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1.
Artigo em Inglês | MEDLINE | ID: mdl-31677796

RESUMO

The prognosis for hepatocellular carcinoma (HCC) is dismal. Long noncoding RNA PVT1 has been linked to malignancies and might be a deleterious therapy target. However, the key events controlling its expression in HCC remain undetermined. Here, we address how PVT1 is fine-regulated and its downstream signaling in hepatoma cells. Interestingly, we found that c-Myc and P53 could divergently regulate PVT1 transcription. Oncoprotein c-Myc enhances PVT1 expression, whereas P53 suppresses its expression. We also identified miR-214 as a crucial, negative regulator of PVT1. Consistently, high miR-214 levels were significantly correlated with diminished PVT1 expression in HCC specimens. Silencing of PVT1 by ectopic miR-214 or siRNAs markedly inhibited viability and invasion of HCC cells. In opposition, inhibition of endogenous miR-214 promoted PVT1 expression and enhanced cell proliferation. Notably, oncogenic GDF15 is a potential downstream target of the miR-214-PVT1 signaling. Collectively, our results show that the c-Myc/P53/miR-214-PVT1-GDF15 axis is implicated in HCC development, shedding light on the mechanistic actions of PVT1 and representing potential targets for HCC clinical intervention.

2.
J Dairy Sci ; 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31677837

RESUMO

Donkey milk has been widely shown to be an ideal substitute for human milk because of its similar composition. However, alterations to the composition of donkey milk during lactation have not been well studied. In this study, untargeted metabolomics with ultra-high-performance liquid tandem chromatography quadrupole time-of-flight mass spectrometry were used to analyze and compare the metabolites in donkey colostrum (DC) and mature milk (DMM). Two hundred seventy metabolites were characterized in both DC and DMM. Fifty-two of the metabolites in the DC were significantly different from those in the DMM; 8 were downregulated and 44 were upregulated. This demonstrated that the composition of the donkey milk changed with lactation. Additionally, the interactions and metabolic pathways were further analyzed to explore the mechanisms that altered the milk during lactation. Our results provide comprehensive insights into the alterations in donkey milk during lactation. The results will aid in future investigations into the nutrition of donkey milk and provide practical information for the dairy industry.

4.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 41(5): 702-708, 2019 Oct 30.
Artigo em Chinês | MEDLINE | ID: mdl-31699204

RESUMO

Alzheimer's disease(AD)is a central nervous system disease characterized by progressive cognitive dysfunction and memory loss.Increasing evidences suggest that ß amyloid(Aß)plays a critical role and may be a upstream molecule in AD pathogenesis involving both genetic and environmental factors.Aß accumulation and its related inflammation are considered early events preceding neurodegeneration and neuronal loss in AD brain.However,all strategies and compounds targeting Aß deposition have failed in clinical trials,implying complexity of AD pathogenesis.This article reviews Aß hypothesis and its related mechanisms,pathophysiological process,and therapeutics of AD.

5.
Diabetes Care ; 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31582428

RESUMO

OBJECTIVE: We evaluated the associations of long-term changes in consumption of sugary beverages (including sugar-sweetened beverages and 100% fruit juices) and artificially sweetened beverages (ASBs) with subsequent risk of type 2 diabetes. RESEARCH DESIGN AND METHODS: We followed up 76,531 women in the Nurses' Health Study (1986-2012), 81,597 women in the Nurses' Health Study II (1991-2013), and 34,224 men in the Health Professionals' Follow-up Study (1986-2012). Changes in beverage consumption (in 8-ounce serving/day) were calculated from food frequency questionnaires administered every 4 years. Multivariable Cox proportional regression models were used to calculate hazard ratios for diabetes associated with changes in beverage consumption. Results of the three cohorts were pooled using an inverse variance-weighted, fixed-effect meta-analysis. RESULTS: During 2,783,210 person-years of follow-up, we documented 11,906 incident cases of type 2 diabetes. After adjustment for BMI and initial and changes in diet and lifestyle covariates, increasing total sugary beverage intake (including both sugar-sweetened beverages and 100% fruit juices) by >0.50 serving/day over a 4-year period was associated with a 16% (95% CI 1%, 34%) higher diabetes risk in the subsequent 4 years. Increasing ASB consumption by >0.50 serving/day was associated with 18% (2-36%) higher diabetes risk. Replacing one daily serving of sugary beverage with water, coffee or tea, but not ASB, was associated with a 2-10% lower diabetes risk. CONCLUSIONS: Increasing consumption of sugary beverages or ASBs was associated with a higher risk of type 2 diabetes, albeit the latter may be affected by reverse causation and surveillance bias.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31574201

RESUMO

While esters are frequently used as traditional electrophiles in substitution chemistry, their application in cross-coupling chemistry is still in its infancy. This work demonstrates that methyl esters can be used as coupling electrophiles in Ni-catalyzed Heck-type reactions through the challenging cleavage of the C(acyl)-O bond under relatively mild reaction conditions at either 80 or 100 °C. With the σ-NiII intermediate generated from the insertion of acyl NiII species into the tethered C=C bond, carbonyl-retentive products were formed by domino Heck/Suzuki-Miyaura coupling and Heck/reduction pathways when organoboron and mild hydride nucleophiles are used.

7.
Chemistry ; 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31642548

RESUMO

Local eight-coordination of the Dy(III) with D 6h symmetry receives much expectation for high-performance single-molecule magnets (SMMs) due to the simultaneous fulfillment of the magnetic axiality and high coordination number (a requisite for the air stability). But the experimental realization is challenging due to the required restriction of six coordination atoms in the equatorial plane of the hexagonal-bipyramid, which is usually too crowded for the central Dy(III) ion. Here we show by using the hexaaza macrocyclic Schiff base ligand and fine-tuning the axial alkoxide/phenol type ligands, a family of hexagonal-bipyramidal Dy(III) complexes, namely [Dy III (L E )(Cl) 2 (H 2 O/CH 3 OH)]Cl·8MeOH 1 , [Dy III (L E )(C 6 F 5 O) 2 (H 2 O)](BPh 4 )·2THF· 2 , [Dy III (L E )(PhO) 2 ](BPh 4 )· 4THF 3 , [Dy III (L E )(4-MeO-PhO) 2 ](BPh 4 )· 3THF 4 , [Dy III (L E )(naPhO) 2 ](BPh 4 )·4THF 5 and [Dy III (L E )(Ph 3 SiO) 2 ](BPh 4 )·4THF 6 (L E = (2E,4R,5R,6E,9E,11R,12R,13E)-4,5,11,12-tetraphenyl-3,6,10,13-tetraaza-1,8(2,6)-dipyridina-cyclotetradecaphane-2,6,9,13-tetraene ), can be isolated . Among them, complexes 3 , 4 and 5 possess near ly perfect D 6h local symmetry . Complex 4 shows the highest effective magnetic reversal barrier 1338(3) K and an open hysteresis temperature 6 K at the field sweeping rate of 1.2 mT/s, which represents a new record for D 6h SMMs.

8.
J Agric Food Chem ; 67(44): 12322-12332, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31638792

RESUMO

The objective of the present study was to reveal the antibacterial mechanism of lactobionic acid (LBA) against methicillin-resistant Staphylococcus aureus (MRSA) using quantitative proteomics by sequential window acquisition of all theoretical mass spectra (SWATH-MS) to analyze 100 differentially expressed proteins after LBA treatment. Furthermore, multiple experiments were conducted to validate the results of the proteomic analysis including reactive oxygen species (ROS), virulence-associated gene expression, and the relative quantification of target proteins and genes by parallel reaction monitoring and quantitative real-time PCR. Combining the ultrastructure observations, proteomic analysis, and our previous research, the mode of LBA action against MRSA was speculated as cell wall damage and loss of membrane integrity; inhibition of DNA repair and protein synthesis; inhibition of virulence factors and biofilm production; induction of oxidative stress; and inhibition of metabolic pathways. These results suggest potential applications for LBA in food safety and pharmaceuticals, considering its multitarget effects against MRSA.

9.
Molecules ; 24(20)2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31614601

RESUMO

To develop new anti-inflammatory agents, a series of 7-O-amide hesperetin derivatives was designed, synthesized and evaluated for anti-inflammatory activity using RAW264.7 cells. All compounds showed inhibitory effect on LPS-induced NO production. Among them, 7-O-(2-(Propylamino)-2-oxoethyl)hesperetin (4d) and 7-O-(2-(Cyclopentylamino)-2-oxoethyl)hesperetin (4k) with hydrophobic side chains exhibited the most potent NO inhibitory activity (IC50 = 19.32 and 16.63 µM, respectively), showing stronger inhibitory effect on the production of pro- inflammatory cytokines tumor necrosis factor (TNF-α), interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) than indomethacin and celecoxib at 10 µM. The structure-activity relationships (SARs) suggested that the 7-O-amide unit was buried in a medium-sized hydrophobic cavity of the bound receptor. Furthermore, compound 4d could also significantly suppress the expression of inducible nitric oxide synthase enzymes (iNOS) and cyclooxygenase-2 (COX-2), through the nuclear factor-kappa B (NF-κB) signaling pathway.

11.
Clin Chim Acta ; 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31654631

RESUMO

BACKGROUND: We evaluated the application value of Xpert MTB/RIF and T-SPOT.TB in the diagnosis of bone and joint tuberculosis. METHODS: One hundred two patients with suspected bone and joint tuberculosis(BJTB) were admitted to Zhengzhou Orthopaedics Hospital, Henan, China from April 2018 to February 2019. The Xpert MTB/RIF and T-SPOT.TB tests were performed using pus specimens and peripheral blood, respectively. The diagnostic performance of Xpert MTB/RIF and T-SPOT.TB tests was evaluated on the basis of the composite reference standard(CRS). RESULT: A Total of 73 suspected BJTB were enrolled and categorized, including 12 confirmed BJTB, 27 probable BJTB and 34 non-BJTB. When CRS was used as the reference, the specificity, PPV and NLR values of the Xpert MTB/RIF assay were significantly higher than those of the T-SPOT.TB assay (97.1% vs. 82.4%, p<0.05; 96.7% vs. 85.4%, p<0.05; 0.26 vs. 0.12, p<0.05). However, the sensitivity, NPV and PLR values of the T-SPOT. TB assay were significantly higher than those of the Xpert MTB/RIF assay(89.7% vs. 74.4%, p<0.05; 87.5% vs. 76.7%, p<0.05; 5.08 vs. 2.52, p<0.05). The AUCs from Xpert MTB/RIF and T-SPOT. TB tests were 0.857 and 0.860, respectively. However, the difference was not statistically significant. The Xpert MTB/RIF and T-SPOT. TB tests demonstrated medium concordance in diagnosing BJTB. CONCLUSION: The sensitivity of T-SPOT.TB test combined with the specificity of Xpert MTB/RIF not only shorten the time of diagnosis but also improve the accuracy of diagnosis of BJTB and reduce the misdiagnosis rate. Therefore, they are useful for early diagnosis of BJTB.

12.
Drug Des Devel Ther ; 13: 3391-3404, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576113

RESUMO

Purpose: It has been reported that approximately 40% of ALI (acute lung injury) incidence resulted from sepsis. Paclitaxel, as a classic anti-cancer drug, plays an important role in the regulation of inflammation. However, we do not know whether it has a protective effect against CLP (cecal ligation and puncture)-induced septic ALI. Our study aims to illuminate the mitigative effects of paclitaxel on sepsis-induced ALI and its relevant mechanisms. Materials and methods: The survival rates and organ injuries were used to evaluate the effects of paclitaxel on CLP mice. The levels of inflammatory cytokines were tested by ELISA. MUC1 siRNA pre-treatment was used to knockdown MUC1 expression in vitro. GO203 was used to inhibit the homodimerization of MUC1-C in vivo. The expression levels of MUC1, TLR 4 and p-NF-κB/p65 were detected by Western blot. Results: Our results showed that paclitaxel improved the survival rates and ameliorated organ injuries especially lung injury in CLP-induced septic mice. These were accompanied by reduced inflammatory cytokines in sera and BALF (bronchoalveolar lavage fluid). We also found paclitaxel could attenuate TLR 4-NF-κB/p65 activation both in lung tissues of septic mice and LPS-stimulated lung type II epithelial cell line A549. At the upstream level, paclitaxel-upregulated expression levels of MUC1 in both in vivo and in vitro experiments. The inhibitory effects of paclitaxel on TLR 4-NF-κB/p65 activation were reversed in lung tissues of septic mice pre-treated with MUC1 inhibitor and in MUC1-knockdown A549 cells. Protection of paclitaxel on sepsis-induced ALI and decrease of inflammatory cytokines were also abolished by inhibition of MUC1. Conclusion: Collectively, these results indicated paclitaxel could significantly alleviate acute lung injury in CLP-induced septic mice and LPS-stimulated lung type II epithelial cell line A549 by activating MUC1 and suppressing TLR-4/NF-κB pathway.

13.
Spectrochim Acta A Mol Biomol Spectrosc ; 226: 117624, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31605965

RESUMO

The structure and hydrogen-bond interaction property of water and a model ionic liquid (IL): 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM][BF4]) were studied using the combination of Fourier transform infrared spectroscopy (FTIR) and density functional theory (DFT) calculations. The O‒D stretching vibration region of the deuterated water was an area of special focus. Excess infrared spectroscopy with enhanced resolution was applied to analyse the original infrared spectra of v(O‒D). It is found that: (1) [BMIM][BF4] forms stable hydrogen-bonds with water in the mixture. (2) The hydrogen-bonds are weak strength, closed shell and electrostatic dominant interactions. The preferred interaction site of [BMIM]+ cation is the hydrogen atom at the C2. (3) Cage hexamer water, cyclic tetramer water, cyclic trimer water, ion cluster-water complex, ion pair-water, and anion-water complexes are identified in the mixture. When the mole fraction of D2O (x(D2O)) is larger than 0.9, ion cluster and ion pair were broken apart into individual cations and anions. The cage hexamer water, cyclic tetramer water, and cyclic trimer water disappear at x(D2O) < 0.8, 0.5, and 0.3, respectively. HDO formed by H/D isotope exchange was detected when x(D2O) is less than 0.3.

14.
Chemistry ; 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31568591

RESUMO

A new supramolecular nanocage, VMOP-31, based on polyoxovanadate as the molecular building block, has been designed and synthesized under solvothermal conditions. The structure of VMOP-31 was determined by single-crystal and powder X-ray diffraction, FTIR spectroscopy, UV/Vis spectrophotometry, and thermogravimetric analysis. The nanocage exhibits octahedral geometry and is constructed of six {V5 O9 Cl(COO)4 } at the vertices and eight TATB (H3 TATB=4,4',4''-(s-triazine-2,4,6-triyl)tribenzoic acid) ligands on the faces. Impressively, VMOP-31 exhibited high efficiency in the inhibition of cell growth of solid tumors, such as human liver cancer cells SMMC-7721, and superior results in the treatment of liver tumors in mice compared with classic cisplatin. Detailed studies revealed that the potential mechanism of cell death induced by VMOP-31 involves cell cycle arrests, DNA damage, and subsequent apoptosis. Moreover, VMOP-31 exhibited negligible side effects in the mice compared with cisplatin. To the best of our knowledge, VMOP-31 is the first supramolecular nanocage applied to hepatic tumors both in vitro and in vivo.

15.
Ren Fail ; 41(1): 937-945, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31599184

RESUMO

The aim of this work was to evaluate the efficacy and safety of botulinum toxin A (BTX-A) treatment in patients with neurogenic detrusor overactivity. PUBMED, EMBASE, and Cochrane Library were identified on 13 May 2017 to identify relevant randomized controlled trials. All data obtained were analyzed using Stata 12.0. Five randomized controlled trials were included in this study. Compared to placebo, the BTX-A groups had significantly fewer urinary incontinence (UI) episodes per day and per week (BTX-A with 300 U for frequency of UI per day at week 2, mean difference (MD): -1.13, 95% confidence interval (CI): -1.89 to -0.37; 200 U; BTX-A with 300 U for frequency of UI per week at week 6, MD: -11.42, 95% CI: -13.91 to -8.93; BTX-A with 200 U for frequency of UI per week at week 6, MD: -10.72, 95% CI: -13.40 to -8.04), increased in maximum cystometric capacity at week 6 (BTX-A with 300 U, MD: 154.88, 95% CI: 133.92-175.84; BTX-A with 200 U, MD: 141.30, 95% CI: 121.28-161.33), decreased maximum detrusor pressure at week 6 (BTX-A with 300 U, MD: -31.72, 95% CI: -37.69 to -25.75; BTX-A with 200 U, MD: -33.47, 95% CI: -39.20 to -27.73). For adverse effects, BTX-A was often associated with more complications and urinary tract infections (BTX-A with 300 U: relative risk (RR):1.42, 95% CI: 1.15-1.76; BTX-A with 200 U: RR: 1.42, 95% CI: 1.11-1.82). This meta-analysis suggests that treatment with BTX-A is effective and safe for neurogenic detrusor overactivity, and recommends using BTX-A with 300 U or with 200 U, as suitable dosage.

16.
Spectrochim Acta A Mol Biomol Spectrosc ; 226: 117641, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31606676

RESUMO

The mixtures of ionic liquid (IL) and acetonitrile (CH3CN) can be used as reaction media, supercapacitors and thermally stable electrolytes. The macroscopic properties of ILs-CH3CN mixtures have been extensively studied. However, some fundamental questions regarding the microscopic properties of ILs-CH3CN mixtures still remain to be answered. In this work, the structure properties and hydrogen-bond interactions of two task-specific ILs, i.e., 1-propylnitrile-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([PCNMIM][Tf2N]) and 1-(2'-hydroxylethyl)-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([C2OHMIM][Tf2N]), and CH3CN were studied using the combination of Fourier transform infrared spectroscopy (FTIR) and density functional theory (DFT) calculations. The aromatic C‒H stretching vibration region of the cation was an area of special focus. Excess infrared spectroscopy with enhanced resolution was applied to analyse the original infrared spectra. It is found that: (1) The two ILs form stable hydrogen-bonds with CH3CN. (2) Ion cluster, ion cluster-acetonitrile, and ion pair-acetonitrile are identified in the mixture. Acetonitrile cannot break apart the strong electronic interaction between the cation and anion in the examined concentration range. (3) The hydrogen-bonds are weak strength, closed shell and electrostatic dominant interactions. (4) The preferred interaction site of [PCNMIM]+ cation is the hydrogen atom at the C2 site, while that of [C2OHMIM]+ cation is the hydrogen atom in the hydroxyl group.

17.
Mycopathologia ; 2019 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31473910

RESUMO

Knowledge about the clinical and laboratory characteristics and prognosis of Talaromyces marneffei infection in children is limited. A retrospective study was conducted on pediatric patients with disseminated T. marneffei infection in a clinical setting. Extracted data included demographic information (age and sex), clinical features, laboratory findings, treatment, and prognosis. Eleven HIV-negative children were enrolled. The male/female ratio was 8:3. The median age of onset was 17.5 months (3.5-84 months). The mortality rate in these children was 36.36% (4/11). Seven children had underlying diseases. All of the children had multiple immunoglobulin abnormalities and immune cell decline. Ten children received voriconazole treatment, and most of the children (7/10) had a complete response to therapy at primary and long-term follow-up assessment; only three children died of talaromycosis. One patient recovered from talaromycosis but died of leukemia. The child who received itraconazole treatment also showed clinical improvement. No adverse events associated with antifungal therapies were recorded during and after the treatment. Talaromycosis is an indicator disease for undiagnosed severe immunodeficiencies in children. Awareness of mycoses in children by pediatricians may prompt diagnosis and timely treatment. Voriconazole is an effective, well-tolerated therapeutic option for disseminated T. marneffei infection in non-HIV-infected children.

18.
Carbohydr Polym ; 225: 115237, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31521291

RESUMO

A series of pH-sensitive carboxymethyl chitosan (CMCS) hydrogels were prepared via ortho ester linkage. DOX-loaded gelatin nanoparticles with an average diameter of around 50 nm were incorporated into hydrogels to obtain hybrid hydrogels (DOX-NPs-Gel), which could be locally implanted into tumor site in any shape. The physicochemical and mechanical properties of these hydrogels could be easily controlled by adjusting the proportion of crosslinking agent. DOX-NPs-Gel showed the pH-dependent degradation and drug release, and only 29.9% of DOX was released within 144 h at pH 7.4, while the cumulative release reached 49.3% and 65% at pH 6.5 and 5.0, respectively. In vivo study demonstrated that the implanted DOX-NPs-Gel efficiently improved DOX accumulation in tumor site through continuously degradation in mildly acidic environment of tumor tissues, and the tumor volume at the end of experiment was only 81.53 mm3, while tumor size reached to 229.22 mm3 and 174.15 mm3 after intravenous treatment with free DOX and DOX-NPs, respectively.

19.
J Med Genet ; 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501240

RESUMO

BACKGROUND: Male infertility is a prevalent issue worldwide, mostly due to the impaired sperm motility. Multiple morphological abnormalities of the sperm flagella (MMAF) present aberrant spermatozoa with absent, short, coiled, bent and irregular-calibre flagella resulting in severely decreased motility. Previous studies reported several MMAF-associated genes accounting for approximately half of MMAF cases. METHODS AND RESULT: We conducted genetic analysis using whole-exome sequencing in 88 Han Chinese MMAF probands. CFAP65 homozygous mutations were identified in four unrelated consanguineous families, and CFAP65 compound heterozygous mutations were found in two unrelated cases with MMAF. All these CFAP65 mutations were null, including four frameshift mutations (c.1775delC [p.Pro592Leufs*8], c.3072_3079dup [p.Arg1027Profs*41], c.1946delC [p.Pro649Argfs*5] and c.1580delT [p.Leu527Argfs*31]) and three stop-gain mutations (c.4855C>T [p.Arg1619*], c.5270T>A [p.Leu1757*] and c.5341G>T [p.Glu1781*]). Additionally, two homozygous CFAP65 variants likely affecting splicing were identified in two MMAF-affected men of Tunisian and Iranian ancestries, respectively. These biallelic variants of CFAP65 were verified by Sanger sequencing and were absent or very rare in large data sets aggregating sequence information from various human populations. CFAP65, encoding the cilia and flagella associated protein 65, is highly and preferentially expressed in the testis. Here we also generated a frameshift mutation in mouse orthologue Cfap65 using CRISPR-Cas9 technology. Remarkably, the phenotypes of Cfap65-mutated male mice were consistent with human MMAF. CONCLUSIONS: Our experimental observations performed on both human subjects and on Cfap65-mutated mice demonstrate that the presence of biallelic mutations in CFAP65 causes the MMAF phenotype and impairs sperm motility.

20.
JAMA Netw Open ; 2(9): e1910915, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31539074

RESUMO

Importance: Observational studies have shown associations of birth weight with type 2 diabetes (T2D) and glycemic traits, but it remains unclear whether these associations represent causal associations. Objective: To test the association of birth weight with T2D and glycemic traits using a mendelian randomization analysis. Design, Setting, and Participants: This mendelian randomization study used a genetic risk score for birth weight that was constructed with 7 genome-wide significant single-nucleotide polymorphisms. The associations of this score with birth weight and T2D were tested in a mendelian randomization analysis using study-level data. The association of birth weight with T2D was tested using both study-level data (7 single-nucleotide polymorphisms were used as an instrumental variable) and summary-level data from the consortia (43 single-nucleotide polymorphisms were used as an instrumental variable). Data from 180 056 participants from 49 studies were included. Main Outcomes and Measures: Type 2 diabetes and glycemic traits. Results: This mendelian randomization analysis included 49 studies with 41 155 patients with T2D and 80 008 control participants from study-level data and 34 840 patients with T2D and 114 981 control participants from summary-level data. Study-level data showed that a 1-SD decrease in birth weight due to the genetic risk score was associated with higher risk of T2D among all participants (odds ratio [OR], 2.10; 95% CI, 1.69-2.61; P = 4.03 × 10-5), among European participants (OR, 1.96; 95% CI, 1.42-2.71; P = .04), and among East Asian participants (OR, 1.39; 95% CI, 1.18-1.62; P = .04). Similar results were observed from summary-level analyses. In addition, each 1-SD lower birth weight was associated with 0.189 SD higher fasting glucose concentration (ß = 0.189; SE = 0.060; P = .002), but not with fasting insulin, 2-hour glucose, or hemoglobin A1c concentration. Conclusions and Relevance: In this study, a genetic predisposition to lower birth weight was associated with increased risk of T2D and higher fasting glucose concentration, suggesting genetic effects on retarded fetal growth and increased diabetes risk that either are independent of each other or operate through alterations of integrated biological mechanisms.

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