Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 12 de 12
Filtrar
1.
Leukemia ; 32(12): 2636-2647, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29895955

RESUMO

Clonal evolution drives tumor progression, chemoresistance and relapse in cancer. Little is known about clonal selection induced by therapeutic pressure in multiple myeloma. To address this issue, we performed large targeted sequencing of bone marrow plasma cells in 43 multiple myeloma patients at diagnosis and at relapse from exactly the same intensive treatment. The most frequently mutated genes at diagnosis were KRAS (35%), NRAS (28%), DIS3 (16%), BRAF, and LRP1B (12% each). At relapse, the mutational burden was unchanged. Many of the mutations were present at the subclonal level at both time points, including driver ones. According to patients and mutations, we observed different scenarios: selection of a very rare subclone present at diagnosis, appearance, or disappearance of mutations, but also stability. Our data highlight that chemoresistance and relapse could be induced by newly acquired mutations in myeloma drivers but also by (sub)clonal mutations preexisting to the treatment. Importantly, no specific mutation or rearrangement was observed at relapse, demonstrating that intensive treatment has a nonspecific effect on clonal selection in multiple myeloma. Finally, we identified 22 cases of biallelic event, including a double event deletion 17p/TP53mut.


Assuntos
Evolução Clonal/genética , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Idoso , Medula Óssea/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia
2.
Am J Hum Genet ; 101(6): 925-938, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29220676

RESUMO

A growing number of single-nucleotide polymorphisms (SNPs) have been associated with body mass index (BMI) and obesity, but whether the effects of these obesity-susceptibility loci are uniform across the BMI distribution remains unclear. We studied the effects of 37 BMI-associated SNPs in 75,230 adults of European ancestry across BMI percentiles by using conditional quantile regression (CQR) and meta-regression (MR) models. The effects of nine SNPs (24%)-rs1421085 (FTO; p = 8.69 × 10-15), rs6235 (PCSK1; p = 7.11 × 10-6), rs7903146 (TCF7L2; p = 9.60 × 10-6), rs11873305 (MC4R; p = 5.08 × 10-5), rs12617233 (FANCL; p = 5.30 × 10-5), rs11672660 (GIPR; p = 1.64 × 10-4), rs997295 (MAP2K5; p = 3.25 × 10-4), rs6499653 (FTO; p = 6.23 × 10-4), and rs3824755 (NT5C2; p = 7.90 × 10-4)-increased significantly across the sample BMI distribution. We showed that such increases stemmed from unadjusted gene interactions that enhanced the effects of SNPs in persons with a high BMI. When 125 height-associated SNPs were analyzed for comparison, only one (<1%), rs6219 (IGF1, p = 1.80 × 10-4), showed effects that varied significantly across height percentiles. Cumulative gene scores of these SNPs (GS-BMI and GS-height) showed that only GS-BMI had effects that increased significantly across the sample distribution (BMI: p = 7.03 × 10-37; height: p = 0.499). Overall, these findings underscore the importance of gene-gene and gene-environment interactions in shaping the genetic architecture of BMI and advance a method for detecting such interactions by using only the sample outcome distribution.


Assuntos
Estatura/genética , Índice de Massa Corporal , Herança Multifatorial/genética , Obesidade/genética , Penetrância , Adulto , Idoso , Idoso de 80 Anos ou mais , Frequência do Gene , Interação Gene-Ambiente , Predisposição Genética para Doença/genética , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , População Branca/genética , Adulto Jovem
3.
PLoS One ; 12(10): e0186218, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29045471

RESUMO

Previous genome wide association studies (GWAS) identified associations of multiple common variants with diastolic and systolic blood pressure traits in adults. However, the contribution of these loci to variations of blood pressure in early life is unclear. We assessed the child and parental contributions of 33 GWAS single-nucleotide polymorphisms (SNPs) for blood pressure in 1,525 participants (515 children, 406 mothers and 237 fathers) of the Family Atherosclerosis Monitoring In early life (FAMILY) study followed-up for 5 years. Two genotype scores for systolic (29 SNPs) and diastolic (24 SNPs) blood pressure were built. Linear mixed-effect regressions showed significant association between rs1378942 in CSK and systolic blood pressure (ß = 0.98±0.46, P = 3.4×10-2). The child genotype scores for diastolic and systolic blood pressure were not associated in children. Nominally significant parental genetic effects were found between the SNPs rs11191548 (CYP17A1) (paternal, ß = 2.78±1.49, P = 6.1×10-2 for SBP and ß = 3.60±1.24, P = 3.7×10-3 for DBP), rs17367504 (MTHFR) (paternal, ß = 2.42±0.93, P = 9.3×10-3 for SBP and ß = 1.89±0.80, P = 1.8×10-2 for DBP and maternal, ß = -1.32±0.60, P = 2.9×10-2 and ß = -1.97±0.77, P = 1.0×10-2, for SBP and DBP respectively) and child blood pressure. Our study supports the view that adult GWAS loci have a limited impact on blood pressure during the five first years of life. The parental genetic effects observed on blood pressure in children may suggest epigenetic mechanisms in the transmission of the risk of hypertension. Further replication is needed to confirm our results.


Assuntos
Pressão Sanguínea/genética , Hipertensão/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Esteroide 17-alfa-Hidroxilase/genética , Quinases da Família src/genética , Adulto , Proteína Tirosina Quinase CSK , Pré-Escolar , Feminino , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/fisiopatologia , Lactente , Masculino , Polimorfismo de Nucleotídeo Único , Fatores de Risco
4.
Sci Rep ; 7(1): 68, 2017 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-28250428

RESUMO

The contribution of polymorphisms associated with adult lipids in early life is unknown. We studied 158 adult lipid polymorphisms in 1440 participants (544 children, 544 mothers and 324 fathers) of the Family Atherosclerosis Monitoring In early life (FAMILY) birth cohort. Total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) measurements were collected at birth, 3 and 5 years of age. Polymorphisms were genotyped using the Illumina Cardio-Metabochip array. Genotype scores (GS) were calculated for TC, HDL-C, LDL-C and TG. Linear and mixed-effects regressions adjusted for sex, age and population stratification were performed. The GS was associated with LDL-C level at 3 and 5 years (ß = 0.017 ± 0.003, P = 2.9 × 10-8; ß = 0.020 ± 0.003, P = 5.7 × 10-9) and from birth to 5 years (ß = 0.013 ± 0.003, P = 2.6 × 10-7). The GS was associated with TC level at 3 and 5 years (ß = 0.009 ± 0.002, P = 9.1 × 10-7; ß = 0.009 ± 0.002, P = 7.7 × 10-6). CETP rs3764261 was associated with the HDL-C level from birth to 5 years (ß = 0.064 ± 0.014, P = 7.4 × 10-6). AMPD3 rs2923084 was associated with the HDL-C level at 5 years (ß = 0.096 ± 0.024, P = 9.7 × 10-5). Known loci associated with blood lipids in adults are associated with TC, LDL-C and HDL-C, but not TG in early life. Genetically predisposed children may benefit from early lipid lowering preventative strategies.


Assuntos
HDL-Colesterol/sangue , LDL-Colesterol/sangue , Técnicas de Genotipagem/métodos , Polimorfismo Genético , Triglicerídeos/sangue , AMP Desaminase/genética , Adulto , Pré-Escolar , Proteínas de Transferência de Ésteres de Colesterol/genética , Pai , Feminino , Estudos de Associação Genética , Humanos , Recém-Nascido , Desequilíbrio de Ligação , Masculino
5.
J Clin Oncol ; 35(9): 963-967, 2017 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-28297630

RESUMO

Multiple myeloma (MM) is characterized by wide variability in the chromosomal/genetic changes present in tumor plasma cells. Genetically, MM can be divided into two groups according to ploidy and hyperdiploidy versus nonhyperdiploidy. Several studies in gene expression profiling attempted to identify subentities in MM without convincing results. These studies mostly confirmed the cytogenetic data and subclassified patients according to 14q32 translocations and ploidy. More-recent data that are based on whole-exome sequencing have confirmed this heterogeneity and show many gene mutations but without a unifying mutation. These newer studies have shown the frequent alteration of the mitogen-activated protein kinase pathway. The most interesting data have demonstrated subclonality in all patients with MM, including subclonal mutations of supposed driver genes KRAS, NRAS, and BRAF.


Assuntos
Mieloma Múltiplo/genética , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Mutação , Ploidias
6.
J Neuroinflammation ; 13(1): 132, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27245576

RESUMO

BACKGROUND: T cell-derived opioids play a key role in the control of inflammatory pain. However, the nature of opioids produced by T cells is still matter of debate in mice. Whereas ß-endorphin has been found in T lymphocytes by using antibody-based methods, messenger RNA (mRNA) quantification shows mainly mRNA encoding for enkephalins. The objective of the study is to elucidate the nature of T cell-derived opioids responsible for analgesia and clarify discrepancy of the results at the protein and genetic levels. METHODS: CD4(+) T lymphocytes were isolated from wild-type and enkephalin-deficient mice. mRNA encoding for ß-endorphin and enkephalin was quantified by RT-qPCR. The binding of commercially available polyclonal anti-endorphin antibodies to lymphocytes from wild-type or enkephalin knockout mice was assessed by cytofluorometry. Opioid-mediated analgesic properties of T lymphocytes from wild-type and enkephalin-deficient mice were compared in a model of inflammation-induced somatic pain by measuring sensitivity to mechanical stimuli using calibrated von Frey filaments. RESULTS: CD4(+) T lymphocytes expressed high level of mRNA encoding for enkephalins but not for ß-endorphin in mice. Anti-ß-endorphin polyclonal IgG antibodies are specific for ß-endorphin but cross-react with enkephalins. Anti-ß-endorphin polyclonal antibodies bound to wild-type but not enkephalin-deficient CD4(+) T lymphocytes. Endogenous regulation of inflammatory pain by wild-type T lymphocytes was completely abolished when T lymphocytes were deficient in enkephalins. Pain behavior of immune-deficient (i.e., without B and T lymphocytes) mice was superimposable to that of mice transferred with enkephalin-deficient lymphocytes. CONCLUSIONS: Rabbit polyclonal anti-ß-endorphin serum IgG bind to CD4(+) T lymphocytes because of their cross-reactivity towards enkephalins. Thus, staining of T lymphocytes by anti-ß-endorphin polyclonal IgG reported in most of studies in mice is because of their binding to enkephalins. In mice, CD4(+) T lymphocytes completely lose their analgesic opioid-mediated activity when lacking enkephalins.


Assuntos
Analgesia/métodos , Linfócitos T CD4-Positivos/metabolismo , Encefalinas/metabolismo , Medição da Dor/métodos , Dor/metabolismo , Dor/prevenção & controle , Sequência de Aminoácidos , Animais , Linfócitos T CD4-Positivos/imunologia , Encefalinas/genética , Encefalinas/imunologia , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Dor/imunologia , Coelhos , Distribuição Aleatória
7.
PLoS One ; 11(4): e0152107, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27049325

RESUMO

BACKGROUND: Metabolic abnormalities that lead to type 2 diabetes mellitus begin in early childhood. OBJECTIVES: We investigate whether common genetic variants identified in adults have an effect on glucose in early life. METHODS: 610 newborns, 463 mothers, and 366 fathers were included in the present study. Plasma glucose and anthropometric characteristics were collected at birth, 3, and 5 years. After quality assessment, 37 SNPs, which have demonstrated an association with fasting plasma glucose at the genome-wide threshold in adults, were studied. Quantitative trait disequilibrium tests and mixed-effects regressions were conducted to estimate an effect of the SNPs on glucose. RESULTS: Risk alleles for 6 loci increased glucose levels from birth to 5 years of age (ADCY5, ADRA2A, CDKAL1, CDKN2A/B, GRB10, and TCF7L2, 4.85x10-3 ≤ P ≤ 4.60x10-2). Together, these 6 SNPs increase glucose by 0.05 mmol/L for each risk allele in a genotype score (P = 6.33x10-5). None of the associations described in the present study have been reported previously in early childhood. CONCLUSION: Our data support the notion that a subset of loci contributing to plasma glucose variation in adults has an effect at birth and in early life.


Assuntos
Alelos , Glicemia/análise , Predisposição Genética para Doença , Adenilil Ciclases/genética , Adulto , Pré-Escolar , Quinase 5 Dependente de Ciclina/genética , Inibidor de Quinase Dependente de Ciclina p15/genética , Diabetes Mellitus Tipo 2/genética , Feminino , Proteína Adaptadora GRB10/genética , Genes p16 , Humanos , Lactente , Recém-Nascido , Masculino , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Receptores Adrenérgicos alfa 2/genética , tRNA Metiltransferases
8.
PLoS One ; 10(3): e0118925, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25742008

RESUMO

Bioinformatics tools have gained popularity in biology but little is known about their validity. We aimed to assess the early contribution of 415 single nucleotide polymorphisms (SNPs) associated with eight cardio-metabolic traits at the genome-wide significance level in adults in the Family Atherosclerosis Monitoring In earLY Life (FAMILY) birth cohort. We used the popular web-based tool SNAP to assess the availability of the 415 SNPs in the Illumina Cardio-Metabochip genotyped in the FAMILY study participants. We then compared the SNAP output with the Cardio-Metabochip file provided by Illumina using chromosome and chromosomal positions of SNPs from NCBI Human Genome Browser (Genome Reference Consortium Human Build 37). With the HapMap 3 release 2 reference, 201 out of 415 SNPs were reported as missing in the Cardio-Metabochip by the SNAP output. However, the Cardio-Metabochip file revealed that 152 of these 201 SNPs were in fact present in the Cardio-Metabochip array (false negative rate of 36.6%). With the more recent 1000 Genomes Project release, we found a false-negative rate of 17.6% by comparing the outputs of SNAP and the Illumina product file. We did not find any 'false positive' SNPs (SNPs specified as available in the Cardio-Metabochip by SNAP, but not by the Cardio-Metabochip Illumina file). The Cohen's Kappa coefficient, which calculates the percentage of agreement between both methods, indicated that the validity of SNAP was fair to moderate depending on the reference used (the HapMap 3 or 1000 Genomes). In conclusion, we demonstrate that the SNAP outputs for the Cardio-Metabochip are invalid. This study illustrates the importance of systematically assessing the validity of bioinformatics tools in an independent manner. We propose a series of guidelines to improve practices in the fast-moving field of bioinformatics software implementation.


Assuntos
Biologia Computacional , Genoma Humano , Software , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único
9.
J Mol Med (Berl) ; 91(9): 1109-15, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23640704

RESUMO

We investigated the effect of 24 obesity-predisposing single nucleotide polymorphisms (SNPs), separately and in combination, on snacking behavior in three European populations. The 24 SNPs were genotyped in 7,502 subjects (1,868 snackers and 5,634 non-snackers). We tested the hypothesis that obesity risk variants or a genetic risk score increases snacking using a logistic regression adjusted for sex, age, and body mass index. The obesity genetic risk score was not associated with snacking (odds ratio (OR) = 1.00 [0.98-1.02], P value = 0.48). The obesity risk variants of two SNPs (rs925946 and rs7498665) close to the BDNF and SH2B1 genes showed nominal evidence of association with increased snacking (OR = 1.09 [1.01-1.17], P value = 0.0348 and OR = 1.11 [1.04-1.19], P value = 0.00703, respectively) but did not survive Bonferroni corrections for multiple testing. The associations of rs925946 and rs7498665 obesity risk variants with increased BMI (ß = 0.180 [0.022-0.339], P value = 0.0258 and ß = 0.166 [0.019-0.313], P value = 0.0271, respectively) were slightly attenuated after adjusting for snacking (ß = 0.151 [-0.006 to 0.309], P value = 0.0591 and ß = 0.152 [0.006-0.297], P value = 0.0413). Our data suggest that genetic predisposition to obesity does not significantly contribute to snacking behavior. The nominal associations of rs925946 and rs7498665 obesity risk variants near the BDNF and SH2B1 genes with increased snacking deserve further investigation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Obesidade/genética , Lanches/fisiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Predisposição Genética para Doença , Variação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Razão de Chances , Fenótipo , Polimorfismo de Nucleotídeo Único , População Branca/genética , Adulto Jovem
10.
BMC Cancer ; 8: 326, 2008 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-18992148

RESUMO

BACKGROUND: Sporadic colorectal cancers (CRC) are multifactorial diseases resulting from the combined effects of numerous genetic, environmental and behavioral risk factors. Genetic association studies have suggested low-penetrance alleles of extremely varied genes to be involved in susceptibility to CRC in Caucasian populations. METHODS: Through a large genetic association study based on 1023 patients with sporadic CRC and 1121 controls, we tested a panel of these low-penetrance alleles to find out whether they could determine "genotypic profiles" at risk for CRC among individuals of the French population. We examined 52 polymorphisms of 35 genes - drawn from inflammation, xenobiotic detoxification, one-carbon, insulin signaling, and DNA repair pathways - for their possible contribution to colorectal carcinogenesis. The risk of cancer associated with these polymorphisms was assessed by calculation of odds ratios (OR) using multivariate analyses and logistic regression. RESULTS: Whereas all these polymorphisms had previously been found to be associated with CRC risk, especially in Caucasian populations, we were able to replicate the association for only five of them. Three SNPs were shown to increase CRC risk: PTGS1 c.639C>A (p.Gly213Gly), IL8 c.-352T>A, and MTHFR c.1286A>C (p.Ala429Glu). On the contrary, two other SNPs, PLA2G2A c.435+230C>T and PPARG c.1431C>T (p.His477His), were associated with a decrease in CRC risk. Further analyses highlighted genotypic combinations having a greater predisposing effect on CRC (OR 1.97, 95%CI 1.31-2.97, p = 0.0009) than the allelic variants that were examined separately. CONCLUSION: The identification of CRC-predisposing combinations, composed of alleles PTGS1 c.639A, PLA2G2A c.435+230C, PPARG c.1431C, IL8 c.-352A, and MTHFR c.1286C, highlights the importance of inflammatory processes in susceptibility to sporadic CRC, as well as a possible crosstalk between inflammation and one-carbon pathways.


Assuntos
Alelos , Neoplasias Colorretais/genética , Penetrância , Adulto , Idoso , Estudos de Casos e Controles , Feminino , França , Predisposição Genética para Doença , Genótipo , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Polimorfismo de Nucleotídeo Único
11.
Genet Test ; 11(4): 373-9, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17931073

RESUMO

The MUTYH gene encodes a key glycosylase of the base-excision repair system that is involved in maintaining genomic DNA stability against oxidative damage. Biallelic germline MUTYH mutations have been proved to greatly predispose to non-familial adenomatous polyposis (FAP) and non-hereditary non-polyposis colorectal cancer (HNPCC) familial recessive forms of colorectal cancer with multiple adenomas. To date, there is still much debate over the impact of monoallelic germline MUTYH mutations on colorectal carcinogenesis. To evaluate their role in the susceptibility to sporadic colon and rectum cancers, we screened 1024 French sporadic colorectal cancer cases and 1121 French healthy controls for Caucasian MUTYH-associated polyposis mutations, including already known mutations p.Gly382Asp and p.Tyr165Cys, and new mutation p.Val479Phe. We observed a nonstatistically significant association between these MUTYH mutations at a heterozygous state and an increase in colorectal cancer risk (odds ratio [OR] 1.26, 95% confidence interval [CI] 0.70-2.27). As a result, we conclude that heterozygous MUTYH mutations do not play a major role in sporadic colorectal carcinogenesis although a modest effect on this process cannot be ruled out.


Assuntos
Neoplasias Colorretais/genética , DNA Glicosilases/genética , Predisposição Genética para Doença , Adulto , Idoso , Idoso de 80 Anos ou mais , Substituição de Aminoácidos , Estudos de Coortes , Análise Mutacional de DNA , Feminino , França , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação
12.
Cancer Epidemiol Biomarkers Prev ; 16(7): 1460-7, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17627011

RESUMO

Susceptibility to sporadic colorectal cancers (CRC) is generally thought to be the sum of complex interactions between environmental and genetic factors, all of which contribute independently, producing only a modest effect on the whole phenomenon. However, to date, most research has concealed the notion of interaction and merely focused on dissociate analyses of risk factors to highlight associations with CRC. By contrast, we have chosen a combinative approach here to explore the joint effects of several factors at a time. Through an association study based on 1,023 cases and 1,121 controls, we examined the influence on CRC risk of environmental factors coanalyzed with combinations of six single nucleotide polymorphisms located in cytochrome P450 genes (c.-163A>C and c.1548T>C in CYP1A2, g.-1293G>C and g.-1053C>T in CYP2E1, c.1294C>G in CYP1B1, and c.430C>T in CYP2C9). Whereas separate analyses of the SNPs showed no effect on CRC risk, three allelic variant combinations were found to be associated with a significant increase in CRC risk in interaction with an excessive red meat consumption, thereby exacerbating the intrinsic procarcinogenic effect of this dietary factor. One of these three predisposing combinations was also shown to interact positively with obesity. Provided that they are validated, our results suggest the need to develop robust combinative methods to improve genetic investigations into the susceptibility to CRC.


Assuntos
Neoplasias Colorretais/etiologia , Sistema Enzimático do Citocromo P-450/genética , Dieta , Carne , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Hidrocarboneto de Aril Hidroxilases/genética , Estudos de Casos e Controles , Estudos de Coortes , Neoplasias Colorretais/epidemiologia , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP1B1 , Citocromo P-450 CYP2C9 , Citocromo P-450 CYP2E1/genética , Feminino , França/epidemiologia , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...