Objective: This study aimed to investigate the association between single-nucleotide polymorphisms (SNPs) ofPCSK1 (proprotein convertase subtilisin/kexin type 1) related to obesity and nonalcoholic fatty liver disease...Objective: This study aimed to investigate the association between single-nucleotide polymorphisms (SNPs) ofPCSK1 (proprotein convertase subtilisin/kexin type 1) related to obesity and nonalcoholic fatty liver disease (NAFLD).Methods: In this case-control observational study, four candidate SNPs (rs6234, rs155971, rs6232, rs3811951) ofPCSK1 were genotyped in 732 NAFLD patients and 823 healthy control participants, all of whom were of ethnic Han Chinese descent. All participants came from Shanghai, China, and joined our study during 2015 to 2016. The frequencies of each allele and genotype, paired linkage disequilibrium, and haplotype were calculated on the SHEsis platform. In addition to SHEsis, five different genetic models (codominant, dominant, recessive, overdominant, and log-additive) were employed to identify the correlation between genotype frequency and NAFLD. This study was approved by the Medical Ethics Committee of Shanghai University of Traditional Chinese Medicine (approved No. 2017LCSY069).Results: In a comparison of NAFLD patients and healthy participants, none of the fourPCSK1 SNPs were significantly correlated with the occurrence of NAFLD (P>0.05), in either genotypic or allelic distribution. The recessive model of rs3811951 appeared to show a correlation (odds ratio=1.077;95% confidence interval=0.924-1.256;P=0.04), but there was no statistical significance after Bonferroni correction (Pcorr>0.0125).Conclusions: Four obesity-relatedPCSK1 SNPs (rs6234, rs155971, rs6232, rs3811951) showed no significant correlation with the development of NAFLD in a Han Chinese population.展开更多
Background:New fuid biomarkers for Alzheimer’s disease(AD)that reveal synaptic and neural network dysfunc‑tions are needed for clinical practice and therapeutic trial design.Dense core vesicle(DCV)cargos are promisin...Background:New fuid biomarkers for Alzheimer’s disease(AD)that reveal synaptic and neural network dysfunc‑tions are needed for clinical practice and therapeutic trial design.Dense core vesicle(DCV)cargos are promising cerebrospinal fuid(CSF)indicators of synaptic failure in AD patients.However,their value as biomarkers has not yet been determined.Methods:Immunoassays were performed to analyze the secretory proteins prohormone convertases PC1/3 and PC2,carboxypeptidase E(CPE),secretogranins SgIII and SgII,and Cystatin C in the cerebral cortex(n=45,provided by Bellvitge University Hospital)and CSF samples(n=66,provided by The Sant Pau Initiative on Neurodegeneration cohort)from AD patients(n=56)and age-matched controls(n=55).Results:In AD tissues,most DCV proteins were aberrantly accumulated in dystrophic neurites and activated astro‑cytes,whereas PC1/3,PC2 and CPE were also specifcally accumulated in hippocampal granulovacuolar degeneration bodies.AD individuals displayed an overall decline of secretory proteins in the CSF.Interestingly,in AD patients,the CSF levels of prohormone convertases strongly correlated inversely with those of neurodegeneration markers and directly with cognitive impairment status.Conclusions:These results demonstrate marked alterations of neuronal-specifc prohormone convertases in CSF and cortical tissues of AD patients.The neuronal DCV cargos are biomarker candidates for synaptic dysfunction and neurodegeneration in AD.展开更多
基金Innovation Funding in Shanghai(Nos.20JC1418600 and 18JC1413100)National Nature Science Foundation of China(Nos.82071262 and 81671326)+2 种基金Natural Science Foundation of Shanghai(Nos.20ZR1427200 and 20511101900)Shanghai Municipal Science and Technology Major Project(No.2017SHZDZX01)Shanghai Leading Academic Discipline Project(No.B205).
文摘Objective: This study aimed to investigate the association between single-nucleotide polymorphisms (SNPs) ofPCSK1 (proprotein convertase subtilisin/kexin type 1) related to obesity and nonalcoholic fatty liver disease (NAFLD).Methods: In this case-control observational study, four candidate SNPs (rs6234, rs155971, rs6232, rs3811951) ofPCSK1 were genotyped in 732 NAFLD patients and 823 healthy control participants, all of whom were of ethnic Han Chinese descent. All participants came from Shanghai, China, and joined our study during 2015 to 2016. The frequencies of each allele and genotype, paired linkage disequilibrium, and haplotype were calculated on the SHEsis platform. In addition to SHEsis, five different genetic models (codominant, dominant, recessive, overdominant, and log-additive) were employed to identify the correlation between genotype frequency and NAFLD. This study was approved by the Medical Ethics Committee of Shanghai University of Traditional Chinese Medicine (approved No. 2017LCSY069).Results: In a comparison of NAFLD patients and healthy participants, none of the fourPCSK1 SNPs were significantly correlated with the occurrence of NAFLD (P>0.05), in either genotypic or allelic distribution. The recessive model of rs3811951 appeared to show a correlation (odds ratio=1.077;95% confidence interval=0.924-1.256;P=0.04), but there was no statistical significance after Bonferroni correction (Pcorr>0.0125).Conclusions: Four obesity-relatedPCSK1 SNPs (rs6234, rs155971, rs6232, rs3811951) showed no significant correlation with the development of NAFLD in a Han Chinese population.
基金This work was supported by grants from the Spanish Ministry of Economy and Competitiveness(BFU2016-80868-R,MINECO/FEDER,to FA)the Spanish Ministry of Science and Innovation(PID2019-107738RB-I00,MICINN/FEDER,to FA)+2 种基金the Catalonian Government(2017SGR1255 to FA,2014SGR-0235 to AL,PERIS SLT006/17/125 to DA)the Carlos III Institute of Health,Spain(PI18/00435 to DA,PI14/1561 and PI17/01896 to AL)and the CIBERNED program(Program 1,Alzheimer Disease to AL and IF),partly funded by Fondo Europeo de Desar‑rollo Regional(FEDER),Unión Europea,“Una manera de hacer Europa”,and BBVA Foundation(to AL)We are grateful to the Generalitat de Catalunya(NB),the Ministry of Education and Vocational Training(NB)and the Universitat de Barcelona(VP)for fnancial support.
文摘Background:New fuid biomarkers for Alzheimer’s disease(AD)that reveal synaptic and neural network dysfunc‑tions are needed for clinical practice and therapeutic trial design.Dense core vesicle(DCV)cargos are promising cerebrospinal fuid(CSF)indicators of synaptic failure in AD patients.However,their value as biomarkers has not yet been determined.Methods:Immunoassays were performed to analyze the secretory proteins prohormone convertases PC1/3 and PC2,carboxypeptidase E(CPE),secretogranins SgIII and SgII,and Cystatin C in the cerebral cortex(n=45,provided by Bellvitge University Hospital)and CSF samples(n=66,provided by The Sant Pau Initiative on Neurodegeneration cohort)from AD patients(n=56)and age-matched controls(n=55).Results:In AD tissues,most DCV proteins were aberrantly accumulated in dystrophic neurites and activated astro‑cytes,whereas PC1/3,PC2 and CPE were also specifcally accumulated in hippocampal granulovacuolar degeneration bodies.AD individuals displayed an overall decline of secretory proteins in the CSF.Interestingly,in AD patients,the CSF levels of prohormone convertases strongly correlated inversely with those of neurodegeneration markers and directly with cognitive impairment status.Conclusions:These results demonstrate marked alterations of neuronal-specifc prohormone convertases in CSF and cortical tissues of AD patients.The neuronal DCV cargos are biomarker candidates for synaptic dysfunction and neurodegeneration in AD.
