Objective: To evaluate gene polymorphisms and their association with susceptibility to dengue.Methods: A retrospective case-control study was performed with 262 subjects,comprising 78 dengue fever(DF) patients, 49 den...Objective: To evaluate gene polymorphisms and their association with susceptibility to dengue.Methods: A retrospective case-control study was performed with 262 subjects,comprising 78 dengue fever(DF) patients, 49 dengue hemorrhagic fever(DHF) patients and 135 healthy controls. Genotypic and allelic profiles were identified using polymerase chain reaction based in real time and amplification-refractory mutation system.Results: We observed a protective association of IL-10(-819 C/T) C allele(P = 0.028,OR = 0.56, CI = 0.34–0.91) against DHF, while the C/T(P = 0.047, OR = 2.10,CI = 1.01–4.38) and T/T(P = 0.008, OR = 3.82, CI = 1.38–10.59) genotypes were associated with DHF and DF, respectively. The dominant model TNFA-308 GA + AA(P = 0.043, OR = 0.45, CI = 0.20–1.00) genotypes were found to have protective effect against dengue infection. A protective association among the IFNG(+874 A/T) A/T genotype against DF(P = 0.02, OR = 0.46, CI = 0.24–0.89) and DHF(P = 0.034,OR = 0.43, CI = 0.19–0.95) was observed. When the studied single-nucleotide polymorphism was analyzed in combination, the combination GTA(P = 0.022, OR = 2.95,CI = 1.18–7.41) was statistically significantly associated with susceptibility to DF and the combination GCT(P = 0.035, OR = 0.28, CI = 0.08–0.90) with protection against the development of DHF.Conclusions: This research identifies the association of the IFNG(+874 A/T), TNFA(-308 G/A), IL-10(-819 C/T) genotypes as a factor for protection, susceptibility and severity to dengue.展开更多
Non-structural protein 1(NS1)is an important virulence factor of the highly pathogenic H5N1 avian influenza virus.A five-amino-acid(5 aa)deletion at position 80–84 and an aspartic acid to glutamic acid substitution a...Non-structural protein 1(NS1)is an important virulence factor of the highly pathogenic H5N1 avian influenza virus.A five-amino-acid(5 aa)deletion at position 80–84 and an aspartic acid to glutamic acid substitution at position 92(D92E)are two major NS1 mutations that are highly correlated with enhanced virulence.To investigate the effect of these mutations in H5N1 virulence,three H5N1-NS1 variants were constructed:NS51(lacking 5 aa at position 80–84),NS51(I)(carrying a 5-aa insertion at position 80–84)and NS51(IM)(carrying both the 5-aa insertion and the D92E mutation).We examined the effects of these mutations on interferon(IFN)induction,tumor-necrosis factor(TNF)a response,p53 activity and apoptosis.We found that the D92E mutation eliminated NS1’s repressive effect on IFN induction,while the 5-aa deletion resulted in enhanced resistance to TNFa responses.We also observed that all three variants exhibited a similar suppressive effect on p53 transcriptional activity,although none of them significantly influenced apoptosis of host cells.Our findings shed new light on the role of NS1 in the pathogenicity of H5N1 virus.展开更多
In the past 20 years,patients with rheumatoid arthritis(RA),Crohn’s disease(CD),and other immune diseases have witnessed the impact of a great treatment advance with the availability of biological TNFa inhibitors.Wit...In the past 20 years,patients with rheumatoid arthritis(RA),Crohn’s disease(CD),and other immune diseases have witnessed the impact of a great treatment advance with the availability of biological TNFa inhibitors.With 5 approved anti-TNFa biologics on the market and soon available biosimilars,patients have more treatment options and have benefited from understanding the biology of TNFa.Nevertheless,many unmet needs remain for people living with TNFa-related diseases,namely some side effects and tolerance of current anti-TNFa biologics and resistance to therapies.Furthermore,common diseases such as osteoarthritis and back/neck pain may respond to anti-TNFa therapies at early onset of symptoms.Development of new TNFa inhibitors focusing on TNFR1 specific inhibitors,preferably small molecules that can be delivered orally,is much needed.展开更多
基金supported by the Fundacao de Amparo a Pesquisa de Alagoas(FAPEAL)–Programa Primeiros Projetos(PPP/2011)
文摘Objective: To evaluate gene polymorphisms and their association with susceptibility to dengue.Methods: A retrospective case-control study was performed with 262 subjects,comprising 78 dengue fever(DF) patients, 49 dengue hemorrhagic fever(DHF) patients and 135 healthy controls. Genotypic and allelic profiles were identified using polymerase chain reaction based in real time and amplification-refractory mutation system.Results: We observed a protective association of IL-10(-819 C/T) C allele(P = 0.028,OR = 0.56, CI = 0.34–0.91) against DHF, while the C/T(P = 0.047, OR = 2.10,CI = 1.01–4.38) and T/T(P = 0.008, OR = 3.82, CI = 1.38–10.59) genotypes were associated with DHF and DF, respectively. The dominant model TNFA-308 GA + AA(P = 0.043, OR = 0.45, CI = 0.20–1.00) genotypes were found to have protective effect against dengue infection. A protective association among the IFNG(+874 A/T) A/T genotype against DF(P = 0.02, OR = 0.46, CI = 0.24–0.89) and DHF(P = 0.034,OR = 0.43, CI = 0.19–0.95) was observed. When the studied single-nucleotide polymorphism was analyzed in combination, the combination GTA(P = 0.022, OR = 2.95,CI = 1.18–7.41) was statistically significantly associated with susceptibility to DF and the combination GCT(P = 0.035, OR = 0.28, CI = 0.08–0.90) with protection against the development of DHF.Conclusions: This research identifies the association of the IFNG(+874 A/T), TNFA(-308 G/A), IL-10(-819 C/T) genotypes as a factor for protection, susceptibility and severity to dengue.
基金We are grateful to Dr William Ba-Thein for helpful discussion and editing of the manuscript.We thank Dr Xu Liyan for the use of a TD20/20 luminometer.This work was supported by the National Natural Science Foundation of China(No.30771988and No.30972766)Specialized Research Fund for the Doctoral Program of Higher Education(No.20094402110004)+3 种基金Guangdong Natural Science Foundation(No.8151503102000022 and 9451503102003499)Outstanding Young Scientists Foundation of Guangdong Province Education Department(No.LYM08056)State Key Lab of Agriculture Microbiology Open Foundation(No.AML200910)Shantou University Medical College Research Foundation.
文摘Non-structural protein 1(NS1)is an important virulence factor of the highly pathogenic H5N1 avian influenza virus.A five-amino-acid(5 aa)deletion at position 80–84 and an aspartic acid to glutamic acid substitution at position 92(D92E)are two major NS1 mutations that are highly correlated with enhanced virulence.To investigate the effect of these mutations in H5N1 virulence,three H5N1-NS1 variants were constructed:NS51(lacking 5 aa at position 80–84),NS51(I)(carrying a 5-aa insertion at position 80–84)and NS51(IM)(carrying both the 5-aa insertion and the D92E mutation).We examined the effects of these mutations on interferon(IFN)induction,tumor-necrosis factor(TNF)a response,p53 activity and apoptosis.We found that the D92E mutation eliminated NS1’s repressive effect on IFN induction,while the 5-aa deletion resulted in enhanced resistance to TNFa responses.We also observed that all three variants exhibited a similar suppressive effect on p53 transcriptional activity,although none of them significantly influenced apoptosis of host cells.Our findings shed new light on the role of NS1 in the pathogenicity of H5N1 virus.
基金the Department of Veterans Affairs Healthcare Network,a Penn Center for Musculoskeletal Disorders(PCMD)pilot grant(P30-AR050950-10 Pilot)a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases(NIAMS,R21 AR071623).
文摘In the past 20 years,patients with rheumatoid arthritis(RA),Crohn’s disease(CD),and other immune diseases have witnessed the impact of a great treatment advance with the availability of biological TNFa inhibitors.With 5 approved anti-TNFa biologics on the market and soon available biosimilars,patients have more treatment options and have benefited from understanding the biology of TNFa.Nevertheless,many unmet needs remain for people living with TNFa-related diseases,namely some side effects and tolerance of current anti-TNFa biologics and resistance to therapies.Furthermore,common diseases such as osteoarthritis and back/neck pain may respond to anti-TNFa therapies at early onset of symptoms.Development of new TNFa inhibitors focusing on TNFR1 specific inhibitors,preferably small molecules that can be delivered orally,is much needed.
