nxian Yu

Prematurity, chorioamnionitis, and the development of recurrent wheezing: A prospective birth cohort study

BACKGROUNDnPrematurity (< 37 weeks) has been inconsistently associated with asthma and wheezing. Chorioamnionitis may promote both prematurity and inflammatory pathways in infants airways.nnnOBJECTIVEnTo investigate the relationship of prematurity and chorioamnionitis with the development of early childhood recurrent wheezing.nnnMETHODSnThe Boston Birth Cohort (n = 1096) were followed prospectively from birth to a mean age of 2.2 +/- 2 years. Perinatal and postnatal clinical data and placental pathology were collected. The primary outcome was recurrent wheezing (> or =2 physician documented episodes). Secondary outcomes included physician-diagnosed asthma, food allergy, and eczema. Preterm children were grouped by gestational age into moderately (33-36.9 weeks) and very preterm (< 33 weeks) with and without chorioamnionitis, and compared with term children without chorioamnionitis (reference group). Chorioamnionitis was diagnosed either by intrapartum fever or by placental histology findings. Logistic regression models were performed to investigate the independent and joint associations of degree of prematurity and chorioamnionitis.nnnRESULTSnPrematurity was associated with recurrent wheezing (odds ratio [OR], 1.7; 95% CI, 1.2-2.6). However, when subjects were grouped by degree of prematurity with or without chorioamnionitis, the highest risk of wheezing (OR, 4.0; 95% CI, 2.0-8.0) and physician-diagnosed asthma (OR, 4.4; 95% CI, 2.2-8.7) was present in the very preterm children with chorioamnionitis. The effect on both wheezing (OR, 5.4; 95% CI, 2.4-12.0) and asthma (OR, 5.2; 95% CI, 2.3-11.9) was greater in African Americans. Neither prematurity nor chorioamnionitis was associated with food allergy or eczema.nnnCONCLUSIONnWe found a strong joint effect of prematurity and chorioamnionitis on early childhood wheezing. This effect was stronger in African American subjects.

Differential Patterns of 27 Cord Blood Immune Biomarkers Across Gestational Age

OBJECTIVES. Inflammation has been associated with preterm delivery and adverse neonatal outcomes such as cerebral palsy and chronic lung disease. However, no study to date has simultaneously examined a wide range of inflammatory mediators and their relationship to gestational age. We sought to describe the distribution of immune biomarkers in cord blood across gestational age and to investigate the association between biomarker level patterns and preterm birth. PATIENTS AND METHODS. As part of a large-scale molecular epidemiological study of preterm birth conducted at Boston Medical Center, this study analyzed both clinical and biomarker data from 927 births. Twenty-seven biomarkers were simultaneously quantified by immunoassay. The associations between the quartiles of 27 biomarkers and 3 gestational groups (≤32, 33–36, and ≥37 weeks) were analyzed. Biomarkers found to be significant were further analyzed for dose-response correlation with preterm birth by logistic regression, adjusted for pertinent demographic and clinical factors. RESULTS. The 27 biomarkers could be classified into 1 of 3 groups: (1) biomarkers increased in preterm birth (interleukin [IL]-2, IL-4, IL-5, IL-8, IL-10, monocyte chemoattractant protein 1, macrophage inflammatory protein [MIP]-1α, MIP-1β, soluble IL-6 receptor α, tumor necrosis factor α, soluble tumor necrosis factor receptor I, and TREM-1 [triggering receptor expressed on myeloid cells 1]); (2) biomarkers decreased in preterm birth (brain-derived neurotrophic factor, IL-1β, IL-18, matrix metalloproteinase 9, and neurotrophin 3); and (3) biomarkers not associated with preterm birth (IL-6, IL-12, IL-17, granulocyte/macrophage colony-stimulating factor, interferon γ, macrophage migration inhibitory factor, neurotrophin 4, RANTES [regulated on activation, normal T-cell expressed and secreted], transforming growth factor β, and tumor necrosis factor β). CONCLUSIONS. Biomarkers have different directions of association with prematurity; for significant biomarkers, the strength of association increases with biomarker concentration. Our results provide important information that could be used to guide additional studies aimed at determining mechanisms that contribute to preterm birth.

Familial aggregation of food allergy and sensitization to food allergens: a family‐based study

Background The increasing prevalence of food allergy (FA) is a growing clinical and public health problem. The contribution of genetic factors to FA remains largely unknown.

Maternal preconception body mass index and offspring cord blood DNA methylation: Exploration of early life origins of disease

Maternal obesity is associated with a variety of common diseases in the offspring. One possible underlying mechanism could be maternal obesity induced alterations in DNA methylation. However, this hypothesis is yet to be tested. We performed epigenomic mapping of cord blood among 308 Black mother‐infant pairs delivered at term at the Boston Medical Center using the Illumina HumanMethylation27 BeadChip. Linear regression and pathway analyses were conducted to evaluate the associations between DNA methylation levels and prepregnancy maternal BMI (<25, 25–30, ≥30 kg/m2). The methylation levels of 20 CpG sites were associated with maternal BMI at a significance level of P‐value <10−4 in the overall sample, and boys and girls, separately. One CpG site remained statistically significant after correction for multiple comparisons (FDR corrected P‐value = 0.04) and was annotated to a potential cancer gene, ZCCHC10. Some of the other CpG site annotated genes appear to be critical to the development of cancers and cardiovascular diseases (i.e., WNT16, C18orf8, ANGPTL2, SAPCD2, ADCY3, PRR16, ERBB2, DOK2, PLAC1). Significant findings from pathway analysis, such as infectious and inflammatory and lipid metabolism pathways, lends support for the potential impact of maternal BMI on the above stated disorders. This study demonstrates that prepregnancy maternal BMI might lead to alterations in offspring DNA methylation in genes relevant to the development of a range of complex chronic diseases, providing evidence of trans‐generational influence on disease susceptibility via epigenetic mechanism. Environ. Mol. Mutagen. 55:223–230, 2014.

Maternal cigarette smoking, metabolic gene polymorphisms, and preterm delivery: new insights on G£E interactions and pathogenic pathways

Preterm delivery (PTD, <37xa0weeks of gestation) is a significant clinical and public health problem. Previously, we reported that maternal smoking and metabolic gene polymorphisms of CYP1A1 MspI and GSTT1 synergistically increase the risk of low birth weight. This study investigates the relationship between maternal smoking and metabolic gene polymorphisms of CYP1A1 MspI and GSTT1 with preterm delivery (PTD) as a whole and preterm subgroups. This case–control study included 1,749 multi-ethnic mothers (571 with PTD and 1,178 controls) enrolled at Boston Medical Center. After adjusting covariates, regression analyses were performed to identify individual and joint associations of maternal smoking, two functional variants of CYP1A1 and GSTT1 with PTD. We observed a moderate effect of maternal smoking on PTD (ORxa0=xa01.6; 95% CI: 1.1–2.2). We found that compared to non-smoking mothers with low-risk genotypes, there was a significant joint association of maternal smoking, CYP1A1(Aa/aa) and GSTT1 (absent) genotypes with gestational age (βxa0=xa0−3.37; SExa0=xa00.86; Pxa0=xa09xa0×xa010−5) and with PTD (ORxa0=xa05.8; 95% CI: 2.0–21.1), respectively. Such joint association was particularly strong in certain preterm subgroups, including spontaneous PTD (ORxa0=xa08.3; 95% CI: 2.7–30.6), PTDxa0<xa032xa0weeks (ORxa0=xa011.1; 95% CI: 2.9–47.7), and PTD accompanied by histologic chorioamnionitis (ORxa0=xa015.6; 95% CI: 4.1–76.7). Similar patterns were observed across ethnic groups. Taken together, maternal smoking significantly increased the risk of PTD among women with high-risk CYP1A1 and GSTT1 genotypes. Such joint associations were strongest among PTD accompanied by histologic chorioamnionitis.

Genetic and Environmental Contributions to Phenotypic Components of Metabolic Syndrome: A Population-based Twin Study

The increasing prevalence of metabolic syndrome (MS) poses a serious public‐health problem worldwide. Effective prevention and intervention require improved understanding of the factors that contribute to MS. We analyzed data on a large twin cohort to estimate genetic and environmental contributions to MS and to major MS components and their intercorrelations: waist circumference (WC), systolic (SBP) and diastolic blood pressure (DBP), fasting plasma glucose (FPG), triglycerides (TGs), and high‐density lipoprotein–cholesterol (HDL‐C). We applied structural equation modeling to determine genetic and environmental structure of MS and its major components, using 1,617 adult female twin pairs recruited from rural China. The heritability estimate for MS was 0.42 (95% confidence interval (CI): 0.00–0.83) in this sample with low MS prevalence (4.4%). For MS components, heritability estimates were statistically significant and ranged from 0.13 to 0.64 highest for WC, followed by TG, SBP, DBP, HDL‐C, and FPG. HDL‐C was mainly influenced by common environmental factors (0.62, 95% CI: 0.58–0.62), whereas the other five MS components were largely influenced by unique environmental factors (0.32–0.44). Bivariate Cholesky decomposition analysis indicated that the clinical clustering of MS components may be explained by shared genetic and/or environmental factors. Our study underscores the importance of examining MS components as intercorrelated traits, and to carefully consider environmental and genetic factors in studying MS etiology.

Placental Inflammatory Response Is Associated With Poor Neonatal Growth: Preterm Birth Cohort Study

OBJECTIVE: We sought to determine whether placental markers of intrauterine inflammation were associated with poor weight gain among premature infants in the neonatal period. METHODS: We reviewed 697 preterm births prospectively enrolled as part of an ongoing molecular epidemiological study. Placental markers and serial weight gain were analyzed for premature infants who were hospitalized for ≥21 days (N = 256). Placentas were examined for maternal inflammatory response (MIR), defined as subchorionitis, chorioamnionitis, deciduitis, or free membranitis, and fetal inflammatory response (FIR), defined as inflammation extending to the umbilical cord or chorionic plate. Multivariate linear regression and stratified analyses were performed. RESULTS: Decreases in weight gain at day 21 were associated with the presence of either MIR or FIR (β coefficient = −4.63 ± 1.41; P = .001). The association was stronger with FIR than MIR (P for trend = .0027) and persisted in the remaining hospitalized infants at day 28 (n = 223; β coefficient = −5.53 ± 1.85; P = .0028). Mean body weights were similar among the 3 groups by corrected age of 36 weeks or discharge, whichever came first. Associations between placental inflammation and poor growth persisted among infants with prenatal corticosteroid exposure and/or neonatal complications and remained marginally significant in the nonexposed groups. Among infants without intrauterine growth restriction, significant association persisted (n = 186; β coefficient = −5.68 ± 1.56; P = .0003). CONCLUSIONS: Placental inflammation is associated with poor neonatal growth. MIR and FIR may be useful markers for identifying infants at risk for postnatal growth failure.

Cord blood biomarkers of the fetal inflammatory response

Objective. In current, neonatal practice, clinical signs of intrauterine infection (IUI) are often non-specific. From a large panel of immune biomarkers, we seek to identify cord blood markers that are most strongly associated with the fetal inflammatory response (FIR), a specific placental lesion associated with serious neonatal complications. Methods. We used multiplex immunoassay to measure 27 biomarkers, selected as part of an NIH-funded study of preterm birth, according to gestational age (GA) and extent of placental inflammation: involvement of chorion, amnion, decidua (maternal inflammatory response, MIR); extension to umbilical cord or chorionic plate (FIR). We used false-discovery rate (FDR < 5%, P < 0.001) to account for multiple comparisons. Results. Among 506 births (GA 23–42 weeks), IL-1β increased with FIR among preterm subgroups (P = 0.0001 for <32 weeks; P = 0.0009 for 33–36 weeks). IL-6 and IL-8 increased with FIR among preterm and full-term infants (P < 0.0001). P-trend for IL-6 and IL-8 with MIR versus FIR was <0.0001. Comparison with respect to clinical IUI yielded persistent elevation with FIR even when clinical signs were absent. The remaining 24 markers were not significantly associated. Conclusion. We conclude that among 27 cord blood biomarkers, IL-1β, IL-6 and IL-8 are selectively associated with FIR. These markers may be clinically useful indicators of extensive IUI associated with poor neonatal outcome.

CYP2C9*3 allelic variant is associated with metabolism of irbesartan in Chinese population

ObjectiveThere is considerable variability in the individual pharmaceutical dosages required to achieve optimal therapeutic effects, which may be due to environmental or genetic factors. The objective of this study was to test the presence of the CYP2C9*3 allelic variant in the Chinese population and to investigate the association of this variant with both metabolism and therapeutic efficacy of irbesartan on essential hypertension.MethodsIn this study, we enrolled 711 subjects from Taihu County and 376 subjects from Dongzhi County in Anhui Province, China. All subjects received a single oral dose of 150xa0mg irbesartan daily for 28xa0days. The plasma concentration of irbesartan at 24xa0h after dosing on the 27th day and at 6xa0h after dosing on the 28th day was detected using fluorescence-high-performance liquid chromatography. CYP2C9 genotypes were determined using polymerase chain reaction—restriction fragment length polymorphism.ResultsNo CYP2C9*2 allele was found in 235 Chinese samples and was removed from further study. The mean frequency of the CYP2C9*3 allele was 3.65%, while no CYP2C9*3/*3 genotype was detected. Multiple linear regression analyses revealed that the CYP2C9*3 allele carriers had significantly higher irbesartan concentrations in plasma at 6xa0h (Taihu: P<0.0001; Dongzhi: P=0.03) and 24xa0h (Taihu: P<0.0001; Dongzhi: P=0.00013) after dosing. No significant association was found between the CYP2C9*3 allelic variant and the therapeutic effect of irbesartan on essential hypertension.ConclusionOur study suggests that the CYP2C9*3 plays an important role in the metabolism of irbesartan and/or is in linkage disequilibrium with another potential CYP2C9 allele, both of which possibly modify the pharmacokinetics of irbesartan.

The combined association of psychosocial stress and chronic hypertension with preeclampsia

OBJECTIVEnThis study aims to evaluate perceived lifetime stress, perceived stress during pregnancy, chronic hypertension, and their joint association with preeclampsia risk.nnnSTUDY DESIGNnThis study includes 4314 women who delivered a singleton live birth at the Boston Medical Center from October 1998 through February 2008. Chronic hypertension was defined as hypertension diagnosed before pregnancy. Information regarding lifetime stress and perceived stress during pregnancy was collected by questionnaire. Preeclampsia was diagnosed by clinical criteria.nnnRESULTSnLifetime stress (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.6-2.9), perceived stress during pregnancy (OR, 1.7; 95% CI, 1.3-2.2), and chronic hypertension (OR, 10.4; 95% CI, 7.5-14.4) were each associated with an increased risk of preeclampsia. Compared to normotensive pregnancy with low lifetime stress, both normotensive pregnancy with high lifetime stress (OR, 2.1; 95% CI, 1.6-2.9) and pregnancy with chronic hypertension and low lifetime stress (OR, 10.2; 95% CI, 7.0-14.9) showed an increased risk of preeclampsia, while pregnancy with high lifetime stress and chronic hypertension yielded the highest risk of preeclampsia (OR, 21.3; 95% CI, 10.2-44.3). The joint association of perceived stress during pregnancy and chronic hypertension with preeclampsia was very similar to that of the joint association of lifetime stress and chronic hypertension with preeclampsia.nnnCONCLUSIONnThis finding indicates that high psychosocial stress and chronic hypertension can act in combination to increase the risk of preeclampsia up to 20-fold. This finding underscores the importance of efforts to prevent, screen, and manage chronic hypertension, along with those to reduce psychosocial stress, particularly among women with chronic hypertension.