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Association mapping using crop cultivars allows identification of genetic loci of direct relevance to breeding. Here, 150 U.K. wheat (Triticum aestivum L.) cultivars genotyped with 23,288 single nucleotide polymorphisms (SNPs) were used for genome-wide association studies (GWAS) using historical phenotypic data for grain protein content, Hagberg falling number (HFN), test weight, and grain yield. Power calculations indicated experimental design would enable detection of quantitative trait loci (QTL) explaining ≥20% of the variation (PVE) at a relatively high power of >80%, falling to 40% for detection of a SNP with an R2 ≥ .5 with the same QTL. Genome-wide association studies identified marker-trait associations for all four traits. For HFN (h 2 = .89), six QTL were identified, including a major locus on chromosome 7B explaining 49% PVE and reducing HFN by 44 s. For protein content (h 2 = 0.86), 10 QTL were found on chromosomes 1A, 2A, 2B, 3A, 3B, and 6B, together explaining 48.9% PVE. For test weight, five QTL were identified (one on 1B and four on 3B; 26.3% PVE). Finally, 14 loci were identified for grain yield (h 2 = 0.95) on eight chromosomes (1A, 2A, 2B, 2D, 3A, 5B, 6A, 6B; 68.1% PVE), of which five were located within 16 Mbp of genetic regions previously identified as under breeder selection in European wheat. Our study demonstrates the utility of exploiting historical crop datasets, identifying genomic targets for independent validation, and ultimately for wheat genetic improvement.
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Emerging data show a rise in colorectal cancer (CRC) incidence in young men and women that is often chemoresistant. One potential risk factor is an alteration in the microbiome. Here, we investigated the role of TGF-ß signaling on the intestinal microbiome and the efficacy of chemotherapy for CRC induced by azoxymethane and dextran sodium sulfate in mice. We used two genotypes of TGF-ß-signaling-deficient mice (Smad4+/- and Smad4+/-Sptbn1+/-), which developed CRC with similar phenotypes and had similar alterations in the intestinal microbiome. Using these mice, we evaluated the intestinal microbiome and determined the effect of dysfunctional TGF-ß signaling on the response to the chemotherapeutic agent 5-Fluoro-uracil (5FU) after induction of CRC. Using shotgun metagenomic sequencing, we determined gut microbiota composition in mice with CRC and found reduced amounts of beneficial species of Bacteroides and Parabacteroides in the mutants compared to the wild-type (WT) mice. Furthermore, the mutant mice with CRC were resistant to 5FU. Whereas the abundances of E. boltae, B.dorei, Lachnoclostridium sp., and Mordavella sp. were significantly reduced in mice with CRC, these species only recovered to basal amounts after 5FU treatment in WT mice, suggesting that the alterations in the intestinal microbiome resulting from compromised TGF-ß signaling impaired the response to 5FU. These findings could have implications for inhibiting the TGF-ß pathway in the treatment of CRC or other cancers.
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Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Fluoruracila/farmacologia , Microbioma Gastrointestinal/fisiologia , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta/metabolismo , Animais , Antineoplásicos/farmacologia , Azoximetano/farmacologia , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/microbiologia , Neoplasias Colorretais/microbiologia , Sulfato de Dextrana/farmacologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Proteína Smad4/metabolismoRESUMO
OBJECTIVE: Observational studies have shown that increased plasma urate is associated with lower risk of Parkinson's disease (PD), but these studies were not designed to test causality. If a causal relationship exists, then modulating plasma urate levels could be a potential preventive avenue for PD. We used a large two-sample Mendelian randomization (MR) design to assess for a causal relationship between plasma urate and PD risk. METHODS: We used a genetic instrument consisting of 31 independent loci for plasma urate on a case-control genome-wide association study data set, which included 13,708 PD cases and 95,282 controls. Individual effect estimates for each SNP were combined using the inverse-variance weighted (IVW) method. Two additional methods, MR-Egger and a penalized weighted median (PWM)-based approach, were used to assess potential bias attributed to pleiotropy or invalid instruments. RESULTS: We found no evidence for a causal relationship between urate and PD, with an effect estimate from the IVW method of odds ratio (OR) 1.03 (95% confidence interval [CI], 0.88-1.20) per 1-standard-deviation increase in plasma urate levels. MR Egger and PWM analyses yielded similar estimates (OR, 0.99 [95% CI, 0.83-1.17] and 0.99 [95% CI, 0.86-1.14], respectively). INTERPRETATION: We did not find evidence for a linear causal protective effect by urate on PD risk. The associations observed in previous observational studies may be, in part, attributed to confounding or reverse causality. In the context of the present findings, strategies to elevate circulating urate levels may not reduce overall PD risk. Ann Neurol 2018;84:191-199.
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Variação Genética/genética , Análise da Randomização Mendeliana/métodos , Doença de Parkinson/sangue , Doença de Parkinson/genética , Polimorfismo de Nucleotídeo Único/genética , Ácido Úrico/sangue , Biomarcadores/sangue , Bases de Dados Genéticas/tendências , Humanos , Doença de Parkinson/diagnósticoRESUMO
Colorectal cancer (CRC) accounts for ~9% of all cancers in the Veteran population, a fact which has focused a great deal of the attention of the VA's research and development efforts. A field-based meeting of CRC experts was convened to discuss both challenges and opportunities in precision medicine for CRC. This group, designated as the VA Colorectal Cancer Cell-genomics Consortium (VA4C), discussed advances in CRC biology, biomarkers, and imaging for early detection and prevention. There was also a discussion of precision treatment involving fluorescence-guided surgery, targeted chemotherapies and immunotherapies, and personalized cancer treatment approaches. The overarching goal was to identify modalities that might ultimately lead to personalized cancer diagnosis and treatment. This review summarizes the findings of this VA field-based meeting, in which much of the current knowledge on CRC prescreening and treatment was discussed. It was concluded that there is a need and an opportunity to identify new targets for both the prevention of CRC and the development of effective therapies for advanced disease. Also, developing methods integrating genomic testing with tumoroid-based clinical drug response might lead to more accurate diagnosis and prognostication and more effective personalized treatment of CRC.
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Neoplasias Colorretais , Medicina de Precisão/métodos , Saúde dos Veteranos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/terapia , Terapia Combinada , Detecção Precoce de Câncer/métodos , Humanos , PrognósticoRESUMO
BACKGROUND & AIMS: Development of hepatocellular carcinoma (HCC) is associated with alterations in the transforming growth factor-beta (TGF-ß) signaling pathway, which regulates liver inflammation and can have tumor suppressor or promoter activities. Little is known about the roles of specific members of this pathway at specific of HCC development. We took an integrated approach to identify and validate the effects of changes in this pathway in HCC and identify therapeutic targets. METHODS: We performed transcriptome analyses for a total of 488 HCCs that include data from The Cancer Genome Atlas. We also screened 301 HCCs reported in the Catalogue of Somatic Mutations in Cancer and 202 from Cancer Genome Atlas for mutations in genome sequences. We expressed mutant forms of spectrin beta, non-erythrocytic 1 (SPTBN1) in HepG2, SNU398, and SNU475 cells and measured phosphorylation, nuclear translocation, and transcriptional activity of SMAD family member 3 (SMAD3). RESULTS: We found somatic mutations in at least 1 gene whose product is a member of TGF-ß signaling pathway in 38% of HCC samples. SPTBN1 was mutated in the largest proportion of samples (12 of 202, 6%). Unsupervised clustering of transcriptome data identified a group of HCCs with activation of the TGF-ß signaling pathway (increased transcription of genes in the pathway) and a group of HCCs with inactivation of TGF-ß signaling (reduced expression of genes in this pathway). Patients with tumors with inactivation of TGF-ß signaling had shorter survival times than patients with tumors with activation of TGF-ß signaling (P = .0129). Patterns of TGF-ß signaling correlated with activation of the DNA damage response and sirtuin signaling pathways. HepG2, SNU398, and SNU475 cells that expressed the D1089Y mutant or with knockdown of SPTBN1 had increased sensitivity to DNA crosslinking agents and reduced survival compared with cells that expressed normal SPTBN1 (controls). CONCLUSIONS: In genome and transcriptome analyses of HCC samples, we found mutations in genes in the TGF-ß signaling pathway in almost 40% of samples. These correlated with changes in expression of genes in the pathways; up-regulation of genes in this pathway would contribute to inflammation and fibrosis, whereas down-regulation would indicate loss of TGF-ß tumor suppressor activity. Our findings indicate that therapeutic agents for HCCs can be effective, based on genetic features of the TGF-ß pathway; agents that block TGF-ß should be used only in patients with specific types of HCCs.
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Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Mutação/genética , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta/fisiologia , Idoso , Carcinoma Hepatocelular/mortalidade , Estudos de Casos e Controles , Análise por Conglomerados , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: The implications of different adiposity measures on cardiovascular disease etiology remain unclear. In this article, we quantify and contrast causal associations of central adiposity (waist-to-hip ratio adjusted for body mass index [WHRadjBMI]) and general adiposity (body mass index [BMI]) with cardiometabolic disease. METHODS: Ninety-seven independent single-nucleotide polymorphisms for BMI and 49 single-nucleotide polymorphisms for WHRadjBMI were used to conduct Mendelian randomization analyses in 14 prospective studies supplemented with coronary heart disease (CHD) data from CARDIoGRAMplusC4D (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics; combined total 66 842 cases), stroke from METASTROKE (12 389 ischemic stroke cases), type 2 diabetes mellitus from DIAGRAM (Diabetes Genetics Replication and Meta-analysis; 34 840 cases), and lipids from GLGC (Global Lipids Genetic Consortium; 213 500 participants) consortia. Primary outcomes were CHD, type 2 diabetes mellitus, and major stroke subtypes; secondary analyses included 18 cardiometabolic traits. RESULTS: Each one standard deviation (SD) higher WHRadjBMI (1 SD≈0.08 U) associated with a 48% excess risk of CHD (odds ratio [OR] for CHD, 1.48; 95% confidence interval [CI], 1.28-1.71), similar to findings for BMI (1 SD≈4.6 kg/m2; OR for CHD, 1.36; 95% CI, 1.22-1.52). Only WHRadjBMI increased risk of ischemic stroke (OR, 1.32; 95% CI, 1.03-1.70). For type 2 diabetes mellitus, both measures had large effects: OR, 1.82 (95% CI, 1.38-2.42) and OR, 1.98 (95% CI, 1.41-2.78) per 1 SD higher WHRadjBMI and BMI, respectively. Both WHRadjBMI and BMI were associated with higher left ventricular hypertrophy, glycemic traits, interleukin 6, and circulating lipids. WHRadjBMI was also associated with higher carotid intima-media thickness (39%; 95% CI, 9%-77% per 1 SD). CONCLUSIONS: Both general and central adiposity have causal effects on CHD and type 2 diabetes mellitus. Central adiposity may have a stronger effect on stroke risk. Future estimates of the burden of adiposity on health should include measures of central and general adiposity.
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Adiposidade/genética , Distribuição da Gordura Corporal/métodos , Doença das Coronárias/genética , Diabetes Mellitus Tipo 2/genética , Análise da Randomização Mendeliana/métodos , Acidente Vascular Cerebral/genética , Doença das Coronárias/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Humanos , Estudos Longitudinais , Estudos Observacionais como Assunto/métodos , Polimorfismo de Nucleotídeo Único/genética , Estudos Prospectivos , Acidente Vascular Cerebral/epidemiologiaRESUMO
BACKGROUND AND AIMS: Annexin-A2 (AnxA2) is an endogenous inhibitor of proprotein convertase subtilisin/kexin type-9 (PCSK9). The repeat-one (R1) domain of AnxA2 binds to PCSK9, blocking its ability to promote degradation of low-density lipoprotein cholesterol-receptors (LDL-R) and thereby regulate low-density lipoprotein cholesterol (LDL-C) levels. Here we identify variants in ANXA2 influencing LDL-C levels and we determine the molecular mechanisms of their effects. RESULTS: The ANXA2 single nucleotide polymorphism (SNP) genotype-phenotype association was examined using the Second-Northwick-Park Heart Study (NPHSII) (nâ¼2700) and the UCL-LSHTM-Edinburgh-Bristol (UCLEB) consortium (nâ¼14,600). The ANXA2-R1 domain coding-SNP rs17845226 (V98L) associated with LDL-C, homozygotes for the minor allele having ≈18.8% higher levels of LDL-C (p = 0.004), and higher risk of coronary heart disease (CHD) (p = 0.04). The SNP is in modest linkage disequilibrium (r2 > 0.5) with two intergenic SNPs, rs17191344 and rs11633032. Both SNPs showed allele-specific protein binding, and the minor alleles caused significant reduction in reporter gene expression (≈18%, p < 0.001). In the expression quantitative trait loci (eQTL) study, minor allele homozygotes have significantly lower levels of ANXA2-mRNA expression (p = 1.36 × 10-05). CONCLUSIONS: Both rs11633032 and rs17191344 SNPs are functional variants, where the minor alleles create repressor-binding protein sites for transcription factors that contribute to reduced ANXA2 gene expression. Lower AnxA2 levels could increase plasma levels of PCSK9 and thus increase LDL-C levels and risk of CHD. This supports, for the first time in humans, previous observations in mouse models that changes in the levels of AnxA2 directly influence plasma LDL-C levels, and thus implicate this protein as a potential therapeutic target for LDL-C lowering.
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Anexina A2/genética , LDL-Colesterol/sangue , Doença das Coronárias/sangue , Doença das Coronárias/genética , Polimorfismo de Nucleotídeo Único , Anexina A2/metabolismo , Biomarcadores/sangue , Biologia Computacional , Doença das Coronárias/diagnóstico , Bases de Dados Genéticas , Feminino , Frequência do Gene , Genes Reporter , Estudos de Associação Genética , Predisposição Genética para Doença , Células Hep G2 , Heterozigoto , Homozigoto , Humanos , Células K562 , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Fenótipo , Pró-Proteína Convertase 9/metabolismo , Locos de Características Quantitativas , Transfecção , Reino UnidoRESUMO
Exposure to genotoxins such as ethanol-derived acetaldehyde leads to DNA damage and liver injury and promotes the development of cancer. We report here a major role for the transforming growth factor ß/mothers against decapentaplegic homolog 3 adaptor ß2-Spectrin (ß2SP, gene Sptbn1) in maintaining genomic stability following alcohol-induced DNA damage. ß2SP supports DNA repair through ß2SP-dependent activation of Fanconi anemia complementation group D2 (Fancd2), a core component of the Fanconi anemia complex. Loss of ß2SP leads to decreased Fancd2 levels and sensitizes ß2SP mutants to DNA damage by ethanol treatment, leading to phenotypes that closely resemble those observed in animals lacking both aldehyde dehydrogenase 2 and Fancd2 and resemble human fetal alcohol syndrome. Sptbn1-deficient cells are hypersensitive to DNA crosslinking agents and have defective DNA double-strand break repair that is rescued by ectopic Fancd2 expression. Moreover, Fancd2 transcription in response to DNA damage/transforming growth factor ß stimulation is regulated by the ß2SP/mothers against decapentaplegic homolog 3 complex. CONCLUSION: Dysfunctional transforming growth factor ß/ß2SP signaling impacts the processing of genotoxic metabolites by altering the Fanconi anemia DNA repair pathway. (Hepatology 2017;65:678-693).
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Proteína do Grupo de Complementação D2 da Anemia de Fanconi/genética , Instabilidade Genômica/genética , Prenhez , Espectrina/genética , Fator de Crescimento Transformador beta2/genética , Análise de Variância , Animais , Animais Recém-Nascidos , Dano ao DNA/genética , Reparo do DNA/genética , Etanol/farmacologia , Feminino , Transtornos do Espectro Alcoólico Fetal/genética , Transtornos do Espectro Alcoólico Fetal/patologia , Humanos , Imuno-Histoquímica , Peroxidação de Lipídeos/genética , Camundongos , Camundongos Transgênicos , Gravidez , Reação em Cadeia da Polimerase em Tempo Real/métodos , Transdução de SinaisRESUMO
MOTIVATION: Fine mapping is a widely used approach for identifying the causal variant(s) at disease-associated loci. Standard methods (e.g. multiple regression) require individual level genotypes. Recent fine mapping methods using summary-level data require the pairwise correlation coefficients ([Formula: see text]) of the variants. However, haplotypes rather than pairwise [Formula: see text], are the true biological representation of linkage disequilibrium (LD) among multiple loci. In this article, we present an empirical iterative method, HAPlotype Regional Association analysis Program (HAPRAP), that enables fine mapping using summary statistics and haplotype information from an individual-level reference panel. RESULTS: Simulations with individual-level genotypes show that the results of HAPRAP and multiple regression are highly consistent. In simulation with summary-level data, we demonstrate that HAPRAP is less sensitive to poor LD estimates. In a parametric simulation using Genetic Investigation of ANthropometric Traits height data, HAPRAP performs well with a small training sample size (N < 2000) while other methods become suboptimal. Moreover, HAPRAP's performance is not affected substantially by single nucleotide polymorphisms (SNPs) with low minor allele frequencies. We applied the method to existing quantitative trait and binary outcome meta-analyses (human height, QTc interval and gallbladder disease); all previous reported association signals were replicated and two additional variants were independently associated with human height. Due to the growing availability of summary level data, the value of HAPRAP is likely to increase markedly for future analyses (e.g. functional prediction and identification of instruments for Mendelian randomization). AVAILABILITY AND IMPLEMENTATION: The HAPRAP package and documentation are available at http://apps.biocompute.org.uk/haprap/ CONTACT: : jie.zheng@bristol.ac.uk or tom.gaunt@bristol.ac.ukSupplementary information: Supplementary data are available at Bioinformatics online.
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Mapeamento Cromossômico/métodos , Haplótipos , Polimorfismo de Nucleotídeo Único , Software , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Desequilíbrio de Ligação , Característica Quantitativa Herdável , Tamanho da AmostraRESUMO
Cancer stem cells have established mechanisms that contribute to tumor heterogeneity as well as resistance to therapy. Over 40% of hepatocellular carcinomas (HCCs) are considered to be clonal and arise from a stem-like/cancer stem cell. Moreover, HCC is the second leading cause of cancer death worldwide, and an improved understanding of cancer stem cells and targeting these in this cancer are urgently needed. Multiple studies have revealed etiological patterns and multiple genes/pathways signifying initiation and progression of HCC; however, unlike the transforming growth factor ß (TGF-ß) pathway, loss of p53 and/or activation of ß-catenin do not spontaneously drive HCC in animal models. Despite many advances in cancer genetics that include identifying the dominant role of TGF-ß signaling in gastrointestinal cancers, we have not reached an integrated view of genetic mutations, copy number changes, driver pathways, and animal models that support effective targeted therapies for these common and lethal cancers. Moreover, pathways involved in stem cell transformation into gastrointestinal cancers remain largely undefined. Identifying the key mechanisms and developing models that reflect the human disease can lead to effective new treatment strategies. In this review, we dissect the evidence obtained from mouse and human liver regeneration, and mouse genetics, to provide insight into the role of TGF-ß in regulating the cancer stem cell niche. (Hepatology Communications 2017;1:477-493).
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BACKGROUND: The Low-Density Lipoprotein Receptor (LDLR) SNP rs6511720 (G>T), located in intron-1 of the gene, has been identified in genome-wide association studies (GWAS) as being associated with lower plasma levels of LDL-C and a lower risk of coronary heart disease (CHD). Whether or not rs6511720 is itself functional or a marker for a functional variant elsewhere in the gene is not known. METHODS: The association of LDLR SNP rs6511720 with incidence of CHD and levels of LDL-C was determined by reference to CARDIoGRAM, C4D and Global lipids genetics consortium (GLGC) data. SNP annotation databases were used to identify possible SNP function and prioritization. Luciferase reporter assays in the liver cell line Huh7 were used to measure the effect of variant genotype on gene expression. Electrophoretic Mobility Shift Assays (EMSAs) were used to identify the Transcription Factors (TFs) involved in gene expression regulation. RESULTS: The phenotype-genotype analysis showed that the rs6511720 minor allele is associated with lower level of LDL-C [beta = -0.2209, p = 3.85 x10-262], and lower risk of CHD [log (OR) = 0.1155, p = 1.04 x10-7]. Rs6511720 is in complete linkage. Rs6511720 is in complete linkage disequilibrium (LD) with three intron-1 SNPs (rs141787760, rs60173709, rs57217136). Luciferase reporter assays in Huh7 cells showed that the rare alleles of both rs6511720 and rs57217136 caused a significant increase in LDLR expression compared to the common alleles (+29% and +24%, respectively). Multiplex Competitor-EMSAs (MC-EMSA) identified that the transcription factor serum response element (SRE) binds to rs6511720, while retinoic acid receptor (RAR) and signal transducer and activator of transcription 1 (STAT1) bind to rs57217136. CONCLUSION: Both LDLR rs6511720 and rs57217136 are functional variants. Both these minor alleles create enhancer-binding protein sites for TFs and may contribute to increased LDLR expression, which is consequently associated with reduced LDL-C levels and 12% lower CHD risk.
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LDL-Colesterol/metabolismo , Doença da Artéria Coronariana/genética , Receptores de LDL/genética , Receptores de LDL/metabolismo , Linhagem Celular , Ensaio de Desvio de Mobilidade Eletroforética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Íntrons/genética , Desequilíbrio de Ligação/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
IMPORTANCE: Low-density lipoprotein cholesterol (LDL-C) is causally related to coronary artery disease (CAD), but the relevance of high-density lipoprotein cholesterol (HDL-C) and triglycerides (TGs) is uncertain. Lowering of LDL-C levels by statin therapy modestly increases the risk of type 2 diabetes, but it is unknown whether this effect is specific to statins. OBJECTIVE: To investigate the associations of 3 routinely measured lipid fractions with CAD and diabetes through mendelian randomization (MR) using conventional MR and making use of newer approaches, such as multivariate MR and MR-Egger, that address the pleiotropy of genetic instruments where relevant. DESIGN, SETTING, AND PARTICIPANTS: Published data from genome-wide association studies were used to construct genetic instruments and then applied to investigate associations between lipid fractions and the risk of CAD and diabetes using MR approaches that took into account pleiotropy of genetic instruments. The study was conducted from March 12 to December 31, 2015. MAIN OUTCOMES AND MEASURES: Coronary artery disease and diabetes. RESULTS: Genetic instruments composed of 130 single-nucleotide polymorphisms (SNPs) were used for LDL-C (explaining 7.9% of its variance), 140 SNPs for HDL-C (6.6% of variance), and 140 SNPs for TGs (5.9% of variance). A 1-SD genetically instrumented elevation in LDL-C levels (equivalent to 38 mg/dL) and TG levels (equivalent to 89 mg/dL) was associated with higher CAD risk; odds ratios (ORs) were 1.68 (95% CI, 1.51-1.87) for LDL-C and 1.28 (95% CI, 1.13-1.45) for TGs. The corresponding OR for HDL-C (equivalent to a 16-mg/dL increase) was 0.95 (95% CI, 0.85-1.06). All 3 lipid traits were associated with a lower risk of type 2 diabetes. The ORs were 0.79 (95% CI, 0.71-0.88) for LDL-C and 0.83 (95% CI, 0.76-0.90) for HDL-C per 1-SD elevation. For TG, the MR estimates for diabetes were inconsistent, with MR-Egger giving an OR of 0.83 (95%CI, 0.72-0.95) per 1-SD elevation. CONCLUSIONS AND RELEVANCE: Routinely measured lipid fractions exhibit contrasting associations with the risk of CAD and diabetes. Increased LDL-C, HDL-C, and possibly TG levels are associated with a lower risk of diabetes. This information will be relevant to the design of clinical trials of lipid-modifying agents, which should carefully monitor participants for dysglycemia and the incidence of diabetes.
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HDL-Colesterol , LDL-Colesterol , Doença da Artéria Coronariana/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , HDL-Colesterol/análise , HDL-Colesterol/genética , LDL-Colesterol/análise , LDL-Colesterol/genética , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/prevenção & controle , Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla , Humanos , Lipídeos , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
Disruption of the TGF-ß pathway is associated with liver fibrosis and suppression of liver tumorigenesis, conditions associated with low Vitamin D (VD) levels. However, potential contributions of VD to liver tumor progression in the context of TGF-ß signaling remain unexplored. Our analyses of VD deprivation (VDD) in in vivo models of liver tumor formation revealed striking three-fold increases in tumor burden in Smad3(+/-) mice, with a three-fold increase in TLR7 expression compared to controls. ChIP and transcriptional assays confirm Smad3 binding at two TLR7 promoter SBE sites. Molecular interactions between TGF-ß pathway and VDD were validated clinically, where an absence of VD supplementation was associated with low TGF-ß pathway member expression levels and ß-catenin activation in fibrotic/cirrhotic human liver tissues. Subsequent supplementing VD led to restoration of TGF-ß member expression with lower ß-catenin levels. Bioinformatics analysis provides positive supportive correlation between somatic mutations for VD-related genes and the TGF-ß pathway. We conclude that VDD promotes tumor growth in the context of Smad3 disruption, potentially through regulation of TLR7 expression and ß-catenin activation. VD could therefore be a strong candidate for liver cancer prevention in the context of aberrant Smad3 signaling.
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Neoplasias Hepáticas Experimentais/patologia , Glicoproteínas de Membrana/metabolismo , Proteína Smad3/genética , Receptor 7 Toll-Like/metabolismo , Fator de Crescimento Transformador beta/genética , Deficiência de Vitamina D/complicações , Proteínas Wnt/metabolismo , Animais , Humanos , Neoplasias Hepáticas Experimentais/complicações , Masculino , Camundongos , Camundongos Transgênicos , Transdução de Sinais , Vitamina D/administração & dosagemRESUMO
Mendelian randomization (MR) studies typically assess the pathogenic relevance of environmental exposures or disease biomarkers, using genetic variants that instrument these exposures. The approach is gaining popularity-our systematic review reveals a greater than 10-fold increase in MR studies published between 2004 and 2015. When the MR paradigm was first proposed, few biomarker- or exposure-related genetic variants were known, most having been identified by candidate gene studies. However, genome-wide association studies (GWAS) are now providing a rich source of potential instruments for MR analysis. Many early reviews covering the concept, applications and analytical aspects of the MR technique preceded the surge in GWAS, and thus the question of how best to select instruments for MR studies from the now extensive pool of available variants has received insufficient attention. Here we focus on the most common category of MR studies-those concerning disease biomarkers. We consider how the selection of instruments for MR analysis from GWAS requires consideration of: the assumptions underlying the MR approach; the biology of the biomarker; the genome-wide distribution, frequency and effect size of biomarker-associated variants (the genetic architecture); and the specificity of the genetic associations. Based on this, we develop guidance that may help investigators to plan and readers interpret MR studies.
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Biomarcadores , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana/métodos , Polimorfismo de Nucleotídeo Único , Causalidade , Variação Genética , HumanosRESUMO
Red blood cell (RBC) traits are routinely measured in clinical practice as important markers of health. Deviations from the physiological ranges are usually a sign of disease, although variation between healthy individuals also occurs, at least partly due to genetic factors. Recent large scale genetic studies identified loci associated with one or more of these traits; further characterization of known loci and identification of new loci is necessary to better understand their role in health and disease and to identify potential molecular mechanisms. We performed meta-analysis of Metabochip association results for six RBC traits-hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV) and red blood cell count (RCC)-in 11 093 Europeans from seven studies of the UCL-LSHTM-Edinburgh-Bristol (UCLEB) Consortium. We identified 394 non-overlapping SNPs in five loci at genome-wide significance: 6p22.1-6p21.33 (with HFE among others), 6q23.2 (with HBS1L among others), 6q23.3 (contains no genes), 9q34.3 (only ABO gene) and 22q13.1 (with TMPRSS6 among others), replicating previous findings of association with RBC traits at these loci and extending them by imputation to 1000 Genomes. We further characterized associations between ABO SNPs and three traits: hemoglobin, hematocrit and red blood cell count, replicating them in an independent cohort. Conditional analyses indicated the independent association of each of these traits with ABO SNPs and a role for blood group O in mediating the association. The 15 most significant RBC-associated ABO SNPs were also associated with five cardiometabolic traits, with discordance in the direction of effect between groups of traits, suggesting that ABO may act through more than one mechanism to influence cardiometabolic risk.
Assuntos
Sistema ABO de Grupos Sanguíneos/genética , Replicação do DNA/genética , Eritrócitos/fisiologia , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Etnicidade , Europa (Continente) , Estudo de Associação Genômica Ampla , HumanosRESUMO
RATIONALE: Hypoadiponectinemia correlates with several coronary heart disease (CHD) risk factors. However, it is unknown whether adiponectin is causally implicated in CHD pathogenesis. OBJECTIVE: We aimed to investigate the causal effect of adiponectin on CHD risk. METHODS AND RESULTS: We undertook a Mendelian randomization study using data from genome-wide association studies consortia. We used the ADIPOGen consortium to identify genetic variants that could be used as instrumental variables for the effect of adiponectin. Data on the association of these genetic variants with CHD risk were obtained from CARDIoGRAM (22 233 CHD cases and 64 762 controls of European ancestry) and from CARDIoGRAMplusC4D Metabochip (63 746 cases and 130 681 controls; ≈ 91% of European ancestry) consortia. Data on the association of genetic variants with adiponectin levels and with CHD were combined to estimate the influence of blood adiponectin on CHD risk. In the conservative approach (restricted to using variants within the adiponectin gene as instrumental variables), each 1 U increase in log blood adiponectin concentration was associated with an odds ratio for CHD of 0.83 (95% confidence interval, 0.68-1.01) in CARDIoGRAM and 0.97 (95% confidence interval, 0.84-1.12) in CARDIoGRAMplusC4D Metabochip. Findings from the liberal approach (including variants in any locus across the genome) indicated a protective effect of adiponectin that was attenuated to the null after adjustment for known CHD predictors. CONCLUSIONS: Overall, our findings do not support a causal role of adiponectin levels in CHD pathogenesis.
Assuntos
Adiponectina/fisiologia , Doença das Coronárias/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Análise da Randomização Mendeliana/métodos , Polimorfismo de Nucleotídeo Único/genética , Humanos , Fatores de RiscoRESUMO
Mutational processes and signatures that drive early tumorigenesis are centrally important for early cancer prevention. Yet, to date, biomarkers and risk factors for polyps (adenomas) that inordinately and rapidly develop into colon cancer remain poorly defined. Here, we describe surprisingly high mutational profiles through whole-genome sequence (WGS) analysis in 2 of 4 pairs of benign colorectal adenoma tissue samples. Unsupervised hierarchical clustered transcriptomic analysis of a further 7 pairs of adenomas reveals distinct mutational signatures regardless of adenoma size. Transitional single nucleotide substitutions of C:G>T:A predominate in the adenoma mutational spectrum. Strikingly, we observe mutations in the TGF-ß pathway and CEA-associated genes in 4 out of 11 adenomas, overlapping with the Wnt pathway. Immunohistochemical labeling reveals a nearly 5-fold increase in CEA levels in 23% of adenoma samples with a concomitant loss of TGF-ß signaling. We also define a functional role by which the CEA B3 domain interacts with TGFBR1, potentially inactivating the tumor suppressor function of TGF-ß signaling. Our study uncovers diverse mutational processes underlying the transition from early adenoma to cancer. This has broad implications for biomarker-driven targeting of CEA/TGF-ß in high-risk adenomas and may lead to early detection of aggressive adenoma to CRC progression.
Assuntos
Adenoma/genética , Antígeno Carcinoembrionário/genética , Colo/metabolismo , Neoplasias do Colo/genética , Regulação Neoplásica da Expressão Gênica , Mutação/genética , Fator de Crescimento Transformador beta/genética , Adenoma/metabolismo , Adenoma/patologia , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Western Blotting , Antígeno Carcinoembrionário/metabolismo , Movimento Celular , Proliferação de Células , Células Cultivadas , Colo/patologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Progressão da Doença , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Técnicas Imunoenzimáticas , Imunoprecipitação , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismoRESUMO
Beckwith-Wiedemann syndrome (BWS) is a human stem cell disorder, and individuals with this disease have a substantially increased risk (~800-fold) of developing tumors. Epigenetic silencing of ß2-spectrin (ß2SP, encoded by SPTBN1), a SMAD adaptor for TGF-ß signaling, is causally associated with BWS; however, a role of TGF-ß deficiency in BWS-associated neoplastic transformation is unexplored. Here, we have reported that double-heterozygous Sptbn1+/- Smad3+/- mice, which have defective TGF-ß signaling, develop multiple tumors that are phenotypically similar to those of BWS patients. Moreover, tumorigenesis-associated genes IGF2 and telomerase reverse transcriptase (TERT) were overexpressed in fibroblasts from BWS patients and TGF-ß-defective mice. We further determined that chromatin insulator CCCTC-binding factor (CTCF) is TGF-ß inducible and facilitates TGF-ß-mediated repression of TERT transcription via interactions with ß2SP and SMAD3. This regulation was abrogated in TGF-ß-defective mice and BWS, resulting in TERT overexpression. Imprinting of the IGF2/H19 locus and the CDKN1C/KCNQ1 locus on chromosome 11p15.5 is mediated by CTCF, and this regulation is lost in BWS, leading to aberrant overexpression of growth-promoting genes. Therefore, we propose that loss of CTCF-dependent imprinting of tumor-promoting genes, such as IGF2 and TERT, results from a defective TGF-ß pathway and is responsible at least in part for BWS-associated tumorigenesis as well as sporadic human cancers that are frequently associated with SPTBN1 and SMAD3 mutations.