RESUMO
BACKGROUND: American men of African ancestry (AA) have higher prostate cancer incidence and mortality rates compared with American men of European ancestry (EA). Differences in genetic susceptibility mechanisms may contribute to this disparity. METHODS: To gain insights into the regulatory mechanisms of prostate cancer susceptibility variants, we tested the association between SNPs and DNA methylation (DNAm) at nearby CpG sites across the genome in benign and cancer prostate tissue from 74 AA and 74 EA men. Genome-wide SNP data (from benign tissue) and DNAm were generated using Illumina arrays. RESULTS: Among AA men, we identified 6,298 and 2,641 cis-methylation QTLs (meQTL; FDR of 0.05) in benign and tumor tissue, respectively, with 6,960 and 1,700 detected in EA men. We leveraged genome-wide association study (GWAS) summary statistics to identify previously reported prostate cancer GWAS signals likely to share a common causal variant with a detected meQTL. We identified nine GWAS-meQTL pairs with strong evidence of colocalization (four in EA benign, three in EA tumor, two in AA benign, and three in AA tumor). Among these colocalized GWAS-meQTL pairs, we identified colocalizing expression quantitative trait loci (eQTL) impacting four eGenes with known roles in tumorigenesis. CONCLUSIONS: These findings highlight epigenetic regulatory mechanisms by which prostate cancer-risk SNPs can modify local DNAm and/or gene expression in prostate tissue. IMPACT: Overall, our findings showed general consistency in the meQTL landscape of AA and EA men, but meQTLs often differ by tissue type (normal vs. cancer). Ancestry-based linkage disequilibrium differences and lack of AA representation in GWAS decrease statistical power to detect colocalization for some regions.
Assuntos
Metilação de DNA , Neoplasias da Próstata , Masculino , Humanos , Negro ou Afro-Americano/genética , Estudo de Associação Genômica Ampla , Neoplasias da Próstata/epidemiologia , Variação Genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Inorganic arsenic is highly toxic and carcinogenic to humans. Exposed individuals vary in their ability to metabolize arsenic, and variability in arsenic metabolism efficiency (AME) is associated with risks of arsenic-related toxicities. Inherited genetic variation in the 10q24.32 region, near the arsenic methyltransferase (AS3MT) gene, is associated with urine-based measures of AME in multiple arsenic-exposed populations. To identify potential causal variants in this region, we applied fine mapping approaches to targeted sequencing data generated for exposed individuals from Bangladeshi, American Indian, and European American populations (n = 2,357, 557, and 648 respectively). We identified three independent association signals for Bangladeshis, two for American Indians, and one for European Americans. The size of the confidence sets for each signal varied from 4 to 85 variants. There was one signal shared across all three populations, represented by the same SNP in American Indians and European Americans (rs191177668) and in strong linkage disequilibrium (LD) with a lead SNP in Bangladesh (rs145537350). Beyond this shared signal, differences in LD patterns, minor allele frequency (MAF) (e.g., rs12573221 ~13% in Bangladesh ~0.2% among American Indians), and/or heterogeneity in effect sizes across populations likely contributed to the apparent population specificity of the additional identified signals. One of our potential causal variants influences AS3MT expression and nearby DNA methylation in numerous GTEx tissue types (with rs4919690 as a likely causal variant). Several SNPs in our confidence sets overlap transcription factor binding sites and cis-regulatory elements (from ENCODE). Taken together, our analyses reveal multiple potential causal variants in the 10q24.32 region influencing AME, including a variant shared across populations, and elucidate potential biological mechanisms underlying the impact of genetic variation on AME.
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Intoxicação por Arsênico , Arsênio , Arsenicais , Humanos , Arsênio/toxicidade , Arsênio/metabolismo , Intoxicação por Arsênico/genética , Arsenicais/metabolismo , Metilação de DNA , Metiltransferases/genética , Metiltransferases/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Cromossomos Humanos Par 10RESUMO
BACKGROUND: Arsenic exposure increases the risk of several cancers in humans and contributes to genomic instability. Somatic loss of the Y chromosome (LoY) is a potential biomarker of genomic instability and cancer risk. Smoking is associated with LoY, but few other carcinogens have been investigated. We tested the cross-sectional association between arsenic exposure and LoY in leukocytes among genotyped Bangladeshi men (age 20-70 years) from the Health Effects of Arsenic Longitudinal Study. METHODS: We extracted the median of logR-ratios from probes on the Y chromosome (mLRR-chrY) from genotyping arrays (n = 1364) and estimated the percentage of cells with LoY (% LoY) from mLRR-chrY. We evaluated the association between arsenic exposure (measured in drinking water and urine) and LoY using multivariable linear and logistic regression models. The association between LoY and incident arsenic-induced skin lesions was also examined. RESULTS: Ten percent of genotyped men had LoY in at least 5% of cells and % LoY increased with age. Among men randomly selected for genotyping (n = 778), higher arsenic in drinking water, arsenic consumed and urinary arsenic were associated with increased % LoY (P = 0.006, P = 0.06 and P = 0.13, respectively). LoY was associated with increased risk of incident skin lesions (P = 0.008). CONCLUSION: Arsenic exposure was associated with increased LoY, providing additional evidence that arsenic contributes to genomic instability. LoY was associated with developing skin lesions, a risk factor for cancer, suggesting that LoY may be a biomarker of susceptibility in arsenic-exposed populations. The effect of arsenic on somatic events should be further explored in cancer-prone tissue types.
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Arsênio , Água Potável , Neoplasias , Masculino , Humanos , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Estudos Longitudinais , Arsênio/toxicidade , Estudos Transversais , Cromossomos Humanos Y/genética , Neoplasias/genética , Fatores de Risco , Instabilidade GenômicaRESUMO
BACKGROUND: Common genetic variation in the arsenic methyltransferase (AS3MT) gene region is known to be associated with arsenic metabolism efficiency (AME), measured as the percentage of dimethylarsinic acid (DMA%) in the urine. Rare, protein-altering variants in AS3MT could have even larger effects on AME, but their contribution to AME has not been investigated. OBJECTIVES: We estimated the impact of rare, protein-coding variation in AS3MT on AME using a multi-population approach to facilitate the discovery of population-specific and shared causal rare variants. METHODS: We generated targeted DNA sequencing data for the coding regions of AS3MT for three arsenic-exposed cohorts with existing data on arsenic species measured in urine: Health Effects of Arsenic Longitudinal Study (HEALS, n=2,434), Strong Heart Study (SHS, n=868), and New Hampshire Skin Cancer Study (NHSCS, n=666). We assessed the collective effects of rare (allele frequency <1%), protein-altering AS3MT variants on DMA%, using multiple approaches, including a test of the association between rare allele carrier status (yes/no) and DMA% using linear regression (adjusted for common variants in 10q24.32 region, age, sex, and population structure). RESULTS: We identified 23 carriers of rare-protein-altering AS3MT variant across all cohorts (13 in HEALS and 5 in both SHS and NHSCS), including 6 carriers of predicted loss-of-function variants. DMA% was 6-10% lower in carriers compared with noncarriers in HEALS [ß=-9.4 (95% CI: -13.9, -4.8)], SHS [ß=-6.9 (95% CI: -13.6, -0.2)], and NHSCS [ß=-8.7 (95% CI: -15.6, -2.2)]. In meta-analyses across cohorts, DMA% was 8.7% lower in carriers [ß=-8.7 (95% CI: -11.9, -5.4)]. DISCUSSION: Rare, protein-altering variants in AS3MT were associated with lower mean DMA%, an indicator of reduced AME. Although a small percentage of the population (0.5-0.7%) carry these variants, they are associated with a 6-10% decrease in DMA% that is consistent across multiple ancestral and environmental backgrounds. https://doi.org/10.1289/EHP8152.
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Arsênio , Ácido Cacodílico , Estudos Longitudinais , Metiltransferases/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Introducción: La estrecha relación que existe entre diabetes mellitus tipo 2 y obesidad ha dado lugar a la creación del término "diabesidad", considerándose la nueva enfermedad del siglo XXI. La dupla entre estas produce grave lesión en el tejido hepático, músculo esquelético y sistema cardiovascular. Es importante un estilo de vida saludable y buena adherencia farmacológica para combatir esta pandemia. Objetivo: Describir aspectos generales acerca de la fisiopatología y el tratamiento de la diabesidad. Método: Se realizó una búsqueda bibliográfica no sistemática en las bases de datos Science Direct, EMBASE, LILACS, Redalyc, SciELO y PubMed. Los criterios de inclusión fueron publicaciones en inglés y español, en las que el título, palabras clave o resumen incluyen información pertinente al objetivo de estudio, periodicidad no mayor de cinco años. En la búsqueda se obtuvieron 50 artículos, de los cuales fueron seleccionados 35. Conclusión: La insulinorresistencia es el factor determinante para la progresión hacia diabetes mellitus tipo 2, en calidad de respuesta del tejido adiposo frente a altos niveles de ácidos grasos libres (lipotoxicidad), consecuencia de la obesidad, obligando al páncreas a secretar grandes cantidades de insulina, que con el tiempo compromete su funcionalidad. En la actualidad, existen diversas alternativas no farmacológicas, farmacológicas y quirúrgicas para el abordaje de la diabesidad, donde la prevención representa un aspecto de vital importancia(AU)
Introduction: The close relation among diabetes mellitus type 2 and obesity has led to the creation of the term "diabesity," considering it the new disease of XXI century. The fusion of these two diseases produces severe lesions in the hepatic tissue, the skeletal muscle and the cardiovascular system. It is important a healthy lifestyle and a good pharmacological adherence to fight this so called pandemic. Objective: Describe general aspects related to the physiopathology and treatment of diabesity. Method: It was carried out a non-systematic bibliographic search in databases like Science Direct, EMBASE, LILACS, Redalyc, SciELO and PubMed. The inclusion criteria were publications in English and Spanish language, with a periodicity of no more than 5 years, in which the title, keywords and abstract included information that will be relevant for the objective of the study. In the search 50 articles were found, of which 35 were selected. Conclusions: Insulin resistance is the key factor for the progression towards diabetes mellitus type 2, as a response of the adipose tissue to high levels of free fatty acids (lipotoxicity), which is a consequence of obesity, and obligates the pancreas to secrete big amounts of insulin that as time goes by compromises its functionality. Nowadays, there are different non-pharmacological, pharmacological and surgical alternatives to address the diabesity, in which prevention represents an aspect of vital importance(AU)
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Humanos , Resistência à Insulina , Diabetes Mellitus Tipo 2/fisiopatologia , Estilo de Vida Saudável , Obesidade/fisiopatologia , Literatura de Revisão como Assunto , Bases de Dados Bibliográficas , Diabetes Mellitus Tipo 2/terapia , Obesidade/terapiaRESUMO
Telomere shortening is a hallmark of aging. Telomere length (TL) in blood cells has been studied extensively as a biomarker of human aging and disease; however, little is known regarding variability in TL in nonblood, disease-relevant tissue types. Here, we characterize variability in TLs from 6391 tissue samples, representing >20 tissue types and 952 individuals from the Genotype-Tissue Expression (GTEx) project. We describe differences across tissue types, positive correlation among tissue types, and associations with age and ancestry. We show that genetic variation affects TL in multiple tissue types and that TL may mediate the effect of age on gene expression. Our results provide the foundational knowledge regarding TL in healthy tissues that is needed to interpret epidemiological studies of TL and human health.
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Envelhecimento/genética , Homeostase do Telômero/genética , Encurtamento do Telômero/genética , Telômero/fisiologia , Marcadores Genéticos , Variação Genética , Humanos , Especificidade de ÓrgãosRESUMO
Leukocyte telomere length (LTL) is a heritable trait with two potential sources of heritability (h2): inherited variation in non-telomeric regions (e.g., SNPs that influence telomere maintenance) and variability in the lengths of telomeres in gametes that produce offspring zygotes (i.e., "direct" inheritance). Prior studies of LTL h2 have not attempted to disentangle these two sources. Here, we use a novel approach for detecting the direct inheritance of telomeres by studying the association between identity-by-descent (IBD) sharing at chromosome ends and phenotypic similarity in LTL. We measured genome-wide SNPs and LTL for a sample of 5069 Bangladeshi adults with substantial relatedness. For each of the 6318 relative pairs identified, we used SNPs near the telomeres to estimate the number of chromosome ends shared IBD, a proxy for the number of telomeres shared IBD (Tshared). We then estimated the association between Tshared and the squared pairwise difference in LTL ((ΔLTL)2) within various classes of relatives (siblings, avuncular, cousins, and distant), adjusting for overall genetic relatedness (Ï). The association between Tshared and (ΔLTL)2 was inverse among all relative pair types. In a meta-analysis including all relative pairs (Ï > 0.05), the association between Tshared and (ΔLTL)2 (P = 0.01) was stronger than the association between Ï and (ΔLTL)2 (P = 0.43). Our results provide strong evidence that telomere length (TL) in parental germ cells impacts TL in offspring cells and contributes to LTL h2 despite telomere "reprogramming" during embryonic development. Applying our method to larger studies will enable robust estimation of LTL h2 attributable to direct transmission of telomeres.
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Leucócitos/metabolismo , Leucócitos/patologia , Pais , Polimorfismo de Nucleotídeo Único , Homeostase do Telômero , Telômero/genética , Adolescente , Adulto , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto JovemRESUMO
BACKGROUND: Chronic arsenic exposure is associated with increased risk for arsenical skin lesions, cancer, and other adverse health outcomes. One potential mechanism of arsenic toxicity is telomere dysfunction. However, prior epidemiological studies of arsenic exposure, telomere length (TL), and skin lesion are small and cross-sectional. We investigated the associations between arsenic exposure and TL and between baseline TL and incident skin lesion risk among individuals participating in the Health Effects of Arsenic Longitudinal Study in Bangladesh (2000-2009). METHODS: Quantitative PCR was used to measure the average TL of peripheral blood DNA collected at baseline. The association between baseline arsenic exposure (well water and urine) and TL was estimated in a randomly-selected subcohort (nâ¯=â¯1469). A nested case-control study (466 cases and 464 age- and sex-matched controls) was used to estimate the association between baseline TL and incident skin lesion risk (diagnosed <â¯8 years after baseline). RESULTS: No association was observed between arsenic exposure (water or urine) and TL. Among incident skin lesion cases and matched controls, we observed higher skin lesion risk among individuals with shorter TL (Ptrend =â¯1.5 × 10-5) with odds ratios of 2.60, 1.59, and 1.10 for the first (shortest), second, and third TL quartiles compared to the fourth (longest). CONCLUSIONS: Arsenic exposure was not associated with TL among Bangladeshi adults, suggesting that leukocyte TL may not reflect a primary mode of action for arsenic's toxicity. However, short TL was associated with increased skin lesion risk, and may be a biomarker of arsenic susceptibility modifying arsenic's effect on skin lesion risk.
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Arsênio , Exposição Ambiental , Telômero , Adulto , Arsênio/toxicidade , Bangladesh , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Estudos Longitudinais , Masculino , Telômero/efeitos dos fármacosRESUMO
BACKGROUND: Leucocyte telomere length (TL) is a potential biomarker of ageing and risk for age-related disease. Leucocyte TL is heritable and shows substantial differences by race/ethnicity. Recent genome-wide association studies (GWAS) report ~10 loci harbouring SNPs associated with leucocyte TL, but these studies focus primarily on populations of European ancestry. OBJECTIVE: This study aims to enhance our understanding of genetic determinants of TL across populations. METHODS: We performed a GWAS of TL using data on 5075 Bangladeshi adults. We measured TL using one of two technologies (qPCR or a Luminex-based method) and used standardised variables as TL phenotypes. RESULTS: Our results replicate previously reported associations in the TERC and TERT regions (P=2.2×10-8 and P=6.4×10-6, respectively). We observed a novel association signal in the RTEL1 gene (intronic SNP rs2297439; P=2.82×10-7) that is independent of previously reported TL-associated SNPs in this region. The minor allele for rs2297439 is common in South Asian populations (≥0.25) but at lower frequencies in other populations (eg, 0.07 in Northern Europeans). Among the eight other previously reported association signals, all were directionally consistent with our study, but only rs8105767 (ZNF208) was nominally significant (P=0.003). SNP-based heritability estimates were as high as 44% when analysing close relatives but much lower when analysing distant relatives only. CONCLUSIONS: In this first GWAS of TL in a South Asian population, we replicate some, but not all, of the loci reported in prior GWAS of individuals of European ancestry, and we identify a novel second association signal at the RTEL1 locus.
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Povo Asiático/genética , DNA Helicases/genética , Estudo de Associação Genômica Ampla , Telômero/genética , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
La urticaria está caracterizada por vasodilatación e incremento de la permeabilidad vascular de la piel que aparecen como múltiples placas o ronchas edematosas muy puriginosas de color rojo. Existe evidencia que la Urticaria Crónica puede ser de origen autoinmune en un 30-50% de los casos, el resto corresponde a urticarias físicas, vasculitis urticarianas y las denominadas pseudoalergias. Se ha asociado la infección por H. pylori en el tracto gastrointestinal superior como agente causal de la UC. Sin embargo existe gran controversia con este hecho lo cual no permite llegar a una conclusión definitiva de la posible relación entre la infección por Helicobarter pylori y su asociación con Urticaria Crónica Autoinmune. En este estudio se evalúan 20 pacientes adultos con diagnóstico de Urticaria Crónica y 40 adultos normales como grupo control. Se determinaron las concentraciones de anticuerpos IgG e IgA contra H. pylori en el suero de ambos grupos, para esto se utilizó un inmunoensayo enzimático (EIA). Se demostró que la prevalencia de IgG e IgA contra H. pylori en el grupo control y en el grupo de pacientes fue similar 40% de IgG positiva en el grupo control versus 42.5% en el grupo de pacientes. Los valores de IgA fueron 45% positivo en los pacientes y 67,5% en el grupo control asimismo los anticuerpos IgG e IgA de los pacientes fueron asociados con la prueba de suero autólogo, encontrando que IgG e IgA es más frecuentemente positiva en el grupo de pacientes con PSA positiva (p<0.05). La prevalencia de anticuerpos IgG e IgA contra H. pylori es similar en los pacientes con Urticaria Crónica y sin Urticaria Crónica, la presencia de anticuerpos contra H. pylori está asociada con Urticaria Crónica Autoinmune.
Urticaria is characterized by vasodilatation and an increase of vascular permeability of the skin which show as multiple, very itchy, edematous patches or hives, red in color. There is evidence that Chronic Urticaria could have an autoinmune origin in 30-50% of the cases; the rest corresponds to physical urticaria, urticarian vasculitis, and the so-called pseudo-allergies. Infection of the superior gastrointestinal tract with H. pylori has been associated as a causal agent of CU. However, there exists a great controversy regarding this fact, which does not allow for a definite conclusion on the possible relation between the infection with Helicobacter pylori and its relationship with Autoinmune Chronic Urticaria. In this study 20 adult patients, diagnosed with Chronic Urticaria, were evaluated; with 40 normal adults as control group. The concentrations of serum antibodies IgG and IgA against H. pylori were determined for both groups, for which an Enzymatic Immunoassay (EIA) was used. The prevalence of IgG and IgA against H. pylori in the control group and the group of patients was shown to be similar 40% of IgG positive in the control group versus 42.5% in the group of patients. The values of IgA were 45% positive among the patients and 67.5% among the control group; in the same manner, the antibodies IgG and IgA of the patients were tied in with the autologous serum test, finding that IgG and IgA is more often positive in the group of patients that test positive for PSA (p<0.05). The prevalence of antibodies IgG and IgA against H. Pylori is similar in patients with Chronic Urticaria and without Chronic Urticaria, the presence of antibodies against H. Pylori is linked with Autoimmune Chronic Urticaria.