Genetic diseases seriously threaten human health and have always been one of the refractory conditions facing humanity.Currently,gene therapy drugs such as siRNA,shRNA,antisense oligonucleotide,CRISPR/Cas9 system,plas...Genetic diseases seriously threaten human health and have always been one of the refractory conditions facing humanity.Currently,gene therapy drugs such as siRNA,shRNA,antisense oligonucleotide,CRISPR/Cas9 system,plasmid DNA and miRNA have shown great potential in biomedical applications.To avoid the degradation of gene therapy drugs in the body and effectively deliver them to target tissues,cells and organelles,the development of excellent drug delivery vehicles is of utmost importance.Viral vectors are the most widely used delivery vehicles for gene therapy in vivo and in vitro due to their high transfection efficiency and stable transgene expression.With the development of nanotechnology,novel nanocarriers are gradually replacing viral vectors,emerging superior performance.This review mainly illuminates the current widely used gene therapy drugs,summarizes the viral vectors and non-viral vectors that deliver gene therapy drugs,and sums up the application of gene therapy to treat genetic diseases.Additionally,the challenges and opportunities of the field are discussed from the perspective of developing an effective nano-delivery system.展开更多
Previous studies on genetic diseases predominantly focused on protein-coding variations, overlooking the vast noncoding regions in the human genome. The development of high-throughput sequencing technologies and funct...Previous studies on genetic diseases predominantly focused on protein-coding variations, overlooking the vast noncoding regions in the human genome. The development of high-throughput sequencing technologies and functional genomics tools has enabled the systematic identification of functional noncoding variants. These variants can impact gene expression, regulation, and chromatin conformation, thereby contributing to disease pathogenesis. Understanding the mechanisms that underlie the impact of noncoding variants on genetic diseases is indispensable for the development of precisely targeted therapies and the implementation of personalized medicine strategies. The intricacies of noncoding regions introduce a multitude of challenges and research opportunities. In this review, we introduce a spectrum of noncoding variants involved in genetic diseases, along with research strategies and advanced technologies for their precise identification and in-depth understanding of the complexity of the noncoding genome. We will delve into the research challenges and propose potential solutions for unraveling the genetic basis of rare and complex diseases.展开更多
Background Newborn screening(NBS)is an important and successful public health program that helps improve the long-term clinical outcomes of newborns by providing early diagnosis and treatment of certain inborn disease...Background Newborn screening(NBS)is an important and successful public health program that helps improve the long-term clinical outcomes of newborns by providing early diagnosis and treatment of certain inborn diseases.The develop-ment of next-generation sequencing(NGS)technology provides new opportunities to expand current newborn screening methodologies.Methods We designed a a newborn genetic screening(NBGS)panel targeting 135 genes associated with 75 inborn disorders by multiplex PCR combined with NGS.With this panel,a large-scale,multicenter,prospective multidisease analysis was conducted on dried blood spot(DBS)profiles from 21,442 neonates nationwide.Results We presented the positive detection rate and carrier frequency of diseases and related variants in different regions;and 168(0.78%)positive cases were detected.Glucose-6-Phosphate Dehydrogenase deficiency(G6PDD)and phenylketonuria(PKU)had higher prevalence rates,which were significantly different in different regions.The positive detection of G6PD variants was quite common in south China,whereas PAH variants were most commonly identified in north China.In addi-tion,NBGS identified 3 cases with DUOX2 variants and one with SLC25A13 variants,which were normal in conventional NBS,but were confirmed later as abnormal in repeated biochemical testing after recall.Eighty percent of high-frequency gene carriers and 60%of high-frequency variant carriers had obvious regional differences.On the premise that there was no significant difference in birth weight and gestational age,the biochemical indicators of SLC22A5 c.1400C>G and ACADSB c.1165A>G carriers were significantly different from those of non-carriers.Conclusions We demonstrated that NBGS is an effective strategy to identify neonates affected with treatable diseases as a supplement to current NBS methods.Our data also showed that the prevalence of diseases has significant regional charac-teristics,which provides a theoretical basis for screening diseases in different regions.展开更多
Animal models are extensively used in all aspects of biomedical research,with substantial contributions to our understanding of diseases,the development of pharmaceuticals,and the exploration of gene functions.The fie...Animal models are extensively used in all aspects of biomedical research,with substantial contributions to our understanding of diseases,the development of pharmaceuticals,and the exploration of gene functions.The field of genome modification in rabbits has progressed slowly.However,recent advancements,particularly in CRISPR/Cas9-related technologies,have catalyzed the successful development of various genome-edited rabbit models to mimic diverse diseases,including cardiovascular disorders,immunodeficiencies,agingrelated ailments,neurological diseases,and ophthalmic pathologies.These models hold great promise in advancing biomedical research due to their closer physiological and biochemical resemblance to humans compared to mice.This review aims to summarize the novel gene-editing approaches currently available for rabbits and present the applications and prospects of such models in biomedicine,underscoring their impact and future potential in translational medicine.展开更多
Inherited metabolic liver diseases arise from genetic mutations that lead to dis-ruptions in liver metabolic pathways and are predominantly observed in pedia-tric populations.The spectrum of genetic metabolic liver di...Inherited metabolic liver diseases arise from genetic mutations that lead to dis-ruptions in liver metabolic pathways and are predominantly observed in pedia-tric populations.The spectrum of genetic metabolic liver disorders is diverse,encompassing a range of conditions associated with aberrations in iron,copper,carbohydrate,lipid,protein,and amino acid metabolism.Historically,research in the domain of genetic metabolic liver diseases has predominantly concentrated on hepatic parenchymal cell alterations.Nevertheless,emerging studies suggest that inherited metabolic liver diseases exert significant influences on the immune microenvironment,both within the liver and systemically.This review endeavors to encapsulate the immunological features of genetic metabolic liver diseases,aiming to expand the horizons of researchers in this discipline,and to elucidate the underlying pathophysiological mechanisms pertinent to hereditary metabolic liver diseases and to propose innovative therapeutic approaches.展开更多
Approximately 40% of pheochromocytoma and paraganglioma(PPGL) cases are familial, typically presenting earlier with more complex symptoms. This paper synthesizes literature and guidelines to inform on clinical charact...Approximately 40% of pheochromocytoma and paraganglioma(PPGL) cases are familial, typically presenting earlier with more complex symptoms. This paper synthesizes literature and guidelines to inform on clinical characteristics and perioperative care for PPGL. Pheochromocytoma in von Hippel-Lindau(VHL) disease exhibits heightened secretion activity without significant perioperative hemodynamic changes. Tumors in multiple endocrine neoplasia type 2(MEN2) have a stronger endocrine function, which may induce hemodynamic fluctuations during surgery. Therefore, pheochromocytoma screening is essential at all stages of MEN2. Neurofibromatosis type 1(NF1) often presents multisystem lesions and can result in difficult airway. Pheochromocytoma should be evaluated when NF1 patients present hypertension. Pheochromocytoma and paraganglioma type 5 may present multiple lesions of pheochromocytoma or paraganglioma. In summary, hereditary PPGLs may present with severe lesions in other systems, beyond tumor function. A multi-disciplinary team(MDT) approach is often invaluable in perioperative management.展开更多
N6-methyladenosine(m^(6)A)has been established as the most prevalent chemical modification in message RNA(mRNA),playing an essential role in determining the fate of RNA molecules.Dysregulation of m^(6)A has been revea...N6-methyladenosine(m^(6)A)has been established as the most prevalent chemical modification in message RNA(mRNA),playing an essential role in determining the fate of RNA molecules.Dysregulation of m^(6)A has been revealed to lead to abnormal physiological conditions and cause various types of human diseases.Recent studies have delineated the genetic regulatory maps for m^(6)A methylation by mapping the quantitative trait loci of m^(6)A(m^(6)A-QTLs),thereby building up the regulatory circuits linking genetic variants,m^(6)A,and human complex traits.Here,we review the recent discoveries concerning the genetic regulatory maps of m^(6)A,describing the methodological and technical details of m^(6)A-QTL identification,and introducing the key findings of the cis-and trans-acting drivers of m^(6)A.We further delve into the tissue-and ethnicity-specificity of m^(6)A-QTL,the association with other molecular phenotypes in light of genetic regulation,the regulators underlying m^(6)A genetics,and importantly,the functional roles of m^(6)A in mediating human complex diseases.Lastly,we discuss potential research avenues that can accelerate the translation of m^(6)A genetics studies toward the development of therapies for human genetic diseases.展开更多
AIM: Genetic polymorphism in enzymes of carcinogen metabolism has been found to have the influence on the susceptibility to cancer. Cytochrome P450 2E1 (CYP2E1) is considered to play an important role in the metabolic...AIM: Genetic polymorphism in enzymes of carcinogen metabolism has been found to have the influence on the susceptibility to cancer. Cytochrome P450 2E1 (CYP2E1) is considered to play an important role in the metabolic activation of procarcinogens such as N-nitrosoamines and low molecular weight organic compounds. The purpose of this study is to determine whether CYP450 2E1 polymorphisms are associated with risks of gastric cancer. METHODS: We conducted a population based case-control study in Changle county, Fujian Province, a high-risk region of gastric cancer in China. Ninety-one incident gastric cancer patients and ninety-four healthy controls were included in our study. Datas including demographic characteristics, diet intake, and alcohol and tobacco consumption of individuals in our study were completed by a standardized questionnaire.PCR-RFLP revealed three genotypes:heterozygote (C1/C2) and two homozygotes (C1/C1 and C2/C2) in CYP2E1. RESULTS: The frequency of variant genotypes (C1/C2 and C2/C2) in gastric cancer cases and controls was 36.3% and 24.5%, respectively. The rare homozygous C2/C2 genotype was found in 6 individuals in gastric cancer group(6.6%), whereas there was only one in the control group (1.1%). However, there was no statistically significant difference between the two groups (two-tailed Fisher's exact test P=0.066). Individuals in gastric cancer group were more likely to carry genotype C1/C2 (odds ratio, OR=1.50) and C2/C2 (OR=7.34) than individuals in control group (chi(2) =4.597, for trend P=0.032). The frequencies of genotypes with the C2 allele (C1/C2 and C2/C2 genotypes) were compared with those of genotypes without C2 allele (C1/C1 genotype) among individuals in gastric cancer group and control group according to the pattern of gastric cancer risk factors. The results show that individuals who exposed to these gastric cancer risk factors and carry the C2 allele seemed to have a higher risk of developing gastric cancer. CONCLUSION: Polymorphism of CYP2E1 gene may have some effect in the development of gastric cancer in Changle county, Fujian Province.展开更多
AIM:To evaluate the association between CYP1A1 and GSTs genetic polymorphisms and susceptibility to esophageal squamous cell carcinoma(SCC)and esophageal adenocarcinoma(ADC)in a high risk area of northwest of France. ...AIM:To evaluate the association between CYP1A1 and GSTs genetic polymorphisms and susceptibility to esophageal squamous cell carcinoma(SCC)and esophageal adenocarcinoma(ADC)in a high risk area of northwest of France. METHODS:A case-control study was conducted to investigate the genetic polymorphisms of these enzymes (CYPIAI*2C and GSTP1 exon 7 Val alleles,GSTMI*2/*2 and GSTTl *2/*2 null genotypes).A total of 79 esophageal cancer cases and 130 controls were recruited. RESULTS:GSTMI*2/*2 and CYPIAI*IA/*2C genotype frequencies were higher among squamous cell carcinomas at a level dose to statistical significance(OR =1.83,95% CI 0.88-3.83,P=0.11;OR=3.03,95% CI 0.93-9.90,P=0.07, respectively).For GSTP1 polymorphism,no difference was found between controls and cases,whatever their histological status.Lower frequency of GSTT1 deletion was observed in ADC group compared to controls with a statistically significant difference(OR=13.31,95% CI 1.66-106.92,P<0.01). CONCLUSION:In SCC,our results are consistent with the strong association of this kind of tumour with tobacco exposure.In ADC,our results suggest 3 distinct hypotheses: (1)activation of exogenous procarcinogens,such as small halogenated compounds by GSTT1;(2)contribution of GSTT1 to the inflammatory response of esophageal mucosa,which is known to be a strong risk factor for ADC, possibly through leukotriene synthesis;(3)higher sensitivity to the inflammatory process associated with intracellular depletion of glutathione.展开更多
There are an estimated 10000 monogenic diseases affecting tens of millions of individuals worldwide.The application of CRISPR/Cas genome editing tools to treat monogenic diseases is an emerging strategy with the poten...There are an estimated 10000 monogenic diseases affecting tens of millions of individuals worldwide.The application of CRISPR/Cas genome editing tools to treat monogenic diseases is an emerging strategy with the potential to generate personalized treatment approaches for these patients.CRISPR/Cas-based systems are programmable and sequence-specific genome editing tools with the capacity to generate base pair resolution manipulations to DNA or RNA.The complexity of genomic insults resulting in heritable disease requires patientspecific genome editing strategies with consideration of DNA repair pathways,and CRISPR/Cas systems of different types,species,and those with additional enzymatic capacity and/or delivery methods.In this review we aim to discuss broad and multifaceted therapeutic applications of CRISPR/Cas gene editing systems including in harnessing of homology directed repair,non-homologous end joining,microhomology-mediated end joining,and base editing to permanently correct diverse monogenic diseases.展开更多
To define "ethnicity" in the context of perinatal care is a tough job. The word makes us think: "racial, social, cultural, national…". An ethnic group is generally considered a group of people wit...To define "ethnicity" in the context of perinatal care is a tough job. The word makes us think: "racial, social, cultural, national…". An ethnic group is generally considered a group of people with a common history, usually(but not always) a common religion and language, sharing aspects of culture such as nutrition and traditions concerning pregnancy, childbirth, the way they care for children. As procreation occurs mostly ingroup, every ethnic group will demonstrate a higher prevalence of, more or less well-known, genes and their connected diseases. For some populations, such as Ashkenazi Jewish people, the prevalence and associated risks of these autosomal diseases are well known, as in the case of "Jewish genetic disease", and specific screening programs are available.展开更多
Typically,inherited metabolic diseases arise from point mutations in genes encoding metabolic enzymes. Although some of these mutations directly affect amino acid residues in the active sites of these enzymes,the majo...Typically,inherited metabolic diseases arise from point mutations in genes encoding metabolic enzymes. Although some of these mutations directly affect amino acid residues in the active sites of these enzymes,the majority do not. It is now well accepted that the majority of these disease-associated mutations exert their effects through alteration of protein stability,which causes a reduction in enzymatic activity. This finding suggests a way to predict the severity of newly discovered mutations. In silico prediction of the effects of amino acid sequence alterations on protein stability often correlates with disease severity. However,no stability prediction tool is perfect and,in general,better results are obtained if the predictions from a variety of tools are combined and then interpreted. In addition to predicted alterations to stability,the degree of conservation of a particular residue can also be a factor which needs to be taken into account: alterations to highly conserved residues are more likely to be associated with severe forms of the disease. The approach has been successfully applied in a variety of inherited metabolic diseases,but further improvements are necessary to enable robust translation into clinically useful tools.展开更多
Totally three articles regarding associations of Nurrl gene mutations, LRRK2 gene polymorphism sites $1647T and R1398H, and polymorphism of PARK2 gene mutations with Han Chinese patients with Parkinson＇s disease were...Totally three articles regarding associations of Nurrl gene mutations, LRRK2 gene polymorphism sites $1647T and R1398H, and polymorphism of PARK2 gene mutations with Han Chinese patients with Parkinson＇s disease were published in Neural Regeneration Research. We hope that our readers find these papers useful to their research.展开更多
In this post-genomic era, more and more susceptibility loci of many possible genetic diseases are published. As our knowledge about these susceptibility loci is limited and partial, we should be very careful and respo...In this post-genomic era, more and more susceptibility loci of many possible genetic diseases are published. As our knowledge about these susceptibility loci is limited and partial, we should be very careful and responsible when patients seek genetic counseling about these possible genetic diseases. We should apply Confucius' s principle about knowledge and information to genetic conseling, and tell the truth to our patients about what we know and what we do not know. Like many other cancers, breast cancer is a very complicated, multifactorial disease; genetic factors, lifestyles and eating habits, environmental factors, and viral infections might be involved in breast cancer; hence, it is difficult to figure out the real etiology of breast cancer. It is not crystal clear that a person who carries mutations of the breast cancer 1, early onset and/or breast cancer 2, early onset genes would eventually get breast cancer in her/his lifetime. No person should undergo a preventive double mastectomy, unless we know the etiology of breast cancer someday.展开更多
To confirm resistance and genetic rules of Xikemai 6 against physiological races of wheat stripe rust,physiological races CYR31,CYR32 and CYR33,Su11-4 and V26 were inoculated in Xikemai 6 and Mingxian 169 and their hy...To confirm resistance and genetic rules of Xikemai 6 against physiological races of wheat stripe rust,physiological races CYR31,CYR32 and CYR33,Su11-4 and V26 were inoculated in Xikemai 6 and Mingxian 169 and their hybrid progenies F_1,F_2 and F_3 at adult plant stage on March 2015. The results showed that the resistance of Xikemai 6 against CYR31 was controlled by 2 pairs of dominant genes and a pair of recessive genes; the resistance against CYR32 was controlled by three pairs of dominant resistant genes（ two pairs of genes performed cumulative effect）; the resistance against CYR33 was controlled by a pair of dominant genes and a pair of recessive genes; the resistance against Su11-4 was controlled by a pair of dominant genes and a pair of recessive genes independently or collaboratively; the resistance against V26 was controlled by a pair of dominant genes independently. Due to good performance of Xikemai 6 in test and production,as well as years of resistance identification and genetic analysis,Xikemai 6 was proved to be an excellent cultivar with good resistance against stripe rust,and the inheritance of its resistance was stable,so Xikemai 6 could be used as a germplasm resource and resistance material with excellent comprehensive character. Molecular marker and localization could be further studied,to provide new resistance parents for disease-resistant breeding of wheat.展开更多
Background:The serum vitamin D level varies widely by population,and studies have linked vitamin D levels with the risk of type 2 diabetes mellitus(T2DM).However,the relationship is inconsistent and the impact of vita...Background:The serum vitamin D level varies widely by population,and studies have linked vitamin D levels with the risk of type 2 diabetes mellitus(T2DM).However,the relationship is inconsistent and the impact of vitamin D on T2DM among East Chinese adults is unclear.The study aimed to investigate the association between serum 25-hydroxyvitamin D(25[OH]D)levels and the risk of T2DM and evaluated whether the association is modified by genetic predisposition.Methods:In the Survey on Prevalence in East China for Metabolic Diseases and Risk Factors(SPECT-China)cohort,1862 participants free of T2DM at baseline were included.A weighted genetic risk score was calculated with 28 variants associated with T2DM.Hierarchical logistic models were used to examine the association of serum 25(OH)D and genetic risk with T2DM.Results:After a 5-year follow-up,132 cases of T2DM were documented.We observed no significant association between quartiles of serum 25(OH)D and T2DM risk after multivariable adjustment(χ^(2)=0.571,P_(for trend)=0.426).Compared to those in the lowest quartile of 25(OH)D,the odds ratios(ORs)(95%confidence interval[CI])for participants with increased quartiles were 1.29(0.74-2.25),1.35(0.77-2.36),and 1.27(0.72-2.24),respectively.We observed a positive association of glycated hemoglobin(HbA1c)with 25(OH)D at baseline(β=1.752,P=0.001)and after follow-up(β=1.385,P=0.003),and a negative association of ln conversion homeostasis model assessment(HOMA)-βwith 25(OH)D at baseline(β=-0.982,P=0.021).There was no significant interaction between 25(OH)D and diabetes genetic predisposition on the risk of T2DM(χ^(2)=2.710,P_(for interaction)=0.100).The lowest OR(95%CI)of T2DM was among participants with low genetic risk and the highest quartile of 25(OH)D(0.17[0.05-0.62]).Conclusion:Serum 25(OH)D may be irrelevant to the risk of incident T2DM among East Chinese adults regardless of genetic predisposition.展开更多
Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States, with over 38000 deaths in 2013. The opportunity to detect pancreatic cancer while it is still curable is dependent on ou...Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States, with over 38000 deaths in 2013. The opportunity to detect pancreatic cancer while it is still curable is dependent on our ability to identify and screen high-risk populations before their symptoms arise. Risk factors for developing pancreatic cancer include multiple genetic syndromes as well as modifiable risk factors. Genetic conditions include hereditary breast and ovarian cancer syndrome, Lynch Syndrome, familial adenomatous polyposis, Peutz-Jeghers Syndrome, familial atypical multiple mole melanoma syndrome, hereditary pancreatitis, cystic fibrosis, and ataxia-telangiectasia; having a genetic predisposition can raise the risk of developing pancreatic cancer up to 132-fold over the general population. Modifiable risk factors, which include tobacco exposure, alcohol use, chronic pancreatitis, diet, obesity, diabetes mellitus, as well as certain abdominal surgeries and infections, have also been shown to increase the risk of pancreatic cancer development. Several largevolume centers have initiated such screening protocols, and consensus-based guidelines for screening high-riskgroups have recently been published. The focus of this review will be both the genetic and modifiable risk factors implicated in pancreatic cancer, as well as a review of screening strategies and their diagnostic yields.展开更多
AIM:To study the relationship between ABO blood groups and carcinoma of esophagus and cardia in Chaoshan inhabitants of China, which is a unique Littoral high-risk area of esophageal carcinoma in China. The poor commu...AIM:To study the relationship between ABO blood groups and carcinoma of esophagus and cardia in Chaoshan inhabitants of China, which is a unique Littoral high-risk area of esophageal carcinoma in China. The poor communication and transportation in the past has made Chaoshan a relatively closed area and kept its culture and custure of old China thousand years ago. METHODS: Data on age, sex, ABO blood type and X-ray or pathological diagnose of the patients with carcinoma of esophagus or cardia were collected from the Tumor Hospital. First Affiliated Hospital, Second Affiliated Hospital of Shantou University Medical College; and the Central Hospital of Shantou and the Central Hospital of Jieyang. A total of 6685 patients with esophageal carcinoma (EC) and 2955 patients with cardiac cancer (CC) in Chaoshan district were retrospectively assessed for their association with ABO blood groups. RESULTS: The distribution of ABO blood groups in patients with EC or CC was similar to the normal local population in Chaoshan. However, blood group B in male patients with CC and in the patients with carcinoma in the upper third esophagus was 2.3% and 4.7% higher than the corresponding controls. The relative risk B O was 1.1415 (P【0.05) and 1.2696 (P【0.05), respectively. No relationship was found between ABO blood groups and tumor differentiation. CONCLUSION: ABO blood group B is associated with the incidence of CC in male individuals and carcinoma in the upper third esophagus. The distribution of ABO blood groups varies in the different geographical and ethnic groups. As a result, proper controls are very important for such studies.展开更多
基金supported by the National Natural Science Foundation of China(No.51472115)Double Firstclass Innovation Team of China Pharmaceutical University(CPU2018GY40).
文摘Genetic diseases seriously threaten human health and have always been one of the refractory conditions facing humanity.Currently,gene therapy drugs such as siRNA,shRNA,antisense oligonucleotide,CRISPR/Cas9 system,plasmid DNA and miRNA have shown great potential in biomedical applications.To avoid the degradation of gene therapy drugs in the body and effectively deliver them to target tissues,cells and organelles,the development of excellent drug delivery vehicles is of utmost importance.Viral vectors are the most widely used delivery vehicles for gene therapy in vivo and in vitro due to their high transfection efficiency and stable transgene expression.With the development of nanotechnology,novel nanocarriers are gradually replacing viral vectors,emerging superior performance.This review mainly illuminates the current widely used gene therapy drugs,summarizes the viral vectors and non-viral vectors that deliver gene therapy drugs,and sums up the application of gene therapy to treat genetic diseases.Additionally,the challenges and opportunities of the field are discussed from the perspective of developing an effective nano-delivery system.
基金supported by the National Key Research and Development Program of China(82030030)the 1·3·5 Project for Disciplines of Excellence,West China Hospital+1 种基金Sichuan University(ZYJC20002)to H.YuanSichuan Science and Technology Program(2022YFS0211)to K.Wu.
文摘Previous studies on genetic diseases predominantly focused on protein-coding variations, overlooking the vast noncoding regions in the human genome. The development of high-throughput sequencing technologies and functional genomics tools has enabled the systematic identification of functional noncoding variants. These variants can impact gene expression, regulation, and chromatin conformation, thereby contributing to disease pathogenesis. Understanding the mechanisms that underlie the impact of noncoding variants on genetic diseases is indispensable for the development of precisely targeted therapies and the implementation of personalized medicine strategies. The intricacies of noncoding regions introduce a multitude of challenges and research opportunities. In this review, we introduce a spectrum of noncoding variants involved in genetic diseases, along with research strategies and advanced technologies for their precise identification and in-depth understanding of the complexity of the noncoding genome. We will delve into the research challenges and propose potential solutions for unraveling the genetic basis of rare and complex diseases.
基金the Foundation of National Key R&D Program of China of Research on Application Demonstration and Evaluation of Comprehensive Prevention And Control Technology of Birth Defects(Grant No.2018YFC1002700)Zhejiang R&D Research Project Research on New Technologies for Birth Health,Birth Safety and Perinatal Disease Diagnosis and Treatment(Grant No.2021C03099).
文摘Background Newborn screening(NBS)is an important and successful public health program that helps improve the long-term clinical outcomes of newborns by providing early diagnosis and treatment of certain inborn diseases.The develop-ment of next-generation sequencing(NGS)technology provides new opportunities to expand current newborn screening methodologies.Methods We designed a a newborn genetic screening(NBGS)panel targeting 135 genes associated with 75 inborn disorders by multiplex PCR combined with NGS.With this panel,a large-scale,multicenter,prospective multidisease analysis was conducted on dried blood spot(DBS)profiles from 21,442 neonates nationwide.Results We presented the positive detection rate and carrier frequency of diseases and related variants in different regions;and 168(0.78%)positive cases were detected.Glucose-6-Phosphate Dehydrogenase deficiency(G6PDD)and phenylketonuria(PKU)had higher prevalence rates,which were significantly different in different regions.The positive detection of G6PD variants was quite common in south China,whereas PAH variants were most commonly identified in north China.In addi-tion,NBGS identified 3 cases with DUOX2 variants and one with SLC25A13 variants,which were normal in conventional NBS,but were confirmed later as abnormal in repeated biochemical testing after recall.Eighty percent of high-frequency gene carriers and 60%of high-frequency variant carriers had obvious regional differences.On the premise that there was no significant difference in birth weight and gestational age,the biochemical indicators of SLC22A5 c.1400C>G and ACADSB c.1165A>G carriers were significantly different from those of non-carriers.Conclusions We demonstrated that NBGS is an effective strategy to identify neonates affected with treatable diseases as a supplement to current NBS methods.Our data also showed that the prevalence of diseases has significant regional charac-teristics,which provides a theoretical basis for screening diseases in different regions.
基金supported by the National Natural Science Foundation of China (31970574)。
文摘Animal models are extensively used in all aspects of biomedical research,with substantial contributions to our understanding of diseases,the development of pharmaceuticals,and the exploration of gene functions.The field of genome modification in rabbits has progressed slowly.However,recent advancements,particularly in CRISPR/Cas9-related technologies,have catalyzed the successful development of various genome-edited rabbit models to mimic diverse diseases,including cardiovascular disorders,immunodeficiencies,agingrelated ailments,neurological diseases,and ophthalmic pathologies.These models hold great promise in advancing biomedical research due to their closer physiological and biochemical resemblance to humans compared to mice.This review aims to summarize the novel gene-editing approaches currently available for rabbits and present the applications and prospects of such models in biomedicine,underscoring their impact and future potential in translational medicine.
基金Supported by Shanghai Science and Technology Development Foundation(Outstanding Academic Leader),No.23XD1423100National Natural Science Foundation,No.82241221 and No.92059205。
文摘Inherited metabolic liver diseases arise from genetic mutations that lead to dis-ruptions in liver metabolic pathways and are predominantly observed in pedia-tric populations.The spectrum of genetic metabolic liver disorders is diverse,encompassing a range of conditions associated with aberrations in iron,copper,carbohydrate,lipid,protein,and amino acid metabolism.Historically,research in the domain of genetic metabolic liver diseases has predominantly concentrated on hepatic parenchymal cell alterations.Nevertheless,emerging studies suggest that inherited metabolic liver diseases exert significant influences on the immune microenvironment,both within the liver and systemically.This review endeavors to encapsulate the immunological features of genetic metabolic liver diseases,aiming to expand the horizons of researchers in this discipline,and to elucidate the underlying pathophysiological mechanisms pertinent to hereditary metabolic liver diseases and to propose innovative therapeutic approaches.
文摘Approximately 40% of pheochromocytoma and paraganglioma(PPGL) cases are familial, typically presenting earlier with more complex symptoms. This paper synthesizes literature and guidelines to inform on clinical characteristics and perioperative care for PPGL. Pheochromocytoma in von Hippel-Lindau(VHL) disease exhibits heightened secretion activity without significant perioperative hemodynamic changes. Tumors in multiple endocrine neoplasia type 2(MEN2) have a stronger endocrine function, which may induce hemodynamic fluctuations during surgery. Therefore, pheochromocytoma screening is essential at all stages of MEN2. Neurofibromatosis type 1(NF1) often presents multisystem lesions and can result in difficult airway. Pheochromocytoma should be evaluated when NF1 patients present hypertension. Pheochromocytoma and paraganglioma type 5 may present multiple lesions of pheochromocytoma or paraganglioma. In summary, hereditary PPGLs may present with severe lesions in other systems, beyond tumor function. A multi-disciplinary team(MDT) approach is often invaluable in perioperative management.
基金supported by the National Natural Science Foundation of China(32370609 and 92353301 to X.X.)funding from Liangzhu Laboratory at Zhejiang University and the State Key Laboratory of Transvascular Implantation Devices at Zhejiang University.
文摘N6-methyladenosine(m^(6)A)has been established as the most prevalent chemical modification in message RNA(mRNA),playing an essential role in determining the fate of RNA molecules.Dysregulation of m^(6)A has been revealed to lead to abnormal physiological conditions and cause various types of human diseases.Recent studies have delineated the genetic regulatory maps for m^(6)A methylation by mapping the quantitative trait loci of m^(6)A(m^(6)A-QTLs),thereby building up the regulatory circuits linking genetic variants,m^(6)A,and human complex traits.Here,we review the recent discoveries concerning the genetic regulatory maps of m^(6)A,describing the methodological and technical details of m^(6)A-QTL identification,and introducing the key findings of the cis-and trans-acting drivers of m^(6)A.We further delve into the tissue-and ethnicity-specificity of m^(6)A-QTL,the association with other molecular phenotypes in light of genetic regulation,the regulators underlying m^(6)A genetics,and importantly,the functional roles of m^(6)A in mediating human complex diseases.Lastly,we discuss potential research avenues that can accelerate the translation of m^(6)A genetics studies toward the development of therapies for human genetic diseases.
基金Supported by Natural Science Foundation of Fujian Province,China,No.C001009
文摘AIM: Genetic polymorphism in enzymes of carcinogen metabolism has been found to have the influence on the susceptibility to cancer. Cytochrome P450 2E1 (CYP2E1) is considered to play an important role in the metabolic activation of procarcinogens such as N-nitrosoamines and low molecular weight organic compounds. The purpose of this study is to determine whether CYP450 2E1 polymorphisms are associated with risks of gastric cancer. METHODS: We conducted a population based case-control study in Changle county, Fujian Province, a high-risk region of gastric cancer in China. Ninety-one incident gastric cancer patients and ninety-four healthy controls were included in our study. Datas including demographic characteristics, diet intake, and alcohol and tobacco consumption of individuals in our study were completed by a standardized questionnaire.PCR-RFLP revealed three genotypes:heterozygote (C1/C2) and two homozygotes (C1/C1 and C2/C2) in CYP2E1. RESULTS: The frequency of variant genotypes (C1/C2 and C2/C2) in gastric cancer cases and controls was 36.3% and 24.5%, respectively. The rare homozygous C2/C2 genotype was found in 6 individuals in gastric cancer group(6.6%), whereas there was only one in the control group (1.1%). However, there was no statistically significant difference between the two groups (two-tailed Fisher's exact test P=0.066). Individuals in gastric cancer group were more likely to carry genotype C1/C2 (odds ratio, OR=1.50) and C2/C2 (OR=7.34) than individuals in control group (chi(2) =4.597, for trend P=0.032). The frequencies of genotypes with the C2 allele (C1/C2 and C2/C2 genotypes) were compared with those of genotypes without C2 allele (C1/C1 genotype) among individuals in gastric cancer group and control group according to the pattern of gastric cancer risk factors. The results show that individuals who exposed to these gastric cancer risk factors and carry the C2 allele seemed to have a higher risk of developing gastric cancer. CONCLUSION: Polymorphism of CYP2E1 gene may have some effect in the development of gastric cancer in Changle county, Fujian Province.
基金Supported by the Grants From Ligue Nationale Contre le Cancer,Comités Départementaux de la Manche,de l'Orne et du Calvados and from Université de Metz
文摘AIM:To evaluate the association between CYP1A1 and GSTs genetic polymorphisms and susceptibility to esophageal squamous cell carcinoma(SCC)and esophageal adenocarcinoma(ADC)in a high risk area of northwest of France. METHODS:A case-control study was conducted to investigate the genetic polymorphisms of these enzymes (CYPIAI*2C and GSTP1 exon 7 Val alleles,GSTMI*2/*2 and GSTTl *2/*2 null genotypes).A total of 79 esophageal cancer cases and 130 controls were recruited. RESULTS:GSTMI*2/*2 and CYPIAI*IA/*2C genotype frequencies were higher among squamous cell carcinomas at a level dose to statistical significance(OR =1.83,95% CI 0.88-3.83,P=0.11;OR=3.03,95% CI 0.93-9.90,P=0.07, respectively).For GSTP1 polymorphism,no difference was found between controls and cases,whatever their histological status.Lower frequency of GSTT1 deletion was observed in ADC group compared to controls with a statistically significant difference(OR=13.31,95% CI 1.66-106.92,P<0.01). CONCLUSION:In SCC,our results are consistent with the strong association of this kind of tumour with tobacco exposure.In ADC,our results suggest 3 distinct hypotheses: (1)activation of exogenous procarcinogens,such as small halogenated compounds by GSTT1;(2)contribution of GSTT1 to the inflammatory response of esophageal mucosa,which is known to be a strong risk factor for ADC, possibly through leukotriene synthesis;(3)higher sensitivity to the inflammatory process associated with intracellular depletion of glutathione.
文摘There are an estimated 10000 monogenic diseases affecting tens of millions of individuals worldwide.The application of CRISPR/Cas genome editing tools to treat monogenic diseases is an emerging strategy with the potential to generate personalized treatment approaches for these patients.CRISPR/Cas-based systems are programmable and sequence-specific genome editing tools with the capacity to generate base pair resolution manipulations to DNA or RNA.The complexity of genomic insults resulting in heritable disease requires patientspecific genome editing strategies with consideration of DNA repair pathways,and CRISPR/Cas systems of different types,species,and those with additional enzymatic capacity and/or delivery methods.In this review we aim to discuss broad and multifaceted therapeutic applications of CRISPR/Cas gene editing systems including in harnessing of homology directed repair,non-homologous end joining,microhomology-mediated end joining,and base editing to permanently correct diverse monogenic diseases.
文摘To define "ethnicity" in the context of perinatal care is a tough job. The word makes us think: "racial, social, cultural, national…". An ethnic group is generally considered a group of people with a common history, usually(but not always) a common religion and language, sharing aspects of culture such as nutrition and traditions concerning pregnancy, childbirth, the way they care for children. As procreation occurs mostly ingroup, every ethnic group will demonstrate a higher prevalence of, more or less well-known, genes and their connected diseases. For some populations, such as Ashkenazi Jewish people, the prevalence and associated risks of these autosomal diseases are well known, as in the case of "Jewish genetic disease", and specific screening programs are available.
文摘Typically,inherited metabolic diseases arise from point mutations in genes encoding metabolic enzymes. Although some of these mutations directly affect amino acid residues in the active sites of these enzymes,the majority do not. It is now well accepted that the majority of these disease-associated mutations exert their effects through alteration of protein stability,which causes a reduction in enzymatic activity. This finding suggests a way to predict the severity of newly discovered mutations. In silico prediction of the effects of amino acid sequence alterations on protein stability often correlates with disease severity. However,no stability prediction tool is perfect and,in general,better results are obtained if the predictions from a variety of tools are combined and then interpreted. In addition to predicted alterations to stability,the degree of conservation of a particular residue can also be a factor which needs to be taken into account: alterations to highly conserved residues are more likely to be associated with severe forms of the disease. The approach has been successfully applied in a variety of inherited metabolic diseases,but further improvements are necessary to enable robust translation into clinically useful tools.
文摘Totally three articles regarding associations of Nurrl gene mutations, LRRK2 gene polymorphism sites $1647T and R1398H, and polymorphism of PARK2 gene mutations with Han Chinese patients with Parkinson＇s disease were published in Neural Regeneration Research. We hope that our readers find these papers useful to their research.
文摘In this post-genomic era, more and more susceptibility loci of many possible genetic diseases are published. As our knowledge about these susceptibility loci is limited and partial, we should be very careful and responsible when patients seek genetic counseling about these possible genetic diseases. We should apply Confucius' s principle about knowledge and information to genetic conseling, and tell the truth to our patients about what we know and what we do not know. Like many other cancers, breast cancer is a very complicated, multifactorial disease; genetic factors, lifestyles and eating habits, environmental factors, and viral infections might be involved in breast cancer; hence, it is difficult to figure out the real etiology of breast cancer. It is not crystal clear that a person who carries mutations of the breast cancer 1, early onset and/or breast cancer 2, early onset genes would eventually get breast cancer in her/his lifetime. No person should undergo a preventive double mastectomy, unless we know the etiology of breast cancer someday.
基金Supported by Key Research Project of Wheat Breeding in Sichuan Province(2011NZ0098-3-18)
文摘To confirm resistance and genetic rules of Xikemai 6 against physiological races of wheat stripe rust,physiological races CYR31,CYR32 and CYR33,Su11-4 and V26 were inoculated in Xikemai 6 and Mingxian 169 and their hybrid progenies F_1,F_2 and F_3 at adult plant stage on March 2015. The results showed that the resistance of Xikemai 6 against CYR31 was controlled by 2 pairs of dominant genes and a pair of recessive genes; the resistance against CYR32 was controlled by three pairs of dominant resistant genes（ two pairs of genes performed cumulative effect）; the resistance against CYR33 was controlled by a pair of dominant genes and a pair of recessive genes; the resistance against Su11-4 was controlled by a pair of dominant genes and a pair of recessive genes independently or collaboratively; the resistance against V26 was controlled by a pair of dominant genes independently. Due to good performance of Xikemai 6 in test and production,as well as years of resistance identification and genetic analysis,Xikemai 6 was proved to be an excellent cultivar with good resistance against stripe rust,and the inheritance of its resistance was stable,so Xikemai 6 could be used as a germplasm resource and resistance material with excellent comprehensive character. Molecular marker and localization could be further studied,to provide new resistance parents for disease-resistant breeding of wheat.
基金Clinical Research Plan of SHDC(No.SHDC2020CR4006)Shanghai Ninth People’s Hospital(No.YBKB202218)+1 种基金Shanghai Municipal Human Resources and Social Security Bureau(No.2020074)National Natural Science Foundation of China(No.82170870)
文摘Background:The serum vitamin D level varies widely by population,and studies have linked vitamin D levels with the risk of type 2 diabetes mellitus(T2DM).However,the relationship is inconsistent and the impact of vitamin D on T2DM among East Chinese adults is unclear.The study aimed to investigate the association between serum 25-hydroxyvitamin D(25[OH]D)levels and the risk of T2DM and evaluated whether the association is modified by genetic predisposition.Methods:In the Survey on Prevalence in East China for Metabolic Diseases and Risk Factors(SPECT-China)cohort,1862 participants free of T2DM at baseline were included.A weighted genetic risk score was calculated with 28 variants associated with T2DM.Hierarchical logistic models were used to examine the association of serum 25(OH)D and genetic risk with T2DM.Results:After a 5-year follow-up,132 cases of T2DM were documented.We observed no significant association between quartiles of serum 25(OH)D and T2DM risk after multivariable adjustment(χ^(2)=0.571,P_(for trend)=0.426).Compared to those in the lowest quartile of 25(OH)D,the odds ratios(ORs)(95%confidence interval[CI])for participants with increased quartiles were 1.29(0.74-2.25),1.35(0.77-2.36),and 1.27(0.72-2.24),respectively.We observed a positive association of glycated hemoglobin(HbA1c)with 25(OH)D at baseline(β=1.752,P=0.001)and after follow-up(β=1.385,P=0.003),and a negative association of ln conversion homeostasis model assessment(HOMA)-βwith 25(OH)D at baseline(β=-0.982,P=0.021).There was no significant interaction between 25(OH)D and diabetes genetic predisposition on the risk of T2DM(χ^(2)=2.710,P_(for interaction)=0.100).The lowest OR(95%CI)of T2DM was among participants with low genetic risk and the highest quartile of 25(OH)D(0.17[0.05-0.62]).Conclusion:Serum 25(OH)D may be irrelevant to the risk of incident T2DM among East Chinese adults regardless of genetic predisposition.
文摘Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States, with over 38000 deaths in 2013. The opportunity to detect pancreatic cancer while it is still curable is dependent on our ability to identify and screen high-risk populations before their symptoms arise. Risk factors for developing pancreatic cancer include multiple genetic syndromes as well as modifiable risk factors. Genetic conditions include hereditary breast and ovarian cancer syndrome, Lynch Syndrome, familial adenomatous polyposis, Peutz-Jeghers Syndrome, familial atypical multiple mole melanoma syndrome, hereditary pancreatitis, cystic fibrosis, and ataxia-telangiectasia; having a genetic predisposition can raise the risk of developing pancreatic cancer up to 132-fold over the general population. Modifiable risk factors, which include tobacco exposure, alcohol use, chronic pancreatitis, diet, obesity, diabetes mellitus, as well as certain abdominal surgeries and infections, have also been shown to increase the risk of pancreatic cancer development. Several largevolume centers have initiated such screening protocols, and consensus-based guidelines for screening high-riskgroups have recently been published. The focus of this review will be both the genetic and modifiable risk factors implicated in pancreatic cancer, as well as a review of screening strategies and their diagnostic yields.
基金Supported ty the Key Teacher Fund,Ministry of Education of China and Sir Li Ka-Ching Foundation.
文摘AIM:To study the relationship between ABO blood groups and carcinoma of esophagus and cardia in Chaoshan inhabitants of China, which is a unique Littoral high-risk area of esophageal carcinoma in China. The poor communication and transportation in the past has made Chaoshan a relatively closed area and kept its culture and custure of old China thousand years ago. METHODS: Data on age, sex, ABO blood type and X-ray or pathological diagnose of the patients with carcinoma of esophagus or cardia were collected from the Tumor Hospital. First Affiliated Hospital, Second Affiliated Hospital of Shantou University Medical College; and the Central Hospital of Shantou and the Central Hospital of Jieyang. A total of 6685 patients with esophageal carcinoma (EC) and 2955 patients with cardiac cancer (CC) in Chaoshan district were retrospectively assessed for their association with ABO blood groups. RESULTS: The distribution of ABO blood groups in patients with EC or CC was similar to the normal local population in Chaoshan. However, blood group B in male patients with CC and in the patients with carcinoma in the upper third esophagus was 2.3% and 4.7% higher than the corresponding controls. The relative risk B O was 1.1415 (P【0.05) and 1.2696 (P【0.05), respectively. No relationship was found between ABO blood groups and tumor differentiation. CONCLUSION: ABO blood group B is associated with the incidence of CC in male individuals and carcinoma in the upper third esophagus. The distribution of ABO blood groups varies in the different geographical and ethnic groups. As a result, proper controls are very important for such studies.
