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1.
J Clin Immunol ; 40(1): 203-210, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31828694

RESUMEN

Mannose-binding lectin (MBL)-associated serine protease-2 (MASP-2) is an indispensable enzyme for the activation of the lectin pathway of complement. Its deficiency is classified as a primary immunodeficiency associated to pyogenic bacterial infections, inflammatory lung disease, and autoimmunity. In Europeans, MASP-2 deficiency, due to homozygosity for c.359A > G (p.D120G), occurs in 7 to 14/10,000 individuals. We analyzed the presence of the p.D120G mutation in adults (increasing the sample size of our previous studies) and children. Different groups of patients (1495 adults hospitalized with community-acquired pneumonia, 186 adults with systemic lupus erythematosus, 103 pediatric patients with invasive pneumococcal disease) and control individuals (1119 healthy adult volunteers, 520 adult patients without history of relevant infectious diseases, and a pediatric control group of 311 individuals) were studied. Besides our previously reported MASP-2-deficient healthy adults, we found a new p.D120G homozygous individual from the pediatric control group. We also reviewed p.D120G homozygous individuals reported so far: a total of eleven patients with a highly heterogeneous range of disorders and nine healthy controls (including our four MASP-2-deficient individuals) have been identified by chance in association studies. Individuals with complete deficiencies of several pattern recognition molecules of the lectin pathway (MBL, collectin-10 and collectin-11, and ficolin-3) as well as of MASP-1 and MASP-3 have also been reviewed. Cumulative evidence suggests that MASP-2, and even other components of the LP, are largely redundant in human defenses and that individuals with MASP-2 deficiency do not seem to be particularly prone to infectious or autoimmune diseases.


Asunto(s)
Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/deficiencia , Enfermedades de Inmunodeficiencia Primaria/genética , Transducción de Señal/genética , Adulto , Niño , Infecciones Comunitarias Adquiridas/genética , Femenino , Genotipo , Humanos , Lectinas/genética , Lupus Eritematoso Sistémico/genética , Masculino , Lectina de Unión a Manosa/genética , Mutación/genética
2.
Eur Respir J ; 41(1): 131-9, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22523362

RESUMEN

The role of mannose-binding lectin (MBL) deficiency (MBL2; XA/O and O/O genotypes) in host defences remains controversial. The surfactant proteins (SP)-A1, -A2 and -D, other collectins whose genes are located near MBL2, are part of the first-line lung defence against infection. We analysed the role of MBL on susceptibility to pneumococcal infection and the existence of linkage disequilibrium (LD) among the four genes. We studied 348 patients with pneumococcal community-acquired pneumonia (P-CAP) and 2,110 controls. A meta-analysis of MBL2 genotypes in susceptibility to P-CAP and to invasive pneumococcal disease (IPD) was also performed. The extent of LD of MBL2 with SFTPA1, SFTPA2 and SFTPD was analysed. MBL2 genotypes did not associate with either P-CAP or bacteraemic P-CAP in the case-control study. The MBL-deficient O/O genotype was significantly associated with higher risk of IPD in a meta-analysis, whereas the other MBL-deficient genotype (XA/O) showed a trend towards a protective role. We showed the existence of LD between MBL2 and SP genes. The data do not support a role of MBL deficiency on susceptibility to P-CAP or to IPD. LD among MBL2 and SP genes must be considered in studies on the role of MBL in infectious diseases.


Asunto(s)
Lectina de Unión a Manosa/genética , Neumonía Neumocócica/genética , Infecciones Comunitarias Adquiridas/genética , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos
3.
Crit Care Med ; 39(6): 1388-93, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21317643

RESUMEN

OBJECTIVE: To assess the potential association of the functional polymorphism rs1801274 in the receptor IIa for the Fc portion of immunoglobin G (FcγRIIa) gene (FCGR2A-H131R) with the susceptibility to and the severity of community-acquired pneumonia (CAP). DESIGN: Multicenter prospective and observational study. SETTING: Four university hospitals in Spain. PATIENTS: FCGR2A-H131R polymorphism was determined in 1,262 patients with CAP and in 1,224 in the subject control group. MEASUREMENTS AND MAIN RESULTS: Severe sepsis was recorded in 366 patients. No significant differences in genotype or allele frequencies were seen among patients with CAP or pneumococcal CAP (PCAP) and controls. Patients with bacteremic PCAP (B-PCAP) had significantly higher frequencies of FCGR2A-H/H131 genotypes than those with nonbacteremic PCAP (p = .00016, odds ratio = 2.9, 95% confidence interval 1.58-5.3). The differences remained significant when adjusting for pneumonia severity index, hospital of origin, and intensive care unit admission (p = .0012, odds ratio = 2.83, 95% confidence interval 1.51-5.32). B-PCAP was associated with a significantly higher severity of the disease, evaluated as sepsis severity (p = .000007, odds ratio = 4.40, 95% confidence interval 2.31-8.39), multiorgan dysfunction syndrome (0.00048, odds ratio = 3.29, 95% confidence interval 1.69-6.41), intensive care unit admission, acute renal failure, and acute respiratory distress syndrome. CONCLUSIONS: Our results do not support a role of FCGR2A-H131R polymorphism in susceptibility to CAP or PCAP. However, we provide the insight that homozygosity for FCGR2A-H131 predisposes B-PCAP, which was associated with higher severity in our study.


Asunto(s)
Bacteriemia/genética , Neumonía Neumocócica/genética , Polimorfismo de Nucleótido Simple/genética , Receptores de IgG/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Estudios de Cohortes , Infecciones Comunitarias Adquiridas/genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad
4.
Crit Care ; 15(1): R57, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21310059

RESUMEN

INTRODUCTION: Genetic variability of the pulmonary surfactant proteins A and D may affect clearance of microorganisms and the extent of the inflammatory response. The genes of these collectins (SFTPA1, SFTPA2 and SFTPD) are located in a cluster at 10q21-24. The objective of this study was to evaluate the existence of linkage disequilibrium (LD) among these genes, and the association of variability at these genes with susceptibility and outcome of community-acquired pneumonia (CAP). We also studied the effect of genetic variability on SP-D serum levels. METHODS: Seven non-synonymous polymorphisms of SFTPA1, SFTPA2 and SFTPD were analyzed. For susceptibility, 682 CAP patients and 769 controls were studied in a case-control study. Severity and outcome were evaluated in a prospective study. Haplotypes were inferred and LD was characterized. SP-D serum levels were measured in healthy controls. RESULTS: The SFTPD aa11-C allele was significantly associated with lower SP-D serum levels, in a dose-dependent manner. We observed the existence of LD among the studied genes. Haplotypes SFTPA1 6A(2) (P = 0.0009, odds ration (OR) = 0.78), SFTPA(2) 1A(0) (P = 0.002, OR = 0.79), SFTPA1-SFTPA2 6A2-1A(0) (P = 0.0005, OR = 0.77), and SFTPD-SFTPA1-SFTPA(2)C-6A2-1A(0) (P = 0.00001, OR = 0.62) were underrepresented in patients, whereas haplotypes SFTPA2 1A(10) (P = 0.00007, OR = 6.58) and SFTPA1-SFTPA2 6A(3)-1A (P = 0.0007, OR = 3.92) were overrepresented. Similar results were observed in CAP due to pneumococcus, though no significant differences were now observed after Bonferroni corrections. 1A(10) and 6A-1A were associated with higher 28-day and 90-day mortality, and with multi-organ dysfunction syndrome (MODS) and acute respiratory distress syndrome (ARDS) respectively. SFTPD aa11-C allele was associated with development of MODS and ARDS. CONCLUSIONS: Our study indicates that missense single nucleotide polymorphisms and haplotypes of SFTPA1, SFTPA2 and SFTPD are associated with susceptibility to CAP, and that several haplotypes also influence severity and outcome of CAP.


Asunto(s)
Infecciones Comunitarias Adquiridas/genética , Predisposición Genética a la Enfermedad , Desequilibrio de Ligamiento , Neumonía/genética , Proteína A Asociada a Surfactante Pulmonar/genética , Proteína D Asociada a Surfactante Pulmonar/genética , Estudios de Casos y Controles , Infecciones Comunitarias Adquiridas/sangre , Haplotipos/genética , Humanos , Mutación Missense/genética , Neumonía/sangre , Polimorfismo de Nucleótido Simple/genética , Pronóstico , Estudios Prospectivos , Proteína D Asociada a Surfactante Pulmonar/sangre , Índice de Severidad de la Enfermedad
5.
ERJ Open Res ; 7(1)2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33532473

RESUMEN

This study found no association of the top two associated FER variants with severity of community-acquired pneumonia. Precise characterisation of phenotypes may be required in order to unravel the genetic mechanisms predisposing to poor outcome in sepsis. https://bit.ly/3jc9SmR.

6.
J Allergy Clin Immunol ; 122(2): 368-74, 374.e1-2, 2008 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-18582923

RESUMEN

BACKGROUND: Community-acquired pneumonia (CAP) is the leading cause of death from infection in developed countries. Mannose-binding lectin (MBL) and MBL-associated serine protease 2 (MASP-2) deficiencies are common primary immunodeficiencies the clinical penetrance of which remains controversial. MBL is a serum lectin that mediates phagocytosis and activates the lectin pathway of complement involving MASP-2. OBJECTIVE: We sought to evaluate the significance of MBL deficiency (O/O genotypes) and insufficiency (O/O plus XA/O genotypes), as well as MASP-2 deficiency (D105G mutation), in the susceptibility to and severity and outcome of CAP in adults. METHODS: MBL and MASP-2 serum levels, as well as lectin pathway activity with regard to MBL2 and MASP2 genotypes, were measured in healthy control subjects. For susceptibility, 848 patients with CAP, 1447 healthy control subjects, and a control group of 519 patients without relevant infectious diseases were studied in a case-control study. Severity and outcome were evaluated in a prospective study of the 848 patients. RESULTS: We found similar frequencies of MBL2 and MASP2 alleles and genotypes among patients and control subjects. However, in a multivariate analysis MBL insufficiency was associated with the development of the most severe forms of sepsis (P = .007), acute respiratory failure (P = .009), multiorgan dysfunction syndrome (P = .036), intensive care unit admission (P = .020), and death (P = .003). CONCLUSION: Our large study suggests that MBL plays a redundant role in human defenses against primary infection, at least in adults with CAP, and provides, for the first time, evidence that MBL insufficiency predisposes to higher severity and fatal outcome in patients with CAP, irrespective of the causal microorganisms.


Asunto(s)
Lectina de Unión a Manosa/genética , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/genética , Neumonía Bacteriana/genética , Adulto , Anciano , Alelos , Estudios de Casos y Controles , Infecciones Comunitarias Adquiridas/genética , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Estimación de Kaplan-Meier , Masculino , Lectina de Unión a Manosa/sangre , Lectina de Unión a Manosa/deficiencia , Lectina de Unión a Manosa/fisiología , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/análisis , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/deficiencia , Persona de Mediana Edad , Neumonía Bacteriana/metabolismo , Neumonía Bacteriana/fisiopatología , Neumonía Neumocócica/genética , Neumonía Neumocócica/metabolismo , Neumonía Neumocócica/fisiopatología , Polimorfismo Genético , Estudios Prospectivos , Índice de Severidad de la Enfermedad
7.
Intensive Care Med ; 38(2): 256-62, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22113815

RESUMEN

PURPOSE: Conflicting results about the role of genetic variability at IL6, particularly the -174 G/C single nucleotide polymorphism (SNP), in sepsis have been reported. We studied the genetic variability at IL6 in patients with community-acquired pneumonia (CAP) and pneumococcal CAP (P-CAP). METHODS: This was a multicenter, prospective observational study. IL6 -174 was analyzed in 1,227 white Spanish patients with CAP (306 with P-CAP). IL6 1753 C/G (N = 750), 2954 G/C (N = 845), and haplotypes defined by these SNPs were also studied. RESULTS: In CAP patients the genotype -174 GG were associated with protection against acute respiratory distress syndrome (ARDS) (p = 0.008, OR = 0.4, 95% CI 0.2-0.8). No other significant associations were observed. However, in patients with P-CAP multivariate analysis adjusted for age, gender, co-morbidity, hospital of origin, and severity (pneumonia severity index, PSI) showed that the IL6 -174 GG genotype was protective against the development of ARDS (p = 0.002, OR = 0.25, 95% CI 0.07-0.79), septic shock (p = 0.006, OR = 0.46, 95% CI 0.18-0.79), and multiple organ dysfunction syndrome (p = 0.02, OR = 0.53, 95% CI 0.27-0.89). P-CAP patients homozygous for IL6 -174 G also showed a higher survival in a logistic regression analysis adjusted for age, gender, co-morbidity, hospital of origin, and PSI (p = 0.048, OR = 0.27, 95% CI 0.07-0.98). CONCLUSIONS: Our results indicate that the IL-6 -174 GG genotype is associated with lower severity and mortality in patients with P-CAP. This effect was higher than that observed in patients with CAP irrespective of the causal pathogen involved. Our results highlight the importance of the causal pathogen in genetic epidemiological studies in sepsis.


Asunto(s)
Interleucina-6/genética , Neumonía Neumocócica/genética , Infecciones Comunitarias Adquiridas/genética , Infecciones Comunitarias Adquiridas/mortalidad , Femenino , Mortalidad Hospitalaria , Humanos , Masculino , Persona de Mediana Edad , Neumonía Neumocócica/mortalidad , Polimorfismo Genético , Regiones Promotoras Genéticas , Estudios Prospectivos , Índice de Severidad de la Enfermedad
8.
Respir Med ; 104(3): 440-7, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19900796

RESUMEN

BACKGROUND: Several studies have investigated single nucleotide polymorphisms (SNP) in candidate genes associated with susceptibility, severity or outcome in patients with community-acquired pneumonia (CAP) with conflicting results. METHODS: Multi-centre, prospective observational study. We studied 1162 white Spanish patients with CAP and 1413 controls. Severe forms of sepsis were recorded in 325 patients. Subjects were genotyped for the following polymorphisms: TNF -238 and -308, LTA +252, IL6 -174, IL1RN 86bp variable number of tandem repeats and TNFRSF1B+676 (TNFR2 M196R). RESULTS: No significant differences in genotype or allele frequencies were seen among patients and controls. We did not find any association between TNF, LTA, IL6 and IL1RN polymorphisms with disease severity or outcome. Analysis of 28-day mortality showed a significant difference in the distribution of TNFRSF1B+676 G/T genotypes (p=0.0129). Sequential Kaplan-Meier survival analysis of TNFRSF1B+676 G/T polymorphism showed a protective role of the GT genotype. Cox regression analysis adjusted for age, gender, hospital of origin and comorbidities showed that patients with GT genotypes had lower mortality rates compared to patients with GG or TT genotypes (p=0.02; HR 0.53; 95% CI 0.31-0.90 for 90-day survival; p=0.01; HR 0.41; 95% CI 0.21-0.81 for 28-day survival and p=0.049; HR 0.48; 95% CI 0.23-0.997 for 15-day survival). CONCLUSIONS: Our study does not support a role for the controversial studied polymorphisms of the TNF, LTA, IL6 and IL1RN genes in the susceptibility or outcome of CAP. A protective role of heterozygosity for the functionally relevant TNFRSF1B+676 polymorphism in the outcome of CAP was observed.


Asunto(s)
Predisposición Genética a la Enfermedad/genética , Neumonía/genética , Polimorfismo de Nucleótido Simple/genética , Factor de Necrosis Tumoral alfa/genética , Anciano , Infecciones Comunitarias Adquiridas/genética , Genotipo , Humanos , Interleucina-6/genética , Linfotoxina-alfa/genética , Masculino , Persona de Mediana Edad , Neumonía/fisiopatología , Pronóstico , Estudios Prospectivos , Receptores del Factor de Necrosis Tumoral/genética , Índice de Severidad de la Enfermedad , Resultado del Tratamiento
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