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1.
Nat Commun ; 10(1): 4505, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31582752

RESUMO

The human gut is inhabited by a complex and metabolically active microbial ecosystem. While many studies focused on the effect of individual microbial taxa on human health, their overall metabolic potential has been under-explored. Using whole-metagenome shotgun sequencing data in 1,004 twins, we first observed that unrelated subjects share, on average, almost double the number of metabolic pathways (82%) than species (43%). Then, using 673 blood and 713 faecal metabolites, we found metabolic pathways to be associated with 34% of blood and 95% of faecal metabolites, with over 18,000 significant associations, while species showed less than 3,000 associations. Finally, we estimated that the microbiome was involved in a dialogue between 71% of faecal, and 15% of blood, metabolites. This study underlines the importance of studying the microbial metabolic potential rather than focusing purely on taxonomy to find therapeutic and diagnostic targets, and provides a unique resource describing the interplay between the microbiome and the systemic and faecal metabolic environments.

2.
Twin Res Hum Genet ; : 1-7, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31526404

RESUMO

TwinsUK is the largest cohort of community-dwelling adult twins in the UK. The registry comprises over 14,000 volunteer twins (14,838 including mixed, single and triplets); it is predominantly female (82%) and middle-aged (mean age 59). In addition, over 1800 parents and siblings of twins are registered volunteers. During the last 27 years, TwinsUK has collected numerous questionnaire responses, physical/cognitive measures and biological measures on over 8500 subjects. Data were collected alongside four comprehensive phenotyping clinical visits to the Department of Twin Research and Genetic Epidemiology, King's College London. Such collection methods have resulted in very detailed longitudinal clinical, biochemical, behavioral, dietary and socioeconomic cohort characterization; it provides a multidisciplinary platform for the study of complex disease during the adult life course, including the process of healthy aging. The major strength of TwinsUK is the availability of several 'omic' technologies for a range of sample types from participants, which includes genomewide scans of single-nucleotide variants, next-generation sequencing, metabolomic profiles, microbiomics, exome sequencing, epigenetic markers, gene expression arrays, RNA sequencing and telomere length measures. TwinsUK facilitates and actively encourages sharing the 'TwinsUK' resource with the scientific community - interested researchers may request data via the TwinsUK website (http://twinsuk.ac.uk/resources-for-researchers/access-our-data/) for their own use or future collaboration with the study team. In addition, further cohort data collection is planned via the Wellcome Open Research gateway (https://wellcomeopenresearch.org/gateways). The current article presents an up-to-date report on the application of technological advances, new study procedures in the cohort and future direction of TwinsUK.

3.
J Exp Clin Cancer Res ; 38(1): 373, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31439019

RESUMO

BACKGROUND: An increasing number of anticancer agents has been proposed in recent years with the attempt to overcome treatment-resistant cancer cells and particularly cancer stem cells (CSC), the major culprits for tumour resistance and recurrence. However, a huge obstacle to treatment success is the ineffective delivery of drugs within the tumour environment due to limited solubility, short circulation time or inconsistent stability of compounds that, together with concomitant dose-limiting systemic toxicity, contribute to hamper the achievement of therapeutic drug concentrations. The synthetic retinoid Fenretinide (4-hydroxy (phenyl)retinamide; 4-HPR) formerly emerged as a promising anticancer agent based on pre-clinical and clinical studies. However, a major limitation of fenretinide is traditionally represented by its poor aqueous solubility/bioavailability due to its hydrophobic nature, that undermined the clinical success of previous clinical trials. METHODS: Here, we developed a novel nano-micellar fenretinide formulation called bionanofenretinide (Bio-nFeR), based on drug encapsulation in an ion-pair stabilized lipid matrix, with the aim to raise fenretinide bioavailability and antitumour efficacy. RESULTS: Bio-nFeR displayed marked antitumour activity against lung, colon and melanoma CSC both in vitro and in tumour xenografts, in absence of mice toxicity. Bio-nFeR is suitable for oral administration, reaching therapeutic concentrations within tumours and an unprecedented therapeutic activity in vivo as single agent. CONCLUSION: Altogether, our results indicate Bio-nFeR as a novel anticancer agent with low toxicity and high activity against tumourigenic cells, potentially useful for the treatment of solid tumours of multiple origin.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31403758

RESUMO

Body site is highly relevant for melanoma: it affects prognosis and varies according to the patient's sex. The distribution of naevi, a major risk factor for melanoma, at different body sites also varies according to sex in childhood. Using naevus counts at different body sites in 492 unrelated adults from both sexes, we observed that women have an increased number of naevi on the lower limbs compared to men (p = 8.5 × 10-5 ), showing that a high naevus count on this site persists from childhood throughout life. Then, using data from 3,232 twins, we observed, in women, the lowest naevus count heritability on the trunk (26%), and the highest on the lower limbs (69%). Finally, we showed that, in 2,864 women, six genomic loci previously associated with both naevus count and melanoma risk (IRF4, DOCK8, MTAP, 9q31.2, KITLG and PLA2G6) have an effect on naevus count that is body site-specific, but whose effect sizes are predominantly stronger on the lower limbs. Sex-specific genetic influence on naevus count at different sites may explain differences in site-specific melanoma incidence as well as prognosis between sexes.

5.
Sci Rep ; 9(1): 9782, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278313

RESUMO

Niemann Pick type C (NPC) disease is a rare neurovisceral disorder. Mutations in npc1 gene induce an intracellular accumulation of unesterified cholesterol in the endosomal/lysosomal system causing cell death. We recently showed that stimulation of adenosine A2A receptors (A2AR) restores cholesterol accumulation in late endosomes/lysosomes in human NPC fibroblasts and neural cell lines transiently transfected with NPC1 siRNA, suggesting that these receptors might be targeted to contrast the disease. Since NPC1 disease is characterized by dysmyelination and maturational arrest of oligodendrocyte progenitors (OPs), in this study, we investigated whether A2AR stimulation could promote oligodendrocyte differentiation and myelin formation, thus overcoming these important neurological abnormalities. We developed a NPC1 pharmacological model, in which primary cultures of OPs are exposed to a cholesterol transport inhibitor to induce a NPC1-like phenotype characterized by several typical features such as (i) cholesterol accumulation, (ii) altered mitochondrial morphology and membrane potential, (iii) defect of autophagy and (iv) maturation arrest. The A2AR agonist CGS21680 normalized all NPC1-like features. The ability of CGS21680 of rescuing OP from maturational arrest and promoting their differentiation to mature OL, suggests that A2AR stimulation might be exploited to correct dysmyelination in NPC1, further supporting their therapeutic potential in the disease.

7.
Nat Commun ; 10(1): 1731, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31043596

RESUMO

Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis and vasculopathy. CXCL4 represents an early serum biomarker of severe SSc and likely contributes to inflammation via chemokine signaling pathways, but the exact role of CXCL4 in SSc pathogenesis is unclear. Here, we elucidate an unanticipated mechanism for CXCL4-mediated immune amplification in SSc, in which CXCL4 organizes "self" and microbial DNA into liquid crystalline immune complexes that amplify TLR9-mediated plasmacytoid dendritic cell (pDC)-hyperactivation and interferon-α production. Surprisingly, this activity does not require CXCR3, the CXCL4 receptor. Importantly, we find that CXCL4-DNA complexes are present in vivo and correlate with type I interferon (IFN-I) in SSc blood, and that CXCL4-positive skin pDCs coexpress IFN-I-related genes. Thus, we establish a direct link between CXCL4 overexpression and the IFN-I-gene signature in SSc and outline a paradigm in which chemokines can drastically modulate innate immune receptors without being direct agonists.


Assuntos
DNA Bacteriano/metabolismo , Interferon-alfa/metabolismo , Fator Plaquetário 4/metabolismo , Escleroderma Sistêmico/imunologia , Receptor Toll-Like 9/metabolismo , Adulto , Idoso , Biópsia , Estudos de Casos e Controles , DNA Bacteriano/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Voluntários Saudáveis , Humanos , Interferon-alfa/imunologia , Cristais Líquidos , Masculino , Pessoa de Meia-Idade , Fator Plaquetário 4/imunologia , Receptores CXCR3/imunologia , Receptores CXCR3/metabolismo , Escleroderma Sistêmico/microbiologia , Escleroderma Sistêmico/patologia , Pele/citologia , Pele/imunologia , Pele/microbiologia , Pele/patologia , Receptor Toll-Like 9/imunologia
8.
Mol Metab ; 24: 98-107, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30956117

RESUMO

OBJECTIVE: Genome wide association studies (GWAS) for type 2 diabetes (T2D) have identified genetic loci that often localise in non-coding regions of the genome, suggesting gene regulation effects. We combined genetic and transcriptomic analysis from human islets obtained from brain-dead organ donors or surgical patients to detect expression quantitative trait loci (eQTLs) and shed light into the regulatory mechanisms of these genes. METHODS: Pancreatic islets were isolated either by laser capture microdissection (LCM) from surgical specimens of 103 metabolically phenotyped pancreatectomized patients (PPP) or by collagenase digestion of pancreas from 100 brain-dead organ donors (OD). Genotyping (> 8.7 million single nucleotide polymorphisms) and expression (> 47,000 transcripts and splice variants) analyses were combined to generate cis-eQTLs. RESULTS: After applying genome-wide false discovery rate significance thresholds, we identified 1,173 and 1,021 eQTLs in samples of OD and PPP, respectively. Among the strongest eQTLs shared between OD and PPP were CHURC1 (OD p-value=1.71 × 10-24; PPP p-value = 3.64 × 10-24) and PSPH (OD p-value = 3.92 × 10-26; PPP p-value = 3.64 × 10-24). We identified eQTLs in linkage-disequilibrium with GWAS loci T2D and associated traits, including TTLL6, MLX and KIF9 loci, which do not implicate the nearest gene. We found in the PPP datasets 11 eQTL genes, which were differentially expressed in T2D and two genes (CYP4V2 and TSEN2) associated with HbA1c but none in the OD samples. CONCLUSIONS: eQTL analysis of LCM islets from PPP led us to identify novel genes which had not been previously linked to islet biology and T2D. The understanding gained from eQTL approaches, especially using surgical samples of living patients, provides a more accurate 3-dimensional representation than those from genetic studies alone.

9.
Cell Death Dis ; 10(3): 201, 2019 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-30814510

RESUMO

The pressure towards innovation and creation of new model systems in regenerative medicine and cancer research has fostered the development of novel potential therapeutic applications. Kidney injuries provoke a high request of organ transplants making it the most demanding system in the field of regenerative medicine. Furthermore, renal cancer frequently threaten patients' life and aggressive forms still remain difficult to treat. Ethical issues related to the use of embryonic stem cells, has fueled research on adult, patient-specific pluripotent stem cells as a model for discovery and therapeutic development, but to date, normal and cancerous renal experimental models are lacking. Several research groups are focusing on the development of organoid cultures. Since organoids mimic the original tissue architecture in vitro, they represent an excellent model for tissue engineering studies and cancer therapy testing. We established normal and tumor renal cell carcinoma organoids previously maintained in a heterogeneous multi-clone stem cell-like enriching medium. Starting from adult normal kidney specimens, we were able to isolate and propagate organoid 3D-structures composed of both differentiated and undifferentiated cells while expressing nephron specific markers. Furthermore, we were capable to establish organoids derived from cancer tissues although with a success rate inferior to that of their normal counterpart. Cancer cultures displayed epithelial and mesenchymal phenotype while retaining tumor specific markers. Of note, tumor organoids recapitulated neoplastic masses when orthotopically injected into immunocompromised mice. Our data suggest an innovative approach of long-term establishment of normal- and cancer-derived renal organoids obtained from cultures of fleshly dissociated adult tissues. Our results pave the way to organ replacement pioneering strategies as well as to new models for studying drug-induced nephrotoxicity and renal diseases. Along similar lines, deriving organoids from renal cancer patients opens unprecedented opportunities for generation of preclinical models aimed at improving therapeutic treatments.

10.
Eur J Pharm Biopharm ; 137: 23-36, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30779978

RESUMO

The use of nanomaterials is increasing but the real risk associated with their use in humans has to be defined. In fact, nanomaterials tend to accumulate in organs over a long period of time and are slowly degraded or eliminated by the body. Exosomes are nanovesicles actively shuttle molecules, including chemical products and metals, through the body. Macrophages scavenge the body from both organic and inorganic substances, and they use to release high amounts of exosomes. We hypothesized that macrophages may have a role in eliminating nanomaterials through their exosomes. We treated human primary macrophages with 20 nm gold nanoparticles (AuNPs), analyzing the presence of AuNPs in both cells and the released exosomes by the implementation of different techniques, including SP-ICP-MS and NTA. We showed that macrophages endocytosed AuNPs and released them through exosomes. Our study on one hand provide the evidence for a new methodology in the early identification of the nanomaterials levels in exposed subjects. On the other hand we depict a way our body shuttle virtually intact nanoparticles through macrophage-released exosomes.


Assuntos
Exossomos/metabolismo , Ouro/química , Macrófagos/metabolismo , Nanopartículas Metálicas/análise , Células Cultivadas , Humanos , Espectrometria de Massas/métodos , Nanopartículas Metálicas/administração & dosagem
11.
J Enzyme Inhib Med Chem ; 34(1): 272-278, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30734594

RESUMO

Acidity and hypoxia are crucial phenotypes of tumour microenvironment both contributing to the selection of malignant cells under a micro evolutionistic pressure. During the tumour progression, nanovesicles, called exosomes and the metalloenzyme carbonic anhydrase IX (CA IX) affect the tumour growth and proliferation. Exosomes are released into the tumour microenvironment and spilt all over the body, while CA IX is a tumour-associated protein overexpressed in many different solid tumours. In the present study, to better understand the relationships between exosomes and CA IX, it has been used an in vitro cellular model of cells cultured in different pH conditions. The results showed that the acidic microenvironment induced upregulation of both expression and activity of CA IX in cancer cells and their exosomes, together with increasing the number of released exosomes. These data strongly support the importance of CA IX as a cancer biomarker and as a valuable target of new anticancer therapies.


Assuntos
Antígenos de Neoplasias/metabolismo , Anidrase Carbônica IX/metabolismo , Exossomos/metabolismo , Neoplasias da Próstata/metabolismo , Antígenos de Neoplasias/biossíntese , Anidrase Carbônica IX/biossíntese , Linhagem Celular Tumoral , Exossomos/patologia , Humanos , Concentração de Íons de Hidrogênio , Masculino , Microscopia Confocal , Neoplasias da Próstata/patologia
13.
Nat Commun ; 9(1): 4774, 2018 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-30429480

RESUMO

The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, UK, and USA comprising 52,506 individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs in KITLG and a region of 9q32. In a bivariate analysis combining the nevus results with a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B, DOCK8, and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level. Overall, we conclude that most nevus genes affect melanoma risk (KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis.

14.
Cancers (Basel) ; 10(10)2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30301144

RESUMO

Exosomes are extracellular nanovesicles primarily involved in the pathogenesis of many diseases including cancer. This study was set out from recent evidence that extracellular acidity may increase the exosome release by cancer cells. However, this preliminary evidence did not provide solid information on whether the pH-dependent exosome over-release represents a common feature of all cancers. To the purpose of demonstrating that cancer acidity is a major determinant in inducing an increased exosome release by human cancer cells, we evaluated human tumor cell lines deriving from either colon, breast, prostate cancers, melanoma, or osteosarcoma. All cell lines were cultured in either the current 7.4 pH or the typical pH of cancer that is 6.5. The levels of released extracellular vesicles were measured by protein counts, nanoparticle tracking analysis (NTA), and nanoscale flow cytometry. The results showed that pH 6.5 induced a remarkable increase in exosome release, and buffering the medium significantly reduced the exosome release in all cancers. With these results, we provide, for the first time, evidence that tumor acidity and exosome levels represent common cancer phenotypes.

15.
Front Immunol ; 9: 1936, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30279686

RESUMO

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis. A third of psoriatic patients develop PsA via unknown mechanisms. No reliable diagnostic markers are available for PsA, or prognostic biomarkers for PsA development in psoriasis. We previously uncovered a pro-inflammatory role for cathelicidin LL37 in lesional psoriasis skin. LL37 binds nucleic acids and stimulates plasmacytoid/myeloid dendritic cells (pDC, mDCs) to secrete type I interferon (IFN-I) and pro-inflammatory factors. LL37 becomes an autoantigen for psoriatic Th1-Th17/CD8 T cells. Anti-LL37 antibodies were detected in systemic lupus erythematosus, an autoimmune disease characterized by neutrophil-extracellular-traps release (NETosis) in target organs. LL37 can be substrate of irreversible post-translational modifications, citrullination or carbamylation, linked to neutrophil activity. Here we analyzed inflammatory factors, included LL37, in PsA and psoriasis plasma and PsA synovial fluids (SF)/biopsies. We show that LL37 (as a product of infiltrating neutrophils) and autoantibodies to LL37 are elevated in PsA, but not OA SF. Anti-LL37 antibodies correlate with clinical inflammatory markers. Anti-carbamylated/citrullinated-LL37 antibodies are present in PsA SF/plasma and, at lower extent, in psoriasis plasma, but not in controls. Plasma anti-carbamylated-LL37 antibodies correlate with PsA (DAS44) but not psoriasis (PASI) disease activity. Ectopic lymphoid structures, and deposition of immunoglobulin-(Ig)G-complexes (IC) co-localizing with infiltrating neutrophils, are observed in PsA and not OA synovial tissues (ST). Activated complement (C5a, C9), GM-CSF and IFN-I are up-regulated in PsA and not OA synovia and in PsA and psoriasis plasma but not in HD. C9 and GM-CSF levels in PsA SF correlate with clinical inflammatory markers and DAS44 (C9) and with anti-carbamylated/citrullinated-LL37 antibodies (GM-CSF and IFN-I). Thus, we uncover a role for LL37 as a novel PsA autoantibody target and correlation studies suggest participation of anti-LL37 antibodies to PsA pathogenesis. Notably, plasma antibodies to carbamylated-LL37, which correlate with DAS44, suggest their use as new disease activity markers. GM-CSF and complement C5a and C9 elevation may be responsible for autoantigens release by neutrophils and their modification, fueling inflammation and autoreactivity establishment. Finally, targeting GM-CSF, C5a, C9 can be beneficial in PsA.

16.
Appl Microbiol Biotechnol ; 102(20): 8629-8646, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30078138

RESUMO

Owing to the increased cost-effectiveness of high-throughput technologies, the number of studies focusing on the human microbiome and its connections to human health and disease has recently surged. However, best practices in microbiology and clinical research have yet to be clearly established. Here, we present an overview of the challenges and opportunities involved in conducting a metagenomic study, with a particular focus on data processing and analytical methods.


Assuntos
Bactérias/isolamento & purificação , Infecções Bacterianas/microbiologia , Metagenômica , Bactérias/classificação , Bactérias/genética , Protocolos Clínicos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Metagenômica/métodos , Microbiologia
17.
Nephrol Dial Transplant ; 33(12): 2101-2112, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29905852

RESUMO

Immunoglobulin A nephropathy (IgAN) is the most common worldwide primary glomerulonephritis with a strong autoimmune component. The disease shows variability in both clinical phenotypes and endpoints and can be potentially subdivided into more homogeneous subtypes through the identification of specific molecular biomarkers. This review focuses on the role of omics in driving the identification of potential molecular subtypes of the disease through the integration of multilevel data from genomics, transcriptomics, epigenomics, proteomics and metabolomics. First, the identification of molecular biomarkers, including mapping of the full spectrum of common and rare IgAN risk alleles, could permit a more precise stratification of IgAN patients. Second, the analysis of transcriptomic patterns and their modulation by epigenetic factors like microRNAs has the potential to increase our understanding in the pathogenic mechanisms of the disease. Third, the specificity of urinary proteomic and metabolomic signatures and the understanding of their functional relevance may contribute to the development of new non-invasive biomarkers for a better molecular characterization of the renal damage and its follow-up. All these approaches can give information for targeted therapeutic decisions and will support novel clinical decision making. In conclusion, we offer a framework of omic studies and outline barriers and potential solutions that should be used for improving the diagnosis and treatment of the disease. The ongoing decade is exploiting novel high-throughput molecular technologies and computational analyses for improving the diagnosis (precision nephrology) and treatment (personalized therapy) of the IgAN subtypes.

18.
Gigascience ; 7(7)2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29917068

RESUMO

YAMP ("Yet Another Metagenomics Pipeline") is a user-friendly workflow that enables the analysis of whole shotgun metagenomic data while using containerization to ensure computational reproducibility and facilitate collaborative research. YAMP can be executed on any UNIX-like system and offers seamless support for multiple job schedulers as well as for the Amazon AWS cloud. Although YAMP was developed to be ready to use by nonexperts, bioinformaticians will appreciate its flexibility, modularization, and simple customization.


Assuntos
Biologia Computacional/métodos , Metagenômica/métodos , Fluxo de Trabalho , Simulação por Computador , Humanos , Internet , Reprodutibilidade dos Testes , Software
19.
Int J Mol Sci ; 19(5)2018 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-29783743

RESUMO

In this study, we report how the cholera toxin (CT) A subunit (CTA), the enzyme moiety responsible for signaling alteration in host cells, enters the exosomal pathway, secretes extracellularly, transmits itself to a cell population. The first evidence for long-term transmission of CT's toxic effect via extracellular vesicles was obtained in Chinese hamster ovary (CHO) cells. To follow the CT intracellular route towards exosome secretion, we used a novel strategy for generating metabolically-labeled fluorescent exosomes that can be counted by flow cytometry assay (FACS) and characterized. Our results clearly show the association of CT with exosomes, together with the heat shock protein 90 (HSP90) and Protein Disulfide Isomerase (PDI) molecules, proteins required for translocation of CTA across the ER membrane into the cytoplasm. Confocal microscopy showed direct internalization of CT containing fluorescent exo into CHO cells coupled with morphological changes in the recipient cells that are characteristic of CT action. Moreover, Me665 cells treated with CT-containing exosomes showed an increase in Adenosine 3',5'-Cyclic Monophosphate (cAMP) level, reaching levels comparable to those seen in cells exposed directly to CT. Our results prompt the idea that CT can exploit an exosome-mediated cell communication pathway to extend its pathophysiological action beyond an initial host cell, into a multitude of cells. This finding could have implications for cholera disease pathogenesis and epidemiology.


Assuntos
Fatores de Ribosilação do ADP/metabolismo , Toxina da Cólera/metabolismo , Exossomos/metabolismo , Animais , Células CHO , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Cólera/etiologia , Toxina da Cólera/química , Toxina da Cólera/toxicidade , Cricetinae , Cricetulus , AMP Cíclico/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Isomerases de Dissulfetos de Proteínas/metabolismo , Subunidades Proteicas/metabolismo , Transporte Proteico
20.
Nat Commun ; 9(1): 1684, 2018 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-29739929

RESUMO

The skin's tendency to sunburn rather than tan is a major risk factor for skin cancer. Here we report a large genome-wide association study of ease of skin tanning in 176,678 subjects of European ancestry. We identify significant association with tanning ability at 20 loci. We confirm previously identified associations at six of these loci, and report 14 novel loci, of which ten have never been associated with pigmentation-related phenotypes. Our results also suggest that variants at the AHR/AGR3 locus, previously associated with cutaneous malignant melanoma the underlying mechanism of which is poorly understood, might act on disease risk through modulation of tanning ability.

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