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1.
Int J Cancer ; 2021 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-33521941

RESUMO

China has made rapid progress in reducing the incidence of HBV infection in the past three decades, along with a rapidly changing lifestyle and aging population. We aimed to develop and validate an up-to-date liver cancer risk prediction model with routinely available predictors and evaluate its applicability for screening guidance. Using data from the China Kadoorie Biobank, we included 486 285 participants in this analysis. Fifteen risk factors were included in the model. Flexible parametric survival models were used to estimate the 10-year absolute risk of liver cancer. Decision curve analysis was performed to evaluate the net benefit of the model to quantify clinical utility. A total of 2706 participants occurred liver cancer over the 4 814 320 person-years of follow-up. Excellent discrimination of the model was observed in both development and validation datasets, with c-statistics (95% CI) of 0.80 (0.79-0.81) and 0.80 (0.78-0.82) respectively, as well as excellent calibration of observed and predicted risks. Decision curve analysis revealed that use of the model in selecting participants for screening improved benefit at a threshold of 2% 10-year risk, compared to current guideline of screening all HBsAg carriers. Our model was more sensitive than current guideline for cancer screening (28.17% vs 25.96%). We developed and validated a CKB-PLR (Prediction for Liver cancer Risk Based on the China Kadoorie Biobank Study) model to predict the absolute risk of liver cancer for both HBsAg seropositive and seronegative populations. Application of the model is beneficial for precisely identifying the high-risk groups among the general population.

2.
BMC Med ; 19(1): 14, 2021 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-33487165

RESUMO

BACKGROUND: The World Health Organization (WHO) in 2015 stated that every effort should be made to provide cesarean delivery (CD) for women in need. In China, the two-child policy largely prompts the number of advanced age childbirth, which raises the possibility of an increasing number of women who need a c-section. The aim of this study was to assess the trends in the overall and medical indication-classified CD rates in the era of the two-child policy in Jiangsu, China. METHODS: A retrospective cross-sectional study of 291,448 women who delivered in 11 hospitals in Jiangsu province between 2012 and 2019 was conducted. Medical cesarean indication for each woman was ascertained by manually reviewing the medical records. The 291,448 women were divided into two subgroups according to the presence of the indications: the indicated group (7.80%) and the non-indicated group (92.20%). We then fitted joinpoint regression and log-binomial regression models to estimate trends in the CD rates across the study period. RESULTS: The overall CD rate was observed with a declining trend from 52.51% in 2012-2015 to 49.76% in 2016-2019 (adjusted RR, 0.92; 95% CI, 0.91-0.93; P < 0.001), along with an annual percentage change (APC) to be - 1.0 (95% CI, - 2.1 to 0.0) across the period. The participants were then divided into two subgroups according to the presence of medical CD indications: the indicated group (7.80%) and the non-indicated group (92.20%).We found the declining trend was most pronounced in the non-indicated group, with the CD rates decreased from 50.02% in 2012-2015 to 46.27% in 2016-2019 (adjusted RR, 0.90; 95% CI, 0.89-0.90; P < 0.001). By contrast, we observed a steady trend in the CD rate of the indicated group, which maintained from 87.47% in 2012-2015 to 86.57% in 2016-2019 (P = 0.448). In the indicated group, a higher risk of adverse pregnancy outcomes was revealed for those women who delivered vaginally as compared with those who received c-section. We further investigated that women with following specific indications had a higher proportion of vaginal delivery, i.e., pregnancy complications, fetal macrosomia, and pregnancy complicated with tumor (34.70%, 10.84%, and 16.34%, respectively). Women with the above 3 indications were observed with a higher risk of adverse pregnancy outcomes if delivered vaginally. The incidence rates of the medical indications among the general population increased considerably over the 8-year period (P < 0.001). CONCLUSIONS: Although the overall CD rate apparently decreased in the recent years, along with the decline of the unnecessary CD rate, a considerable proportion of indicated women were not provided with CD service in Jiangsu, China. Instead of targeting the overall CD rate, we need to take actions to reduce unnecessary CD rate and provide adequate c-section service for women with indications, particularly for those with underlying diseases and suspected fetal macrosomia.

3.
Eur J Epidemiol ; 2021 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-33420872

RESUMO

Coronavirus disease 2019 (COVID-19) deteriorates suddenly primarily due to excessive inflammatory injury, and insulin-like growth factor-1 (IGF-1) is implicated in endocrine control of the immune system. However, the effect of IGF-1 levels on COVID-19 prognosis remains unknown. Using UK Biobank resource, we investigated the association between circulating IGF-1 concentrations and mortality risk (available death data updated on 07 Sep 2020) among COVID-19 patients who had pre-diagnostic serum IGF-1 measurements at baseline (2006-2010). Unconditional logistic regression was performed to estimate the odds ratio (OR) and 95% confidence intervals (CIs) of mortality. Among 1670 COVID-19 patients, 415 deaths occurred due to COVID-19. Compared to the lowest quartile of IGF-1 concentrations, the highest quartile was associated with a 41% lower risk of mortality (OR = 0.59, 95% CI 0.41-0.86, P-trend = 0.01). In the continuous model, per 1-standard deviation increment in log-transformed IGF-1 was associated with a 15% reduction in the risk (intraclass correlation coefficients corrected OR = 0.85, 95% CI 0.73-0.99). The association was largely consistent in the various stratified and sensitivity analyses. In conclusion, our data suggest that higher IGF-1 concentrations are associated with a lower risk of COVID-19 mortality. Further studies are required to determine whether and how targeting IGF-1 pathway might improve COVID-19 prognosis.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33398918

RESUMO

AIM: To develop a prediction model to estimate the chances of live birth over multiple cycles of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) treatment. METHODS: A retrospective cohort study was launched in three reproductive centers including 10 824 couples who received 14 106 treatment cycles with known pregnancy outcomes by the end of 2016. Discrete time logistic regression was used to establish the model and a nomogram was developed to predict the chance of live birth on plain paper-based final predictors. RESULTS: Among 10 824 couples, 5809 (53.7%) ended up with a live birth with several successive transplant cycles. What's more, we found that younger female age (p < 0.001), smaller cycle number (p < 0.001), female body mass index (p < 0.001), male factor (p < 0.001), ovulation disorder (p = 0.006), and higher endometrial thickness (p < 0.001) were significantly associated with increased live birth rate. Discrimination of the model expressed by area under the curve (AUC) was 0.66. CONCLUSION: Our study will help shape couples' expectations of their ART outcome, allowing them to plan their treatments more efficiently and prepare emotionally and financially.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33203726

RESUMO

INTRODUCTION: Both environmental and genetic factors contribute to type 2 diabetes (T2D) risk. Dozens of T2D susceptibility loci have been identified by genome-wide association study. However, these loci account for only a small fraction of the familial T2D risk. We hypothesized that the gene-obesity interaction may contribute to the missing heritability. RESEARCH DESIGN AND METHOD: Forty-eight T2D-associated variants were genotyped using the TaqMan OpenArray Genotyping System and iPLEX Sequenom MassARRAY platform in two separate studies. Obesity was defined according to multiple indexes (body mass index (BMI), waist circumference and waist-hip ratio). Multiplicative interactions were tested using general logistic regression to assess the gene-obesity interaction effect on T2D risk among a total of 6206 Chinese Hans. RESULTS: After adjusting for the main effects of genes and obesity, as well as covariates (age, sex, smoking and alcohol consumption status), robust multiplicative interaction effects were observed between rs10811661 in CDKN2A/CDKN2B and multiple obesity indices (p ranged from 0.001 to 0.043 for BMI, waist circumference and waist-hip ratio). Obese individuals with the TT genotype had a drastically higher risk of T2D than normal weight individuals without the risk allele (OR=17.58, p<0.001). There were no significant differences between subgroups in the stratification analysis. Plausible biological explanations were established using a public database. However, there were no significant interaction effects between the other 47 single nucleotide polymorphism (SNPs) and obesity. CONCLUSION: Our findings indicated that the CDKN2A/CDKN2B gene-obesity interaction significantly increases T2D risk in Chinese Hans. The interaction effect identified in our study may help to explain some of the missing heritability in the context of T2D susceptibility. In addition, the interaction effect may play a role in the precise prevention of T2D in Chinese individuals.

6.
Theranostics ; 10(24): 11264-11277, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33042282

RESUMO

Rationale: As the transcriptional products of active enhancers, enhancer RNAs (eRNAs) are essential for the initiation of tumorigenesis. However, the landscape and functional characteristics of eRNAs in Chinese lung adenocarcinoma, and the clinical utility of eRNA-based molecular subtypes remain largely unknown. Methods: A genome-wide profiling of eRNAs was performed in 80 Chinese lung adenocarcinoma patients with RNA-seq data. Functional eRNAs and associated genes were identified between paired adenocarcinoma and adjacent samples. Unsupervised clustering of functional eRNAs was conducted and the associations with molecular characteristics and clinical outcomes were accessed by integrating whole-genome sequencing data and clinical data. Additionally, 481 lung adenocarcinoma patients were used for the validation based on The Cancer Genome Atlas (TCGA) dataset. Results: A total of 3297 eRNAs with sufficient expression were identified, which were globally upregulated in adenocarcinoma samples compared to matched-adjacent pairs (P = 7.61×10-3). Further analyses indicated that these upregulated eRNAs were correlated with copy number amplification (CNA) status (Cor = 0.22, P = 0.045), and eRNA-correlated genes were primarily involved in cell cycle and immune system-related pathways. Based on the co-expression analysis of eRNAs with protein-coding genes, we defined 188 functional eRNAs and their correlated genes were overrepresented in cancer driver genes (ER = 1.98, P = 5.95×10-12) and clinically-actionable genes (ER = 2.19, P = 3.44×10-4). The eRNA-based consensus clustering further identified a novel molecular subtype with immune deficiency and a high-level of genomic alterations, which was associated with poor clinical outcomes of lung adenocarcinoma patients (OS: HR = 1.91, P = 0.015; PFI: HR = 1.64, P = 0.034). Conclusions: The genome-wide identification and characterization of eRNAs reveal novel regulators for the development of lung cancer, which provides a new biological dimension for the understanding of eRNAs during lung carcinogenesis and emphasize the clinical utility of eRNA-based molecular subtypes in the treatment of lung adenocarcinoma.

7.
Lancet Oncol ; 21(10): 1378-1386, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33002439

RESUMO

BACKGROUND: Genetic variants and lifestyle factors have been associated with gastric cancer risk, but the extent to which an increased genetic risk can be offset by a healthy lifestyle remains unknown. We aimed to establish a genetic risk model for gastric cancer and assess the benefits of adhering to a healthy lifestyle in individuals with a high genetic risk. METHODS: In this meta-analysis and prospective cohort study, we first did a fixed-effects meta-analysis of the association between genetic variants and gastric cancer in six independent genome-wide association studies (GWAS) with a case-control study design. These GWAS comprised 21 168 Han Chinese individuals, of whom 10 254 had gastric cancer and 10 914 geographically matched controls did not. Using summary statistics from the meta-analysis, we constructed five polygenic risk scores in a range of thresholds (p=5 × 10-4 p=5 × 10-5 p=5 × 10-6 p=5 × 10-7, and p=5 × 10-8) for gastric cancer. We then applied these scores to an independent, prospective, nationwide cohort of 100 220 individuals from the China Kadoorie Biobank (CKB), with more than 10 years of follow-up. The relative and absolute risk of incident gastric cancer associated with healthy lifestyle factors (defined as not smoking, never consuming alcohol, the low consumption of preserved foods, and the frequent intake of fresh fruits and vegetables), was assessed and stratified by genetic risk (low [quintile 1 of the polygenic risk score], intermediate [quintile 2-4 of the polygenic risk score], and high [quintile 5 of the polygenic risk score]). Individuals with a favourable lifestyle were considered as those who adopted all four healthy lifestyle factors, those with an intermediate lifestyle adopted two or three factors, and those with an unfavourable lifestyle adopted none or one factor. FINDINGS: The polygenic risk score derived from 112 single-nucleotide polymorphisms (p<5 × 10-5) showed the strongest association with gastric cancer risk (p=7·56 × 10-10). When this polygenic risk score was applied to the CKB cohort, we found that there was a significant increase in the relative risk of incident gastric cancer across the quintiles of the polygenic risk score (ptrend<0·0001). Compared with individuals who had a low genetic risk, those with an intermediate genetic risk (hazard ratio [HR] 1·54 [95% CI 1·22-1·94], p=2·67 × 10-4) and a high genetic risk (2·08 [1·61-2·69], p<0·0001) had a greater risk of gastric cancer. A similar increase in the relative risk of incident gastric cancer was observed across the lifestyle categories (ptrend<0·0001), with a higher risk of gastric cancer in those with an unfavourable lifestyle than those with a favourable lifestyle (2·03 [1·46-2·83], p<0·0001). Participants with a high genetic risk and a favourable lifestyle had a lower risk of gastric cancer than those with a high genetic risk and an unfavourable lifestyle (0·53 [0·29-0·99], p=0·048), with an absolute risk reduction of 1·12% (95% CI 0·62-1·56). INTERPRETATION: Chinese individuals at an increased risk of incident gastric cancer could be identified by use of our newly developed polygenic risk score. Compared with individuals at a high genetic risk who adopt an unhealthy lifestyle, those who adopt a healthy lifestyle could substantially reduce their risk of incident gastric cancer. FUNDING: National Key R&D Program of China, National Natural Science Foundation of China, 333 High-Level Talents Cultivation Project of Jiangsu Province, and China Postdoctoral Science Foundation.


Assuntos
Predisposição Genética para Doença/genética , Estilo de Vida Saudável , Neoplasias Gástricas/genética , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático , China/epidemiologia , Feminino , Seguimentos , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/psicologia , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Fatores de Risco , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/psicologia
8.
Biomed Res Int ; 2020: 6739823, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32879886

RESUMO

BRCA1 and BRCA2 as important DNA repair genes have been thoroughly investigated in abundant studies. The potential relationships of BRCA1/2 pathogenic variants between multicancers have been verified in Caucasians but few in Chinese. In this study, we performed a two-stage study to screen BRCA1/2 pathogenic variants or variants of uncertain significance (VUS) with 7580 cancer cases and 4874 cancer-free controls, consisting of a discovery stage with 70 familial breast cancer cases and a subsequent validation stage with 7510 cases (3217 breast cancer, 1133 cervical cancer, 2044 hepatocellular carcinoma, and 1116 colorectal cancer). 48 variants were obtained from 70 familial breast cancer cases after BRCA1/2 exon detection, and finally, 20 pathogenic variants or VUS were selected for subsequent validation. Four recurrent variants in sporadic cases (BRCA1 c.4801A>T, BRCA1 c.3257del, BRCA1 c.440del, and BRCA2 c.7409dup) were identified and three of them were labeled Class 5 by ENIGMA. Two variants (BRCA1 c.3257del and c.440del) were specific in breast cancer cases, while BRCA2 c.7409dup and c.4307T>C were detected in two hepatocellular carcinoma patients and the BRCA1 c.4801A>T variant in one cervical cancer patient, respectively. Moreover, BRCA1 c.3257del was the most frequent variant observed in Chinese sporadic breast cancer and showed increased proliferation of BRCA1 c.3257del-overexpressing triple-negative breast cancer cell lines (MDA-MB-231) in vitro. In addition to the known founder deleterious mutations, our findings highlight that the recurrently pathogenic variants in breast cancer cases could be taken as candidate genetic screening loci for a more efficient genetic screening of the Chinese population.

9.
Front Med ; 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32889700

RESUMO

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.

10.
J Biomed Res ; 34(5): 361-368, 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32981896

RESUMO

There were few studies of cumulative live birth rates (CLBRs) based on multicenter reproductive clinical data from the general Chinese population. Here we report a retrospective cohort study, including 14 311 women with 17 315 cycles, in three reproductive centers to evaluate two estimated parameters of CLBRs with multiple transfer cycles of in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) in a Chinese population. We found that CLBRs were related to female age and endometrial thickness. By the fourth transfer cycle, the conservative and optimal estimates of CLBRs were 52.95% and 77.30% in women under 30 years of age, and 18.17% and 26.51% in those 37 years of age or older, respectively. The two estimates were 44.70% and 63.15% in women with endometrial thickness more than 7 mm, and 32.05% and 46.18% in those with less than 7 mm, respectively. In addition, body mass index (BMI), duration of infertility, and infertility diagnoses may also be related to CLBRs on certain conditions. The findings from this study on CLBRs after multiple transfer cycles of IVF/ICSI treatment on different conditions in the Chinese population should be beneficial to both infertile couples and clinicians.

11.
Diagn Microbiol Infect Dis ; 98(3): 115129, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32739761

RESUMO

Omadacycline and eravacycline are newly approved tetracycline analogues with excellent activity against a broad spectrum of Gram-positive and Gram-negative microorganisms; however, no data are available regarding Helicobacter pylori. The susceptibility of 201 clinical isolates of H. pylori collected in China to omadacycline, eravacycline, and the comparator tetracycline was determined by an agar dilution method. They showed greater activity than tetracycline. The MIC50/90 values of omadacycline, eravacycline, and tetracycline were 0.125/0.25 µg/mL, 0.063/0.125 µg/mL, and 0.25/1 µg/mL, respectively. Omadacycline and eravacycline were potent in vitro against all the isolates tested, including tetracycline-resistant strains, and warrant further investigation as potential antibiotics for H. pylori treatment.

12.
Gut Microbes ; 12(1): 1794466, 2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-32752913

RESUMO

The gut microbiome in newborns may be strongly influenced by their intrinsic host microenvironmental factors (e.g., the gestational age) and has been linked to their short-term growth and potentially future health. It is yet unclear whether early microbiota composition is significantly different in newborns conceived by assisted reproductive technology (ART) when compared with those who were conceived spontaneously. Additionally, little is known about the effect of gut microbiota composition on weight gain in early infancy. We aimed to characterize the features and the determinants of the gut microbiome in ART newborns and to assess the impact of early microbiota composition on their weight gain in early infancy in mother-infant dyads enrolled in the China National Birth Cohort (CNBC). Among 118 neonates born by ART and 91 neonates born following spontaneous conception, we observed significantly reduced gut microbiota α-diversity and declined Bacteroidetes relative abundance in ART neonates. The microbiota composition of ART neonates was largely driven by specific ART treatments, hinting the importance of fetus intrinsic host microenvironment on the early microbial colonization. Following up these neonates for six months after their births, we observed the effects of gut microbiome composition on infant rapid weight gaining. Collectively, we identified features and determinants of the gut microbiota composition in ART neonates, and provided evidence for the importance of microbiota composition in neonatal growth.

13.
Front Genet ; 11: 679, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32754194

RESUMO

Genome-wide association studies (GWAS) have identified several susceptibility loci for gastric cancer (GC), but the majority of identified single-nucleotide polymorphisms (SNPs) fall within the non-coding region and are likely to exert their biological function by modulating gene expression. To systematically estimate expression-associated SNPs (eSNPs) that confer genetic predisposition to GC, we evaluated the associations of 314,203 stomach tissue-specific eSNPs with GC risk in three GWAS datasets (2,631 cases and 4,373 controls). Subsequently, we conducted a gene-based analysis to calculate the cumulative effect of eSNPs through sequence kernel association combined test and Sherlock integrative analysis. At the SNP-level, we identified two novel variants (rs836545 at 7p22.1 and rs1892252 at 6p22.2) associated with GC risk. The risk allele carriers of rs836545-T and rs1892252-G exhibited higher expression levels of DAGLB (P = 3.70 × 10-18) and BTN3A2 (P = 3.20 × 10-5), respectively. Gene-based analyses identified DAGLB and FBXO43 as novel susceptibility genes for GC. DAGLB and FBXO43 were significantly overexpressed in GC tissues than in their adjacent tissues (P = 5.59 × 10-7 and P = 3.90 × 10-6, respectively), and high expression level of these two genes was associated with an unfavorable prognosis of GC patients (P = 1.30 × 10-7 and P = 7.60 × 10-3, respectively). Co-expression genes with these two novel genes in normal stomach tissues were significantly enriched in several cancer-related pathways, including P53, MAPK and TGF-beta pathways. In summary, our findings confirm the importance of eSNPs in dissecting the genetic basis of GC, and the identified eSNPs and relevant genes will provide new insight into the genetic and biological basis for the mechanism of GC development.

14.
Reprod Biol Endocrinol ; 18(1): 89, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32825835

RESUMO

BACKGROUND: Successful implantation and delivery require both the functional embryo and receptive endometrium in assisted reproductive technology (ART) cycles. However, little is known about embryo-endometrial interaction on live-birth. We aimed to investigate the independent effect and interaction of endometrial thickness (EMT) and embryo quality on live-birth in fresh embryo transfer (ET) cycles. METHODS: We conducted a retrospective cohort study including 15,012 ART cycles between 2013 and 2016 in three centers in China. Poisson regression with generalized estimating equations was employed to calculate relative risks (RRs) and 95% confidence intervals (CIs). We estimated the interaction of embryo quality and EMT on live-birth rate (LBR). RESULTS: The LBR per cycle was 42.8% overall. LBR increased with increasing EMT and reached a plateau (50.6 to 54.2%) when EMT was 11 mm or thicker. Embryo quality represented by cumulative score was associated with LBR independently of number of embryos transferred and EMT. LBR was not increased with thicker EMT when only Q1 cleavage-stage embryo transferred (aRR 0.95, 95%CI 0.61-1.46). LBR was not increased significantly with thicker EMT with transfer of two good-quality cleavage-stage embryos and any blastocyst combination except Q1 group. There was significant interaction between EMT and embryo quality on LBR for cleavage-stage ETs (P=0.023). CONCLUSIONS: This study demonstrated the nonlinear EMT-LBR association and the EMT cut-off value of 11 mm which may be of more clinical significance for predicting live-birth. Embryo quality is an independent prognostic tool for LBR. Our finding of significant embryo-endometrial interaction indicates combination of EMT and embryos quality might improve the prognostic value in clinical practice for live-birth in patients undergoing transfer of 1-2 fresh cleavage-stage embryos.

15.
J Clin Endocrinol Metab ; 105(10)2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32620963

RESUMO

CONTEXT: Although an inverse association between vitamin D status and mortality has been reported in observational studies, the precise association shape and optimal vitamin D status remain undetermined. OBJECTIVE: To investigate the association between vitamin D status and risk of all-cause and cause-specific mortality and estimate optimal serum 25-hydroxyvitamin D [25(OH)D] concentrations. DESIGN: Prospective cohort study. SETTING: UK Biobank. PARTICIPANTS: 365 530 participants who had serum 25(OH)D measurements and no history of cardiovascular disease (CVD), cancer, or diabetes at baseline (2006-2010). MAIN OUTCOME MEASURES: All-cause and cause-specific mortality. RESULTS: During a median follow-up of 8.9 (interquartile range: 8.3-9.5) years, 10 175 deaths occurred, including 1841 (18.1%) due to CVD and 5737 (56.4%) due to cancer. The multivariate analyses revealed nonlinear inverse associations, with a decrease in mortality risk appearing to level off at 60 nmol/L of 25(OH)D for all-cause and CVD deaths and at 45 nmol/L for cancer deaths. Compared to participants with 25(OH)D concentrations below the cutoffs, those with higher concentrations had a 17% lower risk for all-cause mortality (hazard ratio [HR]: 0.83, 95% confidence interval [CI]: 0.79-0.86), 23% lower risk for CVD mortality (HR: 0.77, 95% CI: 0.68-0.86), and 11% lower risk for cancer mortality (HR: 0.89, 95% CI: 0.84-0.95). CONCLUSIONS: Higher 25(OH)D concentrations are nonlinearly associated with lower risk of all-cause, CVD, and cancer mortality. The thresholds of 45 to 60 nmol/L might represent an intervention target to reduce the overall risk of premature death, which needs further confirmation in large clinical trials.

16.
Sci Adv ; 6(21): eaay5525, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32671202

RESUMO

The biological effects of susceptibility loci are rarely reported in gastric tumorigenesis. We conducted a large-scale cross-ancestry genetic study in 18,852 individuals and identified the potential causal variant rs3850997 T>G at 16p13 significantly associated with a decreased risk of gastric cancer [odds ratio (OR) = 0.87, 95% confidence interval (CI) = 0.83 to 0.91, P = 2.13 × 10-9]. This risk effect was mediated through the mapped long noncoding RNA GCLET (Gastric Cancer Low-Expressed Transcript; ORindirect = 0.987, 95% CI = 0.975 to 0.999, P = 0.018). Mechanistically, rs3850997 exerted an allele-specific long-range regulatory effect on GCLET by affecting the binding affinity of CTCF. Furthermore, GCLET increased FOXP2 expression by competing with miR-27a-3p, and this regulation remarkably affected in vitro, in vivo, and clinical gastric cancer phenotypes. The findings highlight the genetic functions and implications for the etiology and pathology of cancers.

17.
Arch Toxicol ; 94(8): 2861-2872, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32535685

RESUMO

Structural and numeric centrosome aberrations can induce chromosome segregation errors and promote tumor development and progression. We systematically evaluated associations of 19,603 single nucleotide polymorphisms (SNPs) across 136 centrosome-related genes with gastric cancer (GC) risk using four GWAS datasets with a total of 3771 cases and 5426 controls. We identified two loci at 15p13.3 and 7q11.23 significantly associated with GC risk, whose risk alleles were correlated with increased mRNA expression of CEP72 (P = 7.30 × 10-4) and YWHAG (P = 1.60 × 10-3), respectively. Dual-luciferase reporter assays confirmed that the risk T allele of rs924607 at 15p13.3 significantly increased a promoter activity of the reporter gene, leading to a higher CEP72 expression level. At 7q11.23, the risk haplotype of rs2961037 [G]-rs2961038 [G] significantly elevated an enhancer activity and the expression of YWHAG. Both the mRNA and protein levels of CEP72 and YWHAG were overexpressed in GC tumor tissues compared with peritumor tissues and overexpression of either gene showed an unfavorable prognosis of GC patients. Moreover, knockdown of either CEP72 or YWHAG inhibited GC cell proliferation, migration and invasion and promoted GC cell apoptosis. The genes coexpressed with CEP72 or YWHAG in GC tumor tissues were enriched in the Ras signaling pathway, which was confirmed that knockdown of either one decreased the expression of cyclin D1 but increased the expression of p21 and p27. In conclusion, genetic variants at 15p13.3 and 7q11.23 may confer GC risk via modulating the biological functions of CEP72 and YWHAG, respectively, suggesting the importance of centrosome-regulated genes in GC development.

18.
Liver Int ; 40(9): 2117-2127, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32574393

RESUMO

BACKGROUND & AIMS: Previous genome-wide association studies (GWAS) have identified multiple susceptible variants associated with persistent hepatitis B virus (HBV) infection. However, most of these variants are located in the noncoding regions, which make it difficult to determine the effective genes underlying these associations. We performed a two-stage study, in the first stage we integrated RNA sequencing data of liver tissues and high-density genotyping data from the Genotype-Tissue Expression (GTEx) project with our previous GWAS data to conduct a transcriptome-wide association study (TWAS) on HBV infection. Firstly, the cis-heritable genes were screened by a genetic relatedness matrix of genome-wide complex trait analysis (GCTA) from GTEx data. Then, the genetic expression of 2587 cis-heritable genes was predicted by restricted maximum likelihood (REML) of genome-wide efficient mixed-model association (GEMMA) in our GWAS data with 951 HBV carrier cases and 937 HBV cleared controls. Next, we investigated the associations between predictive expression levels and persistent HBV infection risk. Gene set enrichment analysis (GSEA) was applied to infer the function of the identified genes. To identify the causal single nucleotide polymorphisms (SNPs) of HBV infection risk, we conducted the expression quantitative trait loci (eQTL)-based stepwise logistic regression analysis in the regions around 1 Mb of these genes and validated the association between 994 health controls and 994 HBV-persistent infection cases by genotyping experiment. In the second stage, 1538 HBV-related hepatocellular carcinoma (HCC) cases and 1465 persistent HBV infection controls were collected to determine the effect of these variants on HBV-related HCC as well, which were examined by the additive model in logistic regression analysis. We identified seven genes associated with HBV infection. In the classic human leukocyte antigen (HLA) region, three novel genes BAK1, HLA-DOB and C4A (Z range from -3.95 to -3.64, P range from 7.84 × 10-5 to 2.00 × 10-4 ), as well as two genes (HLA-DPA1 and HLA-DPB1) were reported by previous GWAS. In the non-HLA region, immune related at newly identified loci, PARP9 (Z = 3.69, P = 2.20 × 10-4 ) at 3q21.1. At 22q11.21, we identified TMEM191A (Z = 3.55, P = 3.80 × 10-4 ) as a target gene in addition to the reported non-cis-heritable gene UBE2L3. After further stepwise logistic regression analysis and validation, we identified eight variants independently associated with persistent HBV infection. Among those variants, the additive model showed that two SNPs associated with HBV-related HCC risk (rs9272714 and rs9394194, OR range from 1.20 to 1.25, P range from 1.19 × 10-4 to 3.97 × 10-4 ). By integrating transcriptome data, our study not only identified new susceptibility loci of persistent HBV infection but also determined the potential target genes at reported loci, which provided insight into the genetic aetiology of persistent HBV infection and related HCC.

19.
Cancer Med ; 9(15): 5490-5499, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32543092

RESUMO

Most patients with gastric cancer (GC) are first diagnosed at stage III-IV and surgery resection remains the primary therapeutic modality for these patients. However, clinical staging used for prediction of those patients provides limited information. We collected clinicopathological data and disease-progression information from 508 patients with stage III-IV GC at three Chinese hospitals and 1298 patients from the Surveillance, Epidemiology, and End Results database. Based on the stepwise multivariate regression model, we constructed a novel nomogram to predict overall survival (OS). The performance of discrimination for this model was measured using Harrell's concordance index (C-index) and receiver-operating characteristic curve (ROC), and was validated using calibration plots. Multivariate Cox regression analyses showed that tumor size, age at diagnosis, N stage, tumor grade, and distant metastases were outstanding independent prognostic factors of stage III-IV GC. We developed a nomogram based on these five prognostic predictors. In the training set, the C-index of the nomogram was 0.645 (95% CI: 0.611-0.679), which was higher than that of the American Joint Committee on Cancer TNM system alone (sixth TNM: 0.544; seventh TNM: 0.575; eighth TNM: 0.568). Similar results were observed in validation cohort. Moreover, calibration blots demonstrated good consistency between the actual and predicted OS probabilities. According to the nomogram, GC individuals could be classified into three groups (low-, middle-, and high-risk) (P < .001). Our nomogram complements the current staging system for prediction of individual prognosis with stage III-IV GC, and may be helpful for making individualized treatment decisions.

20.
Biomed Res Int ; 2020: 8781348, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32309442

RESUMO

MicroRNAs (miRNAs) of the miR-30 family are closely linked with tumor metastasis and play key roles in the complex malignant phenotypes of cancers by targeting many tumor-related genes. Deregulated expression of miR-30 family members has been commonly observed in breast cancer. However, associations between the genetic variants in the regulatory region of miR-30 family and the risk of breast cancer are still limited, especially in the Chinese Han population. In the present study, we conducted a case-control analysis wherein 1064 breast cancer patients and 1073 healthy controls underwent genotyping of 10 SNPs in the regulatory region of miR-30 family members. Multivariate logistic regression analyses illustrated that the rs763354 variant in the miR-30a regulatory region was linked with a significant decrease in breast cancer risk in an additive model (adjusted OR = 0.86, 95% CI: 0.75-0.98, P = 0.022). Further, eQTL analyses also indicated that this SNP was associated with miR-30a expression levels in breast cancer samples compiled in the TCGA database (P = 0.020). The Kaplan-Meier plotter showed that breast cancer patients with higher miR-30a expression have significantly better outcomes than do patients expressing low levels of this miRNA (HR = 0.75, 95% CI: 0.61-0.91, P = 0.0041). Together, these findings suggest that the miR-30a rs763354 SNP is an important regulator of breast cancer risk, thus making it a potentially viable prognostic biomarker and one that can be used to guide therapeutic treatment in affected patients.

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