Stem cells play a crucial role in maintaining tissue regenerative capacity and homeostasis.However,mechanisms associated with stem cell senescence require further investigation.In this study,we conducted a proteomic a...Stem cells play a crucial role in maintaining tissue regenerative capacity and homeostasis.However,mechanisms associated with stem cell senescence require further investigation.In this study,we conducted a proteomic analysis of human dental pulp stem cells(HDPSCs)obtained from individuals of various ages.Our findings showed that the expression of NUP62 was decreased in aged HDPSCs.We discovered that NUP62 alleviated senescence-associated phenotypes and enhanced differentiation potential both in vitro and in vivo.Conversely,the knocking down of NUP62 expression aggravated the senescence-associated phenotypes and impaired the proliferation and migration capacity of HDPSCs.Through RNA-sequence and decoding the epigenomic landscapes remodeled induced by NUP62 overexpression,we found that NUP62 helps alleviate senescence in HDPSCs by enhancing the nuclear transport of the transcription factor E2F1.This,in turn,stimulates the transcription of the epigenetic enzyme NSD2.Finally,the overexpression of NUP62 influences the H3K36me2 and H3K36me3 modifications of anti-aging genes(HMGA1,HMGA2,and SIRT6).Our results demonstrated that NUP62 regulates the fate of HDPSCs via NSD2-dependent epigenetic reprogramming.展开更多
Adiponectin secreted by adipose tissue has been implicated in prostate carcinogenesis. Genetic variations in ADIPOQare thought to influence the activity of adiponectin, thus relating to cancer occurrence. In this hosp...Adiponectin secreted by adipose tissue has been implicated in prostate carcinogenesis. Genetic variations in ADIPOQare thought to influence the activity of adiponectin, thus relating to cancer occurrence. In this hospital-based case-control study of 917 prostate cancer （PCa） cases and 1036 cancer-free controls, we evaluated the association of single nucleotide polymorphisms in ADIPOQ with risk of PCa and adiponectin levels in Chinese Han men. Variants of ADIPOQ were genotyped by Taqman polymerase chain reaction method. The plasma adiponectin concentrations were measured by enzyme.linked immunosorbent assay （ELISA） in a subset of cases and controls. We found that the ADIPOQ rs3774262 variant AA genotype was associated with both decreased PCa risk [adjusted odds ratio （OR）： 0.66, 95% confidence interval （CI） =0.48-0.92] and increased plasma adiponectin levels （P= 0.036 and 0,043）, with significant difference by tumor grade, clinical stage, and aggressiveness. A significant interaction between ADIPOQ rs3774262 and body mass index was observed in modifying the risk of PCa （P=6.7 × 10-3）. ADIPOQ rs266729 and rs182052 were not related to PCa risk or plasma adiponectin levels. Our data support that ADIPOQ rs3774262 may affect PCa risk in combination with plasma adiponectin levels in Chinese Han men. It may contribute to the molecular basis for the association between obesity and PCa.展开更多
Dear Editor We report here the performance of prostate cancer antigen 3 （PCA3） and genetic risk score （GRS） in predicting prostate cancer （PCa） from the prostate biopsy. To the best of our knowledge, this is th...Dear Editor We report here the performance of prostate cancer antigen 3 （PCA3） and genetic risk score （GRS） in predicting prostate cancer （PCa） from the prostate biopsy. To the best of our knowledge, this is the first report of simultaneously evaluating these two biomarkers in the same study.展开更多
Programmed silencing ofγ-globin genes in adult erythropoiesis is mediated by several chromatin remodeling complexes,which determine the stage-specific genome architecture in this region.Identification of cis-or trans...Programmed silencing ofγ-globin genes in adult erythropoiesis is mediated by several chromatin remodeling complexes,which determine the stage-specific genome architecture in this region.Identification of cis-or trans-acting mutations contributing to the diverse extent of fetal hemoglobin(Hb F)might illustrate the underlying mechanism ofγ-β-globin switching.Here,we recruit a cohort of 1142β-thalassemia patients and dissect the natural variants in the wholeβ-globin gene cluster through a targeted next-generation sequencing panel.A previously unreported SNP rs7948668,predicted to disrupt the binding motif of IKAROS as a key component of chromatin remodeling complexes,is identified to be significantly associated with higher levels of Hb F and age at onset.Gene-editing on this SNP leads to the elevation of Hb F in both HUDEP-2 and primary CD34+cells while the extent of elevation is amplified in the context ofβ-thalassemia mutations,indicating epistasis effects of the SNP in the regulation of Hb F.Finally,we perform ChIP-qPCR and 4C assays to prove that this variant disrupts the binding motif of IKAROS,leading to enhanced competitiveness of HBG promoters to locus control regions.This study highlights the significance of common regulatory SNPs and provides potential targets for treatingβ-hemoglobinopathy.展开更多
Mitochondria play a key role in lipid metabolism,and mitochondrial DNA(mtDNA)mutations are thus considered to affect obesity susceptibility by altering oxidative phosphorylation and mitochondrial function.In this stud...Mitochondria play a key role in lipid metabolism,and mitochondrial DNA(mtDNA)mutations are thus considered to affect obesity susceptibility by altering oxidative phosphorylation and mitochondrial function.In this study,we investigate mtDNA variants that may affect obesity risk in 2877 Han Chinese individuals from 3 independent populations.The association analysis of 16 basal mtDNA haplogroups with body mass index,waist circumference,and waist-to-hip ratio reveals that only haplogroup M7 is significantly negatively correlated with all three adiposity-related anthropometric traits in the overall cohort,verified by the analysis of a single population,i.e.,the Zhengzhou population.Furthermore,subhaplogroup analysis suggests that M7b1a1 is the most likely haplogroup associated with a decreased obesity risk,and the variation T12811C(causing Y159H in ND5)harbored in M7b1a1 may be the most likely candidate for altering the mitochondrial function.Specifically,we find that proportionally more nonsynonymous mutations accumulate in M7b1a1 carriers,indicating that M7b1a1 is either under positive selection or subject to a relaxation of selective constraints.We also find that nuclear variants,especially in DACT2 and PIEZO1,may functionally interact with M7b1a1.展开更多
Being widespread across the globe,severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)keeps evolving and generating new variants and continuously poses threat to public health,especially to the population with ...Being widespread across the globe,severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)keeps evolving and generating new variants and continuously poses threat to public health,especially to the population with chronic comorbidities.Diabetes mellitus is one of high-risk factors for severe outcome of coronavirus disease 2019(COVID-19).Establishment of animal models that parallel the clinical and pathological features of COVID-19 complicated with diabetes is thus highly essential.Here,in this study,we constructed leptin receptor gene knockout hamsters with the phenotype of diabetes mellitus(db/db),and revealed that the diabetic hamsters were more susceptible to SARS-CoV-2 and its variants than wild-type hamsters.SARS-CoV-2 and its variants induced a stronger immune cytokine response in the lungs of diabetic hamsters than in wild-type hamsters.Comparative histopathology analyses also showed that infection of SARS-CoV-2 and the variants caused more severe lung tissue injury in diabetic hamsters,and may induce serious complications such as diabetic kidney disease and cardiac lesions.Our findings demonstrated that despite the decreased respiratory pathogenicity,the SARS-CoV-2 variants were still capable of impairing other organs such as kidney and heart in diabetic hamsters,suggesting that the risk of evolving SARS-CoV-2 variants to diabetic patients should never be neglected.This hamster model may help better understand the pathogenesis mechanism of severe COVID-19 in patients with diabetes.It will also aid in development and testing of effective therapeutics and prophylactic treatments against SARS-CoV-2 variants among these high-risk populations.展开更多
Shandong province,located in the Lower Yellow River,is one of the birthplaces of ancient Chinese civilization.However,the comprehensive genetic histories of this region have remained largely unknown until now due to a...Shandong province,located in the Lower Yellow River,is one of the birthplaces of ancient Chinese civilization.However,the comprehensive genetic histories of this region have remained largely unknown until now due to a lack of ancient human genomes.Here,we present 21 ancient genomes from Shandong dating from the Warring States period to the Northern Dynasties.Unlike the early Neolithic samples from Shandong,the historical samples are most closely related to post-Late Neolithic populations of the Middle Yellow River Basin,suggesting a population turnover in Shandong from the Neolithic Age to the Historical era.In addition,we detect a close genetic affinity between the historical samples in Shandong and present-day Han Chinese,showing long-term genetic stability in Han Chinese,at least since the Warring States period.展开更多
Background: Musculoskeletal disorders(MSDs) represent a significant global health burden. While physical activity(PA) and physical fitness are both thought to reduce MSD risk, their independent and joint associations ...Background: Musculoskeletal disorders(MSDs) represent a significant global health burden. While physical activity(PA) and physical fitness are both thought to reduce MSD risk, their independent and joint associations with MSD incidence have not been fully explored. This study investigated the independent and combined effects of PA, cardiorespiratory fitness(CRF), grip strength(GS), and GS asymmetry on MSD incidence in a large prospective cohort.Methods: We analyzed data from the UK Biobank cohort(2006-2023), including 406,080 participants aged 37-73 years(age = 55.7 ± 8.2 years,mean ± SD;53.0% female) who were free of MSD at baseline and during the first 2 years of follow-up. PA, derived from self-reported data and expressed in total metabolic equivalent hours per week(MET-h/week);CRF(watts(W)/kilogram(kg)), measured using a cycling exercise test;and GS(kg), measured by hydraulic hand dynamometer, were included as exposures. GS asymmetry was defined by the left-to-right hand strength ratio. MSD incidence was determined via hospital records. Time-to-event associations were analyzed using Cox proportional hazards regression models with restricted cubic splines to account for non-linear relationships. The analysis was conducted in April 2024.Results: Over a median follow-up of 14.7 years, a total of 73,002 incident cases of MSDs were recorded(rheumatoid arthritis: 2923;osteoarthritis:54,955;degenerative spinal diseases: 15,124). Lower self-reported PA(<4.8 MET-h/week) was associated with increased MSD risk(hazard ratio(HR) = 1.0710, 95% confidence interval(95%CI): 1.0623-1.0797). Low CRF(<1.22 W/kg;HR = 1.0941, 95%CI: 1.0596-1.1298), low GS(<27.80 kg;HR = 1.1133, 95%CI: 1.0990-1.1277), and GS asymmetry(HR = 1.1042, 95%CI: 1.0814-1.1274) were also significantly associated with increased MSD risk. Good CRF and GS, and lower GS asymmetry mitigated the higher MSD risk associated with low PA levels.Conclusion: Low levels of PA, CRF, GS, and GS asymmetry were associated with a higher risk of incident MSD. Meanwhile, improvements in CRF, GS, and GS balance could help offset the risk of MSD incidence in populations with insufficient PA.展开更多
China's Northern and Southern Dynasties period(3rd–6th centuries AD)marked a significant era of ethnic integration in northern China.However,previous ancient DNA studies have primarily focused on northern ethnic ...China's Northern and Southern Dynasties period(3rd–6th centuries AD)marked a significant era of ethnic integration in northern China.However,previous ancient DNA studies have primarily focused on northern ethnic groups,with limited research on the genetic formation of the hereditary elite family,especially considering their abundant archaeological record and clear material identity.In this study,we obtain the ancient genome of a hereditary elite family,Gao Bin(高宾,503 AD–572 AD),at 0.6473-fold coverage with 475,132 single-nucleotide polymorphisms(SNPs)on the 1240k panel.His mitochondrial haplogroup belongs to Z4 and Y-haplogroup to O1a1a2b-F2444∗.The genetic profile of Gao Bin is most similar to that of the northern Han Chinese.He can be modeled as deriving all his ancestry from Late Neolithic to Iron Age Yellow River farmers without influence from Northeast Asia,Korea,or the Mongolian Plateau.Our study sheds light on the genetic formation of hereditary elite families in the context of the Southern and Northern Dynasties ethnic integration.展开更多
Evidence has shown that differential transcriptomic profiles among human populations from diverse ancestries,supporting the role of genetic architecture in regulating gene expression alongside environmental stimuli.Ge...Evidence has shown that differential transcriptomic profiles among human populations from diverse ancestries,supporting the role of genetic architecture in regulating gene expression alongside environmental stimuli.Genetic variants that regulate gene expression,known as expression quantitative trait loci(eQTL),are primarily shaped by human migration history and evolutionary forces,likewise,regulation of gene expression in principle could have been influenced by these events.Therefore,a comprehensive understanding of how human evolution impacts eQTL offers important insights into how phenotypic diversity is shaped.Recent studies,however,suggest that eQTL is enriched in genes that are selectively constrained.Whether eQTL is minimally affected by selective pressures remains an open question and requires comprehensive investigations.In addition,such studies are primarily dominated by the major populations of European ancestry,leaving many marginalized populations underrepresented.These observations indicate there exists a fundamental knowledge gap in the role of genomics variation on phenotypic diversity,which potentially hinders precision medicine.This article aims to revisit the abundance of eQTL across diverse populations and provide an overview of their impact from the population and evolutionary genetics perspective,subsequently discuss their influence on phenomics,as well as challenges and opportunities in the applications to precision medicine.展开更多
PCR-DGGE approach was used to analyze bacterial diversity in the bottomsection of seven arctic sea ice samples colleted from the Canada Basin.Thirty-two 16S rDNAsequences were obtained from prominent DGGE bands.The cl...PCR-DGGE approach was used to analyze bacterial diversity in the bottomsection of seven arctic sea ice samples colleted from the Canada Basin.Thirty-two 16S rDNAsequences were obtained from prominent DGGE bands.The closest relatives of these sequences arefound to be those of cultivated or uncultured bacteria from antarctic or arctic sea ice.Phylogenetic analysis clustered these sequences or phylotypes withinα-proteobacteria,γ-proteobacteria and CFB(cytophaga-flexibacter-bacteroides)group.Sequences belonging toγ-proteobacteria were dominant and members of the CFB group were highly abundant.It was suggestedthat the CFB group was the representative of the bottom section of sea ice samples.展开更多
The [-2]proPSA （p2PSA） and its derivatives, the p2PSA-to-free PSA ratio （%p2PSA）, and the Prostate Health Index （PHI） have greatly improved discrimination between men with and without prostate cancer （PCa） in ...The [-2]proPSA （p2PSA） and its derivatives, the p2PSA-to-free PSA ratio （%p2PSA）, and the Prostate Health Index （PHI） have greatly improved discrimination between men with and without prostate cancer （PCa） in prostate biopsies. However, little is known about their performance in cases where a digital rectal examination （DRE） and transrectal ultrasonography （TRUS） are negative. A prospective cohort of 261 consecutive patients in China with negative DRE and TRUS were recruited and underwent prostate biopsies. A serum sample had collected before the biopsy was used to measure various PSA derivatives, including total prostate-specific antigen （tPSA）, free PSA, and p2PSA. For each patient, the free-to-total PSA ratio （%fPSA）, PSA density （PSAD）, p2PSA-to-free PSA ratio （%p2PSA）, and PHI were calculated. Discriminative performance was assessed using the area under the receiver operating characteristic curve （AUC） and the biopsy rate at 91% sensitivity. The AUC scores within the entire cohort with respect to age, tPSA, %fPSA, PSAD, p2PSA, %p2PSA, and PHI were 0.598, 0.751, 0.646, 0.789, 0.814, 0.808, and 0.853, respectively. PHI was the best predictor of prostate biopsy results, especially in patients with a tPSA of 10.1-20 ng ml-1. Compared with other markers, at a sensitivity of 91%, PHI was the most useful for determining which men did not need to undergo biopsy, thereby avoiding unnecessary procedures. The use of PHI could improve the accuracy of PCa detection by predicting prostate biopsy outcomes among men with a negative DRE and TRUS in China.展开更多
The human face is a heritable surface with many complex sensory organs.In recent years,many genetic loci associated with facial features have been reported in different populations,yet there is a lack of studies on th...The human face is a heritable surface with many complex sensory organs.In recent years,many genetic loci associated with facial features have been reported in different populations,yet there is a lack of studies on the Han Chinese population.Here,we report a genome-wide association study of 3D normal human faces of 2,659 Han Chinese with autosegment phenotypes of facial morphology.We identify singlenucleotide polymorphisms(SNPs)encompassing four genomic regions showing significant associations with different facial regions,including SNPs in DENND1 B associated with the chin,SNPs among PISRT1 associated with eyes,SNPs between DCHS2 and SFRP2 associated with the nose,and SNPs in VPS13 B associated with the nose.We replicate 24 SNPs from previously reported genetic loci in different populations,whose candidate genes are DCHS2,SUPT3 H,HOXD1,SOX9,PAX3,and EDAR.These results provide a more comprehensive understanding of the genetic basis of variation in human facial morphology.展开更多
Prostate cancer （PCa） is one of the most common cancers among men in Western developed countries and its incidence has increased considerably in many other parts of the world, including China. The etiology of PCa is...Prostate cancer （PCa） is one of the most common cancers among men in Western developed countries and its incidence has increased considerably in many other parts of the world, including China. The etiology of PCa is largely unknown but is thought to be multifactorial, where inherited genetics plays an important role. In this article, we first briefly review results from studies of familial aggregation and genetic susceptibility to PCa. We then recap key findings of rare and high-penetrance PCa susceptibility genes from linkage studies in PCa families. We devote a significant portion of this article to summarizing discoveries of common and Iow-penetrance PCa risk-associated single-nucleotide polymorphisms （SNPs） from genetic association studies in PCa cases and controls, especially those from genome-wide association studies （GWASs）. A strong focus of this article is to review the literature on the potential clinical utility of these implicated genetic markers. Most of these published studies described PCa risk estimation using a genetic score derived from multiple risk-associated SNPs and its utility in determining the need for prostate biopsy. Finally, we comment on the newly proposed concept of genetic score; the notion is to treat it as a marker for genetic predisposition, similar to family history, rather than a diagnostic marker to discriminate PCa patients from non-cancer patients. Available evidence to date suggests that genetic score is an objective and better measurement of inherited risk of PCa than family history. Another unique feature of this article is the inclusion of genetic association studies of PCa in Chinese and Japanese populations.展开更多
The human microbiota is an aggregate of microorganisms residing in the human body, mostly in the gastrointestinal tract （GIT）. Our gut microbiota evolves with us and plays a pivotal role in human health and disease....The human microbiota is an aggregate of microorganisms residing in the human body, mostly in the gastrointestinal tract （GIT）. Our gut microbiota evolves with us and plays a pivotal role in human health and disease. In recent years, the microbiota has gained increasing attention due to its impact on host metabolism, physiology, and immune system development, but also because the perturbation of the microbiota may result in a number of diseases. The gut microbiota may be linked to malignancies such as gastric cancer and colorectal cancer. It may also be linked to disorders such as nonalcoholic fatty liver disease （NAFLD）; obesity and diabetes, which are characterized as ＂lifestyle diseases＂ of the industrial- ized world; coronary heart disease; and neurological disorders. Although the revolution in molecular technologies has provided us with the necessary tools to study the gut microbiota more accurately, we need to elucidate the relationships between the gut microbiota and several human pathologies more precisely, as understanding the impact that the microbiota plays in various diseases is fundamental for the development of novel therapeutic strategies. Therefore, the aim of this review is to provide the read- er with an updated overview of the importance of the gut microbiota for human health and the poten- tial to manipulate gut microbial composition for purposes such as the treatment of antibiotic-resistant Clostridium difficile （C difficile） infections. The concept of altering the gut community by microbial intervention in an effort to improve health is currently in its infancy. However, the therapeutic implications appear to be very great. Thus, the removal of harmful organisms and the enrichment of beneficial mi- crobes may protect our health, and such efforts will pave the way for the development of more rational treatment options in the future.展开更多
BACKGROUND Disease-related single nucleotide polymorphisms(SNPs)based genetic risk score(GRS)has been proven to provide independent inherited risk other than family history in multiple cancer types.AIM To evaluate the...BACKGROUND Disease-related single nucleotide polymorphisms(SNPs)based genetic risk score(GRS)has been proven to provide independent inherited risk other than family history in multiple cancer types.AIM To evaluate the potential of GRS in the prediction of pancreatic cancer risk.METHODS In this case-control study(254 cases and 1200 controls),we aimed to evaluate the association between GRS and pancreatic ductal adenocarcinoma(PDAC)risk in the Chinese population.The GRS was calculated based on the genotype information of 18 PDAC-related SNPs for each study subject(personal genotyping information of the SNPs)and was weighted by external odd ratios(ORs).RESULTS GRS was significantly different in cases and controls(1.96±3.84 in PDACs vs 1.09±0.94 in controls,P<0.0001).Logistic regression revealed GRS to be associated with PDAC risk[OR=1.23,95%confidence interval(CI):1.13-1.34,P<0.0001].GRS remained significantly associated with PDAC(OR=1.36,95%CI:1.06-1.74,P=0.015)after adjusting for age and sex.Further analysis revealed an association of increased risk for PDAC with higher GRS.Compared with low GRS(<1.0),subjects with high GRS(2.0)were 99%more likely to have PDAC(OR:1.99,95%CI:1.30-3.04,P=0.002).Participants with intermediate GRS(1.0-1.9)were 39%more likely to have PDAC(OR:1.39,95%CI:1.03-1.84,P=0.031).A positive trend was observed(P trend=0.0006).CONCLUSION GRS based on PDAC-associated SNPs could provide independent information on PDAC risk and may be used to predict a high risk PDAC population.展开更多
In China,rare diseases are defined as having a birth incidence of less than 1/10000,or a prevalence of less than 1/10000 or less than 140000 patients.Over 7000 rare diseases affect more than 20 million people in China...In China,rare diseases are defined as having a birth incidence of less than 1/10000,or a prevalence of less than 1/10000 or less than 140000 patients.Over 7000 rare diseases affect more than 20 million people in China.Many conditions are misdiagnosed or undiagnosed and most have no treatment,resulting in a huge burden on patients,their families,and the national economy.At the 297th Shuangqing Forum of the National Natural Science Foundation of China,we highlighted the challenges and potential solutions to achieve precision medicine for undiagnosed and rare diseases.展开更多
Elevated serum prostate-specific antigen （PSA） level is the primaryindication for prostate biopsy for detection of prostate cancer （PCa） in the modern era. The detection rate of PCa from biopsy is typically below ...Elevated serum prostate-specific antigen （PSA） level is the primaryindication for prostate biopsy for detection of prostate cancer （PCa） in the modern era. The detection rate of PCa from biopsy is typically below 30%, especially among patients with PSA levels at 4-10 ng ml-1. In the past several years, additional biomarkers, such as Prostate Health Index, PCA3 and genetic risk score （GRS） derived from multiple PCa risk-associated single nucleotide polymorphisms （SNPs） have been shown to provide added value to PSA in discriminating prostate biopsy outcomes. However,展开更多
基金supported by the National Natural Science Foundation of China(32171347)the Foundation of Leading Talents from Shanghai Health Commission(2022XD038)+1 种基金Training Program for Research Physicians in Innovation,the Funda-mental Research Funds for the Central Universities(YG2023QNA23)Transforma-tion from shanghai hospital development center(SHDC2022CRD002).
文摘Stem cells play a crucial role in maintaining tissue regenerative capacity and homeostasis.However,mechanisms associated with stem cell senescence require further investigation.In this study,we conducted a proteomic analysis of human dental pulp stem cells(HDPSCs)obtained from individuals of various ages.Our findings showed that the expression of NUP62 was decreased in aged HDPSCs.We discovered that NUP62 alleviated senescence-associated phenotypes and enhanced differentiation potential both in vitro and in vivo.Conversely,the knocking down of NUP62 expression aggravated the senescence-associated phenotypes and impaired the proliferation and migration capacity of HDPSCs.Through RNA-sequence and decoding the epigenomic landscapes remodeled induced by NUP62 overexpression,we found that NUP62 helps alleviate senescence in HDPSCs by enhancing the nuclear transport of the transcription factor E2F1.This,in turn,stimulates the transcription of the epigenetic enzyme NSD2.Finally,the overexpression of NUP62 influences the H3K36me2 and H3K36me3 modifications of anti-aging genes(HMGA1,HMGA2,and SIRT6).Our results demonstrated that NUP62 regulates the fate of HDPSCs via NSD2-dependent epigenetic reprogramming.
文摘Adiponectin secreted by adipose tissue has been implicated in prostate carcinogenesis. Genetic variations in ADIPOQare thought to influence the activity of adiponectin, thus relating to cancer occurrence. In this hospital-based case-control study of 917 prostate cancer （PCa） cases and 1036 cancer-free controls, we evaluated the association of single nucleotide polymorphisms in ADIPOQ with risk of PCa and adiponectin levels in Chinese Han men. Variants of ADIPOQ were genotyped by Taqman polymerase chain reaction method. The plasma adiponectin concentrations were measured by enzyme.linked immunosorbent assay （ELISA） in a subset of cases and controls. We found that the ADIPOQ rs3774262 variant AA genotype was associated with both decreased PCa risk [adjusted odds ratio （OR）： 0.66, 95% confidence interval （CI） =0.48-0.92] and increased plasma adiponectin levels （P= 0.036 and 0,043）, with significant difference by tumor grade, clinical stage, and aggressiveness. A significant interaction between ADIPOQ rs3774262 and body mass index was observed in modifying the risk of PCa （P=6.7 × 10-3）. ADIPOQ rs266729 and rs182052 were not related to PCa risk or plasma adiponectin levels. Our data support that ADIPOQ rs3774262 may affect PCa risk in combination with plasma adiponectin levels in Chinese Han men. It may contribute to the molecular basis for the association between obesity and PCa.
文摘Dear Editor We report here the performance of prostate cancer antigen 3 （PCA3） and genetic risk score （GRS） in predicting prostate cancer （PCa） from the prostate biopsy. To the best of our knowledge, this is the first report of simultaneously evaluating these two biomarkers in the same study.
基金supported by the National Natural Science Foundation of China(U20A20353 to X.Xu and 81900185 to Y.Ye).
文摘Programmed silencing ofγ-globin genes in adult erythropoiesis is mediated by several chromatin remodeling complexes,which determine the stage-specific genome architecture in this region.Identification of cis-or trans-acting mutations contributing to the diverse extent of fetal hemoglobin(Hb F)might illustrate the underlying mechanism ofγ-β-globin switching.Here,we recruit a cohort of 1142β-thalassemia patients and dissect the natural variants in the wholeβ-globin gene cluster through a targeted next-generation sequencing panel.A previously unreported SNP rs7948668,predicted to disrupt the binding motif of IKAROS as a key component of chromatin remodeling complexes,is identified to be significantly associated with higher levels of Hb F and age at onset.Gene-editing on this SNP leads to the elevation of Hb F in both HUDEP-2 and primary CD34+cells while the extent of elevation is amplified in the context ofβ-thalassemia mutations,indicating epistasis effects of the SNP in the regulation of Hb F.Finally,we perform ChIP-qPCR and 4C assays to prove that this variant disrupts the binding motif of IKAROS,leading to enhanced competitiveness of HBG promoters to locus control regions.This study highlights the significance of common regulatory SNPs and provides potential targets for treatingβ-hemoglobinopathy.
基金supported by the National Natural Science Foundation of China(32270670,32288101,32271186,and 32200482)the National Basic Research Program of China(2015FY111700)the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-066).
文摘Mitochondria play a key role in lipid metabolism,and mitochondrial DNA(mtDNA)mutations are thus considered to affect obesity susceptibility by altering oxidative phosphorylation and mitochondrial function.In this study,we investigate mtDNA variants that may affect obesity risk in 2877 Han Chinese individuals from 3 independent populations.The association analysis of 16 basal mtDNA haplogroups with body mass index,waist circumference,and waist-to-hip ratio reveals that only haplogroup M7 is significantly negatively correlated with all three adiposity-related anthropometric traits in the overall cohort,verified by the analysis of a single population,i.e.,the Zhengzhou population.Furthermore,subhaplogroup analysis suggests that M7b1a1 is the most likely haplogroup associated with a decreased obesity risk,and the variation T12811C(causing Y159H in ND5)harbored in M7b1a1 may be the most likely candidate for altering the mitochondrial function.Specifically,we find that proportionally more nonsynonymous mutations accumulate in M7b1a1 carriers,indicating that M7b1a1 is either under positive selection or subject to a relaxation of selective constraints.We also find that nuclear variants,especially in DACT2 and PIEZO1,may functionally interact with M7b1a1.
基金supported by the National Natural Science Foundation of Jiangsu Province(BE20197310 to J-M.L.)the National Key R&D Program of China(2021YFF0702500 to J-M.L.and A-M.S.,and the Start-up Funding of Scientific Researches for Postdoc in Guangzhou,Guangdong Province to H-F.L.).
文摘Being widespread across the globe,severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)keeps evolving and generating new variants and continuously poses threat to public health,especially to the population with chronic comorbidities.Diabetes mellitus is one of high-risk factors for severe outcome of coronavirus disease 2019(COVID-19).Establishment of animal models that parallel the clinical and pathological features of COVID-19 complicated with diabetes is thus highly essential.Here,in this study,we constructed leptin receptor gene knockout hamsters with the phenotype of diabetes mellitus(db/db),and revealed that the diabetic hamsters were more susceptible to SARS-CoV-2 and its variants than wild-type hamsters.SARS-CoV-2 and its variants induced a stronger immune cytokine response in the lungs of diabetic hamsters than in wild-type hamsters.Comparative histopathology analyses also showed that infection of SARS-CoV-2 and the variants caused more severe lung tissue injury in diabetic hamsters,and may induce serious complications such as diabetic kidney disease and cardiac lesions.Our findings demonstrated that despite the decreased respiratory pathogenicity,the SARS-CoV-2 variants were still capable of impairing other organs such as kidney and heart in diabetic hamsters,suggesting that the risk of evolving SARS-CoV-2 variants to diabetic patients should never be neglected.This hamster model may help better understand the pathogenesis mechanism of severe COVID-19 in patients with diabetes.It will also aid in development and testing of effective therapeutics and prophylactic treatments against SARS-CoV-2 variants among these high-risk populations.
基金funded by the Shandong Province Humanities and Social Sciences Project“Sorting and Research on Human Bones of Han Dynasty Excavated from the Medical Center Cemetery in Linzi”granted to Zhigang Wu(2022-JCLS-12)the National Key Research and Development Program(2023YFC3303701-02)+5 种基金the National Natural Science Foundation of China(32270667)the Natural Science Foundation of Fujian Province of China(2023J06013)the Major Project of the National Social Science Foundation of China granted to Chuan-Chao Wang(21&ZD285)Open Research Fund of State Key Laboratory of Genetic Engineering at Fudan University(No.SKLGE-2310)Open Research Fund of Forensic Genetics Key Laboratory of the Ministry of Public Security(2023FGKFKT07)Major Special Project of Philosophy and Social Sciences Research of the Ministry of Education(2022JZDZ023).
文摘Shandong province,located in the Lower Yellow River,is one of the birthplaces of ancient Chinese civilization.However,the comprehensive genetic histories of this region have remained largely unknown until now due to a lack of ancient human genomes.Here,we present 21 ancient genomes from Shandong dating from the Warring States period to the Northern Dynasties.Unlike the early Neolithic samples from Shandong,the historical samples are most closely related to post-Late Neolithic populations of the Middle Yellow River Basin,suggesting a population turnover in Shandong from the Neolithic Age to the Historical era.In addition,we detect a close genetic affinity between the historical samples in Shandong and present-day Han Chinese,showing long-term genetic stability in Han Chinese,at least since the Warring States period.
基金supported by research grants from the National Natural Science Foundation of China(No.82001726,82301768)the National Key Research and Development programme of China(No.2024YFC3405800)+3 种基金Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(No.2019-I2M-5-066)Scientific Research Foundation provided by Pudong Hospital affiliated to Fudan University(No.YJYJRC202202)The Talents Training Program of Pudong Hospital affiliated to Fudan University(No.YQ202201)the Shanghai Municipal Science and Technology Major Project(No.2023SHZDZX02)。
文摘Background: Musculoskeletal disorders(MSDs) represent a significant global health burden. While physical activity(PA) and physical fitness are both thought to reduce MSD risk, their independent and joint associations with MSD incidence have not been fully explored. This study investigated the independent and combined effects of PA, cardiorespiratory fitness(CRF), grip strength(GS), and GS asymmetry on MSD incidence in a large prospective cohort.Methods: We analyzed data from the UK Biobank cohort(2006-2023), including 406,080 participants aged 37-73 years(age = 55.7 ± 8.2 years,mean ± SD;53.0% female) who were free of MSD at baseline and during the first 2 years of follow-up. PA, derived from self-reported data and expressed in total metabolic equivalent hours per week(MET-h/week);CRF(watts(W)/kilogram(kg)), measured using a cycling exercise test;and GS(kg), measured by hydraulic hand dynamometer, were included as exposures. GS asymmetry was defined by the left-to-right hand strength ratio. MSD incidence was determined via hospital records. Time-to-event associations were analyzed using Cox proportional hazards regression models with restricted cubic splines to account for non-linear relationships. The analysis was conducted in April 2024.Results: Over a median follow-up of 14.7 years, a total of 73,002 incident cases of MSDs were recorded(rheumatoid arthritis: 2923;osteoarthritis:54,955;degenerative spinal diseases: 15,124). Lower self-reported PA(<4.8 MET-h/week) was associated with increased MSD risk(hazard ratio(HR) = 1.0710, 95% confidence interval(95%CI): 1.0623-1.0797). Low CRF(<1.22 W/kg;HR = 1.0941, 95%CI: 1.0596-1.1298), low GS(<27.80 kg;HR = 1.1133, 95%CI: 1.0990-1.1277), and GS asymmetry(HR = 1.1042, 95%CI: 1.0814-1.1274) were also significantly associated with increased MSD risk. Good CRF and GS, and lower GS asymmetry mitigated the higher MSD risk associated with low PA levels.Conclusion: Low levels of PA, CRF, GS, and GS asymmetry were associated with a higher risk of incident MSD. Meanwhile, improvements in CRF, GS, and GS balance could help offset the risk of MSD incidence in populations with insufficient PA.
基金funded by the National Natural Science Foundation of China(32070576,31801040,and 32270667)Lantai Young Scholars Program of Chinese History Institute(2022LTQN602)+11 种基金the National Social Science Fund of China(19VJX074 and 21CKG022)Priority Research Program of the Chinese Academy of Sciences:Pan-Third Pole Environment Study for a Green Silk Road(Pan-TPE)(XDA2004010101)the National Key Research and Development Program(2023YFC3303701-02)the Natural Science Foundation of Fujian Province of China(2023J06013)the Science and Technology Commission of Shanghai Municipality(18490750300)the National Key Research and Development Program(2020YFE0201600)Shanghai Municipal Science and Technology Major Project(2017SHZDZX01)the Major Project of National Social Science Foundation of China granted to C.C.W.(21&ZD285),S.W.(20&ZD212),and D.L.(21&ZD237)Major Special Project of Philosophy and Social Sciences Research of the Ministry of Education(2022JZDZ023)Open Research Fund of State Key Laboratory of Genetic Engineering at Fudan University(SKLGE-2310)Open Research Fund of Forensic Genetics Key Laboratory of the Ministry of Public Security(2023FGKFKT07)European Research Council(ERC)grant(ERC-2019-ADG-883700-TRAM).
文摘China's Northern and Southern Dynasties period(3rd–6th centuries AD)marked a significant era of ethnic integration in northern China.However,previous ancient DNA studies have primarily focused on northern ethnic groups,with limited research on the genetic formation of the hereditary elite family,especially considering their abundant archaeological record and clear material identity.In this study,we obtain the ancient genome of a hereditary elite family,Gao Bin(高宾,503 AD–572 AD),at 0.6473-fold coverage with 475,132 single-nucleotide polymorphisms(SNPs)on the 1240k panel.His mitochondrial haplogroup belongs to Z4 and Y-haplogroup to O1a1a2b-F2444∗.The genetic profile of Gao Bin is most similar to that of the northern Han Chinese.He can be modeled as deriving all his ancestry from Late Neolithic to Iron Age Yellow River farmers without influence from Northeast Asia,Korea,or the Mongolian Plateau.Our study sheds light on the genetic formation of hereditary elite families in the context of the Southern and Northern Dynasties ethnic integration.
基金supported by the Ministry of Higher Education(MOHE)Malaysia through Fundamental Research Grant Scheme(FRGS)with project code:FRGS/1/2021/STG01/UCSI/01/.SX was funded by the National Natural Science Foundation of China(NSFC)grants 32030020 and 32288101funded by the NSFC grant 32270665.
文摘Evidence has shown that differential transcriptomic profiles among human populations from diverse ancestries,supporting the role of genetic architecture in regulating gene expression alongside environmental stimuli.Genetic variants that regulate gene expression,known as expression quantitative trait loci(eQTL),are primarily shaped by human migration history and evolutionary forces,likewise,regulation of gene expression in principle could have been influenced by these events.Therefore,a comprehensive understanding of how human evolution impacts eQTL offers important insights into how phenotypic diversity is shaped.Recent studies,however,suggest that eQTL is enriched in genes that are selectively constrained.Whether eQTL is minimally affected by selective pressures remains an open question and requires comprehensive investigations.In addition,such studies are primarily dominated by the major populations of European ancestry,leaving many marginalized populations underrepresented.These observations indicate there exists a fundamental knowledge gap in the role of genomics variation on phenotypic diversity,which potentially hinders precision medicine.This article aims to revisit the abundance of eQTL across diverse populations and provide an overview of their impact from the population and evolutionary genetics perspective,subsequently discuss their influence on phenomics,as well as challenges and opportunities in the applications to precision medicine.
基金supported by the National Basic Research Program of China under coutract No.2004CB719601the Science and Technology Basic Work Program of China under coutract No.2003DEB5J057+1 种基金the National Natural Science Foundation of China under contract No.40376001This work is also a part of the Project"Second Chinese National Arctic Research Expedition"or CHINARE-2003 supported by the Ministry of Finance of China and organized by the Chinese Arctic and Antarctic Administration(CAA).
文摘PCR-DGGE approach was used to analyze bacterial diversity in the bottomsection of seven arctic sea ice samples colleted from the Canada Basin.Thirty-two 16S rDNAsequences were obtained from prominent DGGE bands.The closest relatives of these sequences arefound to be those of cultivated or uncultured bacteria from antarctic or arctic sea ice.Phylogenetic analysis clustered these sequences or phylotypes withinα-proteobacteria,γ-proteobacteria and CFB(cytophaga-flexibacter-bacteroides)group.Sequences belonging toγ-proteobacteria were dominant and members of the CFB group were highly abundant.It was suggestedthat the CFB group was the representative of the bottom section of sea ice samples.
基金We would like to thank all the study participants, urologists, and study coordinators for participating in the study. This work was partially funded by the National Key Basic Research Program Grant 973 （2012CB518301）, the Key Project of the National Natural Science Foundation of China （81130047）, National Natural Science Foundation of China （81202001, 81272835）, China Scholarship Council （CSC）, intramural grants from Fudan University and Huashan Hospital, and a research grant from Beckman Coulter, Inc.
文摘The [-2]proPSA （p2PSA） and its derivatives, the p2PSA-to-free PSA ratio （%p2PSA）, and the Prostate Health Index （PHI） have greatly improved discrimination between men with and without prostate cancer （PCa） in prostate biopsies. However, little is known about their performance in cases where a digital rectal examination （DRE） and transrectal ultrasonography （TRUS） are negative. A prospective cohort of 261 consecutive patients in China with negative DRE and TRUS were recruited and underwent prostate biopsies. A serum sample had collected before the biopsy was used to measure various PSA derivatives, including total prostate-specific antigen （tPSA）, free PSA, and p2PSA. For each patient, the free-to-total PSA ratio （%fPSA）, PSA density （PSAD）, p2PSA-to-free PSA ratio （%p2PSA）, and PHI were calculated. Discriminative performance was assessed using the area under the receiver operating characteristic curve （AUC） and the biopsy rate at 91% sensitivity. The AUC scores within the entire cohort with respect to age, tPSA, %fPSA, PSAD, p2PSA, %p2PSA, and PHI were 0.598, 0.751, 0.646, 0.789, 0.814, 0.808, and 0.853, respectively. PHI was the best predictor of prostate biopsy results, especially in patients with a tPSA of 10.1-20 ng ml-1. Compared with other markers, at a sensitivity of 91%, PHI was the most useful for determining which men did not need to undergo biopsy, thereby avoiding unnecessary procedures. The use of PHI could improve the accuracy of PCa detection by predicting prostate biopsy outcomes among men with a negative DRE and TRUS in China.
基金funded by the Max-Planck-Gesellschaft Partner Group Grant(K.T.)the National Natural Science Foundation of China(31371267,31322030,and 91331108,K.T.+10 种基金91631307,S.W.30890034,31271338,L.J.and 31525014,91731303,31771388,31961130380,and 32041008,S.X.)supported by the National Basic Research Program(2015FY111700,L.J.)Shanghai Municipal Science and Technology Major Project(2017SHZDZX01,L.J.,S.X.,and S.W.)the Ministry of Education(311016,L.J.)Strategic Priority Research Program of the Chinese Academy of Sciences(CAS)(XDB13040000,S.X.and S.W.)the UK Royal Society-Newton Advanced Fellowship(NAFn R1n191094)Key Research Program of Frontier Sciences(QYZDJ-SSW-SYS009)of the Chinese Academy of Sciencesthe support of a National Thousand Young Talents Award and a Max Planck-CAS Paul Gerson Unna Independent Research Group Leadership Award(S.W.)the Science and Technology Commission of Shanghai Municipality(16JC1400504,S.W.)。
文摘The human face is a heritable surface with many complex sensory organs.In recent years,many genetic loci associated with facial features have been reported in different populations,yet there is a lack of studies on the Han Chinese population.Here,we report a genome-wide association study of 3D normal human faces of 2,659 Han Chinese with autosegment phenotypes of facial morphology.We identify singlenucleotide polymorphisms(SNPs)encompassing four genomic regions showing significant associations with different facial regions,including SNPs in DENND1 B associated with the chin,SNPs among PISRT1 associated with eyes,SNPs between DCHS2 and SFRP2 associated with the nose,and SNPs in VPS13 B associated with the nose.We replicate 24 SNPs from previously reported genetic loci in different populations,whose candidate genes are DCHS2,SUPT3 H,HOXD1,SOX9,PAX3,and EDAR.These results provide a more comprehensive understanding of the genetic basis of variation in human facial morphology.
基金This work was partially funded by the National Key Basic Research Program Grant 973 （No.2012CB518301） to JX, the Key Project of the National Natural Science Foundation of China （No.81130047） to IX, intramural grants from Fudan University ＇Thousand Talents Program＇ and Huashan Hospital to JX and the National Institutes of Health （No.NCI CA129684） to IX.
文摘Prostate cancer （PCa） is one of the most common cancers among men in Western developed countries and its incidence has increased considerably in many other parts of the world, including China. The etiology of PCa is largely unknown but is thought to be multifactorial, where inherited genetics plays an important role. In this article, we first briefly review results from studies of familial aggregation and genetic susceptibility to PCa. We then recap key findings of rare and high-penetrance PCa susceptibility genes from linkage studies in PCa families. We devote a significant portion of this article to summarizing discoveries of common and Iow-penetrance PCa risk-associated single-nucleotide polymorphisms （SNPs） from genetic association studies in PCa cases and controls, especially those from genome-wide association studies （GWASs）. A strong focus of this article is to review the literature on the potential clinical utility of these implicated genetic markers. Most of these published studies described PCa risk estimation using a genetic score derived from multiple risk-associated SNPs and its utility in determining the need for prostate biopsy. Finally, we comment on the newly proposed concept of genetic score; the notion is to treat it as a marker for genetic predisposition, similar to family history, rather than a diagnostic marker to discriminate PCa patients from non-cancer patients. Available evidence to date suggests that genetic score is an objective and better measurement of inherited risk of PCa than family history. Another unique feature of this article is the inclusion of genetic association studies of PCa in Chinese and Japanese populations.
基金This work was supported by grants from the National Natural Science Foundation of China （21375144 and 21105115） and the National Basic Research Program of China （2012CB934004）.
文摘The human microbiota is an aggregate of microorganisms residing in the human body, mostly in the gastrointestinal tract （GIT）. Our gut microbiota evolves with us and plays a pivotal role in human health and disease. In recent years, the microbiota has gained increasing attention due to its impact on host metabolism, physiology, and immune system development, but also because the perturbation of the microbiota may result in a number of diseases. The gut microbiota may be linked to malignancies such as gastric cancer and colorectal cancer. It may also be linked to disorders such as nonalcoholic fatty liver disease （NAFLD）; obesity and diabetes, which are characterized as ＂lifestyle diseases＂ of the industrial- ized world; coronary heart disease; and neurological disorders. Although the revolution in molecular technologies has provided us with the necessary tools to study the gut microbiota more accurately, we need to elucidate the relationships between the gut microbiota and several human pathologies more precisely, as understanding the impact that the microbiota plays in various diseases is fundamental for the development of novel therapeutic strategies. Therefore, the aim of this review is to provide the read- er with an updated overview of the importance of the gut microbiota for human health and the poten- tial to manipulate gut microbial composition for purposes such as the treatment of antibiotic-resistant Clostridium difficile （C difficile） infections. The concept of altering the gut community by microbial intervention in an effort to improve health is currently in its infancy. However, the therapeutic implications appear to be very great. Thus, the removal of harmful organisms and the enrichment of beneficial mi- crobes may protect our health, and such efforts will pave the way for the development of more rational treatment options in the future.
文摘BACKGROUND Disease-related single nucleotide polymorphisms(SNPs)based genetic risk score(GRS)has been proven to provide independent inherited risk other than family history in multiple cancer types.AIM To evaluate the potential of GRS in the prediction of pancreatic cancer risk.METHODS In this case-control study(254 cases and 1200 controls),we aimed to evaluate the association between GRS and pancreatic ductal adenocarcinoma(PDAC)risk in the Chinese population.The GRS was calculated based on the genotype information of 18 PDAC-related SNPs for each study subject(personal genotyping information of the SNPs)and was weighted by external odd ratios(ORs).RESULTS GRS was significantly different in cases and controls(1.96±3.84 in PDACs vs 1.09±0.94 in controls,P<0.0001).Logistic regression revealed GRS to be associated with PDAC risk[OR=1.23,95%confidence interval(CI):1.13-1.34,P<0.0001].GRS remained significantly associated with PDAC(OR=1.36,95%CI:1.06-1.74,P=0.015)after adjusting for age and sex.Further analysis revealed an association of increased risk for PDAC with higher GRS.Compared with low GRS(<1.0),subjects with high GRS(2.0)were 99%more likely to have PDAC(OR:1.99,95%CI:1.30-3.04,P=0.002).Participants with intermediate GRS(1.0-1.9)were 39%more likely to have PDAC(OR:1.39,95%CI:1.03-1.84,P=0.031).A positive trend was observed(P trend=0.0006).CONCLUSION GRS based on PDAC-associated SNPs could provide independent information on PDAC risk and may be used to predict a high risk PDAC population.
文摘In China,rare diseases are defined as having a birth incidence of less than 1/10000,or a prevalence of less than 1/10000 or less than 140000 patients.Over 7000 rare diseases affect more than 20 million people in China.Many conditions are misdiagnosed or undiagnosed and most have no treatment,resulting in a huge burden on patients,their families,and the national economy.At the 297th Shuangqing Forum of the National Natural Science Foundation of China,we highlighted the challenges and potential solutions to achieve precision medicine for undiagnosed and rare diseases.
基金I thank for the contributions of study populations, data analysis and discussion to this paper from Drs S Lilly Zheng and lielin Sun from Wake Forest School of Medicine Dr Henrik Gronberg from Karolinska Institutet of Sweden+2 种基金 Mr Haitao Chen from School of Life Science, Fudan University, China Dr Qiang Ding, Ms Fang Liu and Xiaoling Lin from Fudan Institute of Urology, Fudan University, China Drs Yinghao Sun, Shangchen Ren and Zhensheng Zhang from Changhai Hospital, China and Dr Donna P Ankerst from Technical University Munich, Germany. This work was partially funded by the National Key Basic Research Program Grant 973 （No. 2012CB518301）, the Key Project of the National Natural Science Foundation of China （No. 81130047）, intramural grants from Fudan University and Huashan Hospital and the National Institutes of Health （No. NCI CA 129684）.
文摘Elevated serum prostate-specific antigen （PSA） level is the primaryindication for prostate biopsy for detection of prostate cancer （PCa） in the modern era. The detection rate of PCa from biopsy is typically below 30%, especially among patients with PSA levels at 4-10 ng ml-1. In the past several years, additional biomarkers, such as Prostate Health Index, PCA3 and genetic risk score （GRS） derived from multiple PCa risk-associated single nucleotide polymorphisms （SNPs） have been shown to provide added value to PSA in discriminating prostate biopsy outcomes. However,
