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1.
Bioinformatics ; 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31504159

RESUMO

SUMMARY: The NanoStringTM nCounter® is a platform for the targeted quantification of expression data in biofluids and tissues. While software by the manufacturer is available in addition to third parties packages, they do not provide a complete quality control (QC) pipeline. Here, we present NACHO ('NAnostring quality Control dasHbOard'), a comprehensive QC R-package. The package consists of three subsequent steps: summarize, visualize and normalize. The summarize function collects all the relevant data and stores it in a tidy format, the visualize function initiates a dashboard with plots of the relevant QC outcomes. It contains QC metrics that are measured by default by the manufacturer, but also calculates other insightful measures, including the scaling factors that are needed in the normalization step. In this normalization step, different normalization methods can be chosen to optimally preprocess data. Together, NACHO is a comprehensive method that optimizes insight and preprocessing of nCounter® data. AVAILABILITY AND IMPLEMENTATION: NACHO is available as an R-package on CRAN and the development version on GitHub https://github.com/mcanouil/NACHO. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

2.
Int J Obes (Lond) ; 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31388097

RESUMO

BACKGROUND: Genome-wide association studies (GWAS) have identified more than 250 loci associated with body mass index (BMI) and obesity. However, post-GWAS functional genomic investigations have been inadequate for understanding how these genetic loci physiologically impact disease development. METHODS: We performed a PCR-free expression assay targeting genes located nearby the GWAS-identified SNPs associated with BMI/obesity in a large panel of human tissues. Furthermore, we analyzed several genetic risk scores (GRS) summing GWAS-identified alleles associated with increased BMI in 4236 individuals. RESULTS: We found that the expression of BMI/obesity susceptibility genes was strongly enriched in the brain, especially in the insula (p = 4.7 × 10-9) and substantia nigra (p = 6.8 × 10-7), which are two brain regions involved in addiction and reward. Inversely, we found that top obesity/BMI-associated loci, including FTO, showed the strongest gene expression enrichment in the two brain regions. CONCLUSIONS: Our data suggest for the first time that the susceptibility genes for common obesity may have an effect on eating addiction and reward behaviors through their high expression in substantia nigra and insula, i.e., a different pattern from monogenic obesity genes that act in the hypothalamus and cause hyperphagia. Further epidemiological studies with relevant food behavior phenotypes are necessary to confirm these findings.

3.
Curr Diab Rep ; 19(9): 79, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31385057

RESUMO

PURPOSE OF REVIEW: Non-autoimmune monogenic diabetes (MD) in young people shows a broad spectrum of clinical presentations, which is largely explained by multiple genetic etiologies. This review discusses how the application of state-of-the-art genomics research to precision diagnosis of MD, particularly the various subtypes of maturity-onset diabetes of the young (MODY), has increasingly informed diabetes precision medicine and patient care throughout life. RECENT FINDINGS: Due to extended genetic and clinical heterogeneity of MODY, diagnosis approaches based on next-generation sequencing have been worthwhile to better ascribe a specific subtype to each patient with young-onset diabetes. This guides the best appropriate treatment and clinical follow-up. Early etiological diagnosis of MD and individualized treatment are essential for achieving metabolic targets and avoiding long-term diabetes complications, as well as for drastically decreasing the financial and societal burden of diabetes-related healthcare. Genomic medicine-based practices help to optimize long-term clinical follow-up and patient care management.

4.
Sci Rep ; 9(1): 9439, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31263163

RESUMO

Type 2 diabetes (T2D) affects the health of millions of people worldwide. The identification of genetic determinants associated with changes in glycemia over time might illuminate biological features that precede the development of T2D. Here we conducted a genome-wide association study of longitudinal fasting glucose changes in up to 13,807 non-diabetic individuals of European descent from nine cohorts. Fasting glucose change over time was defined as the slope of the line defined by multiple fasting glucose measurements obtained over up to 14 years of observation. We tested for associations of genetic variants with inverse-normal transformed fasting glucose change over time adjusting for age at baseline, sex, and principal components of genetic variation. We found no genome-wide significant association (P < 5 × 10-8) with fasting glucose change over time. Seven loci previously associated with T2D, fasting glucose or HbA1c were nominally (P < 0.05) associated with fasting glucose change over time. Limited power influences unambiguous interpretation, but these data suggest that genetic effects on fasting glucose change over time are likely to be small. A public version of the data provides a genomic resource to combine with future studies to evaluate shared genetic links with T2D and other metabolic risk traits.

5.
Diabetologia ; 62(9): 1601-1615, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31203377

RESUMO

AIMS/HYPOTHESIS: Here, we describe the characteristics of the Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) epidemiological cohorts at baseline and follow-up examinations (18, 36 and 48 months of follow-up). METHODS: From a sampling frame of 24,682 adults of European ancestry enrolled in population-based cohorts across Europe, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm (based on age, BMI, waist circumference, use of antihypertensive medication, smoking status and parental history of type 2 diabetes) and enrolled into a prospective cohort study (n = 2127) (cohort 1, prediabetes risk). We also recruited people from clinical registries with type 2 diabetes diagnosed 6-24 months previously (n = 789) into a second cohort study (cohort 2, diabetes). Follow-up examinations took place at ~18 months (both cohorts) and at ~48 months (cohort 1) or ~36 months (cohort 2) after baseline examinations. The cohorts were studied in parallel using matched protocols across seven clinical centres in northern Europe. RESULTS: Using ADA 2011 glycaemic categories, 33% (n = 693) of cohort 1 (prediabetes risk) had normal glucose regulation and 67% (n = 1419) had impaired glucose regulation. Seventy-six per cent of participants in cohort 1 was male. Cohort 1 participants had the following characteristics (mean ± SD) at baseline: age 62 (6.2) years; BMI 27.9 (4.0) kg/m2; fasting glucose 5.7 (0.6) mmol/l; 2 h glucose 5.9 (1.6) mmol/l. At the final follow-up examination the participants' clinical characteristics were as follows: fasting glucose 6.0 (0.6) mmol/l; 2 h OGTT glucose 6.5 (2.0) mmol/l. In cohort 2 (diabetes), 66% (n = 517) were treated by lifestyle modification and 34% (n = 272) were treated with metformin plus lifestyle modification at enrolment. Fifty-eight per cent of participants in cohort 2 was male. Cohort 2 participants had the following characteristics at baseline: age 62 (8.1) years; BMI 30.5 (5.0) kg/m2; fasting glucose 7.2 (1.4) mmol/l; 2 h glucose 8.6 (2.8) mmol/l. At the final follow-up examination, the participants' clinical characteristics were as follows: fasting glucose 7.9 (2.0) mmol/l; 2 h mixed-meal tolerance test glucose 9.9 (3.4) mmol/l. CONCLUSIONS/INTERPRETATION: The IMI DIRECT cohorts are intensely characterised, with a wide-variety of metabolically relevant measures assessed prospectively. We anticipate that the cohorts, made available through managed access, will provide a powerful resource for biomarker discovery, multivariate aetiological analyses and reclassification of patients for the prevention and treatment of type 2 diabetes.

7.
Mol Metab ; 24: 98-107, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30956117

RESUMO

OBJECTIVE: Genome wide association studies (GWAS) for type 2 diabetes (T2D) have identified genetic loci that often localise in non-coding regions of the genome, suggesting gene regulation effects. We combined genetic and transcriptomic analysis from human islets obtained from brain-dead organ donors or surgical patients to detect expression quantitative trait loci (eQTLs) and shed light into the regulatory mechanisms of these genes. METHODS: Pancreatic islets were isolated either by laser capture microdissection (LCM) from surgical specimens of 103 metabolically phenotyped pancreatectomized patients (PPP) or by collagenase digestion of pancreas from 100 brain-dead organ donors (OD). Genotyping (> 8.7 million single nucleotide polymorphisms) and expression (> 47,000 transcripts and splice variants) analyses were combined to generate cis-eQTLs. RESULTS: After applying genome-wide false discovery rate significance thresholds, we identified 1,173 and 1,021 eQTLs in samples of OD and PPP, respectively. Among the strongest eQTLs shared between OD and PPP were CHURC1 (OD p-value=1.71 × 10-24; PPP p-value = 3.64 × 10-24) and PSPH (OD p-value = 3.92 × 10-26; PPP p-value = 3.64 × 10-24). We identified eQTLs in linkage-disequilibrium with GWAS loci T2D and associated traits, including TTLL6, MLX and KIF9 loci, which do not implicate the nearest gene. We found in the PPP datasets 11 eQTL genes, which were differentially expressed in T2D and two genes (CYP4V2 and TSEN2) associated with HbA1c but none in the OD samples. CONCLUSIONS: eQTL analysis of LCM islets from PPP led us to identify novel genes which had not been previously linked to islet biology and T2D. The understanding gained from eQTL approaches, especially using surgical samples of living patients, provides a more accurate 3-dimensional representation than those from genetic studies alone.

8.
Int J Mol Sci ; 20(4)2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30769939

RESUMO

The NOD2 gene, involved in innate immune responses to bacterial peptidoglycan, has been found to be closely associated with Crohn's Disease (CD), with an Odds Ratio ranging from 3⁻36. Families with three or more CD-affected members were related to a high frequency of NOD2 gene variations, such as R702W, G908R, and 1007fs, and were reported in the EPIMAD Registry. However, some rare CD multiplex families were described without identification of common NOD2 linked-to-disease variations. In order to identify new genetic variation(s) closely linked with CD, whole exome sequencing was performed on available subjects, comprising four patients in two generations affected with Crohn's disease without R702W and G908R variation and three unaffected related subjects. A rare and, not yet, reported missense variation of the NOD2 gene, N1010K, was detected and co-segregated across affected patients. In silico evaluation and modelling highlighted evidence for an adverse effect of the N1010K variation with regard to CD. Moreover, cumulative characterization of N1010K and 1007fs as a compound heterozygous state in two, more severe CD family members strongly suggests that N1010K could well be a new risk factor involved in Crohn's disease genetic susceptibility.


Assuntos
Doença de Crohn/genética , Predisposição Genética para Doença , Imunidade Inata/genética , Proteína Adaptadora de Sinalização NOD2/genética , Adolescente , Adulto , Alelos , Criança , Doença de Crohn/imunologia , Doença de Crohn/patologia , Feminino , Estudos de Associação Genética , Genótipo , Heterozigoto , Humanos , Masculino , Mutação , Mutação de Sentido Incorreto/genética , Proteína Adaptadora de Sinalização NOD2/química , Proteína Adaptadora de Sinalização NOD2/imunologia , Peptidoglicano/imunologia , Polimorfismo de Nucleotídeo Único , Conformação Proteica , Sequenciamento Completo do Exoma
9.
PLoS One ; 13(10): e0204861, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30307950

RESUMO

The whooping cough agent Bordetella pertussis coordinately regulates the expression of its virulence factors with the two-component system BvgAS. In laboratory conditions, specific chemical modulators are used to trigger phenotypic modulation of B. pertussis from its default virulent Bvg+ phase to avirulent Bvg- or intermediate Bvgi phases, in which no virulence factors or only a subset of them are produced, respectively. Whether phenotypic modulation occurs in the host remains unknown. In this work, recombinant B. pertussis strains harboring BvgS variants were tested in a mouse model of infection and analyzed using transcriptomic approaches. Recombinant BP-BvgΔ65, which is in the Bvgi phase by default and can be up-modulated to the Bvg+ phase in vitro, could colonize the mouse nose but was rapidly cleared from the lungs, while Bvg+-phase strains colonized both organs for up to four weeks. These results indicated that phenotypic modulation, which might have restored the full virulence capability of BP-BvgΔ65, does not occur in mice or is temporally or spatially restricted and has no effect in those conditions. Transcriptomic analyses of this and other recombinant Bvgi and Bvg+-phase strains revealed that two distinct ranges of virulence gene expression allow colonization of the mouse nose and lungs, respectively. We also showed that a recombinant strain expressing moderately lower levels of the virulence genes than its wild type parent was as efficient at colonizing both organs. Altogether, genetic modifications of BvgS generate a range of phenotypic phases, which are useful tools to decipher host-pathogen interactions.

10.
Lipids ; 53(8): 797-807, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30334266

RESUMO

It has been reported that polymorphisms within the gene-encoding enzymes related to alcohol metabolism are associated with levels of serum HDL-cholesterol (HDL-C) in East Asian populations. We evaluated the effects of genetic variants within the aldehyde dehydrogenase-2 (ALDH2) gene and the alcohol dehydrogenase-1B (ADH1B) gene on changes in the lipid profile in an 11-year longitudinal study. We genotyped rs1229984 within ADH1B and rs671 within ALDH2. We combined the genetic data with longitudinal clinical and biochemical data from 2002 to 2013 and designed a retrospective longitudinal study of 1436 Japanese males. There were significant negative relationships between rs671 within ALDH2 and HDL-C levels according to multiple linear regression analysis. Next, we assessed the association between the development of hypo-HDL cholesterolemia and rs1229984 within ADH1B or rs671 within ALDH2. In logistic regression analysis, rs671 A allele homozygote carriers have 2.65 times higher risk of developing hypo-HDL cholesterolemia than G allele homozygote carriers. Even after adjusting for possible confounding factors, a significant association was observed. However, no association between rs1229984 within ADH1B and the development of hypo-HDL cholesterolemia was observed. Rs671 within ALDH2 but not rs1229984 within ADH1B was associated with lower HDL-C levels in Japanese males.

11.
Diabetes Care ; 41(11): 2396-2403, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30254083

RESUMO

OBJECTIVE: Latent autoimmune diabetes in adults (LADA) shares clinical features with both type 1 and type 2 diabetes; however, there is ongoing debate regarding the precise definition of LADA. Understanding its genetic basis is one potential strategy to gain insight into appropriate classification of this diabetes subtype. RESEARCH DESIGN AND METHODS: We performed the first genome-wide association study of LADA in case subjects of European ancestry versus population control subjects (n = 2,634 vs. 5,947) and compared against both case subjects with type 1 diabetes (n = 2,454 vs. 968) and type 2 diabetes (n = 2,779 vs. 10,396). RESULTS: The leading genetic signals were principally shared with type 1 diabetes, although we observed positive genetic correlations genome-wide with both type 1 and type 2 diabetes. Additionally, we observed a novel independent signal at the known type 1 diabetes locus harboring PFKFB3, encoding a regulator of glycolysis and insulin signaling in type 2 diabetes and inflammation and autophagy in autoimmune disease, as well as an attenuation of key type 1-associated HLA haplotype frequencies in LADA, suggesting that these are factors that distinguish childhood-onset type 1 diabetes from adult autoimmune diabetes. CONCLUSIONS: Our results support the need for further investigations of the genetic factors that distinguish forms of autoimmune diabetes as well as more precise classification strategies.

12.
J Clin Lipidol ; 2018 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-30158064

RESUMO

BACKGROUND: Multiple symmetric lipomatosis (MSL) is characterized by upper-body lipomatous masses frequently associated with metabolic and neurological signs. MFN2 pathogenic variants were recently implicated in a very rare autosomal recessive form of MSL. MFN2 encodes mitofusin-2, a mitochondrial fusion protein previously involved in Charcot-Marie-Tooth neuropathy. OBJECTIVE: To investigate the clinical, metabolic, tissular, and molecular characteristics of MFN2-associated MSL. METHODS: We sequenced MFN2 in 66 patients referred for altered fat distribution with one or several lipomas or lipoma-like regions and performed clinical and metabolic investigations in patients with positive genetic testing. Lipomatous tissues were studied in 3 patients. RESULTS: Six patients from 5 families carried a homozygous p.Arg707Trp pathogenic variant, representing the largest reported series of MFN2-associated MSL. Patients presented both lipomatous masses and a lipodystrophic syndrome (lipoatrophy, low leptinemia and adiponectinemia, hypertriglyceridemia, insulin resistance and/or diabetes). Charcot-Marie-Tooth neuropathy was of highly variable clinical severity. Lipomatous tissue mainly contained hyperplastic unilocular adipocytes, with few multilocular cells. It displayed numerous mitochondrial alterations (increased number and size, structural defects). As compared to control subcutaneous fat, mRNA and protein expression of leptin and adiponectin was strikingly decreased, whereas the CITED1 and fibroblast growth factor 21 (FGF21) thermogenic markers were strongly overexpressed. Consistently, serum FGF21 was markedly increased, and 18F-FDG-PET-scan revealed increased fat metabolic activity. CONCLUSION: MFN2-related MSL is a novel mitochondrial lipodystrophic syndrome involving both lipomatous masses and lipoatrophy. Its complex neurological and metabolic phenotype justifies careful clinical evaluation and multidisciplinary care. Low leptinemia and adiponectinemia, high serum FGF21, and increased 18F-FDG body fat uptake may be disease markers.

13.
Sci Signal ; 11(545)2018 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-30154102

RESUMO

Melatonin is produced during the night and regulates sleep and circadian rhythms. Loss-of-function variants in MTNR1B, which encodes the melatonin receptor MT2, a G protein-coupled receptor (GPCR), are associated with an increased risk of type 2 diabetes (T2D). To identify specific T2D-associated signaling pathway(s), we profiled the signaling output of 40 MT2 variants by monitoring spontaneous (ligand-independent) and melatonin-induced activation of multiple signaling effectors. Genetic association analysis showed that defects in the melatonin-induced activation of Gαi1 and Gαz proteins and in spontaneous ß-arrestin2 recruitment to MT2 were the most statistically significantly associated with an increased T2D risk. Computational variant impact prediction by in silico evolutionary lineage analysis strongly correlated with the measured phenotypic effect of each variant, providing a predictive tool for future studies on GPCR variants. Together, this large-scale functional study provides an operational framework for the postgenomic analysis of the multiple GPCR variants present in the human population. The association of T2D risk with signaling pathway-specific defects opens avenues for pathway-specific personalized therapeutic intervention and reveals the potential relevance of MT2 function during the day, when melatonin is undetectable, but spontaneous activity of the receptor occurs.

14.
Front Genet ; 9: 210, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29963075

RESUMO

In observational cohorts, longitudinal data are collected with repeated measurements at predetermined time points for many biomarkers, along with other variables measured at baseline. In these cohorts, time until a certain event of interest occurs is reported and very often, a relationship will be observed between some biomarker repeatedly measured over time and that event. Joint models were designed to efficiently estimate statistical parameters describing this relationship by combining a mixed model for the longitudinal biomarker trajectory and a survival model for the time until occurrence of the event, using a set of random effects to account for the relationship between the two types of data. In this paper, we discuss the implementation of joint models in genetic association studies. First, we check model consistency based on different simulation scenarios, by varying sample sizes, minor allele frequencies and number of repeated measurements. Second, using genotypes assayed with the Metabochip DNA arrays (Illumina) from about 4,500 individuals recruited in the French cohort D.E.S.I.R. (Data from an Epidemiological Study on the Insulin Resistance syndrome), we assess the feasibility of implementing the joint modelling approach in a real high-throughput genomic dataset. An alternative model approximating the joint model, called the Two-Step approach (TS), is also presented. Although the joint model shows more precise and less biased estimators than its alternative counterpart, the TS approach results in much reduced computational times, and could thus be used for testing millions of SNPs at the genome-wide scale.

15.
Int J Obes (Lond) ; 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29713043

RESUMO

BACKGROUND: Obesity is an established risk factor for several common chronic diseases such as breast and colorectal cancer, metabolic and cardiovascular diseases; however, the biological basis for these relationships is not fully understood. To explore the association of obesity with these conditions, we investigated peripheral blood leucocyte (PBL) DNA methylation markers for adiposity and their contribution to risk of incident breast and colorectal cancer and myocardial infarction. METHODS: DNA methylation profiles (Illumina Infinium® HumanMethylation450 BeadChip) from 1941 individuals from four population-based European cohorts were analysed in relation to body mass index, waist circumference, waist-hip and waist-height ratio within a meta-analytical framework. In a subset of these individuals, data on genome-wide gene expression level, biomarkers of glucose and lipid metabolism were also available. Validation of methylation markers associated with all adiposity measures was performed in 358 individuals. Finally, we investigated the association of obesity-related methylation marks with breast, colorectal cancer and myocardial infarction within relevant subsets of the discovery population. RESULTS: We identified 40 CpG loci with methylation levels associated with at least one adiposity measure. Of these, one CpG locus (cg06500161) in ABCG1 was associated with all four adiposity measures (P = 9.07×10-8 to 3.27×10-18) and lower transcriptional activity of the full-length isoform of ABCG1 (P = 6.00×10-7), higher triglyceride levels (P = 5.37×10-9) and higher triglycerides-to-HDL cholesterol ratio (P = 1.03×10-10). Of the 40 informative and obesity-related CpG loci, two (in IL2RB and FGF18) were significantly associated with colorectal cancer (inversely, P < 1.6×10-3) and one intergenic locus on chromosome 1 was inversely associated with myocardial infarction (P < 1.25×10-3), independently of obesity and established risk factors. CONCLUSION: Our results suggest that epigenetic changes, in particular altered DNA methylation patterns, may be an intermediate biomarker at the intersection of obesity and obesity-related diseases, and could offer clues as to underlying biological mechanisms.

16.
Diabetes ; 67(7): 1310-1321, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29728363

RESUMO

In type 2 diabetes (T2D), hepatic insulin resistance is strongly associated with nonalcoholic fatty liver disease (NAFLD). In this study, we hypothesized that the DNA methylome of livers from patients with T2D compared with livers of individuals with normal plasma glucose levels can unveil some mechanism of hepatic insulin resistance that could link to NAFLD. Using DNA methylome and transcriptome analyses of livers from obese individuals, we found that hypomethylation at a CpG site in PDGFA (encoding platelet-derived growth factor α) and PDGFA overexpression are both associated with increased T2D risk, hyperinsulinemia, increased insulin resistance, and increased steatohepatitis risk. Genetic risk score studies and human cell modeling pointed to a causative effect of high insulin levels on PDGFA CpG site hypomethylation, PDGFA overexpression, and increased PDGF-AA secretion from the liver. We found that PDGF-AA secretion further stimulates its own expression through protein kinase C activity and contributes to insulin resistance through decreased expression of insulin receptor substrate 1 and of insulin receptor. Importantly, hepatocyte insulin sensitivity can be restored by PDGF-AA-blocking antibodies, PDGF receptor inhibitors, and by metformin, opening therapeutic avenues. Therefore, in the liver of obese patients with T2D, the increased PDGF-AA signaling contributes to insulin resistance, opening new therapeutic avenues against T2D and possibly NAFLD.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Resistência à Insulina , Fígado/metabolismo , Obesidade/metabolismo , Fator de Crescimento Derivado de Plaquetas/genética , Fator de Crescimento Derivado de Plaquetas/metabolismo , Adulto , Estudos de Casos e Controles , Células Cultivadas , Metilação de DNA , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Epigênese Genética/fisiologia , Feminino , Predisposição Genética para Doença , Humanos , Resistência à Insulina/genética , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/complicações , Obesidade/genética , Obesidade/patologia , Transdução de Sinais/genética , Regulação para Cima/genética
17.
Mol Metab ; 13: 1-9, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29784605

RESUMO

OBJECTIVE: The molecular diagnosis of extreme forms of obesity, in which accurate detection of both copy number variations (CNVs) and point mutations, is crucial for an optimal care of the patients and genetic counseling for their families. Whole-exome sequencing (WES) has benefited considerably this molecular diagnosis, but its poor ability to detect CNVs remains a major limitation. We aimed to develop a method (CoDE-seq) enabling the accurate detection of both CNVs and point mutations in one step. METHODS: CoDE-seq is based on an augmented WES method, using probes distributed uniformly throughout the genome. CoDE-seq was validated in 40 patients for whom chromosomal DNA microarray was available. CNVs and mutations were assessed in 82 children/young adults with suspected Mendelian obesity and/or intellectual disability and in their parents when available (ntotal = 145). RESULTS: CoDE-seq not only detected all of the 97 CNVs identified by chromosomal DNA microarrays but also found 84 additional CNVs, due to a better resolution. When compared to CoDE-seq and chromosomal DNA microarrays, WES failed to detect 37% and 14% of CNVs, respectively. In the 82 patients, a likely molecular diagnosis was achieved in >30% of the patients. Half of the genetic diagnoses were explained by CNVs while the other half by mutations. CONCLUSIONS: CoDE-seq has proven cost-efficient and highly effective as it avoids the sequential genetic screening approaches currently used in clinical practice for the accurate detection of CNVs and point mutations.

18.
Stem Cell Res ; 29: 56-59, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29597128

RESUMO

Heterozygous non-synonymous (p.S142F) mutation in HNF1A leads to maturity-onset diabetes of the young (MODY) type 3, which is a subtype of dominant inherited young-onset non-autoimmune diabetes due to the defect of insulin secretion from pancreatic beta cells. We generated induced pluripotent stem cells (iPSCs) from a patient with HNF1A p.S142F mutation. Cells from this patient, which were reprogrammed by non-integrative viral transduction had normal karyotype, harboured the HNF1A p.S142F mutation, expressed pluripotency hallmarks.

19.
Obesity (Silver Spring) ; 26(3): 474-484, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29464904

RESUMO

OBJECTIVE: Consanguinity has been instrumental in the elucidation of many Mendelian genetic diseases. Here, the unique advantage of consanguineous populations was considered in the quest for genes causing obesity. METHODS: PubMed was searched for articles relevant to consanguinity and obesity published between 1995 and 2016. Some earlier articles of interest were also consulted. RESULTS: Although obesity is the most heritable disorder, even in outbred populations, only 2% to 5% of severe obesity cases have so far been proven to be caused by single gene mutations. In some highly consanguineous populations, a remarkably higher proportion of obesity cases because of known and novel monogenic variants has been identified (up to 30%). CONCLUSIONS: Combining the power conferred by consanguinity with current large-capacity sequencing techniques should bring new genetic factors and molecular mechanisms to the fore, unveiling a large part of the yet-elusive neurohumoral circuitry involved in the regulation of energy homeostasis and appetite. Importantly, the undertaking of such initiatives is destined to unfold novel targets for the development of precision medicine relevant to different forms of obesity.


Assuntos
Consanguinidade , Obesidade/genética , Medicina de Precisão/métodos , Humanos , Mutação
20.
Nat Genet ; 50(2): 175-179, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29311637

RESUMO

Study of monogenic forms of obesity has demonstrated the pivotal role of the central leptin-melanocortin pathway in controlling energy balance, appetite and body weight 1 . The majority of loss-of-function mutations (mostly recessive or co-dominant) have been identified in genes that are directly involved in leptin-melanocortin signaling. These genes, however, only explain obesity in <5% of cases, predominantly from outbred populations 2 . We previously showed that, in a consanguineous population in Pakistan, recessive mutations in known obesity-related genes explain ~30% of cases with severe obesity3-5. These data suggested that new monogenic forms of obesity could also be identified in this population. Here we identify and functionally characterize homozygous mutations in the ADCY3 gene encoding adenylate cyclase 3 in children with severe obesity from consanguineous Pakistani families, as well as compound heterozygous mutations in a severely obese child of European-American descent. These findings highlight ADCY3 as an important mediator of energy homeostasis and an attractive pharmacological target in the treatment of obesity.

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