目的:探讨自噬相关基因4A(autophagy related 4A,ATG4A)及自噬相关基因16L1(autophagy related 16 like 1,ATG16L1)的多态性位点与中国西南地区人群肺结核易感性的关系。方法:采用聚合酶链反应-限制性片段长度多态性技术检测218例肺结...目的:探讨自噬相关基因4A(autophagy related 4A,ATG4A)及自噬相关基因16L1(autophagy related 16 like 1,ATG16L1)的多态性位点与中国西南地区人群肺结核易感性的关系。方法:采用聚合酶链反应-限制性片段长度多态性技术检测218例肺结核患者及248例健康对照者ATG4A基因rs807185位点及ATG16L1基因rs2241880位点的基因型,用logistic回归分析上述2个位点与肺结核病易感的相关性。结果:2组人群中rs807185位点的A等位基因、AT基因型及显性模型AA+AT vs.TT的频率分布存在统计学差异(P<0.05),且在女性中差异更突出。而rs2241880位点的各指标频率分布差异均不明显(P>0.05)。结论:ATG4A基因rs807185位点多态性与中国西南地区人群肺结核易感性呈负相关,而ATG16L1基因rs2241880位点多态性则与该地区人群肺结核易感性无明显相关。展开更多
AIM: To assess whether the polymorphisms of NOD2/ CARD15 , autophagy-related 16-like 1 (ATG16L1 ), and interleukin-23 receptor (IL23R ) genes play a more critical role in the susceptibility of childhood-onset than in ...AIM: To assess whether the polymorphisms of NOD2/ CARD15 , autophagy-related 16-like 1 (ATG16L1 ), and interleukin-23 receptor (IL23R ) genes play a more critical role in the susceptibility of childhood-onset than in adult-onset Crohn’s disease (CD). METHODS: Polymorphisms R702W, G908R, and 3020insC of NOD2/CARD15 ; rs2241880 A/G of ATG16L1 , and rs11209026 (R381Q) of IL23R gene were assessed in 110 childhood-onset CD, 364 adult-onset CD, and 539 healthy individuals. Analysis of polymorphisms R702W, G908R, and 3020insC of NOD2/CARD15 genotyping was performed by allele specific polymerase chain reaction (PCR) or by PCR-restriction fragment length polymor-phism analysis. The polymorphisms rs2241880 A/G of the ATG16L1 , and rs11209026 (R381Q) of the IL23R gene in the children’s cohort were genotyped by PCR and melting curve analysis whereas adult group genotyping was performed using the Affymetrix Genome-Wide Human SNP Array 5.0 (500K). RESULTS: The 3020insC allele in NOD2/CARD15 was significantly higher in childhood than in adult-onset CD (P = 0.0067). Association with at least 1 NOD2/CARD15 variant was specific for ileal disease (with or without co- lonic involvement). Even if the frequency of G allele of the rs2241880 ATG16L1 polymorphism was increased in both paediatric and adult CD patients compared to con- trols (P = 0.017 and P = 0.001, respectively), no difference was observed between the childhood and the adult cohort. The rare Q allele of IL23R rs11209026 polymorphism was underrepresented in both paediatric and adult CD cases (P = 0.0018 and P = 0.04, respectively) and no difference was observed between the childhood and the adult cohort. The presence of the rs2241880 ATG16L1 and rs11209026 IL23R polymorphisms did not influence disease phenotype. CONCLUSION: Polymorphism 3020insC in NOD2/ CARD15 occurs statistically significantly more often in patients with childhood-onset CD than in patients with adult-onset CD. The ATG16L1 and IL23R variants are associated with susceptibility to CD, but not earlyonset disease.展开更多
AIM:To evaluate the association of the autophagy- related 16-like 1 (ATG16L1 ) T300A polymorphism (rs2241880) with predisposition to inflammatory bowel diseases (IBD) by means of meta-analysis.METHODS: Publications ad...AIM:To evaluate the association of the autophagy- related 16-like 1 (ATG16L1 ) T300A polymorphism (rs2241880) with predisposition to inflammatory bowel diseases (IBD) by means of meta-analysis.METHODS: Publications addressing the relationship between rs2241880/T300A polymorphism of ATG16L1 and Crohn's disease (CD) and ulcerative colitis (UC) were selected from the MEDLINE and EMBASE data-bases. To make direct comparisons between the data collected in these studies, the individual authors were contacted when necessary to generate a standardized set of data from these studies. From these data, odds ratio (OR) with 95% confidence interval (CI) were calculated.RESULTS: Twenty-five studies of CD were analyzed, 14 of which involved cases of UC. The variant G allele of ATG16L1 was positively associated with CD (OR=1.32, 95% CI: 1.26-1.39, P<0.00001) and UC (OR =1.06, 95% CI:1.01-1.10, P=0.02). For child-onset IBD, a higher G allele frequency was found for cases of CD (OR=1.35, 95% CI: 1.16-1.57, P=0.0001) than for cases of UC (OR = 0.98, 95% CI: 0.81-1.19, P = 0.84) relative to controls.CONCLUSION: The ATG16L1 T300A polymorphism contributes to susceptibility to CD and UC in adults, but different in children, which implicates a role for autophagy in the pathogenesis of IBD.展开更多
AIM:To investigate the frequency of NOD2, IL23R and ATG16L1 genetic variants in a case-control panel for inflammatory bowel disease (IBD) from Lithuania.METHODS: One hundred and eighty unrelated IBD pa- tients [57 Cro...AIM:To investigate the frequency of NOD2, IL23R and ATG16L1 genetic variants in a case-control panel for inflammatory bowel disease (IBD) from Lithuania.METHODS: One hundred and eighty unrelated IBD pa- tients [57 Crohn's disease (CD) and 123 ulcerative colitis (UC)] and 186 healthy controls were genotyped for the following known genetic susceptibility variants:NOD2-Arg702Trp (rs2066844), Gly908Arg (rs2066845) and Leu1007insC (rs2066847), as well as IL23R-Arg381Gln (rs11209026) and ATG16L1-Thr300Ala (rs2241880).RESULTS:The effect that carriership of at least one NOD2 risk allele predisposes to CD was replicated in the Lithuanian population (41.1% CD vs 16.9% controls, P=2×10-4, OR=3.48,95% CI:1.81-6.72). In the allelic single marker analysis, Leu1007insC was strongly associated with CD (21.4% CD vs 4.7% controls, P=3.687×10-8, OR=5.54, 95% CI:2.85-10.75). Neither the other two NOD2 variants, nor the known variants in IL23R and ATG16L1 were found to be risk factors for CD, UC or IBD. However, our relatively small study population was underpowered to demonstrate such weak to moderate disease associations.CONCLUSION: The results support a strong association between CD susceptibility and the Leu1007insC variant in NOD2 in the Lithuanian study population.展开更多
Crohn’s disease(CD)is driven by the loss of tolerance to intestinal microbiota and excessive production of pro-inflammatory cytokines.These pro-inflammatory cytokines are produced by macrophages and dendritic cells(D...Crohn’s disease(CD)is driven by the loss of tolerance to intestinal microbiota and excessive production of pro-inflammatory cytokines.These pro-inflammatory cytokines are produced by macrophages and dendritic cells(DCs)upon sensing the intestinal microbiota by the pattern recognition receptors(PRRs).Impaired activation of PRR-mediated signaling pathways is associated with chronic gastrointestinal inflammation,as shown by the fact that loss-of-function mutations in the nucleotide-binding oligomerization domain 2 gene increase the risk of CD development.Autophagy is an intracellular degradation process,during which cytoplasmic nutrients and intracellular pathogens are digested.Given that impaired reaction to intestinal microbiota alters signaling pathways mediated by PRRs,it is likely that dysfunction of the autophagic machinery is involved in the development of CD.Indeed,the loss-of-function mutation T300A in the autophagy related 16 like 1(ATG16L1)protein,a critical regulator of autophagy,increases susceptibility to CD.Recent studies have provided evidence that ATG16L1 is involved not only in autophagy,but also in PRR-mediated signaling pathways.ATG16L1 negatively regulates pro-inflammatory cytokine responses of macrophages and DCs after these cells sense the intestinal microbiota by PRRs.Here,we discuss the molecular mechanisms underlying the development of CD in the T300A ATG16L1 mutation by focusing on PRR-mediated signaling pathways.展开更多
目的观察雷公藤甲素对miR-20a及自噬相关16样蛋白L1(autophagy related 16 like protein1,ATG16L1)表达的影响,探讨mi R-20a对雷公藤甲素所致肝细胞毒性的调控作用。方法利用雷公藤甲素处理人正常肝细胞株HL7702和C57BL/6J小鼠,通过qRT-...目的观察雷公藤甲素对miR-20a及自噬相关16样蛋白L1(autophagy related 16 like protein1,ATG16L1)表达的影响,探讨mi R-20a对雷公藤甲素所致肝细胞毒性的调控作用。方法利用雷公藤甲素处理人正常肝细胞株HL7702和C57BL/6J小鼠,通过qRT-PCR和Western blotting检测miR-20a、ATG16L1及自噬标记物微管相关蛋白1轻链3II(microtubuleassociated protein 1 light 3II,LC3II)的表达。利用雷公藤甲素和miR-20a模拟物或抑制物共同处理HL7702细胞,通过qRTPCR和Western blotting检测ATG16L1及LC3II的表达;CCK-8法检测细胞存活率;试剂盒检测乳酸脱氢酶(lactate dehydrogenase,LDH)释放量;ELISA检测半胱氨酸天冬氨酸蛋白酶-3(cystein-asparate protease-3,Caspase-3)和Caspase-9的活性。结果雷公藤甲素显著下调人正常肝细胞或小鼠肝组织中miR-20a表达(P<0.05),上调ATG16L1和LC3II的表达(P<0.05)。mi R-20a模拟物可抑制雷公藤甲素引起的ATG16L1、LC3II表达升高(P<0.05),进一步降低细胞存活率(P<0.05),提高LDH释放量(P<0.05),上调Caspase-3和Caspase-9活性(P<0.05),而miR-20a抑制物具有相反作用。结论miR-20a通过ATG16L1影响自噬过程,参与调节雷公藤甲素肝细胞毒性。展开更多
文摘目的:探讨自噬相关基因4A(autophagy related 4A,ATG4A)及自噬相关基因16L1(autophagy related 16 like 1,ATG16L1)的多态性位点与中国西南地区人群肺结核易感性的关系。方法:采用聚合酶链反应-限制性片段长度多态性技术检测218例肺结核患者及248例健康对照者ATG4A基因rs807185位点及ATG16L1基因rs2241880位点的基因型,用logistic回归分析上述2个位点与肺结核病易感的相关性。结果:2组人群中rs807185位点的A等位基因、AT基因型及显性模型AA+AT vs.TT的频率分布存在统计学差异(P<0.05),且在女性中差异更突出。而rs2241880位点的各指标频率分布差异均不明显(P>0.05)。结论:ATG4A基因rs807185位点多态性与中国西南地区人群肺结核易感性呈负相关,而ATG16L1基因rs2241880位点多态性则与该地区人群肺结核易感性无明显相关。
文摘AIM: To assess whether the polymorphisms of NOD2/ CARD15 , autophagy-related 16-like 1 (ATG16L1 ), and interleukin-23 receptor (IL23R ) genes play a more critical role in the susceptibility of childhood-onset than in adult-onset Crohn’s disease (CD). METHODS: Polymorphisms R702W, G908R, and 3020insC of NOD2/CARD15 ; rs2241880 A/G of ATG16L1 , and rs11209026 (R381Q) of IL23R gene were assessed in 110 childhood-onset CD, 364 adult-onset CD, and 539 healthy individuals. Analysis of polymorphisms R702W, G908R, and 3020insC of NOD2/CARD15 genotyping was performed by allele specific polymerase chain reaction (PCR) or by PCR-restriction fragment length polymor-phism analysis. The polymorphisms rs2241880 A/G of the ATG16L1 , and rs11209026 (R381Q) of the IL23R gene in the children’s cohort were genotyped by PCR and melting curve analysis whereas adult group genotyping was performed using the Affymetrix Genome-Wide Human SNP Array 5.0 (500K). RESULTS: The 3020insC allele in NOD2/CARD15 was significantly higher in childhood than in adult-onset CD (P = 0.0067). Association with at least 1 NOD2/CARD15 variant was specific for ileal disease (with or without co- lonic involvement). Even if the frequency of G allele of the rs2241880 ATG16L1 polymorphism was increased in both paediatric and adult CD patients compared to con- trols (P = 0.017 and P = 0.001, respectively), no difference was observed between the childhood and the adult cohort. The rare Q allele of IL23R rs11209026 polymorphism was underrepresented in both paediatric and adult CD cases (P = 0.0018 and P = 0.04, respectively) and no difference was observed between the childhood and the adult cohort. The presence of the rs2241880 ATG16L1 and rs11209026 IL23R polymorphisms did not influence disease phenotype. CONCLUSION: Polymorphism 3020insC in NOD2/ CARD15 occurs statistically significantly more often in patients with childhood-onset CD than in patients with adult-onset CD. The ATG16L1 and IL23R variants are associated with susceptibility to CD, but not earlyonset disease.
文摘AIM:To evaluate the association of the autophagy- related 16-like 1 (ATG16L1 ) T300A polymorphism (rs2241880) with predisposition to inflammatory bowel diseases (IBD) by means of meta-analysis.METHODS: Publications addressing the relationship between rs2241880/T300A polymorphism of ATG16L1 and Crohn's disease (CD) and ulcerative colitis (UC) were selected from the MEDLINE and EMBASE data-bases. To make direct comparisons between the data collected in these studies, the individual authors were contacted when necessary to generate a standardized set of data from these studies. From these data, odds ratio (OR) with 95% confidence interval (CI) were calculated.RESULTS: Twenty-five studies of CD were analyzed, 14 of which involved cases of UC. The variant G allele of ATG16L1 was positively associated with CD (OR=1.32, 95% CI: 1.26-1.39, P<0.00001) and UC (OR =1.06, 95% CI:1.01-1.10, P=0.02). For child-onset IBD, a higher G allele frequency was found for cases of CD (OR=1.35, 95% CI: 1.16-1.57, P=0.0001) than for cases of UC (OR = 0.98, 95% CI: 0.81-1.19, P = 0.84) relative to controls.CONCLUSION: The ATG16L1 T300A polymorphism contributes to susceptibility to CD and UC in adults, but different in children, which implicates a role for autophagy in the pathogenesis of IBD.
基金Supported by The German Ministry of Education and Research through the National Genome Research Network
文摘AIM:To investigate the frequency of NOD2, IL23R and ATG16L1 genetic variants in a case-control panel for inflammatory bowel disease (IBD) from Lithuania.METHODS: One hundred and eighty unrelated IBD pa- tients [57 Crohn's disease (CD) and 123 ulcerative colitis (UC)] and 186 healthy controls were genotyped for the following known genetic susceptibility variants:NOD2-Arg702Trp (rs2066844), Gly908Arg (rs2066845) and Leu1007insC (rs2066847), as well as IL23R-Arg381Gln (rs11209026) and ATG16L1-Thr300Ala (rs2241880).RESULTS:The effect that carriership of at least one NOD2 risk allele predisposes to CD was replicated in the Lithuanian population (41.1% CD vs 16.9% controls, P=2×10-4, OR=3.48,95% CI:1.81-6.72). In the allelic single marker analysis, Leu1007insC was strongly associated with CD (21.4% CD vs 4.7% controls, P=3.687×10-8, OR=5.54, 95% CI:2.85-10.75). Neither the other two NOD2 variants, nor the known variants in IL23R and ATG16L1 were found to be risk factors for CD, UC or IBD. However, our relatively small study population was underpowered to demonstrate such weak to moderate disease associations.CONCLUSION: The results support a strong association between CD susceptibility and the Leu1007insC variant in NOD2 in the Lithuanian study population.
文摘Crohn’s disease(CD)is driven by the loss of tolerance to intestinal microbiota and excessive production of pro-inflammatory cytokines.These pro-inflammatory cytokines are produced by macrophages and dendritic cells(DCs)upon sensing the intestinal microbiota by the pattern recognition receptors(PRRs).Impaired activation of PRR-mediated signaling pathways is associated with chronic gastrointestinal inflammation,as shown by the fact that loss-of-function mutations in the nucleotide-binding oligomerization domain 2 gene increase the risk of CD development.Autophagy is an intracellular degradation process,during which cytoplasmic nutrients and intracellular pathogens are digested.Given that impaired reaction to intestinal microbiota alters signaling pathways mediated by PRRs,it is likely that dysfunction of the autophagic machinery is involved in the development of CD.Indeed,the loss-of-function mutation T300A in the autophagy related 16 like 1(ATG16L1)protein,a critical regulator of autophagy,increases susceptibility to CD.Recent studies have provided evidence that ATG16L1 is involved not only in autophagy,but also in PRR-mediated signaling pathways.ATG16L1 negatively regulates pro-inflammatory cytokine responses of macrophages and DCs after these cells sense the intestinal microbiota by PRRs.Here,we discuss the molecular mechanisms underlying the development of CD in the T300A ATG16L1 mutation by focusing on PRR-mediated signaling pathways.
文摘目的观察雷公藤甲素对miR-20a及自噬相关16样蛋白L1(autophagy related 16 like protein1,ATG16L1)表达的影响,探讨mi R-20a对雷公藤甲素所致肝细胞毒性的调控作用。方法利用雷公藤甲素处理人正常肝细胞株HL7702和C57BL/6J小鼠,通过qRT-PCR和Western blotting检测miR-20a、ATG16L1及自噬标记物微管相关蛋白1轻链3II(microtubuleassociated protein 1 light 3II,LC3II)的表达。利用雷公藤甲素和miR-20a模拟物或抑制物共同处理HL7702细胞,通过qRTPCR和Western blotting检测ATG16L1及LC3II的表达;CCK-8法检测细胞存活率;试剂盒检测乳酸脱氢酶(lactate dehydrogenase,LDH)释放量;ELISA检测半胱氨酸天冬氨酸蛋白酶-3(cystein-asparate protease-3,Caspase-3)和Caspase-9的活性。结果雷公藤甲素显著下调人正常肝细胞或小鼠肝组织中miR-20a表达(P<0.05),上调ATG16L1和LC3II的表达(P<0.05)。mi R-20a模拟物可抑制雷公藤甲素引起的ATG16L1、LC3II表达升高(P<0.05),进一步降低细胞存活率(P<0.05),提高LDH释放量(P<0.05),上调Caspase-3和Caspase-9活性(P<0.05),而miR-20a抑制物具有相反作用。结论miR-20a通过ATG16L1影响自噬过程,参与调节雷公藤甲素肝细胞毒性。
