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1.
J Mater Sci Mater Med ; 30(9): 107, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31512084

RESUMO

In the present study, collagen hydrogel containing naringin was fabricated, characterized and used as the scaffold for peripheral nerve damage treatment. The collagen was dissolved in acetic acid, naringin added to the collagen solution, and cross-linked with 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide powder (EDC; 0.10 mM) to form the hydrogel. The microstructure, swelling behavior, biodegradation, and cyto/hemocompatibility of the fabricated hydrogels were assessed. Finally, the healing efficacy of the prepared collagen hydrogel loaded with naringin on the sciatic nerve crush injury was assessed in the animal model. The characterization results showed that the fabricated hydrogels have a porous structure containing interconnected pores with the average pore size of 90 µm. The degradation results demonstrated that about 70% of the primary weight of the naringin loaded hydrogel had been lost after 4 weeks of storage in PBS. The in vitro study showed that the proliferation of Schwann cells on the collagen/naringin hydrogel was higher than the control group (tissue culture plate) at both 48 and 72 h after cell seeding and even significantly higher than pure collagen 72 h after cell seeding (*p < 0.005, **p < 0.001). The animal study implied that the sciatic functional index reached to -22.13 ± 3.00 at the end of 60th days post-implantation which was statistically significant (p < 0.05) compared with the negative control (injury without the treatment) (-82.60 ± 1.06), and the pure collagen hydrogel (-59.80 ± 3.20) groups. The hot plate latency test, the compound muscle action potential, and wet weight-loss of the gastrocnemius muscle evaluation confirmed the positive effect of the prepared hydrogels on the healing process of the induced nerve injury. In the final, the histopathologic examinations depicted that the collagen/naringin hydrogel group reduced all the histological changes induced from the nerve injury and showed more resemblance to the normal sciatic nerve, with well-arranged fibers and intact myelin sheath. The overall results implied that the prepared collagen/naringin hydrogel can be utilized as a sophisticated alternative to healing peripheral nerve damages.

2.
J Biomed Mater Res A ; 107(10): 2340-2349, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31161710

RESUMO

Tissue engineering is one of the most promising areas for treatment of various ophthalmic diseases particularly for patients who suffer from limbal stem cell deficiency and this is due to the lack of existence of appropriate matrix for stem cell regeneration. The aim of this research project is to design and fabricate triple layered electrospun nanofibers as a suitable corneal tissue engineering scaffold and the objective is to investigate and perform various in vitro tests to find the most optimum and suitable scaffold for this purpose. Electrospun scaffolds were prepared in three layers. Poly(d, l-lactide-co-glycolide; PLGA, 50:50) nanofibers were electrospun as outer and inner layers of the scaffold and aligned type I collagen nanofibers were electrospun in the middle layer. Furthermore, the scaffolds were cross-linked by 1-ethyl-3-(3 dimethylaminopropyl) carbodiimide hydrochloride and glutaraldehyde. Structural, physical, and mechanical properties of scaffolds were investigated by using N2 adsorption/desorption isotherms, Fourier transform infrared spectroscopy, contact angle measurement, tensile test, degradation, shrinkage analysis, and scanning electron microscopy (SEM). In addition, capability to support cell attachment and viability were characterized by SEM, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, and 4',6-diamidino-2-phenylindole staining. According to the result of Brunauer-Emmett-Teller analysis, specific surface area of electrospun scaffold was about 23.7 m2 g-1 . Tensile tests on cross-linked scaffolds represented more suitable hydrophilicity and tensile behavior. In addition, degradation rate analysis indicated that noncross-linked scaffolds degraded faster than cross-linked one and cross-linking led to controlled shrinkage in the scaffold. The SEM analysis depicted nano-sized fibers in good shape. Also, the in vitro study represented an improved cell attachment and proliferation in the presence of human endometrial stem cells for both cross-linked and noncross-linked samples. The current study suggests the possibility of producing an appropriate substrate for successful cornea tissue engineering with a novel design.

3.
Am J Nephrol ; 49(3): 193-202, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30808845

RESUMO

BACKGROUND: Serum urea level is a heritable trait, commonly used as a diagnostic marker for kidney function. Genome-wide association studies (GWAS) in East-Asian populations identified a number of genetic loci related to serum urea, however there is a paucity of data for European populations. METHODS: We performed a two-stage meta-analysis of GWASs on serum urea in 13,312 participants, with independent replication in 7,379 participants of European ancestry. RESULTS: We identified 6 genome-wide significant single nucleotide polymorphisms (SNPs) in or near 6 loci, of which 2 were novel (POU2AF1 and ADAMTS9-AS2). Replication of East-Asian and Scottish data provided evidence for an additional 8 loci. SNPs tag regions previously associated with anthropometric traits, serum magnesium, and urinary albumin-to-creatinine ratio, as well as expression quantitative trait loci for genes preferentially expressed in kidney and gastro-intestinal tissues. CONCLUSIONS: Our findings provide insights into the genetic underpinnings of urea metabolism, with potential relevance to kidney function.

4.
J Cell Physiol ; 234(8): 12290-12300, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30609022

RESUMO

Acute renal failure (ARF) is a clinical challenge that is highly resistant to treatment, and its high rate of mortality is alarming. Ischemia-reperfusion injury (IRI) is the most common cause of ARF. Especially IRI is implicated in kidney transplantation and can determine graft survival. Although the exact pathophysiology of renal IRI is unknown, the role of inflammatory responses has been elucidated. Because mesenchymal stromal cells (MSCs) have strong immunomodulatory properties, they are under extensive investigation as a therapeutic modality for renal IRI. Extracellular vesicles (EVs) play an integral role in cell-to-cell communication. Because the regenerative potential of the MSCs can be recapitulated by their EVs, the therapeutic appeal of MSC-derived EVs has dramatically increased in the past decade. Higher safety profile and ease of preservation without losing function are other advantages of EVs compared with their producing cells. In the current review, the preliminary results and potential of MSC-derived EVs to alleviate kidney IRI are summarized. We might be heading toward a cell-free approach to treat renal IRI.

5.
Mol Psychiatry ; 2019 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-30626913

RESUMO

Although a genetic basis of depression has been well established in twin studies, identification of genome-wide significant loci has been difficult. We hypothesized that bivariate analyses of findings from a meta-analysis of genome-wide association studies (meta-GWASs) of the broad depression phenotype with those from meta-GWASs of self-reported and recurrent major depressive disorder (MDD), bipolar disorder and schizophrenia would enhance statistical power to identify novel genetic loci for depression. LD score regression analyses were first used to estimate the genetic correlations of broad depression with self-reported MDD, recurrent MDD, bipolar disorder and schizophrenia. Then, we performed four bivariate GWAS analyses. The genetic correlations (rg ± SE) of broad depression with self-reported MDD, recurrent MDD, bipolar disorder and schizophrenia were 0.79 ± 0.07, 0.24 ± 0.08, 0.53 ± 0.09 and 0.57 ± 0.05, respectively. From a total of 20 independent genome-wide significant loci, 13 loci replicated of which 8 were novel for depression. These were MUC21 for the broad depression phenotype with self-reported MDD and ZNF804A, MIR3143, PSORS1C2, STK19, SPATA31D1, RTN1 and TCF4 for the broad depression phenotype with schizophrenia. Post-GWAS functional analyses of these loci revealed their potential biological involvement in psychiatric disorders. Our results emphasize the genetic similarities among different psychiatric disorders and indicate that cross-disorder analyses may be the best way forward to accelerate gene finding for depression, or psychiatric disorders in general.

6.
Am J Hum Genet ; 103(5): 691-706, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30388399

RESUMO

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

7.
Int J Biol Macromol ; 117: 601-609, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-29807077

RESUMO

In the current study, insulin delivering chitosan nanoparticles were coated onto the electrospun poly (ε-caprolactone) (PCL)/Collagen (COLL) to produce a potential wound care material. Electrospun matrices were fabricated from PCL/COLL (1:1 (w/w)) solution. The insulin-loaded chitosan nanoparticles were produced by ionic gelation process and then attached onto the yarns. The dressings were investigated regarding their surface wettability, microstructure, the capacity to absorb water, water vapour permeability, mechanical properties, blood compatibility, microbial penetration, and cellular behavior. Full-thickness excisional wound model was used to assess the in vivo healing capacity of the dressings. Our data showed that after 14 days the wounds covered with PCL/COLL/Cs-Ins wound dressing could reach to nearly full wound closure compared with the sterile gauze which exhibited nearly 45% of wound size reduction. Our results suggest that fabricated scaffolds can be potentially applied in clinical practice for wound treatment.


Assuntos
Quitosana/uso terapêutico , Nanopartículas/uso terapêutico , Pele/efeitos dos fármacos , Cicatrização , Animais , Bandagens , Quitosana/química , Insulina/química , Nanopartículas/química , Ratos , Pele/lesões , Molhabilidade/efeitos dos fármacos
8.
Artif Cells Nanomed Biotechnol ; : 1-11, 2018 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-29458271

RESUMO

The present study aimed to evaluate the efficacy of cellulose acetate/gelatin/nanohydroxyapatite (CA/Gel/nHA) nanocomposite mats as the wound dressing. The dressings were prepared with electrospinning of CA/Gel solutions containing 12.5, 25 and 50 mg nHA. The dressings were evaluated regarding their water uptake capacity, morphology, tensile strength, water vapour transmission rate, wettability and cellular response with L929 cell line. The results showed that the concentration of nHA had a direct correlation with porosity, water contact angle, water uptake, water vapor transmission rate and proliferation. In vivo studies showed that all dressings had higher wound closure percent than the sterile gauze, as the control. The highest wound closure value was achieved in the CA/Gel +25 mg nHA group, which showed 93.5 ± 1.6%. The histological and the histomorphometric examinations of the wounds revealed that the CA/Gel +25 mg nHA dressing had the greatest collagen synthesis, re-epithelialization, neovascularization and also the best cosmetic appearance. Based on our finding, it could be concluded the applicability of electrospun nanofibrous CA/Gel/nHA dressings for successful wound treatment.

9.
J Physiol Sci ; 68(5): 579-587, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28879494

RESUMO

The current study aimed to enhance the efficacy of peripheral nerve regeneration using a hydroxyapatite nanoparticle-containing collagen type I hydrogel. A solution of type I collagen, extracted from the rat tails, was incorporated with hydroxyapatite nanoparticles (with the average diameter of ~212 nm) and crosslinked with 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) to prepare the hydrogel. The Schwann cell cultivation on the prepared hydrogel demonstrated a significantly higher cell proliferation than the tissue culture plate, as positive control, after 48 h (n = 3, P < 0.005) and 72 h (n = 3, P < 0.01). For in vivo evaluation, the prepared hydrogel was administrated on the sciatic nerve crush injury in Wistar rats. Four groups were studied: negative control (with injury but without interventions), positive control (without injury), collagen hydrogel and hydroxyapatite nanoparticle-containing collagen hydrogel. After 12 weeks, the administration of hydroxyapatite nanoparticle-containing collagen significantly (n = 4, P < 0.005) enhanced the functional behavior of the rats compared with the collagen hydrogel and negative control groups as evidenced by the sciatic functional index, hot plate latency and compound muscle action potential amplitude measurements. The overall results demonstrated the applicability of the produced hydrogel for the regeneration of peripheral nerve injuries.


Assuntos
Colágeno Tipo I/farmacologia , Durapatita/química , Hidrogéis/farmacologia , Regeneração Nervosa/efeitos dos fármacos , Células de Schwann/efeitos dos fármacos , Nervo Isquiático/lesões , Animais , Células Cultivadas , Colágeno Tipo I/química , Hidrogéis/química , Masculino , Músculo Esquelético/inervação , Músculo Esquelético/fisiologia , Atrofia Muscular , Nanopartículas , Ratos
10.
Mol Biol Rep ; 44(5): 407-412, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28980161

RESUMO

This is the first study demonstrating the efficacy of menstrual blood-derived stem cell (MenSC) transplantation via a neural guidance conduit, for peripheral nerve regeneration. The synthesized poly (ɛ-caprolactone)/Gelatin conduit, filled with collagen type I and seeded with 3 × 104 MenSCs, was implanted into a rat's 10 mm sciatic nerve defect. The results of hot plate latency, sciatic functional index and weight-loss percentage of wet gastrocnemius muscle demonstrated that the MenSC transplantation had comparable nerve regeneration outcome to autograft, as the gold standard of nerve bridging. The transplantation of MenSCs via a synthetic conduit could ameliorate the functional recovery of sciatic nerve-injured rats which make them a potential candidate for cell therapy of peripheral nervous system disorders.


Assuntos
Regeneração Tecidual Guiada/métodos , Regeneração Nervosa/fisiologia , Nervo Isquiático/fisiologia , Transplante de Células-Tronco/métodos , Células-Tronco/citologia , Adulto , Animais , Células Cultivadas , Feminino , Humanos , Masculino , Menstruação/sangue , Doenças do Sistema Nervoso Periférico/terapia , Ratos , Ratos Wistar , Nervo Isquiático/lesões
11.
Atherosclerosis ; 265: 172-178, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28892714

RESUMO

BACKGROUND AND AIMS: Cross-sectional twin and family studies report a moderate heritability of baseline levels of C-reactive protein (CRP), ranging from 0.10 to 0.65 for different age ranges. Here, we investigated the stability and relative impact of genetic and environmental factors underlying serum levels of CRP, using a longitudinal classical twin design. METHODS: A maximum of 6201 female twins from the TwinsUK registry with up to three CRP measurements (i.e. visit 1 [V1], visit 2 [V2] and visit 3 [V3]) over a 10-year follow-up period were included in this study. Structural equation modeling was applied to dissect the observed phenotypic variance into its genetic and environmental components. To estimate the heritability of CRP as well as its genetic and environmental correlations across different time points, a trivariate model was used. RESULTS: Natural log (ln) CRP levels significantly increased from V1 to V2 (p=4.4 × 10-25) and between V1 and V3 (p=1.2 × 10-15), but not between V2 and V3. The median (IQR) follow-up time between V1 and V3 was 9.58 (8.00-10.46) years. Heritability estimates for CRP were around 50% and constant over time (0.46-0.52). Additionally, adjustment for BMI did not meaningfully change the heritability estimates (0.49-0.51). The genetic correlations between visits were significantly smaller than one, ranging from 0.66 to 0.85. CONCLUSIONS: The present study provides evidence for stable heritability estimates of CRP of around 50% with advancing age. However, between-visit genetic correlations are significantly lower than 1, indicating emergence of new genetic effects on CRP levels with age.


Assuntos
Proteína C-Reativa/análise , Interação Gene-Ambiente , Idoso , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Fatores de Tempo
12.
Mater Sci Eng C Mater Biol Appl ; 81: 366-372, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-28887985

RESUMO

In the present study, cerium oxide (CeO2) nanoparticles were incorporated into poly (ε-caprolactone)/gelatin films in order to develop a potential wound dressing material. The wound dressings were prepared by electrospinning of poly (ε-caprolactone)/gelatin (1:1 (w/w)) solutions containing 1.50%, 3% and 6% (w/w) CeO2 nanoparticles. The electrospun films were evaluated regarding their morphology, contact angle, water-uptake capacity, water vapor transmission rate, tensile strength and cellular response. The film containing 1.50% CeO2 nanoparticles was chosen as the optimal dressing for the in vivo study on full-thickness excisional wounds of rats. The study showed that after 2weeks, the wounds treated with the CeO2 nanoparticle-containing dressing achieved a significant closure to nearly 100% compared with the sterile gauze with the nearly 63% of wound closure. Our results provided evidence supporting the possible applicability of CeO2 nanoparticle-containing wound dressing for a successful wound treatment.


Assuntos
Nanopartículas Metálicas , Animais , Bandagens , Cério , Gelatina , Poliésteres , Ratos , Cicatrização
14.
Hypertension ; 2017 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-28739976

RESUMO

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.

15.
Nat Commun ; 8: 15805, 2017 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-28613276

RESUMO

Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74

16.
Nat Genet ; 48(12): 1462-1472, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27798627

RESUMO

The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.


Assuntos
Ordem de Nascimento , Estudo de Associação Genômica Ampla , Paridade/genética , Locos de Características Quantitativas , Reprodução/genética , Comportamento Reprodutivo/fisiologia , Feminino , Fertilidade/genética , Humanos , Idade Materna , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Gravidez
17.
PLoS Med ; 13(6): e1001976, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27327646

RESUMO

BACKGROUND: C-reactive protein (CRP) is associated with immune, cardiometabolic, and psychiatric traits and diseases. Yet it is inconclusive whether these associations are causal. METHODS AND FINDINGS: We performed Mendelian randomization (MR) analyses using two genetic risk scores (GRSs) as instrumental variables (IVs). The first GRS consisted of four single nucleotide polymorphisms (SNPs) in the CRP gene (GRSCRP), and the second consisted of 18 SNPs that were significantly associated with CRP levels in the largest genome-wide association study (GWAS) to date (GRSGWAS). To optimize power, we used summary statistics from GWAS consortia and tested the association of these two GRSs with 32 complex somatic and psychiatric outcomes, with up to 123,865 participants per outcome from populations of European ancestry. We performed heterogeneity tests to disentangle the pleiotropic effect of IVs. A Bonferroni-corrected significance level of less than 0.0016 was considered statistically significant. An observed p-value equal to or less than 0.05 was considered nominally significant evidence for a potential causal association, yet to be confirmed. The strengths (F-statistics) of the IVs were 31.92-3,761.29 and 82.32-9,403.21 for GRSCRP and GRSGWAS, respectively. CRP GRSGWAS showed a statistically significant protective relationship of a 10% genetically elevated CRP level with the risk of schizophrenia (odds ratio [OR] 0.86 [95% CI 0.79-0.94]; p < 0.001). We validated this finding with individual-level genotype data from the schizophrenia GWAS (OR 0.96 [95% CI 0.94-0.98]; p < 1.72 × 10-6). Further, we found that a standardized CRP polygenic risk score (CRPPRS) at p-value thresholds of 1 × 10-4, 0.001, 0.01, 0.05, and 0.1 using individual-level data also showed a protective effect (OR < 1.00) against schizophrenia; the first CRPPRS (built of SNPs with p < 1 × 10-4) showed a statistically significant (p < 2.45 × 10-4) protective effect with an OR of 0.97 (95% CI 0.95-0.99). The CRP GRSGWAS showed that a 10% increase in genetically determined CRP level was significantly associated with coronary artery disease (OR 0.88 [95% CI 0.84-0.94]; p < 2.4 × 10-5) and was nominally associated with the risk of inflammatory bowel disease (OR 0.85 [95% CI 0.74-0.98]; p < 0.03), Crohn disease (OR 0.81 [95% CI 0.70-0.94]; p < 0.005), psoriatic arthritis (OR 1.36 [95% CI 1.00-1.84]; p < 0.049), knee osteoarthritis (OR 1.17 [95% CI 1.01-1.36]; p < 0.04), and bipolar disorder (OR 1.21 [95% CI 1.05-1.40]; p < 0.007) and with an increase of 0.72 (95% CI 0.11-1.34; p < 0.02) mm Hg in systolic blood pressure, 0.45 (95% CI 0.06-0.84; p < 0.02) mm Hg in diastolic blood pressure, 0.01 ml/min/1.73 m2 (95% CI 0.003-0.02; p < 0.005) in estimated glomerular filtration rate from serum creatinine, 0.01 g/dl (95% CI 0.0004-0.02; p < 0.04) in serum albumin level, and 0.03 g/dl (95% CI 0.008-0.05; p < 0.009) in serum protein level. However, after adjustment for heterogeneity, neither GRS showed a significant effect of CRP level (at p < 0.0016) on any of these outcomes, including coronary artery disease, nor on the other 20 complex outcomes studied. Our study has two potential limitations: the limited variance explained by our genetic instruments modeling CRP levels in blood and the unobserved bias introduced by the use of summary statistics in our MR analyses. CONCLUSIONS: Genetically elevated CRP levels showed a significant potentially protective causal relationship with risk of schizophrenia. We observed nominal evidence at an observed p < 0.05 using either GRSCRP or GRSGWAS-with persistence after correction for heterogeneity-for a causal relationship of elevated CRP levels with psoriatic osteoarthritis, rheumatoid arthritis, knee osteoarthritis, systolic blood pressure, diastolic blood pressure, serum albumin, and bipolar disorder. These associations remain yet to be confirmed. We cannot verify any causal effect of CRP level on any of the other common somatic and neuropsychiatric outcomes investigated in the present study. This implies that interventions that lower CRP level are unlikely to result in decreased risk for the majority of common complex outcomes.


Assuntos
Proteína C-Reativa/genética , Estudo de Associação Genômica Ampla , Cardiopatias/genética , Doenças do Sistema Imunitário/genética , Análise da Randomização Mendeliana , Transtornos Mentais/genética , Doenças Metabólicas/genética , Proteína C-Reativa/metabolismo , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único
18.
BMC Genomics ; 17: 443, 2016 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-27286809

RESUMO

BACKGROUND: Genome-wide association studies (GWAS) have identified multiple genetic loci for C-reactive protein (CRP) and lipids, of which some overlap. We aimed to identify genetic pleiotropy among CRP and lipids in order to better understand the shared biology of chronic inflammation and lipid metabolism. RESULTS: In a bivariate GWAS, we combined summary statistics of published GWAS on CRP (n = 66,185) and lipids, including LDL-cholesterol, HDL-cholesterol, triglycerides, and total cholesterol (n = 100,184), using an empirical weighted linear-combined test statistic. We sought replication for novel CRP associations in an independent sample of 17,743 genotyped individuals, and performed in silico replication of novel lipid variants in 93,982 individuals. Fifty potentially pleiotropic SNPs were identified among CRP and lipids: 21 for LDL-cholesterol and CRP, 20 for HDL-cholesterol and CRP, 21 for triglycerides, and CRP and 20 for total cholesterol and CRP. We identified and significantly replicated three novel SNPs for CRP in or near CTSB/FDFT1 (rs10435719, Preplication: 2.6 × 10(-5)), STAG1/PCCB (rs7621025, Preplication: 1.4 × 10(-3)) and FTO (rs1558902, Preplication: 2.7 × 10(-5)). Seven pleiotropic lipid loci were replicated in the independent set of MetaboChip samples of the Global Lipids Genetics Consortium. Annotating the effect of replicated CRP SNPs to the expression of nearby genes, we observed an effect of rs10435719 on gene expression of FDFT1, and an effect of rs7621025 on PCCB. CONCLUSIONS: Our large scale combined GWAS analysis identified numerous pleiotropic loci for CRP and lipids providing further insight in the genetic interrelation between lipids and inflammation. In addition, we provide evidence for FDFT1, PCCB and FTO to be associated with CRP levels.


Assuntos
Estudo de Associação Genômica Ampla , Inflamação/genética , Metabolismo dos Lipídeos/genética , Herança Multifatorial , Locos de Características Quantitativas , Biomarcadores , Proteína C-Reativa , HDL-Colesterol , Replicação do DNA , Expressão Gênica , Estudos de Associação Genética , Polimorfismo de Nucleotídeo Único , Triglicerídeos
19.
Am J Hum Genet ; 98(4): 680-96, 2016 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-27040690

RESUMO

Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2 × 10(-16)). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure.


Assuntos
Metilação de DNA , Epigênese Genética , Fumar/efeitos adversos , Asma/etiologia , Asma/genética , Criança , Pré-Escolar , Mapeamento Cromossômico , Fenda Labial/etiologia , Fenda Labial/genética , Fissura Palatina/etiologia , Fissura Palatina/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudos de Associação Genética , Humanos , Lactente , Recém-Nascido , Gravidez
20.
Bioinformatics ; 32(10): 1552-4, 2016 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-26803157

RESUMO

UNLABELLED: Genome-wide association study (GWAS) of a biomarker is complicated when the assay procedure of the biomarker is restricted by a Limit of Detection (LOD). Those observations falling outside the LOD cannot be simply discarded, but should be included into the analysis by applying an appropriate statistical method. However, the problem of LOD in GWAS analysis of such biomarkers is usually overlooked. 'lodGWAS' is a flexible, easy-to-use R package that provides a simple and elegant way for GWAS analysis of such biomarkers while simultaneously accommodating the problem of LOD by applying a parametric survival analysis method. AVAILABILITY AND IMPLEMENTATION: http://cran.r-project.org/web/packages/lodGWAS CONTACTS: a.vaez@umcg.nl or i.m.nolte@umcg.nl SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Biomarcadores , Estudo de Associação Genômica Ampla/métodos , Software , Humanos , Limite de Detecção
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