Objective: We hypothesize that genetic variations (single nucleotide polymorphisms-SNPs) in the tumor necrosis factor-α(TNF-α), TNF receptors (TNFRI and TNFRII), interleukin-6 (IL-6) and IL-6 receptor (IL-6R) genes ...Objective: We hypothesize that genetic variations (single nucleotide polymorphisms-SNPs) in the tumor necrosis factor-α(TNF-α), TNF receptors (TNFRI and TNFRII), interleukin-6 (IL-6) and IL-6 receptor (IL-6R) genes predict high-risk status for spontaneous preterm birth (sPTB) in European-American women. In this study we examine the allelic and genotypic variations and the gene-gene interactions in the TNF-α, TNFRs, IL-6, and IL-6R genes in maternal DNA samples by using a case-control model. Study design: Maternal DNA from cases of sPTB after preterm labor (n = 101) and controls (normal term labor and delivery) (n = 321) were genotyped for SNPs in the TNF-α(6), TNFRI (6), TNFRII (7), IL-6 (5), and IL-6R (3) loci. SNPs were tested for both allele and genotype differences (cases vs controls) with the use of standard genetic epidemiologic methods. Multilocus interaction was assessed with multifactor dimensionality reduction analysis (MDR) to test all single and multilocus combinations for the ability to predict sPTB. Results: Few significant allelic and genotypic associations were detected between cases and controls in maternal DNA. Single locus analysis documented independent association of SNPs at-7294 (allele and genotype) of TNFRI and 24660 (genotype) TNFRII loci with sPTB. MDR revealed a significant 3 locus model that includes SNPs -3448 of TNF-α,-7227 of IL-6, and 33314 of IL-6R. This interactive model allowed the successful prediction of pre-to low-risk genotypes is 3.50 (95%CI 2.52-4.87, P < .001). Conclusion: This is the first report to document a multilocus interaction in sPTB that predicts 65.2%of the cases in a European-American sample. Although putatively significant associations with sPTB were seen at a few single locus sites in TNFRI and TNFRII, they were not as predictive as the 3-locus model produced by MDR, suggesting the use of multilocus analyses in gene association studies of complex disease such as sPTB.展开更多
Background： The importance of non-glucose carbohydrates, especially mannose and inositol, for normal development is increasingly recognized. Whether pregnancies complicated by abnormal glucose transfer to the fetus a...Background： The importance of non-glucose carbohydrates, especially mannose and inositol, for normal development is increasingly recognized. Whether pregnancies complicated by abnormal glucose transfer to the fetus also affect the regulation of non-glucose carbohydrates is unknown. In pregnant sheep, maternal insulin infusions were used to reduce glucose supply to the fetus for both short （2-wk） and long （8-wk） durations to test the hypothesis that a maternal insulin infusion would suppress fetal mannose and inositol concentrations. We also used direct fetal insulin infusions （1-wk hyperinsulinemic-isoglycemic clamp） to determine the relative importance of fetal glucose and insulin for regulating non-glucose carbohydrates. Results： A maternal insulin infusion resulted in lower maternal （50%, P 〈 0.01） and fetal （35-45%, P 〈 0.01） mannose concentrations, which were highly correlated （r^2 = 0.69, P 〈 0.01）. A fetal insulin infusion resulted in a 50% reduction of fetal mannose （P 〈 0.05）. Neither maternal nor fetal plasma inositol changed with exogenous insulin infusions. Additionally, maternal insulin infusion resulted in lower fetal sorbitol and fructose （P 〈 0.01）. Conclusions： Chronically decreased glucose supply to the fetus as well as fetal hyperinsulinemia both reduce fetal non-glucose carbohydrates. Given the role of these carbohydrates in protein glycosylation and lipid production, more research on their metabolism in pregnancies complicated by abnormal glucose metabolism is clearly warranted.展开更多
Objective: The objective of this study was to design a method to identify patients at risk for preterm premature rupture of the membranes using a simple assay of salivary proteinase activity. Study design: Saliva samp...Objective: The objective of this study was to design a method to identify patients at risk for preterm premature rupture of the membranes using a simple assay of salivary proteinase activity. Study design: Saliva samples were collected from women in the following groups using Salivette: (1) nonpregnant control; (2) during the second trimester of pregnancy; (3) during active labor at term; (4) women with premature rupture of the membranes before preterm delivery; and (5) postpartum (within 3 hours after delivery at term). Total proteolytic activity in saliva samples was measured by fluorometry using the generic substrate DQ-gelatin in the presence of specific inhibitors to selectively detect matrix metalloproteinase activities. The concentrations of various matrix metalloproteinases in saliva samples were also measured by multiplex bead assay using the Luminex platform. Results: All saliva samples exhibited detectable matrix metalloproteinase activity. Salivary matrix metalloproteinase activity is low in nonpregnant females (0.27 ± 0.15) and increases in samples taken in the second trimester (0.5 ± 0.5) and at term during active labor (1.03 ± 1.2). Samples collected from women with premature rupture of the membranes before preterm delivery had the highest activity (2.5 ± 3.7) followed by postpartum after normal term delivery (2.1 ± 1.6). The matrix metalloproteinase activity was higher in premature rupture of the membranes before preterm delivery samples, compared with all other stages of pregnancy. Multiplexmatrix metalloproteinase assay documented a significant increase in total matrix metalloproteinase- 9 concentration in saliva from premature rupture of the membranes before preterm delivery, compared with any of the other groups. Similarly matrix metalloproteinase-9 activity was also significantly increased in premature rupture of the membranes before preterm delivery group, compared with all others. Conclusion: Herein we report a simple test to monitor proteolytic enzyme activity in saliva during pregnancy. The highest matrix metalloproteinase activity is seen in premature rupture of the membranes before preterm delivery and postpartum samples. Ongoing studies aim to further define salivary proteinase activity in patients at high risk for premature rupture of the membranes before preterm delivery and to evaluate its potential as a predictive test for premature rupture of the membranes before preterm delivery.展开更多
文摘Objective: We hypothesize that genetic variations (single nucleotide polymorphisms-SNPs) in the tumor necrosis factor-α(TNF-α), TNF receptors (TNFRI and TNFRII), interleukin-6 (IL-6) and IL-6 receptor (IL-6R) genes predict high-risk status for spontaneous preterm birth (sPTB) in European-American women. In this study we examine the allelic and genotypic variations and the gene-gene interactions in the TNF-α, TNFRs, IL-6, and IL-6R genes in maternal DNA samples by using a case-control model. Study design: Maternal DNA from cases of sPTB after preterm labor (n = 101) and controls (normal term labor and delivery) (n = 321) were genotyped for SNPs in the TNF-α(6), TNFRI (6), TNFRII (7), IL-6 (5), and IL-6R (3) loci. SNPs were tested for both allele and genotype differences (cases vs controls) with the use of standard genetic epidemiologic methods. Multilocus interaction was assessed with multifactor dimensionality reduction analysis (MDR) to test all single and multilocus combinations for the ability to predict sPTB. Results: Few significant allelic and genotypic associations were detected between cases and controls in maternal DNA. Single locus analysis documented independent association of SNPs at-7294 (allele and genotype) of TNFRI and 24660 (genotype) TNFRII loci with sPTB. MDR revealed a significant 3 locus model that includes SNPs -3448 of TNF-α,-7227 of IL-6, and 33314 of IL-6R. This interactive model allowed the successful prediction of pre-to low-risk genotypes is 3.50 (95%CI 2.52-4.87, P < .001). Conclusion: This is the first report to document a multilocus interaction in sPTB that predicts 65.2%of the cases in a European-American sample. Although putatively significant associations with sPTB were seen at a few single locus sites in TNFRI and TNFRII, they were not as predictive as the 3-locus model produced by MDR, suggesting the use of multilocus analyses in gene association studies of complex disease such as sPTB.
基金supported by National Institutes of Health training grant T32 HD007186-32 (W Hay, PI and PD)supported by NIH Grants R01DK088139 and K08HD060688+5 种基金American Diabetes Association Junior Faculty Award 7-08-JF-51(PJR, PI)provided by the UC Denver DERC (P30DK57516 J. Hutton, PI)supported as a Scholar by NIH Building Interdisciplinary Careers in Women ’ s Health Scholar Award K12HD057022 (J. Regensteiner, PI)a Children ’ s Hospital Colorado Research Institute Research Scholar Award (PI)supported by NIH K01DK090199 (PI) and as a trainee on NIH training grant T32 HD007186-32 (W Hay, PI and PD)
文摘Background： The importance of non-glucose carbohydrates, especially mannose and inositol, for normal development is increasingly recognized. Whether pregnancies complicated by abnormal glucose transfer to the fetus also affect the regulation of non-glucose carbohydrates is unknown. In pregnant sheep, maternal insulin infusions were used to reduce glucose supply to the fetus for both short （2-wk） and long （8-wk） durations to test the hypothesis that a maternal insulin infusion would suppress fetal mannose and inositol concentrations. We also used direct fetal insulin infusions （1-wk hyperinsulinemic-isoglycemic clamp） to determine the relative importance of fetal glucose and insulin for regulating non-glucose carbohydrates. Results： A maternal insulin infusion resulted in lower maternal （50%, P 〈 0.01） and fetal （35-45%, P 〈 0.01） mannose concentrations, which were highly correlated （r^2 = 0.69, P 〈 0.01）. A fetal insulin infusion resulted in a 50% reduction of fetal mannose （P 〈 0.05）. Neither maternal nor fetal plasma inositol changed with exogenous insulin infusions. Additionally, maternal insulin infusion resulted in lower fetal sorbitol and fructose （P 〈 0.01）. Conclusions： Chronically decreased glucose supply to the fetus as well as fetal hyperinsulinemia both reduce fetal non-glucose carbohydrates. Given the role of these carbohydrates in protein glycosylation and lipid production, more research on their metabolism in pregnancies complicated by abnormal glucose metabolism is clearly warranted.
文摘Objective: The objective of this study was to design a method to identify patients at risk for preterm premature rupture of the membranes using a simple assay of salivary proteinase activity. Study design: Saliva samples were collected from women in the following groups using Salivette: (1) nonpregnant control; (2) during the second trimester of pregnancy; (3) during active labor at term; (4) women with premature rupture of the membranes before preterm delivery; and (5) postpartum (within 3 hours after delivery at term). Total proteolytic activity in saliva samples was measured by fluorometry using the generic substrate DQ-gelatin in the presence of specific inhibitors to selectively detect matrix metalloproteinase activities. The concentrations of various matrix metalloproteinases in saliva samples were also measured by multiplex bead assay using the Luminex platform. Results: All saliva samples exhibited detectable matrix metalloproteinase activity. Salivary matrix metalloproteinase activity is low in nonpregnant females (0.27 ± 0.15) and increases in samples taken in the second trimester (0.5 ± 0.5) and at term during active labor (1.03 ± 1.2). Samples collected from women with premature rupture of the membranes before preterm delivery had the highest activity (2.5 ± 3.7) followed by postpartum after normal term delivery (2.1 ± 1.6). The matrix metalloproteinase activity was higher in premature rupture of the membranes before preterm delivery samples, compared with all other stages of pregnancy. Multiplexmatrix metalloproteinase assay documented a significant increase in total matrix metalloproteinase- 9 concentration in saliva from premature rupture of the membranes before preterm delivery, compared with any of the other groups. Similarly matrix metalloproteinase-9 activity was also significantly increased in premature rupture of the membranes before preterm delivery group, compared with all others. Conclusion: Herein we report a simple test to monitor proteolytic enzyme activity in saliva during pregnancy. The highest matrix metalloproteinase activity is seen in premature rupture of the membranes before preterm delivery and postpartum samples. Ongoing studies aim to further define salivary proteinase activity in patients at high risk for premature rupture of the membranes before preterm delivery and to evaluate its potential as a predictive test for premature rupture of the membranes before preterm delivery.
