Publications by authors named "Zhibin Hu"

518 Publications

Diet and Risk of Incident Lung Cancer: A Large Prospective Cohort Study in UK Biobank.

Am J Clin Nutr 2021 Sep 28. Epub 2021 Sep 28.

Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.

Background: Epidemiological evidence remains conflicting regarding diet and risk of lung cancer.

Objectives: We sought to systematically investigate whether dietary factors are associated with the risk of incident lung cancer in the UK Biobank.

Methods: A total of 416,588 participants (54% women) from the UK Biobank were included in the present study. Based on baseline data from FFQs, 3 main dietary patterns were identified by using principal component analysis. Cox proportional hazards models were used to investigate the association of individual food groups and dietary patterns with lung cancer risk.

Results: During a median follow-up of 7.13 y, 1782 incident lung cancer cases were documented. The association analysis showed high intake of red meat and processed meat was associated with an increased risk of lung cancer (HRper 50 g/d: 1.36; 95% CI: 1.13, 1.65 for red meat; HRper 25 g/d: 1.30; 95% CI: 1.10, 1.53 for processed meat). However, the consumption of fruits (HRper 100 g/d: 0.90; 95% CI: 0.84, 0.95), vegetables (HRper 100 g/d: 0.89; 95% CI: 0.81, 0.99), breakfast cereals (HRper 50 g/d: 0.81; 95% CI: 0.74, 0.89), and dietary fiber (HRper 5 g/d: 0.76; 95% CI: 0.69, 0.84) was inversely associated with the risk of lung cancer. For the dietary pattern analysis [quartile (Q) comparison], high adherence to the Prudent pattern (HRQ4 compared with Q1: 0.84; 95% CI: 0.73, 0.96) was associated with a lower risk of lung cancer, whereas the Western pattern (HRQ4 compared with Q1: 1.27; 95% CI: 1.11, 1.46) was associated with a higher risk of lung cancer.

Conclusions: Our study indicated that a diet characterized by high intake of fruits, vegetables, breakfast cereals, and dietary fiber, as well as low intake of red meat and processed meat, was associated with a lower risk of lung cancer.
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http://dx.doi.org/10.1093/ajcn/nqab298DOI Listing
September 2021

Kinetics of SARS-CoV-2 Specific and Neutralizing Antibodies over Seven Months after Symptom Onset in COVID-19 Patients.

Microbiol Spectr 2021 Sep 22:e0059021. Epub 2021 Sep 22.

Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.

To assess the persistence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies produced by natural infection and describe the serological characteristics over 7 months after symptom onset among coronavirus disease 2019 (COVID-19) patients by age and severity group, we followed up COVID-19 convalescent patients confirmed from 1 January to 20 March 2020 in Jiangsu, China and collected serum samples for testing IgM/IgG and neutralizing antibodies against SARS-CoV-2 between 26 August and 28 October 2020. In total, 284 recovered participants with COVID-19 were enrolled in our study. Patients had a mean age of 46.72 years (standard deviation [SD], 17.09), and 138 (48.59%) were male. The median follow-up time after symptom onset was 225.5 (interquartile range [IQR], 219 to 232) days. During the follow-up period (162 to 282 days after symptom onset), the seropositive rate of IgM fluctuated around 25.70% (95% confidence interval [CI], 20.72% to 31.20%) and that of IgG fluctuated around 79.93% (95% CI, 74.79% to 84.43%). Of the 284 patients, 64 participants were tested when discharged from hospital. Compared with that at the acute phase, the IgM/IgG antibody levels and IgM seropositivity have decreased; however, the seropositivity of IgG was not significantly lower at this follow-up (78.13% versus 82.81%). Fifty percent inhibitory dilution (ID) titers of neutralizing antibody for samples when discharged from hospital (geometric mean titer [GMT], 82; 95% CI, 56 to 121) were significantly higher than those at 6 to 7 months after discharge (GMT, 47; 95% CI, 35 to 63) (< 0.001). After 7 months from symptom onset, the convalescent COVID-19 patients continued to have high IgG seropositive; however, many plasma samples decreased neutralizing activity. The long-term characteristics of anti-SARS-CoV-2 antibodies among COVID-19 patients remain largely unclear. Tracking the longevity of these antibodies can provide a forward-looking reference for monitoring COVID-19. We conducted a comprehensive assessment combining the kinetics of specific and neutralizing antibodies over 7 months with age and disease severity and revealed influencing factors of the protection period of convalescent patients. By observing the long-term antibody levels against SARS-CoV-2 and comparing antibody levels at two time points after symptom onset, we found that the convalescent COVID-19 patients continued to have a high IgG seropositive rate; however, their plasma samples decreased neutralizing activity. These findings provide evidence supporting that the neutralizing activity of SARS-CoV-2-infected persons should be monitored and the administration of vaccine may be needed.
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http://dx.doi.org/10.1128/Spectrum.00590-21DOI Listing
September 2021

Intracellular Accumulation of IFN-λ4 Induces ER Stress and Results in Anti-Cirrhotic but Pro-HCV Effects.

Front Immunol 2021 23;12:692263. Epub 2021 Aug 23.

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States.

polymorphisms are inversely associated with the risk of chronic hepatitis C virus (HCV) infection and cirrhosis, two major risk factors for developing hepatocellular carcinoma (HCC). To further explore these inverse associations and their molecular underpinnings, we analyzed polymorphisms represented by the genotype (presence of rs368234815-dG or rs12979860-T alleles) in HCV patients: 2969 from Japan and 2931 from Taiwan. genotype was associated with an increased risk of HCV-related HCC (OR=1.28, 95%CI=1.07-1.52, P=0.0058) in the general population of Japanese patients, but not in Taiwanese patients who achieved treatment-induced viral clearance. genotype was also associated with a decreased risk of cirrhosis (OR=0.66, 95%CI=0.46-0.93, P=0.018, in Taiwanese patients). We then engineered HepG2 cells to inducibly express IFN-λ4 in the presence or absence of interferon lambda receptor 1 (IFNLR1). Induction of IFN-λ4 resulted in its intracellular accumulation, mainly in lysosomes and late endosomes, and increased ER stress, leading to apoptosis and reduced proliferation. We identified the very-low-density lipoprotein receptor (), which facilitates HCV entry into hepatocytes, as a transcript induced by IFN-λ4 but not IFN-λ3. Our results suggest that the molecular mechanisms underlying the anti-cirrhotic but pro-HCV associations observed for polymorphisms are, at least in part, contributed by intracellular accumulation of IFN-λ4 causing ER stress in hepatic cells.
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http://dx.doi.org/10.3389/fimmu.2021.692263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419317PMC
August 2021

Circulating C-reactive protein increases lung cancer risk: Results from a prospective cohort of UK Biobank.

Int J Cancer 2021 Aug 27. Epub 2021 Aug 27.

Department of Epidemiology, School of Public Health, Southeast University, Nanjing, China.

Chronic inflammation has been associated with the development of lung cancer. In this study, we examined the association between C-reactive protein (CRP) and lung cancer in a prospective cohort study and used Mendelian randomization (MR) to clarify the causality. We included 420 977 participants from the UK Biobank (UKB) in the analyses; 1892 thereof were diagnosed with lung cancer during the follow-up. Hazards ratios (HRs) of CRP concentrations were estimated by Cox proportional hazard models and two approaches of MR analysis were performed. Besides, we added CRP concentrations to epidemiological model of lung cancer to evaluate its prediagnostic role through time-dependent receiver operating characteristic curve analysis. Elevated CRP levels were associated with a 22% increased lung cancer risk per 1 SD increase (HR = 1.22, 95% confidence interval [CI] = 1.18-1.26). Positive associations were observed in small cell lung cancer (HR = 1.21, 95% CI = 1.10-1.33), lung adenocarcinoma (HR = 1.17, 95% CI = 1.11-1.23) and lung squamous cell carcinoma (HR = 1.22, 95% CI = 1.14-1.31). No genetical association of circulating CRP levels and lung cancer risk was observed in MR analysis. When added to a risk model of lung cancer, CRP improved the performance of model as long as 8 years among current smokers (basic model: C-statistic = 0.78 [95% CI = 0.75-0.80]; CRP model: C-statistic = 0.79 [95% CI = 0.76-0.81]; P  = .003, P  = .014). Our results did not support the causal association of circulating CRP with lung cancer risk. However, circulating CRP could be a prediagnostic marker of lung cancer as long as 8 years in advance for current smokers.
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http://dx.doi.org/10.1002/ijc.33780DOI Listing
August 2021

Association of maternal diabetes during pregnancy with high refractive error in offspring: a nationwide population-based cohort study.

Diabetologia 2021 Nov 17;64(11):2466-2477. Epub 2021 Aug 17.

Department of Biostatistics, School of Public Health, Fudan University, Shanghai, China.

Aims/hypothesis: We aimed to investigate the associations between maternal diabetes before or during pregnancy and the risk of high refractive error (RE) in offspring until the age of 25 years.

Methods: This nationwide register-based cohort study comprised 2,470,580 individuals born in 1977-2016. The exposure was maternal diabetes during or before pregnancy (type 1 diabetes, type 2 diabetes and gestational diabetes). Cox regression was used to examine the association between maternal diabetes and the risk of high RE in offspring from birth until the age of 25 years, adjusting for multiple potential confounders.

Results: During up to 25 years of follow-up, 553 offspring of mothers with diabetes and 19,695 offspring of mothers without diabetes were diagnosed with high RE. Prenatal exposure to maternal diabetes was associated with a 39% increased risk of high RE: HR 1.39 (95% CI 1.28, 1.51), p < 0.001; standardised cumulative incidence in unexposed offspring at 25 years of age 1.18% (95% CI 1.16%, 1.19%); cumulative incidence difference 0.72% (95% CI 0.51%, 0.94%). The elevated risks were observed for hypermetropia (HR 1.37 [95% CI 1.24, 1.51], p < 0.001), myopia (HR 1.34 [95% CI 1.08, 1.66], p = 0.007) and astigmatism (HR 1.58 [95% CI 1.29, 1.92], p < 0.001). The increased risks were more pronounced among offspring of mothers with diabetic complications (HR 2.05 [95% CI 1.60, 2.64], p < 0.001), compared with those of mothers with diabetes but no diabetic complications (HR 1.18 [95% CI 1.02, 1.37], p = 0.030).

Conclusions/interpretation: Our findings suggest that maternal diabetes during pregnancy is associated with an increased risk of high RE in offspring, in particular among those of mothers with diabetic complications. Early ophthalmological screening should be recommended in offspring of mothers with diabetes diagnosed before or during pregnancy.
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http://dx.doi.org/10.1007/s00125-021-05526-zDOI Listing
November 2021

MiR-96-5p is an oncogene in lung adenocarcinoma and facilitates tumor progression through ARHGAP6 downregulation.

J Appl Genet 2021 Aug 2. Epub 2021 Aug 2.

Department of Cardiothoracic Surgery, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), NO. 158 Shangtang Road, Xiacheng District, Hangzhou, 310014, Zhejiang, China.

Accumulating investigations illustrated that miRNA acts as a key regulator in tumor progression, whereas regulatory role of miR-96-5p in lung adenocarcinoma (LUAD) is warranted. Thus, we sought to probe mechanism of miR-96-5p in this disease. Through bioinformatics analysis, miR-96-5p level in normal tissue and LUAD tissue in TCGA database were obtained. Meanwhile, mRNA expression dataset was analyzed to obtain downregulated mRNAs binding to miR-96-5p. qRT-PCR assessed miR-96-5p and ARHGAP6 mRNA in LUAD. Western blot assessed protein level of ARHGAP6 in LUAD. Dual-luciferase reporter gene detection verified targeting relationship of miR-96-5p and ARHGAP6. Biological functional experiments such as CCK-8, colony formation, scratch healing, and Transwell assessed cell proliferation, migration, and invasion. MiR-96-5p was overexpressed, which fostered LUAD cell proliferation, migration, and invasion. ARHGAP6 was downregulated in LUAD and targeted by miR-96-5p. ARHGAP6 upregulation prominently restored promotion of miR-96-5p on cell progression. MiR-96-5p could stimulate LUAD progression through targeting ARHGAP6. This study generates a novel direction and lays a theoretical basis for targeted therapy.
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http://dx.doi.org/10.1007/s13353-021-00652-1DOI Listing
August 2021

Assisted reproductive technology and birth defects in a Chinese birth cohort study.

Lancet Reg Health West Pac 2021 Feb 22;7:100090. Epub 2021 Jan 22.

State Key Laboratory of Reproductive Medicine, Centre for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China.

Background: It has been consistently shown in several meta-analyses that infants born after ART have an excess of birth defects compared with those after spontaneous conception, however, the prevalence of birth defects among ART offspring in China is incompletely studied. Moreover, it is unclear to what extent the risk of birth defects is associated with parental infertility characteristics, specific ART procedures and twinning.

Methods: In the prospective cohort study, we included women who participated in the cohort, and had pregnancies of at least 20 gestational weeks between August 2016 and May 2019, and followed them until their children reached 1 year of age. Exposures of interest were ART, as well as infertility-related characteristics, certain ART procedures and specific medication usage. The primary outcome was birth defects including both major and minor defects, which we analysed with logistic generalized estimating equations to investigate the association with ART and certain ART characteristics.

Findings: A total of 1,825 women with ART-pregnancy and 3,483 women with spontaneous-pregnancy were included in the analysis. The prevalence of any defects was significantly higher among ART-births than their non-ART counterparts at each follow-up, specifically at prenatal screening (2•2% vs. 1•2%), at delivery (4•9% vs. 2•9%), at 6 months (10•4% vs. 5•3%) and 1 year of age (13•9% vs. 7•0%), and the associations between ART and increased risk of birth defects at each follow-up were similarly robust. Among ART-births, GnRH antagonist regimen for ovulation induction in women was associated with an increased risk of birth defects in their offspring after taking into account potential influencing factors (Multivariable model: adjusted risk ratio [aRR] 1•47, 1•04-2•07). Additionally, mediation through twinning accounted for 31•1% of the risk of ART-associated birth defects.

Interpretation: The results suggest that ART confers an increased risk for birth defects in offspring. The risk is partly attributable to infertility characteristics, certain ovulation induction regimen, and to some extent mediated by twinning. Our findings highlight the importance of long-term follow-up of children conceived via ART for health conditions.

Funding: National Key Research and Development Program of China, National Natural Science Foundation of China and Natural Science Foundation of Jiangsu Province.
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http://dx.doi.org/10.1016/j.lanwpc.2020.100090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315325PMC
February 2021

Genetic Risk for Overall Cancer and the Benefit of Adherence to a Healthy Lifestyle.

Cancer Res 2021 Sep 28;81(17):4618-4627. Epub 2021 Jul 28.

Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.

Cancer site-specific polygenic risk scores (PRS) effectively identify individuals at high risk of individual cancers, but the effectiveness of PRS on overall cancer risk assessment and the extent to which a high genetic risk of overall cancer can be offset by a healthy lifestyle remain unclear. Here, we constructed an incidence-weighted overall cancer polygenic risk score (CPRS) based on 20 cancer site-specific PRSs. Lifestyle was determined according to smoking, alcohol consumption, physical activity, body mass index, and diet. Cox regression by sex was used to analyze associations of genetic and lifestyle factors with cancer incidence using UK Biobank data ( = 442,501). Compared with participants at low genetic risk (bottom quintile of CPRS), those at intermediate (quintiles 2 to 4) or high (top quintile) genetic risk had HRs of 1.27 (95% confidence interval, 1.21-1.34) or 1.91 (1.81-2.02) for overall cancer, respectively, for men, and 1.21 (1.16-1.27) or 1.62 (1.54-1.71), respectively, for women. A joint effect of genetic and lifestyle factors on overall cancer risk was observed, with HRs reaching 2.99 (2.45-3.64) for men and 2.38 (2.05-2.76) for women with high genetic risk and unfavorable lifestyle compared with those with low genetic risk and favorable lifestyle. Among participants at high genetic risk, the standardized 5-year cancer incidence was significantly reduced from 7.23% to 5.51% for men and from 5.77% to 3.69% for women having a favorable lifestyle. In summary, individuals at high genetic risk of overall cancer can be identified by CPRS, and risk can be attenuated by adopting a healthy lifestyle. SIGNIFICANCE: A new indicator of cancer polygenic risk score measures genetic risk for overall cancer, which could identify individuals with high cancer risk to facilitate decision-making about lifestyle modifications for personalized prevention.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-0836DOI Listing
September 2021

Genome-wide gene-smoking interaction study identified novel susceptibility loci for non-small cell lung cancer in Chinese populations.

Carcinogenesis 2021 Oct;42(9):1154-1161

Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China.

Gene-smoking interactions play important roles in the development of non-small cell lung cancer (NSCLC). To identify single-nucleotide polymorphisms (SNPs) that modify the association of smoking behavior with NSCLC risk, we conducted a genome-wide gene-smoking interaction study in Chinese populations. The genome-wide interaction analysis between SNPs and smoking status (ever- versus never-smokers) was carried out using genome-wide association studies of NSCLC, which included 13 327 cases and 13 328 controls. Stratified analysis by histological subtypes was also conducted. We used a genome-wide significance threshold of 5 × 10-8 for identifying significant gene-smoking interactions and 1 × 10-6 for identifying suggestive results. Functional annotation was performed to identify potential functional SNPs and target genes. We identified three novel loci with significant or suggestive gene-smoking interaction. For NSCLC, the interaction between rs2746087 (20q11.23) and smoking status reached genome-wide significance threshold [odds ratio (OR) = 0.63, 95% confidence interval (CI): 0.54-0.74, P = 3.31 × 10-8], and the interaction between rs11912498 (22q12.1) and smoking status reached suggestive significance threshold (OR = 0.72, 95% CI: 0.63-0.82, P = 8.10 × 10-7). Stratified analysis by histological subtypes identified suggestive interactions between rs459724 (5q11.2) and smoking status (OR = 0.61, 95% CI: 0.51-0.73, P = 7.55 × 10-8) in the risk of lung squamous cell carcinoma. Functional annotation indicated that both classic and novel biological processes, including nicotine addiction and airway clearance, may modulate the susceptibility to NSCLC. These novel loci provide new insights into the biological mechanisms underlying NSCLC risk. Independent replication in large-scale studies is needed and experimental studies are warranted to functionally validate these associations.
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http://dx.doi.org/10.1093/carcin/bgab064DOI Listing
October 2021

Air Pollution, Genetic Factors, and the Risk of Lung Cancer: A Prospective Study in the UK Biobank.

Am J Respir Crit Care Med 2021 10;204(7):817-825

Department of Epidemiology, Center for Global Health, School of Public Health, and.

Both genetic and environmental factors contribute to lung cancer, but the degree to which air pollution modifies the impact of genetic susceptibility on lung cancer remains unknown. To investigate whether air pollution and genetic factors jointly contribute to incident lung cancer. We analyzed data from 455,974 participants (53% women) without previous cancer at baseline in the UK Biobank. The concentrations of particulate matter (PM) (PM ⩽2.5 μm in aerodynamic diameter [PM], coarse PM between 2.5 μm and 10 μm in aerodynamic diameter [PM], and PM ⩽10 μm in aerodynamic diameter [PM]), nitrogen dioxide (NO), and nitrogen oxides (NO) were estimated by using land-use regression models, and the association between air pollutants and incident lung cancer was investigated by using a Cox proportional hazard model. Furthermore, we constructed a polygenic risk score and evaluated whether air pollutants modified the effect of genetic susceptibility on the development of lung cancer. The results showed significant associations between the risk of lung cancer and PM (hazard ratio [HR], 1.63; 95% confidence interval [CI], 1.33-2.01; per 5 μg/m), PM (HR, 1.53; 95% CI, 1.20-1.96; per 10 μg/m), NO (HR, 1.10; 95% CI, 1.05-1.15; per 10 μg/m), and NO (HR, 1.13; 95% CI, 1.07-1.18; per 20 μg/m). There were additive interactions between air pollutants and the genetic risk. Compared with participants with low genetic risk and low air pollution exposure, those with high air pollution exposure and high genetic risk had the highest risk of lung cancer (PM: HR, 1.71; 95% CI, 1.45-2.02; PM: HR, 1.77; 95% CI, 1.50-2.10; NO: HR, 1.77; 95% CI, 1.42-2.22; NO: HR, 1.67; 95% CI, 1.43-1.95). Long-term exposure to air pollution may increase the risk of lung cancer, especially in those with high genetic risk.
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http://dx.doi.org/10.1164/rccm.202011-4063OCDOI Listing
October 2021

Whole-exome sequencing reveals common and rare variants in immunologic and neurological genes implicated in achalasia.

Am J Hum Genet 2021 08 30;108(8):1478-1487. Epub 2021 Jun 30.

Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China. Electronic address:

Idiopathic achalasia (IA) is a severe motility disorder characterized by neuronal degeneration in the myenteric plexus, but the etiology remains largely unknown. We performed whole-exome sequencing (WES) in 100 IA-affected individuals and 313 non-IA control subjects and validated the results in 230 IA-affected individuals and 1,760 non-IA control subjects. Common missense variants rs1705003 (CUTA, GenBank: NC_000006.11:g.33385953A>G) and rs1126511 (HLA-DPB1, GenBank: NC_000006.11:g.33048466G>T) at 6p21.32 were reproducibly associated with increased risk of IA (rs1126511: OR = 1.83, p = 2.34 × 10; rs1705003: OR = 2.37, p = 3.21 × 10), meeting exome-wide significance. Both variants can affect the expression of their target genes at the transcript level. An array-based association analysis in 280 affected individuals and 1,121 control subjects determined the same signal at 6p21.32. Further conditional analyses supported that the two missense variants identified in WES-based association study were potential causal variants of IA. For rare variants, the top genes identified by gene-based analysis were significantly enriched in nerve and muscle phenotypic genes in the mouse. Moreover, the functional rare variants in these genes tended to cooccur in IA-affected individuals. In an independent cohort, we successfully validated three rare variants (CREB5, GenBank: NC_000007.13:g.28848865G>T; ESYT3, GenBank: NC_000003.11:g.138183253C>T; and LPIN1, GenBank: NC_000002.11:g.11925128A>G) which heightens the risk of developing IA. Our study identified and validated two common variants and three rare variants associated with IA in immunologic and neurological genes, providing new insight into the etiology of IA.
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http://dx.doi.org/10.1016/j.ajhg.2021.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387277PMC
August 2021

Single-cell RNA-Seq reveals a highly coordinated transcriptional program in mouse germ cells during primordial follicle formation.

Aging Cell 2021 07 26;20(7):e13424. Epub 2021 Jun 26.

Department of Biotechnology, Beijing Institute of Radiation Medicine, Beijing, China.

The assembly of primordial follicles in mammals represents one of the most critical processes in ovarian biology. It directly affects the number of oocytes available to a female throughout her reproductive life. Premature depletion of primordial follicles contributes to the ovarian pathology primary ovarian insufficiency (POI). To delineate the developmental trajectory and regulatory mechanisms of oocytes during the process, we performed RNA-seq on single germ cells from newborn (P0.5) ovaries. Three cell clusters were classified which corresponded to three cell states (germ cell cyst, cyst breakdown, and follicle) in the newborn ovary. By Monocle analysis, a uniform trajectory of oocyte development was built with a series of genes showed dynamic changes along the pseudo-timeline. Gene Ontology term enrichment revealed a significant decrease in meiosis-related genes and a dramatic increase in oocyte-specific genes which marked the transition from a germ cell to a functional oocyte. We then established a network of regulons by using single-cell regulatory network inference and clustering (SCENIC) algorithm and identified possible candidate transcription factors that may maintain transcription programs during follicle formation. Following functional studies further revealed the differential regulation of the identified regulon Id2 and its family member Id1, on the establishment of primordial follicle pool by using siRNA knockdown and genetic modified mouse models. In summary, our study systematically reconstructed molecular cascades in oocytes and identified a series of genes and molecular pathways in follicle formation and development.
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http://dx.doi.org/10.1111/acel.13424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282241PMC
July 2021

Maternal mortality ratio in Jiangsu Province, China: recent trends and associated factors.

BMC Pregnancy Childbirth 2021 Jun 25;21(1):447. Epub 2021 Jun 25.

State Key Laboratory of Reproductive Medicine, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Jiangsu Women and Children Health Hospital, Nanjing, 210036, China.

Background: In recent years, births to older mothers and multiparous mothers have increased rapidly with the change of birth policy in China. And mothers of advanced age are more likely to have maternal complications and poor birth outcomes. We aimed to estimate the recent trends and underlying risk factors of maternal mortality.

Methods: In this systematic assessment, we used data from the National Maternal and Child Health Routine Reporting System (2013-2018), Jiangsu Provincial Maternal Mortality Surveillance System (2017-2018), the Integrated National Mortality Surveillance System (2018), City Statistical Yearbooks (2018), City Health Statistical Yearbooks (2018). The factors associated with maternal mortality ratio (MMR) were explored using the stepwise regression analysis and cluster analysis.

Results: The MMR maintained at low levels between 2013 and 2016 and there was a slight increase in maternal mortality after 2016 in Jiangsu province. With the implementation of the China's universal two child policies, the percentage of multiparous mothers ascended from 34.2% (95% confidence interval (CI) = 34.1-34.3%) in 2013 to 51.4% (95% CI = 51.3-51.6%) in 2018 (beta = 3.88, P < 0.001). Consistently, the percentage of advanced maternal age (≥ 35) increased from 8.4% (95% CI = 8.4-8.5%) in 2013 to 10.4% (95% CI = 10.3-10.4%) in 2018 (beta = 0.50, P = 0.012). And we found that the percentage of multiparous mothers and advanced maternal age among maternal deaths were higher than all pregnant women (P < 0.001). In the stepwise regression analysis, four risk factors were significantly associated with maternal mortality ratio (primary industry of gross domestic product (GDP), rate of delivery in maternal and child health hospital, rate of cesarean section and rate of low birth weight). As the results derived from cluster analysis, the relatively developed regions had lower preventable maternal mortality ratio (43.5% (95% CI = 31.2-56.7%) vs. 62.6% (95% CI = 52.3-72.0%), P = 0.027).

Conclusions: Since the universal two child policy has been associated with changes in health related birth characteristics: women giving birth have been more likely to be multiparous, and more likely to be aged 35 and over. This somewhat magnifies the impact of differences in economic development and obstetric services on MMR. The findings based on prefecture level data suggest that interventions must target economic development, the health system and maternal risk factors in synergy. These approaches will be of great benefit to control or diminish environmental factors associated with preventable deaths and will effectively reduce MMR and narrow the gap among the different regions.
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http://dx.doi.org/10.1186/s12884-021-03897-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235612PMC
June 2021

Association of assisted reproductive technology, germline de novo mutations and congenital heart defects in a prospective birth cohort study.

Cell Res 2021 Aug 9;31(8):919-928. Epub 2021 Jun 9.

State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.

Emerging evidence suggests that children conceived through assisted reproductive technology (ART) have a higher risk of congenital heart defects (CHDs) even when there is no family history. De novo mutation (DNM) is a well-known cause of sporadic congenital diseases; however, whether ART procedures increase the number of germline DNM (gDNM) has not yet been well studied. Here, we performed whole-genome sequencing of 1137 individuals from 160 families conceived through ART and 205 families conceived spontaneously. Children conceived via ART carried 4.59 more gDNMs than children conceived spontaneously, including 3.32 paternal and 1.26 maternal DNMs, after correcting for parental age at conception, cigarette smoking, alcohol drinking, and exercise behaviors. Paternal DNMs in offspring conceived via ART are characterized by C>T substitutions at CpG sites, which potentially affect protein-coding genes and are significantly associated with the increased risk of CHD. In addition, the accumulation of non-coding functional mutations was independently associated with CHD and 87.9% of the mutations were originated from the father. Among ART offspring, infertility of the father was associated with elevated paternal DNMs; usage of both recombinant and urinary follicle-stimulating hormone and high-dosage human chorionic gonadotropin trigger was associated with an increase of maternal DNMs. In sum, the increased gDNMs in offspring conceived by ART were primarily originated from fathers, indicating that ART itself may not be a major reason for the accumulation of gDNMs. Our findings emphasize the importance of evaluating the germline status of the fathers in families with the use of ART.
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http://dx.doi.org/10.1038/s41422-021-00521-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324888PMC
August 2021

Genetic variants associated with expression of contribute to the risk of head and neck cancer in Chinese population.

J Med Genet 2021 Mar 5. Epub 2021 Mar 5.

Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China

Background: Squamous cell carcinoma of the head and neck (SCCHN) is one of the most common cancers worldwide and includes cancers arising from the oral cavity, pharynx and larynx. Genome-wide association studies have found several genetic variants related to the risk of SCCHN; however, they could only explain a small fraction of the heritability. Thus, more susceptibility loci associated with SCCHN need to be identified.

Methods: An association study was conducted by genotyping 555 patients with SCCHN and 1367 controls in a Chinese population. Single-variant association analysis was conducted on 63 373 SNPs, and the promising variants were then confirmed by a two-stage validation with 1875 SCCHN cases and 4637 controls. Bioinformatics analysis and functional assays were applied to uncover the potential pathogenic mechanism of the promising variants and genes associated with SCCHN.

Results: We first identified three novel genetic variants significantly associated with the risk of SCCHN (p=7.45×10 for rs2517611 at 6p22.1, p=1.76×10 for rs2524182 at 6p21.33 and p=2.17×10 for rs3131018 at 6p21.33). Further analysis and biochemical assays showed that rs3094187, which was in a region in high linkage disequilibrium with rs3131018, could modify expression by regulating the binding affinity of the transcription factor to the promoter of . In addition, experiments revealed that the inhibition of may affect several important pathways involved in tumourigenesis and attenuate the cell proliferation and migration of SCCHN.

Conclusion: These findings offer important evidence that functional genetic variants could contribute to development of SCCHN and that may function as a putative susceptibility gene for SCCHN.
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http://dx.doi.org/10.1136/jmedgenet-2020-107410DOI Listing
March 2021

Identification of A-to-I RNA editing profiles and their clinical relevance in lung adenocarcinoma.

Sci China Life Sci 2021 May 27. Epub 2021 May 27.

Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.

Adenosine-to-inosine (A-to-I) RNA editing is a widespread posttranscriptional modification that has been shown to play an important role in tumorigenesis. Here, we evaluated a total of 19,316 RNA editing sites in the tissues of 80 lung adenocarcinoma (LUAD) patients from our Nanjing Lung Cancer Cohort (NJLCC) and 486 LUAD patients from the TCGA database. The global RNA editing level was significantly increased in tumor tissues and was highly heterogeneous across patients. The high RNA editing level in tumors was attributed to both RNA (ADAR1 expression) and DNA alterations (mutation load). Consensus clustering on RNA editing sites revealed a new molecular subtype (EC3) that was associated with the poorest prognosis of LUAD patients. Importantly, the new classification was independent of classic molecular subtypes based on gene expression or DNA methylation. We further proposed a simplified model including eight RNA editing sites to accurately distinguish the EC3 subtype in our patients. The model was further validated in the TCGA dataset and had an area under the curve (AUC) of the receiver operating characteristic curve of 0.93 (95%CI: 0.91-0.95). In addition, we found that LUAD cell lines with the EC3 subtype were sensitive to four chemotherapy drugs. These findings highlighted the importance of RNA editing events in the tumorigenesis of LUAD and provided insight into the application of RNA editing in the molecular subtyping and clinical treatment of cancer.
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http://dx.doi.org/10.1007/s11427-020-1928-0DOI Listing
May 2021

Development and Validation of a Polygenic Risk Score for Stroke in the Chinese Population.

Neurology 2021 08 24;97(6):e619-e628. Epub 2021 May 24.

From the Key Laboratory of Cardiovascular Epidemiology and Department of Epidemiology (Xiangfeng Lu, X.N., Fangchao Liu, Z.L., K.H., L.W., J.L., J.C., S.C., H.L., Xigui Wu, Y.L., J.H., D.G.), State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing; Department of Epidemiology and Biostatistics (C.S., Z.H., H.S.), Center for Global Health, School of Public Health, Nanjing Medical University; Department of Biostatistics and Epidemiology (D.H.), School of Public Health, Shenzhen University Health Science Center, Guangdong; Cardio-Cerebrovascular Control and Research Center (Y.Z., Fanghong Lu), Institute of Basic Medicine, Shandong First Medical University (Shandong Academy of Medical Sciences), Jinan; Tianjin Key Laboratory of Environment, Nutrition and Public Health (X.Y.), Department of Occupational and Environmental Health, School of Public Health, Tianjin Medical University, Tianjin; Division of Epidemiology (Xiaoqing Liu), Guangdong Provincial People's Hospital and Cardiovascular Institute, Guangzhou; Department of Neurology (W.T., Z.R.), Affiliated Yixing People's Hospital of Jiangsu University, People's Hospital of Yixing City, Yixing; Department of Cardiology (L.Y.), Fujian Provincial Hospital, Fuzhou; Center for Chronic and Noncommunicable Disease Control and Prevention (Xianping Wu), Sichuan Center for Disease Control and Prevention, Chengdu; Center for Genetic Epidemiology and Genomics (H.Z.), School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou; Research Unit of Prospective Cohort of Cardiovascular Diseases and Cancer (H.S.), Chinese Academy of Medical Sciences (2019RU038); and Department of Internal Medicine, Division of Cardiovascular Medicine (C.J.W.), and Department of Human Genetics (C.J.W.), University of Michigan, Ann Arbor.

Objective: To construct a polygenic risk score (PRS) for stroke and evaluate its utility in risk stratification and primary prevention for stroke.

Methods: Using a meta-analytic approach and large genome-wide association results for stroke and stroke-related traits in East Asians, we generated a combined PRS (metaPRS) by incorporating 534 genetic variants in a training set of 2,872 patients with stroke and 2,494 controls. We then validated its association with incident stroke using Cox regression models in large Chinese population-based prospective cohorts comprising 41,006 individuals.

Results: During a total of 367,750 person-years (mean follow-up 9.0 years), 1,227 participants developed stroke before age 80 years. Individuals with high polygenic risk had an about 2-fold higher risk of incident stroke compared with those with low polygenic risk (hazard ratio [HR] 1.99, 95% confidence interval [CI] 1.66-2.38), with the lifetime risk of stroke being 25.2% (95% CI 22.5%-27.7%) and 13.6% (95% CI 11.6%-15.5%), respectively. Individuals with both high polygenic risk and family history displayed lifetime risk as high as 41.1% (95% CI 31.4%-49.5%). Individuals with high polygenic risk achieved greater benefits in terms of absolute risk reductions from adherence to ideal fasting blood glucose and total cholesterol than those with low polygenic risk. Maintaining favorable cardiovascular health (CVH) profile could substantially mitigate the increased risk conferred by high polygenic risk to the level of low polygenic risk (from 34.6% to 13.2%).

Conclusions: Our metaPRS has great potential for risk stratification of stroke and identification of individuals who may benefit more from maintaining ideal CVH.

Classification Of Evidence: This study provides Class I evidence that metaPRS is predictive of stroke risk.
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http://dx.doi.org/10.1212/WNL.0000000000012263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424497PMC
August 2021

A multi-omics study links TNS3 and SEPT7 to long-term former smoking NSCLC survival.

NPJ Precis Oncol 2021 May 17;5(1):39. Epub 2021 May 17.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, 02115, USA.

The genetic architecture of non-small cell lung cancer (NSCLC) is relevant to smoking status. However, the genetic contribution of long-term smoking cessation to the prognosis of NSCLC patients remains largely unknown. We conducted a genome-wide association study primarily on the prognosis of 1299 NSCLC patients of long-term former smokers from independent discovery (n = 566) and validation (n = 733) sets, and used in-silico function prediction and multi-omics analysis to identify single nucleotide polymorphisms (SNPs) on prognostics with NSCLC. We further detected SNPs with at least moderate association strength on survival within each group of never, short-term former, long-term former, and current smokers, and compared their genetic similarity at the SNP, gene, expression quantitative trait loci (eQTL), enhancer, and pathway levels. We identified two SNPs, rs34211819 at 7p12.3 (P = 3.90 × 10) and rs1143149 at 7p14.2 (P = 9.75 × 10), were significantly associated with survival of NSCLC patients who were long-term former smokers. Both SNPs had significant interaction effects with years of smoking cessation (rs34211819: P = 8.0 × 10; rs1143149: P = 0.003). In addition, in silico function prediction and multi-omics analysis provided evidence that these QTLs were associated with survival. Moreover, comparison analysis found higher genetic similarity between long-term former smokers and never-smokers, compared to short-term former smokers or current smokers. Pathway enrichment analysis indicated a unique pattern among long-term former smokers that was related to immune pathways. This study provides important insights into the genetic architecture associated with long-term former smoking NSCLC.
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http://dx.doi.org/10.1038/s41698-021-00182-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128887PMC
May 2021

Potential functional variants of KIAA genes are associated with breast cancer risk in a case control study.

Ann Transl Med 2021 Apr;9(7):549

Department of Epidemiology, International Joint Research Center on Environment and Human Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.

Background: KIAA genes identified in the Kazusa cDNA-sequencing project may play important roles in biological processes and are involved in carcinogenesis of many cancers. Genetic variants of KIAA genes are implicated in the abnormal expression of these genes and are linked to susceptibility of several human complex diseases.

Methods: The differentially expressed KIAA genes were screened and identified in The Cancer Genome Atlas (TCGA) database of breast cancer. A total of 48 variants located in the 28 KIAA genes were selected to investigate the associations between polymorphism and breast cancer in 1,032 cases and 1,063 cancer-free controls in a Chinese population.

Results: Two coding variants, which included a SNP rs2306369 in and a SNP rs1205434 in , were identified to be associated with the incidences of breast cancer. Logistic regression analysis showed that the SNP rs2306369 G allele was associated with a decreased risk of breast cancer (additive model: OR =0.81, 95% CI: 0.66-0.99, P=0.038), whereas the SNP rs1205434 A allele was involved with a higher risk of breast cancer (additive model: OR =1.19, 95% CI: 1.02-1.38, P= 0.025). Further stratified analysis revealed that the SNP rs1205434 showed a significant difference for age at menarche strata (heterogeneity test P=0.009). Multiplicative interaction analysis indicated that there was positive multiplicative interaction between the SNP rs1205434 and menarche age (OR =1.09, 95% CI: 1.01-1.17, P=0.036). Additionally, expression quantitative trait loci analysis revealed that the SNP rs1205434 A allele could decrease the expression in the Genotype-Tissue Expression (GTEx) database (P=0.002). The Kaplan-Meier plotter showed that breast cancer patients with high expression have significantly better outcomes than those with low levels of expression (HR =0.84, 95% CI: 0.72-0.99, P=0.033).

Conclusions: The results indicate that the genetic variants (rs2306369 and rs1205434) in the coding region of and respectively may affect Chinese females' breast cancer susceptibility and act as potential predictive biomarkers for breast cancer.
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http://dx.doi.org/10.21037/atm-20-6108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105804PMC
April 2021

Mutations in RNA Methyltransferase Gene Confer High Risk of Outflow Tract Malformation.

Front Cell Dev Biol 2021 21;9:623394. Epub 2021 Apr 21.

State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.

, encoding a cytosine-5 RNA methyltransferase and located in the 7q11.23 locus, is a candidate gene for tetralogy of Fallot (TOF). Deletion of the 7q11.23 locus in humans is linked to cardiac outflow tract (OFT) disorders including TOF. We identified four potential pathogenic mutations in the coding region of and which were enriched in TOF patients by an association study of 132 TOF patients and 2,000 in-house controls ( = 1.44 × 10). We then generated a null ( ) mouse model to validate the human findings by defining the functions of in OFT morphogenesis. The OFT did not develop properly in the deletion embryonic heart. We found a misalignment of the aorta and septum defects caused by the delayed fusion of the membraneous ventricular spetum as an OFT development delay. This caused OFT development delay in 27 of 64 (42.2%) mice. Moreover, we also found OFT development delay in 8 of 51 (15.7%) mice. Further functional experiments showed that the loss of function impaired the 5-methylcytosine (mC) modification and translation efficiency of essential cardiac genes. is required for normal OFT morphogenesis and it regulates the mC modification of essential cardiac genes. Our findings suggest the involvement of in the pathogenesis of TOF.
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http://dx.doi.org/10.3389/fcell.2021.623394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097101PMC
April 2021

SARS-CoV-2 encoded microRNAs are involved in the process of virus infection and host immune response.

J Biomed Res 2021 Jan;35(3):216-227

State Key Laboratory of Reproductive Medicine, Center of Global Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China.

The outbreak of COVID-19 caused by SARS-CoV-2 is spreading worldwide, with the pathogenesis mostly unclear. Both virus and host-derived microRNA (miRNA) play essential roles in the pathology of virus infection. This study aims to uncover the mechanism for SARS-CoV-2 pathogenicity from the perspective of miRNA. We scanned the SARS-CoV-2 genome for putative miRNA genes and miRNA targets and conducted experiments to validate the virus-encoded miRNAs and their regulatory role on the putative targets. One of such virus-encoded miRNAs, MR147-3p, was overexpressed that resulted in significantly decreased transcript levels of all of the predicted targets in human, , , , and in the virus-infected cells. The analysis showed that the immune response and cytoskeleton organization are two of the most notable biological processes regulated by the infection-modulated miRNAs. Additionally, the genomic mutation of SARS-CoV-2 contributed to the changed miRNA repository and targets, suggesting a possible role of miRNAs in the attenuated phenotype of SARS-CoV-2 during its evolution. This study provided a comprehensive view of the miRNA-involved regulatory system during SARS-CoV-2 infection, indicating possible antiviral therapeutics against SARS-CoV-2 through intervening miRNA regulation.
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http://dx.doi.org/10.7555/JBR.35.20200154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193712PMC
January 2021

A cross-tissue transcriptome-wide association study identifies novel susceptibility genes for lung cancer in Chinese populations.

Hum Mol Genet 2021 Aug;30(17):1666-1676

Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China.

Although dozens of susceptibility loci have been identified for lung cancer in genome-wide association studies (GWASs), the susceptibility genes and underlying mechanisms remain unclear. In this study, we conducted a cross-tissue transcriptome-wide association study (TWAS) with UTMOST based on summary statistics from 13 327 lung cancer cases and 13 328 controls and the genetic-expression matrix over 44 human tissues in the Genotype-Tissue Expression (GTEx) project. After further evaluating the associations in each tissue, we revealed 6 susceptibility genes in known loci and identified 12 novel ones. Among those, five novel genes, including DCAF16 (Pcross-tissue = 2.57 × 10-5, PLung = 2.89 × 10-5), CBL (Pcross-tissue = 5.08 × 10-7, PLung = 1.82 × 10-4), ATR (Pcross-tissue = 1.45 × 10-5, PLung = 9.68 × 10-5), GYPE (Pcross-tissue = 1.45 × 10-5, PLung = 2.17 × 10-3) and PARD3 (Pcross-tissue = 5.79 × 10-6, PLung = 4.05 × 10-3), were significantly associated with the risk of lung cancer in both cross-tissue and lung tissue models. Further colocalization analysis indicated that rs7667864 (C > A) and rs2298650 (G > T) drove the GWAS association signals at 4p15.31-32 (OR = 1.09, 95%CI: 1.04-1.12, PGWAS = 5.54 × 10-5) and 11q23.3 (OR = 1.08, 95%CI: 1.04-1.13, PGWAS = 5.55 × 10-5), as well as the expression of DCAF16 (βGTEx = 0.24, PGTEx = 9.81 × 10-15; βNJLCC = 0.29, PNJLCC = 3.84 × 10-8) and CBL (βGTEx = -0.17, PGTEx = 2.82 × 10-8; βNJLCC = -0.32, PNJLCC = 2.61 × 10-7) in lung tissue. Functional annotations and phenotype assays supported the carcinogenic effect of these novel susceptibility genes in lung carcinogenesis.
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http://dx.doi.org/10.1093/hmg/ddab119DOI Listing
August 2021

Comprehensive analyses of m6A regulators and interactive coding and non-coding RNAs across 32 cancer types.

Mol Cancer 2021 04 13;20(1):67. Epub 2021 Apr 13.

State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 211166, China.

N6-Methyladenosine (m6A) is an RNA modification that interacts with numerous coding and non-coding RNAs and plays important roles in the development of cancers. Nonetheless, the clinical impacts of m6A interactive genes on these cancers largely remain unclear since most studies focus only on a single cancer type. We comprehensively evaluated m6A modification patterns, including 23 m6A regulators and 83 interactive coding and non-coding RNAs among 9,804 pan-cancer samples. We used clustering analysis to identify m6A subtypes and constructed the m6A signature based on an unsupervised approach. We used the signatures to identify potential m6A modification targets across the genome. The prognostic value of one target was further validated in 3,444 samples from six external datasets. We developed three distinct m6A modification subtypes with different tumor microenvironment cell infiltration degrees: immunological, intermediate, and tumor proliferative. They were significantly associated with overall survival in 24 of 27 cancer types. Our constructed individual-level m6A signature was associated with survival, tumor mutation burden, and classical pathways. With the signature, we identified 114 novel genes as potential m6A targets. The gene shared most commonly between cancer types, BCL9L, is an oncogene and interacts with m6A patterns in the Wnt signaling pathway. In conclusion, m6A regulators and their interactive genes impact the outcome of various cancers. Evaluating the m6A subtype and the signature of individual tumors may inform the design of adjuvant treatments.
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http://dx.doi.org/10.1186/s12943-021-01362-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045265PMC
April 2021

Child marriage, maternal serum metal exposure, and risk of preterm birth in rural Bangladesh: evidence from mediation analysis.

J Expo Sci Environ Epidemiol 2021 05 6;31(3):571-580. Epub 2021 Apr 6.

State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.

Background: The prevalence of preterm birth in Bangladesh is estimated to be 19.1%, the highest in the world. Although prenatal exposure to several metals has been linked with preterm birth, fewer prospective studies have investigated the socioeconomic factors that affect metal exposure, leading to preterm birth risk.

Objective: We aim to identify novel metal biomarkers and their critical exposure windows, as well as the upstream socioeconomic risk factors for preterm birth in rural Bangladeshi, to shed light for future interventional strategies.

Methods: This study included data from 780 mother-offspring pairs, who were recruited to participate in a prospective birth cohort in Bangladesh (2008-2011). Serum concentrations of 19 metals were measured in the first and second trimesters using inductively coupled plasma mass spectrometry. Mediation analysis was performed to explore the upstream socioeconomic factors that affect the risk of preterm birth mediated via metal exposure concentrations.

Results: Early pregnancy exposure to serum zinc, arsenic, and strontium and mid-pregnancy exposure to barium were significantly associated with risk of preterm birth. Furthermore, younger marriage age was associated with an exponential increase in the risk of preterm birth, and women who married after 18 years old had a considerably lower risk of preterm birth. Mediation analysis indicated that these four elements mediated 30.2% of the effect of marriage age on preterm birth.

Conclusion: This study indicated that maternal serum metal exposure mediates the impact of child marriage on the increased risk of preterm birth via metal exposures. The findings shed light on the mechanisms underlying such association and provide insights into future interventional strategies.
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http://dx.doi.org/10.1038/s41370-021-00319-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134042PMC
May 2021

Relationships between sleep traits and lung cancer risk: a prospective cohort study in UK Biobank.

Sleep 2021 Sep;44(9)

Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.

Study Objectives: To prospectively investigate the association between sleep traits and lung cancer risk, accounting for the interactions with genetic predisposition of lung cancer.

Methods: We included 469 691 individuals free of lung cancer at recruitment from UK Biobank, measuring sleep behaviors with a standardized questionnaire and identifying incident lung cancer cases through linkage to national cancer and death registries. We estimated multivariable-adjusted hazard ratios (HRs) for lung cancer (2177 incident cases) across four sleep traits (sleep duration, chronotype, insomnia, and snoring) and examined the interaction and joint effects with a lung cancer polygenic risk score.

Results: A U-shaped association was observed for sleep duration and lung cancer risk, with an 18% higher risk (95% confidence interval [CI]: 1.07 to 1.30) for short sleepers and a 17% higher risk (95% CI: 1.02 to 1.34) for long sleepers compared with normal sleepers (7-8 h/day). Evening preference was associated with elevated lung cancer risk compared with morning preference (HR: 1.25; 95% CI: 1.07 to 1.46), but no association was found for insomnia or snoring. Compared with participants with favorable sleep traits and low genetic risk, those with both unfavorable sleep duration (<7 hours or >8 hours) or evening preference and high genetic risk showed the greatest lung cancer risk (HRsleep duration: 1.83; 95% CI: 1.47 to 2.27; HRchronotype: 1.85; 95% CI: 1.34 to 2.56).

Conclusions: Both unfavorable sleep duration and evening chronotype were associated with increased lung cancer incidence, especially for those with low to moderate genetic risk. These results indicate that sleep behaviors as modifiable risk factors may have potential implications for lung cancer risk.
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http://dx.doi.org/10.1093/sleep/zsab089DOI Listing
September 2021

Interleukin-17A mediates tobacco smoke-induced lung cancer epithelial-mesenchymal transition through transcriptional regulation of ΔNp63α on miR-19.

Cell Biol Toxicol 2021 Apr 3. Epub 2021 Apr 3.

Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China.

Interleukin-17A (IL-17A) is an essential inflammatory cytokine in the progress of carcinogenesis. Tobacco smoke (TS) is a major risk factor of lung cancer that influences epithelial-mesenchymal transition (EMT) process. However, the potential mechanism by which IL-17A mediates the progression of lung cancer in TS-induced EMT remains elusive. In the present study, it was revealed that the IL-17A level was elevated in lung cancer tissues, especially in tumor tissues of cases with experience of smoking, and a higher IL-17A level was correlated with induction of EMT in those specimens. Moreover, the expression of ΔNp63α was increased in IL-17A-stimulated lung cancer cells. ΔNp63α functioned as a key oncogene that bound to the miR-17-92 cluster promoter and transcriptionally increased the expression of miR-19 in lung cancer cells. Overexpression of miR-19 promoted EMT in lung cancer with downregulation of E-cadherin and upregulation of N-cadherin, while its inhibition suppressed EMT. Finally, the upregulated levels of IL-17A, ΔNp63α, and miR-19 along with the alteration of EMT-associated biomarkers were found in lung tissues of TS-exposed mice. Taken together, the abovementioned results suggest that IL-17A increases ΔNp63α expression, transcriptionally elevates miR-19 expression, and promotes TS-induced EMT in lung cancer. These findings may provide a new insight for the identification of therapeutic targets for lung cancer.
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http://dx.doi.org/10.1007/s10565-021-09594-0DOI Listing
April 2021

Sex-specific associations of circulating testosterone levels with all-cause and cause-specific mortality.

Eur J Endocrinol 2021 May;184(5):723-732

Department of Epidemiology and Biostatistics, International Joint Research Center on Environment and Human Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.

Objective: Testosterone is a critical determinant of health in both genders. However, the relationship between circulating levels of testosterone and mortality remains undetermined.

Methods: We examined the associations of serum total testosterone (TT) and free testosterone (FT) with all-cause and cause-specific mortality in 154 965 men and 93 314 postmenopausal women from UK Biobank. Cox regression models were used to calculate the hazard ratios (HR) and 95% CIs. Given multiple testing, P < 0.005 was considered statistically significant.

Results: Over a median follow-up of 8.9 (inter-quartile range: 8.3-9.5) years, we documented 5754 deaths in men, including 1243 (21.6%) from CVD and 2987 (51.9%) from cancer. In postmenopausal women, 2435 deaths occurred, including 346 (14.2%) from CVD and 1583 (65.0%) from cancer. TT and FT concentrations were inversely associated with all-cause mortality in men, with the multivariable HR of 0.82 (95% CI: 0.75-0.91) and 0.80 (95% CI: 0.73-0.87) for the highest (Q5) vs the lowest quintile (Q1), respectively. In postmenopausal women, TT concentrations showed a positive association with all-cause mortality (HR for Q5 vs Q1 = 1.20, 95% CI: 1.06-1.37). Furthermore, higher TT and FT concentrations were associated with a lower risk of cancer mortality in men (both P for trend = 0.001), whereas TT concentrations were suggestively associated with a higher risk of cancer mortality in postmenopausal women (P for trend = 0.03).

Conclusions: Our findings suggest that high levels of circulating testosterone may be beneficial for all-cause and cancer mortality in men but detrimental in postmenopausal women.
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http://dx.doi.org/10.1530/EJE-20-1253DOI Listing
May 2021

The cancer-testis gene, sensitizes triple-negative breast cancer to PARP1 inhibitors by inducing homologous recombination deficiency.

Cancer Biol Med 2021 02;18(1):74-87

State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China.

Objective: The newly defined cancer-testis (CT) gene, was previously found to play key roles in DNA double-strand break (DSB) repair. In this study, we aimed to investigate the effects and mechanisms of MEIOB in the carcinogenesis of triple-negative breast cancers (TNBCs).

Methods: The Cancer Genome Atlas database was used to quantify the expression of . Cox regression analysis was used to evaluate the association between expression and the prognosis of human TNBC. The effects of MEIOB on cell proliferation and migration in TNBCs were also assessed . Patient-derived xenograft (PDX) models were used to assess the sensitivity of breast cancers with active MEIOB to PARP1 inhibitors.

Results: We confirmed as a CT gene whose expression was restricted to the testes and breast tumors, especially TNBCs. Its activation was significantly associated with poor survival in breast cancer patients [overall, hazard ratio (HR) = 1.90 (1.16-2.06); TNBCs: HR = 7.05 (1.16-41.80)]. In addition, we found that was oncogenic and significantly promoted the proliferation of TNBC cells. Further analysis showed that participated in DSB repair in TNBCs. However, in contrast to its function in meiosis, it mediated homologous recombination deficiency (HRD) through the activation of polyADP-ribose polymerase (PARP)1 by interacting with YBX1. Furthermore, activated MEIOB was shown to confer sensitivity to PARP inhibitors, which was confirmed in PDX models.

Conclusions: played an oncogenic role in TNBC through its involvement in HRD. In addition, dysregulation of sensitized TNBC cells to PARP inhibitors, so may be a therapeutic target of PARP1 inhibitors in TNBC.
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http://dx.doi.org/10.20892/j.issn.2095-3941.2020.0071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877187PMC
February 2021

Association between dietary sodium, potassium intake and lung cancer risk: evidence from the prostate, lung, colorectal and ovarian cancer screening trial and the Women's Health Initiative.

Transl Lung Cancer Res 2021 Jan;10(1):45-56

Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.

Background: Epidemiological studies have reported that dietary mineral intake plays an important role on lung cancer risk, but the association of sodium, potassium intake is still unclear.

Methods: We determined the association between dietary sodium, potassium intake and lung cancer risk based on the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial and the Women's Health Initiative (WHI). Totally 165,409 participants who completed the baseline questionnaire (BQ) and diet history questionnaire (DHQ) were included into the analytical dataset, including 92,984 (44,959 men and 48,025 women) from the PLCO trial and 72,425 (women only) from the WHI cohort. Multivariable Cox proportional hazards regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of incident lung cancer associated with dietary potassium and sodium intake. The dose-response relationship was also described using the spline smoothed curve after adjusting covariates.

Results: After the median follow-up of 8.55 and 18.56 years, 1,278 and 1,631 new cases of lung cancer were identified in the PLCO trial and WHI cohort, respectively. Intake of sodium was significantly associated with the incidence of lung cancer in the PLCO trial after multivariate adjustment for men (HR: 1.19, 95% CI: 1.05-1.35; P for linear trend =0.044). There was a suggestion that lung cancer risk had a quadratic curve correlation with the increase of potassium intake for women (third vs. lowest quintile: HR: 0.72, 95% CI: 0.54-0.96; P for quadratic trend =0.042). The similar results showing an inverse association between potassium intake and lung cancer risk were also observed in the WHI cohort for women (highest vs. lowest quintile: HR: 0.82, 95% CI: 0.70-0.97; P for linear trend =0.009).

Conclusions: Appropriate intake of potassium has a protective effect against lung cancer, while high consumption of sodium is associated with an increased risk of lung cancer.
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http://dx.doi.org/10.21037/tlcr-20-870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867772PMC
January 2021

Prediction and clinical utility of a liver cancer risk model in Chinese adults: A prospective cohort study of 0.5 million people.

Int J Cancer 2021 06 15;148(12):2924-2934. Epub 2021 Feb 15.

Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China.

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.
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http://dx.doi.org/10.1002/ijc.33487DOI Listing
June 2021
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