RESUMO
BACKGROUND: There is a need for new tools for monitoring of the response to TB treatment. Such tools may allow for tailored treatment regimens, and stratify patients initiating TB treatment into different risk groups. We evaluated combinations between previously published host biomarkers and new candidates, as tools for monitoring TB treatment response, and prediction of relapse. METHODS: Serum samples were collected at multiple time points, from patients initiating TB treatment at research sites situated in South Africa (ActionTB study), Brazil and Uganda (TBRU study). Using a multiplex immunoassay platform, we evaluated the concentrations of selected host inflammatory biomarkers in sera obtained from clinically cured patients with and without subsequent relapse within 2 years of TB treatment completion. RESULTS: A total of 130 TB patients, 30 (23%) of whom had confirmed relapse were included in the study. The median time to relapse was 9.7 months in the ActionTB study (n = 12 patients who relapsed), and 5 months (n = 18 patients who relapsed) in the TBRU study. Serum concentrations of several host biomarkers changed during TB treatment with IL-6, IP-10, IL-22 and complement C3 showing potential individually, in predicting relapse. A six-marker signature comprising of TTP, BMI, sICAM-1, IL-22, IL-1ß and complement C3, predicted relapse, prior to the onset of TB treatment with 89% sensitivity and 94% specificity. Furthermore, a 3-marker signature (Apo-CIII, IP-10 and sIL-6R) predicted relapse in samples collected at the end of TB treatment with sensitivity of 71% and specificity of 74%. A previously identified baseline relapse prediction signature (TTP, BMI, TNF-ß, sIL-6R, IL-12p40 and IP-10) also showed potential in the current study. CONCLUSION: Serum host inflammatory biomarkers may be useful in predicting relapse in TB patients prior to the initiation of treatment. Our findings have implications for tailored patient management and require prospective evaluation in larger studies.
Assuntos
Antituberculosos , Biomarcadores , Recidiva , Tuberculose Pulmonar , Humanos , Biomarcadores/sangue , Masculino , Feminino , Adulto , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/diagnóstico , Uganda , África do Sul , Antituberculosos/uso terapêutico , Pessoa de Meia-Idade , Brasil , Adulto Jovem , Quimiocina CXCL10/sangue , Interleucinas/sangue , Citocinas/sangue , Complemento C3/análiseRESUMO
OBJECTIVE: The purpose of this study was to determine whether maternal/fetal single nucleotide polymorphisms (SNPs) in candidate genes are associated with spontaneous preterm labor/delivery. STUDY DESIGN: A genetic association study was conducted in 223 mothers and 179 fetuses (preterm labor with intact membranes who delivered <37 weeks of gestation [preterm birth (PTB)]), and 599 mothers and 628 fetuses (normal pregnancy); 190 candidate genes and 775 SNPs were studied. Single locus/haplotype association analyses were performed; the false discovery rate was used to correct for multiple testing. RESULTS: The strongest single locus associations with PTB were interleukin-6 receptor 1 (fetus; P=.000148) and tissue inhibitor of metalloproteinase 2 (mother; P=.000197), which remained significant after correction for multiple comparisons. Global haplotype analysis indicated an association between a fetal DNA variant in insulin-like growth factor F2 and maternal alpha 3 type IV collagen isoform 1 (global, P=.004 and .007, respectively). CONCLUSION: An SNP involved in controlling fetal inflammation (interleukin-6 receptor 1) and DNA variants in maternal genes encoding for proteins involved in extracellular matrix metabolism approximately doubled the risk of PTB.
Assuntos
Estudos de Associação Genética , Trabalho de Parto Prematuro/genética , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina-6/genética , Adulto , Estudos de Casos e Controles , Chile , Corioamnionite/genética , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Feminino , Ruptura Prematura de Membranas Fetais/genética , Predisposição Genética para Doença , Variação Genética , Haplótipos , Humanos , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional/fisiologia , Pré-Eclâmpsia/genética , Gravidez , Nascimento Prematuro/genética , Adulto JovemRESUMO
Pre-eclampsia (PE) affects 5-7% of pregnancies in the US, and is a leading cause of maternal death and perinatal morbidity and mortality worldwide. To identify genes with a role in PE, we conducted a large-scale association study evaluating 775 SNPs in 190 candidate genes selected for a potential role in obstetrical complications. SNP discovery was performed by DNA sequencing, and genotyping was carried out in a high-throughput facility using the MassARRAY(TM) System. Women with PE (n = 394) and their offspring (n = 324) were compared with control women (n = 602) and their offspring (n = 631) from the same hospital-based population. Haplotypes were estimated for each gene using the EM algorithm, and empirical p values were obtained for a logistic regression-based score test, adjusted for significant covariates. An interaction model between maternal and offspring genotypes was also evaluated. The most significant findings for association with PE were COL1A1 (p = 0.0011) and IL1A (p = 0.0014) for the maternal genotype, and PLAUR (p = 0.0008) for the offspring genotype. Common candidate genes for PE, including MTHFR and NOS3, were not significantly associated with PE. For the interaction model, SNPs within IGF1 (p = 0.0035) and IL4R (p = 0.0036) gave the most significant results. This study is one of the most comprehensive genetic association studies of PE to date, including an evaluation of offspring genotypes that have rarely been considered in previous studies. Although we did not identify statistically significant evidence of association for any of the candidate loci evaluated here after adjusting for multiple testing using the false discovery rate, additional compelling evidence exists, including multiple SNPs with nominally significant p values in COL1A1 and the IL1A region, and previous reports of association for IL1A, to support continued interest in these genes as candidates for PE. Identification of the genetic regulators of PE may have broader implications, since women with PE are at increased risk of death from cardiovascular diseases later in life.