptional activities in stable cell lines using luciferase gene reporter assays. Three mutations showed strong loss-of-function effects (p.T46R, p.H323Y, and p.T714A) and were associated with high intra-family risk for obesity, while the variants with mild or no effects on SIM1 activity were not associated with obesity within families. Our genetic and functional studies demonstrate a firm link between SIM1 loss of function and severe obesity associated with, or independent of, Prader-Willi-like features.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Mutación Missense , Obesidad Mórbida/genética , Síndrome de Prader-Willi/genética , Proteínas Represoras/genética , Adulto , Estudios de Casos y Controles , Preescolar , Análisis Mutacional de ADN , Femenino , Expresión Génica , Frecuencia de los Genes , Genes Reporteros , Estudios de Asociación Genética , Células HEK293 , Humanos , Lactante , Luciferasas/biosíntesis , Luciferasas/genética , Masculino , Persona de Mediana Edad , Modelos Moleculares , Activación Transcripcional , Adulto Joven
15.
Obesity (Silver Spring) ; 20(11): 2278-82, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22447289

RESUMEN

Melanocortin-4 receptor (MC4R) loss-of-function mutations are the commonest genetic cause of human monogenic obesity, so far. The contribution of MC4R coding mutations to severe obesity in the high-obesity prone Greek population has not been investigated to date. We determined the MC4R coding sequence of 510 obese and 469 lean control subjects of Greek origin, and we estimated the prevalence and the penetrance on obesity of MC4R loss-of-function mutations. The functional impact of novel nonsynonymous variants detected was investigated in vitro. We found two novel synonymous mutations (L23L and I102I), four nonsynonymous mutations (T112M, S127L, N274S, and S295L), and two polymorphisms (V103I and I251L) previously described in literature. We also detected a novel mutation (L207V) in a severely obese 69-year-old female patient, although the mutation did not cosegregate with obesity in the corresponding pedigree and had no functional consequences on MC4R protein function. Loss-of-function mutations represented 75% of all nonsynonymous rare mutations identified among lean carriers and only 25% among obese subjects (P = 0.0001). The prevalence of loss-of-function mutations was lower in the obese group than in lean control subjects (0.20 vs. 0.64%) but this difference was not significant. Therefore, the estimated penetrance of deleterious MC4R mutations was very low (6.3%) in heterozygous Greek carriers of MC4R loss-of-function mutations. Our data suggest that MC4R loss-of-function mutations are rare in the Greek population. MC4R genetic deficiency is unlikely to explain the high propensity to develop severe obesity in this specific population.


Asunto(s)
Mutación Missense , Obesidad Mórbida/genética , Receptor de Melanocortina Tipo 4/genética , Anciano , Distribución de la Grasa Corporal , Estudios de Casos y Controles , Femenino , Grecia/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Obesidad Mórbida/epidemiología , Linaje , Fenotipo , Receptor de Melanocortina Tipo 4/deficiencia , Análisis de Secuencia , Transducción de Señal
16.
Obesity (Silver Spring) ; 20(2): 389-95, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21720444

RESUMEN

Twenty-four single-nucleotide polymorphisms (SNPs) have been reproducibly associated with obesity. We performed a follow-up study for obesity in the Greek adult population. A total of 510 obese and 469 lean adults were genotyped for 24 SNPs. We tested the association with obesity status using logistic regression and we evaluated the combined genetic risk of 24 SNPs by calculating the area under the receiver-operating characteristic (ROC) curves. We nominally replicated the association with obesity (BMI ≥30 kg/m(2)) of six SNPs in or near the FTO, MC4R, TMEM18, PRL, AIF1, and PCSK1 loci (1.28 ≤ odds ratio (OR) ≤ 1.35; 0.004 ≤ P ≤ 0.043). The discrimination ability for obesity was slightly stronger (P = 9.59 × 10(-6)) when the genetic information of the 24 SNPs was added to nongenetic risk factors (area under the curve (AUC) = 0.722) in comparison with nongenetic factors analyzed alone (AUC = 0.685). Our data suggest that SNPs in or near the FTO, MC4R, TMEM18, PRL, AIF1, and PCSK1 loci contribute to obesity risk in the Greek population.


Asunto(s)
Proteínas de Ciclo Celular/genética , Proteínas de Unión al ADN/genética , Proteínas de la Membrana/genética , Neuropéptidos/genética , Obesidad/genética , Polimorfismo de Nucleótido Simple , Proteínas Tirosina Fosfatasas/genética , Proteínas/genética , Receptor de Melanocortina Tipo 4/genética , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Proteínas de Unión al Calcio , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Grecia/epidemiología , Humanos , Masculino , Proteínas de Microfilamentos , Persona de Mediana Edad , Obesidad/epidemiología , Factores de Riesgo
17.
PLoS One ; 7(6): e37423, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22701567

RESUMEN

BACKGROUND: Maturity-onset of the young (MODY) is a clinically heterogeneous form of diabetes characterized by an autosomal-dominant mode of inheritance, an onset before the age of 25 years, and a primary defect in the pancreatic beta-cell function. Approximately 30% of MODY families remain genetically unexplained (MODY-X). Here, we aimed to use whole-exome sequencing (WES) in a four-generation MODY-X family to identify a new susceptibility gene for MODY. METHODOLOGY: WES (Agilent-SureSelect capture/Illumina-GAIIx sequencing) was performed in three affected and one non-affected relatives in the MODY-X family. We then performed a high-throughput multiplex genotyping (Illumina-GoldenGate assay) of the putative causal mutations in the whole family and in 406 controls. A linkage analysis was also carried out. PRINCIPAL FINDINGS: By focusing on variants of interest (i.e. gains of stop codon, frameshift, non-synonymous and splice-site variants not reported in dbSNP130) present in the three affected relatives and not present in the control, we found 69 mutations. However, as WES was not uniform between samples, a total of 324 mutations had to be assessed in the whole family and in controls. Only one mutation (p.Glu227Lys in KCNJ11) co-segregated with diabetes in the family (with a LOD-score of 3.68). No KCNJ11 mutation was found in 25 other MODY-X unrelated subjects. CONCLUSIONS/SIGNIFICANCE: Beyond neonatal diabetes mellitus (NDM), KCNJ11 is also a MODY gene ('MODY13'), confirming the wide spectrum of diabetes related phenotypes due to mutations in NDM genes (i.e. KCNJ11, ABCC8 and INS). Therefore, the molecular diagnosis of MODY should include KCNJ11 as affected carriers can be ideally treated with oral sulfonylureas.


Asunto(s)
Diabetes Mellitus Tipo 2/genética , Exoma/genética , Predisposición Genética a la Enfermedad/genética , Canales de Potasio de Rectificación Interna/genética , Secuencia de Bases , Mapeo Cromosómico , Análisis Mutacional de ADN , Francia , Genotipo , Humanos , Escala de Lod , Datos de Secuencia Molecular , Linaje
18.
PLoS One ; 7(11): e49919, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23209618

RESUMEN

OBJECTIVES: Prevention of obesity should start as early as possible after birth. We aimed to build clinically useful equations estimating the risk of later obesity in newborns, as a first step towards focused early prevention against the global obesity epidemic. METHODS: We analyzed the lifetime Northern Finland Birth Cohort 1986 (NFBC1986) (N = 4,032) to draw predictive equations for childhood and adolescent obesity from traditional risk factors (parental BMI, birth weight, maternal gestational weight gain, behaviour and social indicators), and a genetic score built from 39 BMI/obesity-associated polymorphisms. We performed validation analyses in a retrospective cohort of 1,503 Italian children and in a prospective cohort of 1,032 U.S. children. RESULTS: In the NFBC1986, the cumulative accuracy of traditional risk factors predicting childhood obesity, adolescent obesity, and childhood obesity persistent into adolescence was good: AUROC = 0·78[0·74-0.82], 0·75[0·71-0·79] and 0·85[0·80-0·90] respectively (all p<0·001). Adding the genetic score produced discrimination improvements ≤1%. The NFBC1986 equation for childhood obesity remained acceptably accurate when applied to the Italian and the U.S. cohort (AUROC = 0·70[0·63-0·77] and 0·73[0·67-0·80] respectively) and the two additional equations for childhood obesity newly drawn from the Italian and the U.S. datasets showed good accuracy in respective cohorts (AUROC = 0·74[0·69-0·79] and 0·79[0·73-0·84]) (all p<0·001). The three equations for childhood obesity were converted into simple Excel risk calculators for potential clinical use. CONCLUSION: This study provides the first example of handy tools for predicting childhood obesity in newborns by means of easily recorded information, while it shows that currently known genetic variants have very little usefulness for such prediction.


Asunto(s)
Obesidad/epidemiología , Riesgo , Adolescente , Adulto , Peso al Nacer , Índice de Masa Corporal , Niño , Estudios de Cohortes , Femenino , Finlandia/epidemiología , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Obesidad/prevención & control , Población Blanca , Adulto Joven
19.
Diabetes ; 61(2): 383-90, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22210313

RESUMEN

Null mutations in the PCSK1 gene, encoding the proprotein convertase 1/3 (PC1/3), cause recessive monogenic early onset obesity. Frequent coding variants that modestly impair PC1/3 function mildly increase the risk for common obesity. The aim of this study was to determine the contribution of rare functional PCSK1 mutations to obesity. PCSK1 exons were sequenced in 845 nonconsanguineous extremely obese Europeans. Eight novel nonsynonymous PCSK1 mutations were identified, all heterozygous. Seven mutations had a deleterious effect on either the maturation or the enzymatic activity of PC1/3 in cell lines. Of interest, five of these novel mutations, one of the previously described frequent variants (N221D), and the mutation found in an obese mouse model (N222D), affect residues at or near the structural calcium binding site Ca-1. The prevalence of the newly identified mutations was assessed in 6,233 obese and 6,274 lean European adults and children, which showed that carriers of any of these mutations causing partial PCSK1 deficiency had an 8.7-fold higher risk to be obese than wild-type carriers. These results provide the first evidence of an increased risk of obesity in heterozygous carriers of mutations in the PCSK1 gene. Furthermore, mutations causing partial PCSK1 deficiency are present in 0.83% of extreme obesity phenotypes.


Asunto(s)
Mutación , Obesidad/genética , Proproteína Convertasa 1/genética , Adulto , Femenino , Genotipo , Glicosilación , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Proproteína Convertasa 1/química , Proproteína Convertasa 1/deficiencia
20.
Clin Biochem ; 43(6): 549-52, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20132806

RESUMEN

OBJECTIVES: We investigated two genetic markers in pro inflammatory molecules : TNFalpha -308G/A and IL6 -174G/C in order to assess their effect on type 2 diabetes (T2D) and obesity in the Tunisian population. DESIGN AND METHODS: The study sample includes 228 patients with T2D and 300 healthy controls. Genotyping of IL6 -174G/C (rs1800795) was performed using Automated Dye Terminator Sequencing and of TNFalpha -308G/A (rs1800629) using the LightTyper technology. RESULTS: SNPs IL6 -174G/C and TNFalpha -308G/A are associated neither with T2D (p=0.89, p=0.34 respectively) nor with risk for overweight (p=0.86, p=0.12 respectively) in Tunisian population. Bonferroni correction showed that the founded association of IL6 -174G/C SNP with T2D susceptibility restricted to overweight patients (p(nominal)=0.03, p(corrected)=0.0033) is likely to be a random result. CONCLUSION: SNPs IL6 -174G/C and TNFalpha -308G/A are not major contributors to T2D or obesity risk in our Tunisian population.


Asunto(s)
Diabetes Mellitus Tipo 2/genética , Interleucina-6/genética , Obesidad/genética , Polimorfismo de Nucleótido Simple , Factor de Necrosis Tumoral alfa/genética , Adulto , Anciano , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Ligamiento Genético , Predisposición Genética a la Enfermedad , Genética de Población , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Obesidad/epidemiología , Polimorfismo de Nucleótido Simple/fisiología , Regiones Promotoras Genéticas/genética , Factores de Riesgo , Túnez/epidemiología
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