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1.
PLoS Genet ; 10(3): e1004191, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24625632

RESUMEN

Cross-sectional studies have associated short telomere length with smoking, body weight, physical activity, and possibly alcohol intake; however, whether these associations are due to confounding is unknown. We tested these hypotheses in 4,576 individuals from the general population cross-sectionally, and with repeat measurement of relative telomere length 10 years apart. We also tested whether change in telomere length is associated with mortality and morbidity in the general population. Relative telomere length was measured with quantitative polymerase chain reaction. Cross-sectionally at the first examination, short telomere length was associated with increased age (P for trend across quartiles = 3 × 10(-77)), current smoking (P = 8 × 10(-3)), increased body mass index (P = 7 × 10(-14)), physical inactivity (P = 4 × 10(-17)), but not with increased alcohol intake (P = 0.10). At the second examination 10 years later, 56% of participants had lost and 44% gained telomere length with a mean loss of 193 basepairs. Change in leukocyte telomere length during 10 years was associated inversely with baseline telomere length (P<1 × 10(-300)) and age at baseline (P = 1 × 10(-27)), but not with baseline or 10-year inter-observational tobacco consumption, body weight, physical activity, or alcohol intake. Prospectively during a further 10 years follow-up after the second examination, quartiles of telomere length change did not associate with risk of all-cause mortality, cancer, chronic obstructive pulmonary disease, diabetes mellitus, ischemic cerebrovascular disease, or ischemic heart disease. In conclusion, smoking, increased body weight, and physical inactivity were associated with short telomere length cross-sectionally, but not with telomere length change during 10 years observation, and alcohol intake was associated with neither. Also, change in telomere length did not associate prospectively with mortality or morbidity in the general population.


Asunto(s)
Consumo de Bebidas Alcohólicas/genética , Peso Corporal/genética , Actividad Motora/genética , Fumar/genética , Acortamiento del Telómero/genética , Adulto , Índice de Masa Corporal , Femenino , Genética de Población , Humanos , Leucocitos/citología , Masculino , Persona de Mediana Edad , Factores de Riesgo , Telómero/genética
2.
PLoS Genet ; 10(2): e1004129, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24550738

RESUMEN

The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10(-14)). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.


Asunto(s)
Predisposición Genética a la Enfermedad , Variación Genética , Proteínas de Homeodominio/genética , Neoplasias de la Próstata/genética , Alelos , Cromosomas Humanos Par 17/genética , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Neoplasias de la Próstata/patología , Factores de Riesgo
3.
Hum Mol Genet ; 22(24): 5056-64, 2013 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-23900074

RESUMEN

Mean telomere length (TL) in blood cells is heritable and has been reported to be associated with risks of several diseases, including cancer. We conducted a meta-analysis of three GWAS for TL (total n=2240) and selected 1629 variants for replication via the "iCOGS" custom genotyping array. All ∼200 000 iCOGS variants were analysed with TL, and those displaying associations in healthy controls (n = 15 065) were further tested in breast cancer cases (n = 11 024). We found a novel TL association (Ptrend < 4 × 10(-10)) at 3p14.4 close to PXK and evidence (Ptrend < 7 × 10(-7)) for TL loci at 6p22.1 (ZNF311) and 20q11.2 (BCL2L1). We additionally confirmed (Ptrend < 5 × 10(-14)) the previously reported loci at 3q26.2 (TERC), 5p15.3 (TERT) and 10q24.3 (OBFC1) and found supportive evidence (Ptrend < 5 × 10(-4)) for the published loci at 2p16.2 (ACYP2), 4q32.2 (NAF1) and 20q13.3 (RTEL1). SNPs tagging these loci explain TL differences of up to 731 bp (corresponding to 18% of total TL in healthy individuals), however, they display little direct evidence for association with breast, ovarian or prostate cancer risks.


Asunto(s)
Sitios Genéticos , Estudio de Asociación del Genoma Completo , Neoplasias/genética , Homeostasis del Telómero/genética , Telómero/genética , Estudios de Casos y Controles , Mapeo Cromosómico , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Neoplasias/metabolismo , Polimorfismo de Nucleótido Simple , Riesgo , Telómero/metabolismo
4.
Hum Mol Genet ; 22(12): 2520-8, 2013 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-23535824

RESUMEN

Associations between single nucleotide polymorphisms (SNPs) at 5p15 and multiple cancer types have been reported. We have previously shown evidence for a strong association between prostate cancer (PrCa) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (TERT) gene that encodes TERT. To comprehensively evaluate the association between genetic variation across this region and PrCa, we performed a fine-mapping analysis by genotyping 134 SNPs using a custom Illumina iSelect array or Sequenom MassArray iPlex, followed by imputation of 1094 SNPs in 22 301 PrCa cases and 22 320 controls in The PRACTICAL consortium. Multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of TERT that independently associated with PrCa risk. Gene expression analysis of normal prostate tissue showed evidence that SNPs within one of these regions also associated with TERT expression, providing a potential mechanism for predisposition to disease.


Asunto(s)
Cromosomas Humanos Par 5/genética , Predisposición Genética a la Enfermedad , Neoplasias de la Próstata/enzimología , Neoplasias de la Próstata/genética , Telomerasa/genética , Adulto , Estudios de Casos y Controles , Mapeo Cromosómico , Genotipo , Humanos , Desequilibrio de Ligamiento , Masculino , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Telomerasa/metabolismo
5.
Hum Mol Genet ; 22(2): 408-15, 2013 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-23065704

RESUMEN

Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one-third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four GWAS including 5953 cases of aggressive PrCa and 11 463 controls (men without PrCa). We computed association tests for approximately 2.6 million SNPs and followed up the most significant SNPs by genotyping 49 121 samples in 29 studies through the international PRACTICAL and BPC3 consortia. We not only confirmed the association of a PrCa susceptibility locus, rs11672691 on chromosome 19, but also showed an association with aggressive PrCa [odds ratio = 1.12 (95% confidence interval 1.03-1.21), P = 1.4 × 10(-8)]. This report describes a genetic variant which is associated with aggressive PrCa, which is a type of PrCa associated with a poorer prognosis.


Asunto(s)
Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Neoplasias de la Próstata/genética , Sitios de Carácter Cuantitativo , Estudios de Casos y Controles , Progresión de la Enfermedad , Humanos , Masculino , Oportunidad Relativa , Polimorfismo de Nucleótido Simple , Reproducibilidad de los Resultados
6.
Thorax ; 68(5): 429-35, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23268483

RESUMEN

BACKGROUND: A previous case-control study of 100 individuals found that short telomere length was associated with a 28-fold increased risk of chronic obstructive pulmonary disease (COPD). OBJECTIVES: To test the hypothesis that short telomere length is associated with reduced lung function and an increased risk of COPD. METHODS: Observational study of 46 396 individuals from the Danish general population. MEASUREMENTS: Leucocyte telomere length and spirometry were measured. COPD was defined using either fixed forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio <0.70 as suggested by the Global initiative for chronic Obstructive Lung Disease (GOLD) or FEV1/FVC below the lower limit of normal (LLN). RESULTS: Telomere length decreased significantly with increasing age (p<10(-300)). FEV1, FVC and FEV1/FVC decreased with decreasing telomere length quartiles (p trend: 5 × 10(-51), 5 × 10(-35) and 6 × 10(-137), respectively), but the associations attenuated after age and multivariable adjustment. The risk of COPD increased with decreasing telomere length quartile (p trend: p=7 × 10(-92) for GOLD; p=8 × 10(-44) for FEV1/FVC below LLN), but associations also attenuated after adjustment. Unadjusted and multivariable adjusted OR for shortest versus longest telomere length quartiles were 2.06 (95% CI 1.91 to 2.22) and 1.15 (95% CI 1.06 to 1.25) for GOLD and 1.73 (95% CI 1.60 to 1.88) and 1.19 (95% CI 1.09 to 1.30) for FEV1/FVC below LLN, respectively. Per 1000 base pairs decrease in telomere length, the multivariable adjusted OR was 1.07 (95% CI 1.03 to 1.10) for GOLD and 1.07 (95% CI 1.03 to 1.11) for FEV1/FVC below LLN. CONCLUSIONS: Short telomere length is associated with decreased lung function and with increased risk of COPD, but the associations are markedly attenuated after adjustment. Our data support a modest correlation between telomere length and the lung function indices examined.


Asunto(s)
ADN/análisis , Volumen Espiratorio Forzado/genética , Enfermedad Pulmonar Obstructiva Crónica/genética , Telómero , Capacidad Vital/genética , Adulto , Anciano , Dinamarca/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Prevalencia , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Estudios Retrospectivos
7.
Arterioscler Thromb Vasc Biol ; 32(3): 822-9, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22199369

RESUMEN

OBJECTIVE: We tested the hypothesis that short telomere length is associated with increased risk of myocardial infarction, ischemic heart disease, and early death. METHODS AND RESULTS: We measured leukocyte telomere length in 2 prospective studies of 19 838 Danish general population participants from the Copenhagen City Heart Study and the Copenhagen General Population Study. Participants were followed for up to 19 years for incident myocardial infarction (n=929), ischemic heart disease (n=2038), and death (n=4342). Follow-up was 100% complete. Telomere length decreased linearly with increasing age in women and men in both studies (P=7×10(-74) to P=3×10(-125)). Multifactorially adjusted hazard ratios were 1.10 (95% CI 1.01-1.19) for myocardial infarction, 1.06 (1.00-1.11) for ischemic heart disease, and 1.09 (1.05-1.13) for early death per 1000-base pair decrease in telomere length. The multifactorially adjusted hazard ratios for the shortest versus the longest decile of telomere length were 1.49 (1.07-2.07) for myocardial infarction, 1.24 (1.01-1.53) for ischemic heart disease, and 1.25 (1.07-1.46) for early death. CONCLUSION: Short telomere length is associated with only modestly increased risk of myocardial infarction, ischemic heart disease, and early death.


Asunto(s)
Infarto del Miocardio/genética , Infarto del Miocardio/mortalidad , Isquemia Miocárdica/genética , Isquemia Miocárdica/mortalidad , Acortamiento del Telómero , Adulto , Factores de Edad , Anciano , Envejecimiento/genética , Dinamarca/epidemiología , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Reacción en Cadena en Tiempo Real de la Polimerasa , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo
8.
Nat Genet ; 53(1): 65-75, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33398198

RESUMEN

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.


Asunto(s)
Sitios Genéticos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Neoplasias de la Próstata/genética , Grupos Raciales/genética , Humanos , Masculino , Persona de Mediana Edad , Anotación de Secuencia Molecular , Invasividad Neoplásica , Oportunidad Relativa , Neoplasias de la Próstata/diagnóstico , Factores de Riesgo
9.
Clin Chem ; 55(11): 1950-7, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19713276

RESUMEN

BACKGROUND: Arg702Trp, Gly908Arg, and Leu1007fsinsC variants of the NOD2 gene (nucleotide-binding oligomerization domain containing 2; alias, CARD15) influence the risk of Crohn disease. METHODS: We conducted a systematic review to examine whether Arg702Trp, Gly908Arg, and Leu1007fsinsC are equally important risk factors for Crohn disease. In addition, we used studies for which combined information from all genotypes was available to compare risks in simple heterozygotes, compound heterozygotes, and homozygotes. PubMed, EMBASE, and Web of Science were searched. Seventy-five articles (18 727 cases and 17 102 controls) met the inclusion criteria and contributed data to the metaanalyses. RESULTS: The odds ratios per allele for Crohn disease were 2.2 (95% CI, 2.0-2.5) for Arg702Trp, 2.6 (2.2-2.9) for Gly908Arg, and 3.8 (3.4-4.3) for Leu1007fsinsC (z-test results: Arg702Trp vs Gly908Arg, P = 0.03; Arg702Trp vs Leu1007fsinsC, P < 0.001; Gly908Arg vs Leu1007fsinsC, P < 0.001). When all 3 genotypes were combined, odds ratios for Crohn disease were 2.4 (95% CI, 2.0-2.8) for simple heterozygotes, 9.0 (6.0-13.5) for compound heterozygotes, and 6.7 (4.1-10.9) for homozygotes, compared with noncarriers (z-test results: simple heterozygotes vs compound heterozygotes, P < 0.001; simple heterozygotes vs homozygotes, P < 0.001; compound heterozygotes vs homozygotes, P = 0.18). CONCLUSIONS: The per-allele risk of Crohn disease was markedly higher for Leu1007fsinsC than for Arg702Trp and Gly908Arg. Combining all genotypes revealed the risks of Crohn disease for compound heterozygotes and homozygotes to be similar and markedly higher than for simple heterozygotes.


Asunto(s)
Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/genética , Proteína Adaptadora de Señalización NOD2/genética , Alelos , Predisposición Genética a la Enfermedad , Variación Genética , Genotipo , Humanos
10.
BMJ ; 360: j5757, 2018 01 10.
Artículo en Inglés | MEDLINE | ID: mdl-29321194

RESUMEN

OBJECTIVES: To develop and validate a genetic tool to predict age of onset of aggressive prostate cancer (PCa) and to guide decisions of who to screen and at what age. DESIGN: Analysis of genotype, PCa status, and age to select single nucleotide polymorphisms (SNPs) associated with diagnosis. These polymorphisms were incorporated into a survival analysis to estimate their effects on age at diagnosis of aggressive PCa (that is, not eligible for surveillance according to National Comprehensive Cancer Network guidelines; any of Gleason score ≥7, stage T3-T4, PSA (prostate specific antigen) concentration ≥10 ng/L, nodal metastasis, distant metastasis). The resulting polygenic hazard score is an assessment of individual genetic risk. The final model was applied to an independent dataset containing genotype and PSA screening data. The hazard score was calculated for these men to test prediction of survival free from PCa. SETTING: Multiple institutions that were members of international PRACTICAL consortium. PARTICIPANTS: All consortium participants of European ancestry with known age, PCa status, and quality assured custom (iCOGS) array genotype data. The development dataset comprised 31 747 men; the validation dataset comprised 6411 men. MAIN OUTCOME MEASURES: Prediction with hazard score of age of onset of aggressive cancer in validation set. RESULTS: In the independent validation set, the hazard score calculated from 54 single nucleotide polymorphisms was a highly significant predictor of age at diagnosis of aggressive cancer (z=11.2, P<10-16). When men in the validation set with high scores (>98th centile) were compared with those with average scores (30th-70th centile), the hazard ratio for aggressive cancer was 2.9 (95% confidence interval 2.4 to 3.4). Inclusion of family history in a combined model did not improve prediction of onset of aggressive PCa (P=0.59), and polygenic hazard score performance remained high when family history was accounted for. Additionally, the positive predictive value of PSA screening for aggressive PCa was increased with increasing polygenic hazard score. CONCLUSIONS: Polygenic hazard scores can be used for personalised genetic risk estimates that can predict for age at onset of aggressive PCa.


Asunto(s)
Detección Precoz del Cáncer/métodos , Calicreínas/análisis , Polimorfismo de Nucleótido Simple/genética , Antígeno Prostático Específico/análisis , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/genética , Edad de Inicio , Anciano , Estudios de Cohortes , Supervivencia sin Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Valor Predictivo de las Pruebas , Neoplasias de la Próstata/diagnóstico , Medición de Riesgo , Análisis de Supervivencia , Población Blanca/genética
12.
Cancer Epidemiol Biomarkers Prev ; 24(7): 1121-9, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25837820

RESUMEN

BACKGROUND: Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of prostate cancer. METHODS: We genotyped 25 prostate cancer susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS). We estimated empirical odds ratios (OR) for prostate cancer associated with different risk strata defined by PRS and derived age-specific absolute risks of developing prostate cancer by PRS stratum and family history. RESULTS: The prostate cancer risk for men in the top 1% of the PRS distribution was 30.6 (95% CI, 16.4-57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI, 3.2-5.5) fold compared with the median risk. The absolute risk of prostate cancer by age of 85 years was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation = 0.09). CONCLUSIONS: Risk profiling can identify men at substantially increased or reduced risk of prostate cancer. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of prostate cancer. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles. IMPACT: We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs.


Asunto(s)
Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Neoplasias de la Próstata/genética , Medición de Riesgo , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Variación Genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Factores de Riesgo
13.
Prostate Cancer ; 2014: 294575, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25431674

RESUMEN

Although the causes of prostate cancer are largely unknown, previous studies support the role of genetic factors in the development of prostate cancer. CHEK2 plays a critical role in DNA replication by responding to double-stranded breaks. In this review, we provide an overview of the current knowledge of the role of a genetic variant, 1100delC, of CHEK2 on prostate cancer risk and discuss the implication for potential translation of this knowledge into clinical practice. Currently, twelve articles that discussed CHEK2 (∗)1100delC and its association with prostate cancer were identified. Of the twelve prostate cancer studies, five studies had independent data to draw conclusive evidence from. The pooled results of OR and 95% CI were 1.98 (1.23-3.18) for unselected cases and 3.39 (1.78-6.47) for familial cases, indicating that CHEK2 (∗)1100delC mutation is associated with increased risk of prostate cancer. Screening for CHEK2(∗)1100delC should be considered in men with a familial history of prostate cancer.

14.
J Clin Endocrinol Metab ; 99(9): E1671-5, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24762112

RESUMEN

CONTEXT: Obesity is associated with short telomere length. The cause of this association is unknown. OBJECTIVE: We hypothesized that genetically increased body mass index (BMI) is associated with telomere length shortening and that low-grade inflammation might contribute through elevated C-reactive protein. SETTING AND DESIGN: We studied 45,069 individuals from the Copenhagen General Population Study with measurements of leukocyte telomere length, BMI, and C-reactive protein in a Mendelian randomization study. Using the three obesity-associated polymorphisms FTO rs9939609, MC4R rs17782313, and TMEM18 rs6548238, and the CRP promoter polymorphism rs3091244 in instrumental variable analyses, we estimated the associations between genetically increased BMI and telomere length and between genetically increased C-reactive protein and telomere length. RESULTS: In multivariable-adjusted observational analyses, telomere length decreased with seven base pairs (95% confidence interval, -9--5) per unit increase in BMI, and further adjustment for C-reactive protein attenuated this association to -5 base pairs (-8--3). In accordance, instrumental variable analysis showed a non-significant telomere length shortening of six base pairs (-37-25) per unit increase in genetically determined BMI. Furthermore, in observational analyses, telomere length decreased with nine base pairs (-16--2) for a doubling in C-reactive protein, supported by the instrumental variable analyses showing a corresponding genetically determined decrease of 66 base pairs (-124--7). CONCLUSIONS: High BMI is associated with short telomere length observationally. This might possibly be mediated through elevated C-reactive protein, given that genetically elevated C-reactive protein levels are associated with short telomere length.


Asunto(s)
Índice de Masa Corporal , Proteína C-Reactiva/metabolismo , Inflamación/metabolismo , Obesidad/metabolismo , Telómero/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Inflamación/genética , Inflamación/inmunología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Obesidad/genética , Obesidad/inmunología , Polimorfismo Genético , Telómero/genética , Telómero/inmunología , Adulto Joven
15.
Int J Epidemiol ; 43(5): 1473-83, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24906368

RESUMEN

BACKGROUND: High cumulative tobacco consumption is associated with short telomeres and with increased all-cause mortality. We tested the hypothesis that high tobacco consumption is causally associated with short telomeres and with increased all-cause mortality. METHODS: We studied 55,568 individuals including 32,823 ever smokers from the Danish general population, of whom 3430 died during 10 years of follow-up. All had telomere length measured, detailed information on smoking history, and CHRNA3 rs1051730 genotype, which is associated with tobacco consumption, determined. In a Mendelian randomization study, we conducted observational, genetic, and mediation analyses. RESULTS: First, tobacco consumption was 21.1 pack-years in non-carriers, 22.8 in heterozygotes and 24.8 in homozygotes (P-trend<0.001). Second, the observational multivariable adjusted hazard ratio for all-cause mortality was 1.12 [95% confidence interval (CI): 1.09, 1.15] per doubling in tobacco consumption. In Mendelian randomization analysis, the hazard ratio was 1.08 (1.02, 1.14) per minor CHRNA3 allele in ever smokers. Third, in observational analysis telomeres shortened with -13 base pairs (-18, -8) per doubling in tobacco consumption. In Mendelian randomization analysis, the estimate was +3 base pairs (-10, +15) per minor CHRNA3 allele. Finally, individuals with the shortest vs longest telomeres had a multivariable adjusted hazard ratio of 1.30 (1.13, 1.50) for all-cause mortality; however, in mediation analysis short telomeres explained only +0.4% (-3.5%, +4.3%) of the association between high tobacco consumption and increased all-cause mortality. CONCLUSIONS: High tobacco consumption is causally associated with increased all-cause mortality. High cumulative tobacco consumption is associated with short telomeres observationally, but there is no clear genetic association.


Asunto(s)
Análisis de la Aleatorización Mendeliana , Mortalidad , Fumar/genética , Telómero/genética , Tabaquismo/genética , Dinamarca/epidemiología , Femenino , Estudios de Seguimiento , Genotipo , Humanos , Incidencia , Masculino , Análisis Multivariante , Polimorfismo Genético , Factores de Riesgo , Fumar/mortalidad , Tabaquismo/mortalidad
16.
J Natl Cancer Inst ; 105(7): 459-68, 2013 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-23468462

RESUMEN

BACKGROUND: Recent meta-analyses have suggested that short telomere length was associated with increased risk of cancer. We therefore tested the hypotheses that short telomere length was associated with increased risk of cancer and with increased risk of early death after cancer. METHODS: We measured leukocyte telomere length in a prospective study of 47 102 Danish general population participants from the Copenhagen City Heart Study and the Copenhagen General Population Study. Participants were followed for up to 20 years for cancer diagnosis and death. Follow-up was 100% complete. All statistical tests were two-sided. RESULTS: Telomere length decreased linearly with increasing age (P <.001). During follow-up, we observed 3142 first cancers and, among these individuals, 1730 deaths. Decreasing quartiles of telomere length were associated with decreasing survival after cancer (log-rank P <.001). Multivariable-adjusted hazard ratios of early death were 1.31 (95% confidence interval [CI] = 1.14 to 1.52) in individuals in the quartile and 1.43 (95% CI = 1.13 to 1.80) in individuals in the decile with the shortest telomeres vs the longest. Unadjusted hazard ratios of cancer risk were 1.74 (95% CI = 1.58 to 1.93) and 2.00 (95% CI = 1.70 to 2.35) in individuals in the quartile and decile with the shortest vs longest telomeres; however, multivariable adjustment changed these hazard ratios to 0.98 (95% CI = 0.88 to 1.08) and 0.95 (95% CI = 0.80 to 1.11), mainly because of age adjustment. CONCLUSIONS: Short telomere length is associated with reduced survival after cancer but not with cancer risk. The latter contrasts with findings from recent meta-analyses.


Asunto(s)
Leucocitos/patología , Neoplasias/epidemiología , Neoplasias/genética , Telómero/patología , Factores de Edad , Anciano , Dinamarca/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Modelos Lineales , Masculino , Persona de Mediana Edad , Análisis Multivariante , Neoplasias/mortalidad , Neoplasias/patología , Oportunidad Relativa , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , Análisis de Supervivencia , Tasa de Supervivencia , Acortamiento del Telómero
17.
Nat Genet ; 45(4): 371-84, 384e1-2, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23535731

RESUMEN

TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ∼480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10(-8)) and BRCA1 mutation carrier (P = 1.1 × 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10(-12)) and BRCA1 mutation carrier (P = 1.6 × 10(-14)) breast and invasive ovarian (P = 1.3 × 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.


Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias de la Mama/etiología , Sitios Genéticos/genética , Neoplasias Ováricas/etiología , Polimorfismo de Nucleótido Simple/genética , Telomerasa/genética , Telómero/genética , Empalme Alternativo , Neoplasias de la Mama/patología , Estudios de Casos y Controles , Cromatina/genética , Metilación de ADN , Femenino , Perfilación de la Expresión Génica , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Luciferasas/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Neoplasias Ováricas/patología , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Riesgo
18.
Nat Genet ; 45(4): 385-91, 391e1-2, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23535732

RESUMEN

Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (P < 5 × 10(-8)). More than 70 prostate cancer susceptibility loci, explaining ∼30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies.


Asunto(s)
Sitios Genéticos/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple/genética , Neoplasias de la Próstata/etiología , Estudios de Casos y Controles , Conducta Cooperativa , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Metaanálisis como Asunto , Análisis de Secuencia por Matrices de Oligonucleótidos , Neoplasias de la Próstata/patología , Factores de Riesgo
19.
J Invest Dermatol ; 132(2): 299-303, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21956126

RESUMEN

It is possible that reduced function of DNA repair and cell-cycle control genes increases the individual susceptibility to malignant melanoma. As CHEK2 is a cell-cycle master controller, we tested the hypothesis that heterozygosity for the frameshift alteration CHEK2*1100delC is associated with increased risk of malignant melanoma. First, we performed case-control studies of 1,152 Danish and 752 German individuals with malignant melanoma compared with 9,142 Danish and 3,718 German controls. Second, we performed a meta-analysis of CHEK2*1100delC and malignant melanoma, involving 2,619 cases and 17,481 controls. Third, we examined the risk of malignant melanoma associated with CHEK2*1100delC heterozygosity in an analysis stratified for sun exposure, as well as for subtype and location on the body. The odds ratios for malignant melanoma for CHEK2(*)1100del heterozygotes compared with those for noncarriers were 2.01 (95% confidence interval (CI), 1.03-3.91) in Danes, 1.42 (95% CI, 0.46-4.31) in Germans, and 1.79 (95% CI, 1.02-3.17) in Danes and Germans combined. In a meta-analysis, the odds ratio of malignant melanoma for CHEK2*1100delC heterozygotes compared with that for noncarriers was 1.81 (95% CI, 1.07-3.05). Stratifications did not alter these results. CHEK2*1100delC heterozygotes have a twofold risk of malignant melanoma compared with noncarriers.


Asunto(s)
Melanoma/genética , Proteínas Serina-Treonina Quinasas/genética , Neoplasias Cutáneas/genética , Adulto , Anciano , Estudios de Casos y Controles , Quinasa de Punto de Control 2 , Dinamarca , Femenino , Alemania , Heterocigoto , Humanos , Masculino , Melanoma/etiología , Persona de Mediana Edad , Receptor de Melanocortina Tipo 1/genética , Factores de Riesgo , Neoplasias Cutáneas/etiología
20.
J Clin Oncol ; 30(35): 4308-16, 2012 Dec 10.
Artículo en Inglés | MEDLINE | ID: mdl-23109706

RESUMEN

PURPOSE: We tested the hypotheses that CHEK2*1100delC heterozygosity is associated with increased risk of early death, breast cancer-specific death, and risk of a second breast cancer in women with a first breast cancer. PATIENTS AND METHODS: From 22 studies participating in the Breast Cancer Association Consortium, 25,571 white women with invasive breast cancer were genotyped for CHEK2*1100delC and observed for up to 20 years (median, 6.6 years). We examined risk of early death and breast cancer-specific death by estrogen receptor status and risk of a second breast cancer after a first breast cancer in prospective studies. RESULTS: CHEK2*1100delC heterozygosity was found in 459 patients (1.8%). In women with estrogen receptor-positive breast cancer, multifactorially adjusted hazard ratios for heterozygotes versus noncarriers were 1.43 (95% CI, 1.12 to 1.82; log-rank P = .004) for early death and 1.63 (95% CI, 1.24 to 2.15; log-rank P < .001) for breast cancer-specific death. In all women, hazard ratio for a second breast cancer was 2.77 (95% CI, 2.00 to 3.83; log-rank P < .001) increasing to 3.52 (95% CI, 2.35 to 5.27; log-rank P < .001) in women with estrogen receptor-positive first breast cancer only. CONCLUSION: Among women with estrogen receptor-positive breast cancer, CHEK2*1100delC heterozygosity was associated with a 1.4-fold risk of early death, a 1.6-fold risk of breast cancer-specific death, and a 3.5-fold risk of a second breast cancer. This is one of the few examples of a genetic factor that influences long-term prognosis being documented in an extensive series of women with breast cancer.


Asunto(s)
Neoplasias de la Mama/enzimología , Neoplasias de la Mama/genética , Mutación de Línea Germinal , Neoplasias Primarias Secundarias/enzimología , Neoplasias Primarias Secundarias/genética , Proteínas Serina-Treonina Quinasas/genética , Estudios de Casos y Controles , Quinasa de Punto de Control 2 , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Heterocigoto , Humanos , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos
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