Some patients with chronic hepatitis B virus(HBV)infection failed to clear HBV,even persistently continue to produce antibodies to HBV.Here we performed a two stage genome wide association study in a cohort of Chinese...Some patients with chronic hepatitis B virus(HBV)infection failed to clear HBV,even persistently continue to produce antibodies to HBV.Here we performed a two stage genome wide association study in a cohort of Chinese patients designed to discover single nucleotide variants that associate with HBV infection and clearance of HBV.The first stage involved genome wide exome sequencing of 101 cases(HBsAg plus anti-HBs positive)compared with 102 control patients(antiHBs positive,HBsAg negative).Over 80%of individual sequences displayed 209 sequence coverage.Adapters,uncertain bases[10%or low-quality base calls([50%)were filtered and compared to the human reference genome hg19.In the second stage,579 chronic HBV infected cases and 439 HBV clearance controls were sequenced with selected genes from the first stage.Although there were no significant associated gene variants in the first stage,two significant gene associations were discovered when the two stages were assessed in a combined analysis.One association showed rs506121-“T”allele[within the dedicator of cytokinesis 8(DOCK8)gene]was higher in chronic HBV infection group than that in clearance group(P=0.002,OR=0.77,95%CI[0.65,0.91]).The second association involved rs2071676—A allele within the Carbonic anhydrase(CA9)gene that was significantly elevated in chronic HBV infection group compared to the clearance group(P=0.0003,OR=1.35,95%CI[1.15,1.58]).Upon replication these gene associations would suggest the influence of DOCK8 and CA9 as potential risk genetic factors in the persistence of HBV infection.展开更多
In China,an estimated 48.42-82.11 million individuals are affected by rare diseases.This estimate is derived from the Orphanet database,based on the global population of 7.55 billion and China's population of 1.39...In China,an estimated 48.42-82.11 million individuals are affected by rare diseases.This estimate is derived from the Orphanet database,based on the global population of 7.55 billion and China's population of 1.39 billion in 2017(source:National Bureau of Statistics of China)[1,2].展开更多
The entorhinal cortex(EC)-hippocampal(HPC)circuit is particularly vulnerable to Alzheimer's disease(AD)pathol-ogy,yet the underlying molecular mechanisms remain unclear.By employing the high-depth sequencing strat...The entorhinal cortex(EC)-hippocampal(HPC)circuit is particularly vulnerable to Alzheimer's disease(AD)pathol-ogy,yet the underlying molecular mechanisms remain unclear.By employing the high-depth sequencing strategy Smart-seq2,we tracked gene expression changes across various neuron types within this circuit at different stages of AD pathology.We observed a decrease in the extent of gene expression changes in AD versus wild-type(WT)mice as the disease advanced.Functionally,we demonstrate that both mitochondrial and ribosomal pathways were increasingly activated,while neuronal pathways were inhibited with AD progression.Our findings indicate that the reduction of EC-stellate cells disrupts Meg3-mediated energy metabolism,contributing to energy dysfunction in AD.Additionally,we identified GFAP-positive neurons as a distinct population of disease-associated neurons,exhibiting a loss of neuronal-like characteristics,alongside the emergence of glia-and stem-like features.The num-ber of GFAP-positive neurons increased with AD progression,a trend consistently observed in both AD model mice and AD patients.In summary,this study identifies and characterizes GFAP-positive neurons as a novel subtype of disease-associated neurons in AD pathology,providing insights into their potential role in disease progression.展开更多
基金supported by grant from the International Science&Technology Cooperation Program of China(No.2014DFR31200)the National Infrastructure of Chinese Genetic Resources(YCZYPT[2017]01-6)+1 种基金federal funds from the National Cancer Institute,National Institutes of Health,USA(No.N01-CO12400)the National Natural Science Foundation of China(No.30671855)。
文摘Some patients with chronic hepatitis B virus(HBV)infection failed to clear HBV,even persistently continue to produce antibodies to HBV.Here we performed a two stage genome wide association study in a cohort of Chinese patients designed to discover single nucleotide variants that associate with HBV infection and clearance of HBV.The first stage involved genome wide exome sequencing of 101 cases(HBsAg plus anti-HBs positive)compared with 102 control patients(antiHBs positive,HBsAg negative).Over 80%of individual sequences displayed 209 sequence coverage.Adapters,uncertain bases[10%or low-quality base calls([50%)were filtered and compared to the human reference genome hg19.In the second stage,579 chronic HBV infected cases and 439 HBV clearance controls were sequenced with selected genes from the first stage.Although there were no significant associated gene variants in the first stage,two significant gene associations were discovered when the two stages were assessed in a combined analysis.One association showed rs506121-“T”allele[within the dedicator of cytokinesis 8(DOCK8)gene]was higher in chronic HBV infection group than that in clearance group(P=0.002,OR=0.77,95%CI[0.65,0.91]).The second association involved rs2071676—A allele within the Carbonic anhydrase(CA9)gene that was significantly elevated in chronic HBV infection group compared to the clearance group(P=0.0003,OR=1.35,95%CI[1.15,1.58]).Upon replication these gene associations would suggest the influence of DOCK8 and CA9 as potential risk genetic factors in the persistence of HBV infection.
基金supported by the National Key Research and Development Program of China(2022YFC2703100)The Ministry of Finance of the People's Republic of China funded the UPWARDS projectthe National Health Commission of the People's Republic of China(NHC)for supporting this study。
文摘In China,an estimated 48.42-82.11 million individuals are affected by rare diseases.This estimate is derived from the Orphanet database,based on the global population of 7.55 billion and China's population of 1.39 billion in 2017(source:National Bureau of Statistics of China)[1,2].
基金supported by the National Natural Science Foundation of China(Grant Nos.82125009,82330045,32121002,82071185,82172061,and 92149303)the National Key R&D Program of China(Grant Nos.2020YFA0509300,2021YFA0804900,and 2022YFC2703102)+4 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB39000000)CAS Project for Young Scientists in Basic Research(YSBR-013),Plans for Major Provincial Science&Technology Projects(202303a07020004)Hefei Comprehensive National Science Center Hefei Brain Project,Research Funds of Center for Advanced Interdisciplinary Science and Biomedicine of IHM(QYZD20220003)the Major Frontier Research Project of the University of Science and Technology of China(LS9100000002)S&T Program of Shijiazhuang(235790429H).
文摘The entorhinal cortex(EC)-hippocampal(HPC)circuit is particularly vulnerable to Alzheimer's disease(AD)pathol-ogy,yet the underlying molecular mechanisms remain unclear.By employing the high-depth sequencing strategy Smart-seq2,we tracked gene expression changes across various neuron types within this circuit at different stages of AD pathology.We observed a decrease in the extent of gene expression changes in AD versus wild-type(WT)mice as the disease advanced.Functionally,we demonstrate that both mitochondrial and ribosomal pathways were increasingly activated,while neuronal pathways were inhibited with AD progression.Our findings indicate that the reduction of EC-stellate cells disrupts Meg3-mediated energy metabolism,contributing to energy dysfunction in AD.Additionally,we identified GFAP-positive neurons as a distinct population of disease-associated neurons,exhibiting a loss of neuronal-like characteristics,alongside the emergence of glia-and stem-like features.The num-ber of GFAP-positive neurons increased with AD progression,a trend consistently observed in both AD model mice and AD patients.In summary,this study identifies and characterizes GFAP-positive neurons as a novel subtype of disease-associated neurons in AD pathology,providing insights into their potential role in disease progression.
