Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 43
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Artigo em Inglês | MEDLINE | ID: mdl-31689713

RESUMO

OBJECTIVE: Adults with Prader-Willi syndrome (PWS) are at increased risk of developing age-associated diseases early in life and, like in premature ageing syndromes, ageing might be accelerated. We investigated leukocyte telomere length (LTL), a marker of biological age, in young adults with PWS and compared LTL to healthy young adults of similar age. As all young adults with PWS were treated with growth hormone (GH), we also compared LTL in PWS subjects to GH-treated young adults born short for gestational age (SGA). DESIGN: Cross-sectional study in age-matched young adults; 47 with PWS, 135 healthy and 75 born SGA. MEASUREMENTS: LTL measured by quantitative PCR, expressed as T/S ratio. RESULTS: Median (IQR) LTL was 2.6 (2.4; 2.8) at a median (IQR) age of 19.2 (17.7; 21.3) years in PWS, 3.1 (2.9; 3.5) in healthy young adults and 3.1 (2.8; 3.4) in the SGA group. Median LTL in PWS was significantly lower compared to both control groups (p<0.01). In PWS, a lower LTL tended to be associated with a lower total IQ (r=0.35, p=0.08). There was no association between LTL and duration of GH treatment, cumulative GH dose or several risk factors for type 2 diabetes mellitus or cardiovascular disease. CONCLUSIONS: Young adults with PWS have significantly shorter median LTL compared to age-matched healthy young adults and GH-treated young adults born SGA. The shorter telomeres might play a role in the premature ageing in PWS, independent of GH. Longitudinal research is needed to determine the influence of LTL on ageing in PWS.

2.
Sci Rep ; 9(1): 11623, 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31406173

RESUMO

Telomere shortening has been associated with multiple age-related diseases such as cardiovascular disease, diabetes, and dementia. However, the biological mechanisms responsible for these associations remain largely unknown. In order to gain insight into the metabolic processes driving the association of leukocyte telomere length (LTL) with age-related diseases, we investigated the association between LTL and serum metabolite levels in 7,853 individuals from seven independent cohorts. LTL was determined by quantitative polymerase chain reaction and the levels of 131 serum metabolites were measured with mass spectrometry in biological samples from the same blood draw. With partial correlation analysis, we identified six metabolites that were significantly associated with LTL after adjustment for multiple testing: lysophosphatidylcholine acyl C17:0 (lysoPC a C17:0, p-value = 7.1 × 10-6), methionine (p-value = 9.2 × 10-5), tyrosine (p-value = 2.1 × 10-4), phosphatidylcholine diacyl C32:1 (PC aa C32:1, p-value = 2.4 × 10-4), hydroxypropionylcarnitine (C3-OH, p-value = 2.6 × 10-4), and phosphatidylcholine acyl-alkyl C38:4 (PC ae C38:4, p-value = 9.0 × 10-4). Pathway analysis showed that the three phosphatidylcholines and methionine are involved in homocysteine metabolism and we found supporting evidence for an association of lipid metabolism with LTL. In conclusion, we found longer LTL associated with higher levels of lysoPC a C17:0 and PC ae C38:4, and with lower levels of methionine, tyrosine, PC aa C32:1, and C3-OH. These metabolites have been implicated in inflammation, oxidative stress, homocysteine metabolism, and in cardiovascular disease and diabetes, two major drivers of morbidity and mortality.

3.
Arterioscler Thromb Vasc Biol ; 37(10): 1956-1962, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28860221

RESUMO

OBJECTIVE: Cholesterol efflux capacity (CEC) has emerged as a biomarker of coronary artery disease risk beyond plasma high-density lipoprotein (HDL) cholesterol (HDL-C) level. However, the determinants of CEC are incompletely characterized. We undertook a large-scale family-based population study to identify clinical, biochemical, and HDL particle parameter determinants of CEC, characterize reasons for the discordancy with HDL-C, quantify its heritability, and assess its stability over 10 to 12 years. APPROACHES AND RESULTS: CEC was quantified in 1988 individuals from the GRAPHIC (Genetic Regulation of Arterial Pressure of Humans in the Community) cohort, comprising individuals from 2 generations from 520 white nuclear families. Serum lipid and lipoprotein levels were determined by ultracentrifugation or nuclear magnetic resonance and HDL particle size and number quantified by nuclear magnetic resonance. Ninety unrelated individuals had repeat CEC measurements in samples collected after 10 to 12 years. CEC was positively correlated with HDL-C (R=0.62; P<0.0001). Among clinical and biochemical parameters, age, systolic blood pressure, alcohol consumption, serum albumin, triglycerides, phospholipids, and lipoprotein(a) were independently associated with CEC. Among HDL particle parameters, HDL particle number, particle size, and apolipoprotein A-II level were independently associated with CEC. Serum triglyceride level partially explained discordancy between CEC and HDL-C. CEC measurements in samples collected 10 to 12 years apart were strongly correlated (r=0.73; P<0.0001). Heritability of CEC was 0.31 (P=3.89×10-14) without adjustment for HDL-C and 0.13 (P=1.44×10-3) with adjustment. CONCLUSIONS: CEC is a stable trait over time, is influenced by specific clinical, serum, and HDL particle parameters factors beyond HDL-C, can be maintained in persons with a low plasma HDL-C by elevated serum triglyceride level, and is modestly independently heritable.


Assuntos
HDL-Colesterol/sangue , Doença das Coronárias/sangue , Adolescente , Adulto , Transporte Biológico , Biomarcadores/sangue , HDL-Colesterol/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Triglicerídeos/sangue , Adulto Jovem
4.
Neuropsychopharmacology ; 42(12): 2407-2413, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28397798

RESUMO

Telomere length (TL) is a marker of biological aging, and numerous studies have shown associations between TL and somatic or psychiatric disorders. Research also indicates an association between maternal stress during pregnancy and TL in the offspring. The present study investigated possible associations between TL and: (1) maternal perceived stress during pregnancy; (2) a maternal lifetime history of psychiatric disorder (lifetime PD); and (3) paternal age. TL was analyzed in 319 newborns and 318 mothers from a predominantly Caucasian sample (n=273 Caucasian newborns and n=274 Caucasian mothers). Two key findings were observed. First, maternal perceived stress during pregnancy was associated with shorter telomeres in newborns but not with maternal TL. Second, maternal lifetime PD was associated with shorter maternal telomeres, but not with TL in newborns. Paternal age was not associated with TL in newborns. The finding that maternal stress during pregnancy is associated with shorter telomeres in newborns supports the results of smaller previous studies. The fact that a relation between maternal prenatal stress and TL was observed in the offspring but not in mothers may be attributable to a high vulnerability to stress during intrauterine development of a maturing organism. To our knowledge, this is the largest study to date to show that maternal stress during pregnancy but not maternal lifetime PD is associated with shorter telomeres in the offspring.


Assuntos
Complicações na Gravidez/genética , Complicações na Gravidez/psicologia , Estresse Psicológico/genética , Estresse Psicológico/psicologia , Encurtamento do Telômero/fisiologia , Adulto , Estudos de Coortes , Feminino , Humanos , Recém-Nascido , Masculino , Gravidez , Estudos Prospectivos , Autorrelato , Estresse Psicológico/complicações , Telômero/fisiologia
5.
Arterioscler Thromb Vasc Biol ; 37(6): 1050-1057, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28279971

RESUMO

OBJECTIVE: Genome-wide association studies have linked variants at chromosome 10q23 with increased coronary artery disease risk. The disease-associated variants fall in LIPA, which encodes lysosomal acid lipase (LAL), the enzyme responsible for lysosomal cholesteryl ester hydrolysis. Loss-of-function mutations in LIPA result in accelerated atherosclerosis. Surprisingly, the coronary artery disease variants are associated with increased LIPA expression in some cell types. In this study, we address this apparent contradiction. APPROACH AND RESULTS: We investigated a coding variant rs1051338, which is in high linkage disequilibrium (r2=0.89) with the genome-wide association study lead-associated variant rs2246833 and causes a nonsynonymous threonine to proline change within the signal peptide of LAL. Transfection of allele-specific expression constructs showed that the risk allele results in reduced lysosomal LAL protein (P=0.004) and activity (P=0.005). Investigation of LAL localization and turnover showed the risk LAL protein is degraded more quickly. This mechanism was confirmed in disease-relevant macrophages from individuals homozygous for either the nonrisk or risk allele. There was no difference in LAL protein or activity in whole macrophage extracts; however, we found reduced LAL protein (P=0.02) and activity (P=0.026) with the risk genotype in lysosomal extracts, suggesting that the risk genotype affects lysosomal LAL activity. Inhibition of the proteasome resulted in equal amounts of lysosomal LAL protein in risk and nonrisk macrophages. CONCLUSIONS: Our findings show that the coronary artery disease-associated coding variant rs1051338 causes reduced lysosomal LAL protein and activity because of increased LAL degradation, providing a plausible causal mechanism of increased coronary artery disease risk.


Assuntos
Doença da Artéria Coronariana/enzimologia , Doença da Artéria Coronariana/genética , Lisossomos/enzimologia , Macrófagos/enzimologia , Polimorfismo de Nucleotídeo Único , Esterol Esterase/genética , Esterol Esterase/metabolismo , Adulto , Animais , Células COS , Cercopithecus aethiops , Regulação para Baixo , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Homozigoto , Humanos , Desequilíbrio de Ligação , Lisossomos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Masculino , Fenótipo , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Sinais Direcionadores de Proteínas , Transporte Proteico , Proteólise , Fatores de Risco , Transfecção
6.
PLoS One ; 12(2): e0171825, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28178350

RESUMO

BACKGROUND: Small size at birth and rapid growth in early life are associated with increased risk of cardiovascular disease in later life. Short children born small for gestational age (SGA) are treated with growth hormone (GH), inducing catch-up in length. Leukocyte telomere length (LTL) is a marker of biological age and shorter LTL is associated with increased risk of cardiovascular disease. OBJECTIVES: To investigate whether LTL is influenced by birth size, childhood growth and long-term GH treatment. METHODS: We analyzed LTL in 545 young adults with differences in birth size and childhood growth patterns. Previously GH-treated young adults born SGA (SGA-GH) were compared to untreated short SGA (SGA-S), SGA with spontaneous catch-up to a normal body size (SGA-CU), and appropriate for gestational age with a normal body size (AGA-NS). LTL was measured using a quantitative PCR assay. RESULTS: We found a positive association between birth length and LTL (p = 0.04), and a trend towards a positive association between birth weight and LTL (p = 0.08), after adjustments for gender, age, gestational age and adult body size. Weight gain during infancy and childhood and fat mass percentage were not associated with LTL. Female gender and gestational age were positively associated with LTL, and smoking negatively. After adjustments for gender, age and gestational age, SGA-GH had a similar LTL as SGA-S (p = 0.11), SGA-CU (p = 0.80), and AGA-NS (p = 0.30). CONCLUSIONS: Larger size at birth is positively associated with LTL in young adulthood. Growth patterns during infancy and childhood are not associated with LTL. Previously GH-treated young adults born SGA have similar LTL as untreated short SGA, SGA with spontaneous catch-up and AGA born controls, indicating no adverse effects of GH-induced catch-up in height on LTL.


Assuntos
Peso ao Nascer , Tamanho Corporal , Desenvolvimento Humano , Hormônio do Crescimento Humano/farmacologia , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Homeostase do Telômero/efeitos dos fármacos , Telômero , Adolescente , Adulto , Feminino , Humanos , Masculino , Adulto Jovem
7.
PLoS One ; 12(1): e0170765, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28125671

RESUMO

Telomere length has garnered interest due to the potential role it may play as a biomarker for the cellular aging process. Telomere measurements obtained from blood-derived DNA are often used in epidemiological studies. However, the invasive nature of blood draws severely limits sample collection, particularly with children. Buccal cells are commonly sampled for DNA isolation and thus may present a non-invasive alternative for telomere measurement. Buccal and leukocyte derived DNA obtained from samples collected at the same time period were analyzed for telomere repeat mass (TRM). TRM was measured in buccal-derived DNA samples from individuals for whom previous TRM data from blood samples existed. TRM measurement was performed by qPCR and was normalized to the single copy 36B4 gene relative to a reference DNA sample (K562). Correlations between TRM from blood and buccal DNA were obtained and also between the same blood DNA samples measured in separate laboratories. Using the classical twin design, TRM heritability was estimated (N = 1892, MZ = 1044, DZ = 775). Buccal samples measured for TRM showed a significant correlation with the blood-1 (R = 0.39, p < 0.01) and blood-2 (R = 0.36, p < 0.01) samples. Sex and age effects were observed within the buccal samples as is the norm within blood-derived DNA. The buccal, blood-1, and blood-2 measurements generated heritability estimates of 23.3%, 47.6% and 22.2%, respectively. Buccal derived DNA provides a valid source for the determination of TRM, paving the way for non-invasive projects, such as longitudinal studies in children.


Assuntos
DNA/genética , Leucócitos Mononucleares/metabolismo , Mucosa Bucal/metabolismo , Telômero/química , Adolescente , Adulto , Fatores Etários , Idoso , Criança , DNA/isolamento & purificação , Primers do DNA/química , Feminino , Humanos , Células K562 , Leucócitos Mononucleares/química , Masculino , Pessoa de Meia-Idade , Mucosa Bucal/química , Reação em Cadeia da Polimerase em Tempo Real , Padrões de Referência , Fatores Sexuais , Irmãos , Gêmeos Dizigóticos , Gêmeos Monozigóticos
8.
Cancer Epidemiol Biomarkers Prev ; 25(7): 1043-9, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27197291

RESUMO

BACKGROUND: Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. Shorter mean telomere length in leukemic cells has been associated with more aggressive disease. Germline polymorphisms in telomere maintenance genes affect telomere length and may contribute to CLL susceptibility. METHODS: We collected genome-wide data from two groups of patients with CLL (N = 273) and two control populations (N = 5,725). In ancestry-adjusted case-control comparisons, we analyzed eight SNPs in genes definitively associated with inter-individual variation in leukocyte telomere length (LTL) in prior genome-wide association studies: ACYP2, TERC, NAF1, TERT, OBFC1, CTC1, ZNF208, and RTEL1 RESULTS: Three of the eight LTL-associated SNPs were associated with CLL risk at P < 0.05, including those near: TERC [OR, 1.46; 95% confidence interval (CI), 1.15-1.86; P = 1.8 × 10(-3)], TERT (OR = 1.23; 95% CI, 1.02-1.48; P = 0.030), and OBFC1 (OR, 1.36; 95% CI, 1.08-1.71; P = 9.6 × 10(-3)). Using a weighted linear combination of the eight LTL-associated SNPs, we observed that CLL patients were predisposed to longer LTL than controls in both case-control sets (P = 9.4 × 10(-4) and 0.032, respectively). CLL risk increased monotonically with increasing quintiles of the weighted linear combination. CONCLUSIONS: Genetic variants in TERC, TERT, and OBFC1 are associated with both longer LTL and increased CLL risk. Because the human CST complex competes with shelterin for telomeric DNA, future work should explore the role of OBFC1 and other CST complex genes in leukemogenesis. IMPACT: A genetic predisposition to longer telomere length is associated with an increased risk of CLL, suggesting that the role of telomere length in CLL etiology may be distinct from its role in disease progression. Cancer Epidemiol Biomarkers Prev; 25(7); 1043-9. ©2016 AACR.


Assuntos
Biomarcadores Tumorais/genética , Predisposição Genética para Doença , Variação Genética , Leucemia Linfocítica Crônica de Células B/genética , Homeostase do Telômero/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla , Humanos , Leucócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
9.
Carcinogenesis ; 37(6): 576-582, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27207662

RESUMO

Aberrant telomere lengthening is an important feature of cancer cells in adults and children. In addition to somatic mutations, germline polymorphisms in telomere maintenance genes impact telomere length. Whether these telomere-associated polymorphisms affect risk of childhood malignancies remains largely unexplored. We collected genome-wide data from three groups with pediatric malignancies [neuroblastoma (N = 1516), acute lymphoblastic leukemia (ALL) (N = 958) and osteosarcoma (N = 660)] and three control populations (N = 6892). Using case-control comparisons, we analyzed eight single nucleotide polymorphisms (SNPs) in genes definitively associated with interindividual variation in leukocyte telomere length (LTL) in prior genome-wide association studies: ACYP2, TERC, NAF1, TERT, OBFC1, CTC1, ZNF208 and RTEL1 Six of these SNPs were associated (P < 0.05) with neuroblastoma risk, one with leukemia risk and one with osteosarcoma risk. The allele associated with longer LTL increased cancer risk for all these significantly associated SNPs. Using a weighted linear combination of the eight LTL-associated SNPs, we observed that neuroblastoma patients were predisposed to longer LTL than controls, with each standard deviation increase in genotypically estimated LTL associated with a 1.15-fold increased odds of neuroblastoma (95%CI = 1.09-1.22; P = 7.9×10(-7)). This effect was more pronounced in adolescent-onset neuroblastoma patients (OR = 1.46; 95%CI = 1.03-2.08). A one standard deviation increase in genotypically estimated LTL was more weakly associated with osteosarcoma risk (OR = 1.10; 95%CI = 1.01-1.19; P = 0.017) and leukemia risk (OR = 1.07; 95%CI = 1.00-1.14; P = 0.044), specifically for leukemia patients who relapsed (OR = 1.19; 95%CI = 1.01-1.40; P = 0.043). These results indicate that genetic predisposition to longer LTL is a newly identified risk factor for neuroblastoma and potentially for other cancers of childhood.


Assuntos
Predisposição Genética para Doença , Neuroblastoma/genética , Polimorfismo de Nucleotídeo Único , Proteínas/genética , Homeostase do Telômero , Adolescente , Neoplasias Ósseas/genética , Estudos de Casos e Controles , Criança , Estudo de Associação Genômica Ampla , Humanos , Leucócitos/fisiologia , Osteossarcoma/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adulto Jovem
10.
Aging (Albany NY) ; 8(1): 77-94, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26797767

RESUMO

Leukocyte telomere length (LTL) is considered one of the most predictive markers of biological aging. The aim of this study was to identify novel pathways regulating LTL using a metabolomics approach. To this end, we tested associations between 280 blood metabolites and LTL in 3511 females from TwinsUK and replicated our results in the KORA cohort. We furthermore tested significant metabolites for associations with several aging-related phenotypes, gene expression markers and epigenetic markers to investigate potential underlying pathways. Five metabolites were associated with LTL: Two lysolipids, 1-stearoylglycerophosphoinositol (P=1.6×10(-5)) and 1-palmitoylglycerophosphoinositol (P=1.6×10(-5)), were found to be negatively associated with LTL and positively associated with phospholipase A2 expression levels suggesting an involvement of fatty acid metabolism and particularly membrane composition in biological aging. Moreover, two gamma-glutamyl amino acids, gamma-glutamyltyrosine (P=2.5×10(-6)) and gamma-glutamylphenylalanine (P=1.7×10(-5)), were negatively correlated with LTL. Both are products of the glutathione cycle and markers for increased oxidative stress. Metabolites were also correlated with functional measures of aging, i.e. higher blood pressure and HDL cholesterol levels and poorer lung, liver and kidney function. Our results suggest an involvement of altered fatty acid metabolism and increased oxidative stress in human biological aging, reflected by LTL and age-related phenotypes of vital organ systems.


Assuntos
Leucócitos/metabolismo , Homeostase do Telômero , Telômero/metabolismo , Adulto , Fatores Etários , Idoso , Envelhecimento/sangue , Envelhecimento/genética , Biomarcadores/sangue , Metabolismo Energético , Ácidos Graxos/metabolismo , Feminino , Alemanha , Humanos , Metabolômica/métodos , Pessoa de Meia-Idade , Estresse Oxidativo , Fenótipo , Sistema de Registros , Telômero/genética , Gêmeos/genética , Reino Unido
11.
PLoS One ; 10(11): e0143951, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26619005

RESUMO

BACKGROUND: Subjects born preterm have an increased risk for age-associated diseases, such as cardiovascular disease in later life, but the underlying causes are largely unknown. Shorter leukocyte telomere length (LTL), a marker of biological age, is associated with increased risk of cardiovascular disease. OBJECTIVES: To compare LTL between subjects born preterm and at term and to assess if LTL is associated with other putative cardiovascular risk factors at young adult age. METHODS: We measured mean LTL in 470 young adults. LTL was measured using a quantitative PCR assay and expressed as T/S ratio. We analyzed the influence of gestational age on LTL and compared LTL between subjects born preterm (n = 186) and at term (n = 284). Additionally, we analyzed the correlation between LTL and potential risk factors of cardiovascular disease. RESULTS: Gestational age was positively associated with LTL (r = 0.11, p = 0.02). Subjects born preterm had shorter LTL (mean (SD) T/S ratio = 3.12 (0.44)) than subjects born at term (mean (SD) T/S ratio = 3.25 (0.46)), p = 0.003). The difference remained significant after adjustment for gender and size at birth (p = 0.001). There was no association of LTL with any one of the putative risk factors analyzed. CONCLUSIONS: Young adults born preterm have shorter LTL than young adults born at term. Although we found no correlation between LTL and risk for CVD at this young adult age, this biological ageing indicator may contribute to CVD and other adult onset diseases at a later age in those born preterm.


Assuntos
Envelhecimento/genética , Doenças Cardiovasculares/genética , Leucócitos/citologia , Telômero/genética , Adulto , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Adulto Jovem
12.
Oncotarget ; 6(40): 42468-77, 2015 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-26646793

RESUMO

Telomere maintenance has emerged as an important molecular feature with impacts on adult glioma susceptibility and prognosis. Whether longer or shorter leukocyte telomere length (LTL) is associated with glioma risk remains elusive and is often confounded by the effects of age and patient treatment. We sought to determine if genotypically-estimated LTL is associated with glioma risk and if inherited single nucleotide polymorphisms (SNPs) that are associated with LTL are glioma risk factors. Using a Mendelian randomization approach, we assessed differences in genotypically-estimated relative LTL in two independent glioma case-control datasets from the UCSF Adult Glioma Study (652 patients and 3735 controls) and The Cancer Genome Atlas (478 non-overlapping patients and 2559 controls). LTL estimates were based on a weighted linear combination of subject genotype at eight SNPs, previously associated with LTL in the ENGAGE Consortium Telomere Project. Mean estimated LTL was 31bp (5.7%) longer in glioma patients than controls in discovery analyses (P = 7.82x10-8) and 27bp (5.0%) longer in glioma patients than controls in replication analyses (1.48x10-3). Glioma risk increased monotonically with each increasing septile of LTL (O.R.=1.12; P = 3.83x10-12). Four LTL-associated SNPs were significantly associated with glioma risk in pooled analyses, including those in the telomerase component genes TERC (O.R.=1.14; 95% C.I.=1.03-1.28) and TERT (O.R.=1.39; 95% C.I.=1.27-1.52), and those in the CST complex genes OBFC1 (O.R.=1.18; 95% C.I.=1.05-1.33) and CTC1 (O.R.=1.14; 95% C.I.=1.02-1.28). Future work is needed to characterize the role of the CST complex in gliomagenesis and further elucidate the complex balance between ageing, telomere length, and molecular carcinogenesis.


Assuntos
Neoplasias Encefálicas/genética , Predisposição Genética para Doença/genética , Glioma/genética , Leucócitos/metabolismo , Telômero/genética , Adulto , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Modelos Estatísticos , Polimorfismo de Nucleotídeo Único , Fatores de Risco
13.
Nat Commun ; 6: 8570, 2015 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-26490707

RESUMO

Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the 'transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.


Assuntos
Envelhecimento/sangue , Transcriptoma , Biomarcadores/sangue , Metilação de DNA , Grupo com Ancestrais do Continente Europeu , Perfilação da Expressão Gênica , Humanos
17.
Twin Res Hum Genet ; 18(2): 198-209, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25744032

RESUMO

Shorter telomere length (TL) has found to be associated with lower birth weight and with lower cognitive ability and psychiatric disorders. However, the direction of causation of these associations and the extent to which they are genetically or environmentally mediated are unclear. Within-pair comparisons of monozygotic (MZ) and dizygotic (DZ) twins can throw light on these questions. We investigated correlations of within pair differences in telomere length, IQ, and anxiety/depression in an initial sample from Brisbane (242 MZ pairs, 245 DZ same sex (DZSS) pairs) and in replication samples from Amsterdam (514 MZ pairs, 233 DZSS pairs) and Melbourne (19 pairs selected for extreme high or low birth weight difference). Intra-pair differences of birth weight and telomere length were significantly correlated in MZ twins, but not in DZSS twins. Greater intra-pair differences of telomere length were observed in the 10% of MZ twins with the greatest difference in birth weight compared to the bottom 90% in both samples and also in the Melbourne sample. Intra-pair differences of telomere length and IQ, but not of TL and anxiety/depression, were correlated in MZ twins, and to a smaller extent in DZSS twins. Our findings suggest that the same prenatal effects that reduce birth weight also influence telomere length in MZ twins. The association between telomere length and IQ is partly driven by the same prenatal effects that decrease birth weight.


Assuntos
Inteligência/genética , Homeostase do Telômero , Gêmeos Monozigóticos/genética , Adolescente , Ansiedade/genética , Criança , Pré-Escolar , Depressão/genética , Feminino , Humanos , Lactente , Recém-Nascido de Baixo Peso , Recém-Nascido , Estudos Longitudinais , Masculino , Gêmeos Dizigóticos/genética
18.
J Med Genet ; 52(3): 157-62, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25624462

RESUMO

BACKGROUND: Leucocyte telomere length (LTL), which is fashioned by multiple genes, has been linked to a host of human diseases, including sporadic melanoma. A number of genes associated with LTL have already been identified through genome-wide association studies. The main aim of this study was to establish whether DCAF4 (DDB1 and CUL4-associated factor 4) is associated with LTL. In addition, using ingenuity pathway analysis (IPA), we examined whether LTL-associated genes in the general population might partially explain the inherently longer LTL in patients with sporadic melanoma, the risk for which is increased with ultraviolet radiation (UVR). RESULTS: Genome-wide association (GWA) meta-analysis and de novo genotyping of 20 022 individuals revealed a novel association (p=6.4×10(-10)) between LTL and rs2535913, which lies within DCAF4. Notably, eQTL analysis showed that rs2535913 is associated with decline in DCAF4 expressions in both lymphoblastoid cells and sun-exposed skin (p=4.1×10(-3) and 2×10(-3), respectively). Moreover, IPA revealed that LTL-associated genes, derived from GWA meta-analysis (N=9190), are over-represented among genes engaged in melanoma pathways. Meeting increasingly stringent p value thresholds (p<0.05, <0.01, <0.005, <0.001) in the LTL-GWA meta-analysis, these genes were jointly over-represented for melanoma at p values ranging from 1.97×10(-169) to 3.42×10(-24). CONCLUSIONS: We uncovered a new locus associated with LTL in the general population. We also provided preliminary findings that suggest a link of LTL through genetic mechanisms with UVR and melanoma in the general population.


Assuntos
Proteínas de Transporte/genética , Leucócitos/citologia , Melanoma/genética , Homeostase do Telômero/genética , Alelos , Proteínas de Transporte/biossíntese , Proteínas de Transporte/sangue , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Melanoma/sangue , Melanoma/patologia , Fatores de Risco , Telômero/genética
19.
Int J Epidemiol ; 44(5): 1673-83, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25239152

RESUMO

BACKGROUND: Telomere length is a putative biomarker of ageing, morbidity and mortality. Its application is hampered by lack of widely applicable reference ranges and uncertainty regarding the present limits of measurement reproducibility within and between laboratories. METHODS: We instigated an international collaborative study of telomere length assessment: 10 different laboratories, employing 3 different techniques [Southern blotting, single telomere length analysis (STELA) and real-time quantitative PCR (qPCR)] performed two rounds of fully blinded measurements on 10 human DNA samples per round to enable unbiased assessment of intra- and inter-batch variation between laboratories and techniques. RESULTS: Absolute results from different laboratories differed widely and could thus not be compared directly, but rankings of relative telomere lengths were highly correlated (correlation coefficients of 0.63-0.99). Intra-technique correlations were similar for Southern blotting and qPCR and were stronger than inter-technique ones. However, inter-laboratory coefficients of variation (CVs) averaged about 10% for Southern blotting and STELA and more than 20% for qPCR. This difference was compensated for by a higher dynamic range for the qPCR method as shown by equal variance after z-scoring. Technical variation per laboratory, measured as median of intra- and inter-batch CVs, ranged from 1.4% to 9.5%, with differences between laboratories only marginally significant (P = 0.06). Gel-based and PCR-based techniques were not different in accuracy. CONCLUSIONS: Intra- and inter-laboratory technical variation severely limits the usefulness of data pooling and excludes sharing of reference ranges between laboratories. We propose to establish a common set of physical telomere length standards to improve comparability of telomere length estimates between laboratories.


Assuntos
Envelhecimento/genética , DNA/genética , Telômero/genética , Biomarcadores , Southern Blotting , Humanos , Cooperação Internacional , Reação em Cadeia da Polimerase em Tempo Real , Reprodutibilidade dos Testes
20.
Eur J Epidemiol ; 29(9): 629-38, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25064619

RESUMO

Oxidative stress and inflammation are major contributors to accelerated age-related relative telomere length (RTL) shortening. Both conditions are strongly linked to leptin and adiponectin, the most prominent adipocyte-derived protein hormones. As high leptin levels and low levels of adiponectin have been implicated in inflammation, one expects adiponectin to be positively associated with RTL while leptin should be negatively associated. Within the ENGAGE consortium, we investigated the association of RTL with adiponectin and leptin in seven independent cohorts with a total of 11,448 participants. We performed partial correlation analysis on Z-transformed RTL and LN-transformed leptin/adiponectin, adjusting for age and sex. In extended models we adjusted for body mass index (BMI) and C-reactive protein (CRP). Adiponectin showed a borderline significant association with RTL. This appeared to be determined by a single study and when the outlier study was removed, this association disappeared. The association between RTL and leptin was highly significant (r = -0.05; p = 1.81 × 10(-7)). Additional adjustment for BMI or CRP did not change the results. Sex-stratified analysis revealed no difference between men and women. Our study suggests that high leptin levels are associated with short RTL.


Assuntos
Adiponectina/genética , Proteína C-Reativa/metabolismo , Leptina/genética , Telômero/genética , Adiponectina/sangue , Adulto , Biomarcadores/sangue , Índice de Massa Corporal , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Inflamação , Leptina/sangue , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA