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1.  Nrf2 regulates gene-environment interactions in an animal model of intrauterine inflammation: Implications for preterm birth and prematurity 
Scientific Reports  2017;7:40194.
Preterm birth (PTB) is the leading cause of neonatal mortality, and surviving infants are at increased risk for lifelong disabilities. Intrauterine inflammation is an etiological factor that drives PTB, and oxidative stress is associated with PTB. Nuclear erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that is the key regulator of the response to oxidative and inflammatory stress. Here, we used the established mouse model of intrauterine inflammation-induced PTB to determine whether Nrf2 is a modifier of susceptibility to PTB and prematurity-related morbidity and mortality in the offspring. We determined that Nr2-deficient (Nrf2−/−) mice exhibited a greater sensitivity to intrauterine inflammation, as indicated by decreased time to delivery, reduced birthweight, and 100% mortality. Placentas from preterm Nrf2−/− mice showed elevated levels of markers of inflammation, oxidative stress, and cell death, and transcriptomic analysis identified numerous key signaling pathways that were differentially expressed between wild-type (WT) and Nrf2−/− mice in both preterm and control samples. Thus, Nrf2 could be a critical factor for gene-environment interactions that may determine susceptibility to PTB. Further studies are needed to determine if Nrf2 is a viable therapeutic target in women who are at risk for PTB and associated complications in the affected offspring.
PMCID: PMC5223218  PMID: 28071748
2.  Hygiene factors associated with childhood food allergy and asthma 
Allergy and Asthma Proceedings  2016;37(6):e140-e146.
Childhood food allergy and asthma rates are increasing. The hygiene hypothesis has been proposed as an explanation for the increased incidence of allergic disease.
To describe the association of childhood food allergy and asthma with hygiene factors, such as the number of siblings, antibiotic use, infection history, pet exposure, child care exposure, and maternal–child factors.
Children ages 0–21 years old (N = 1359) were recruited for a cross-sectional family-based study, including children with food allergy and children without food allergy, and their siblings. We assessed the associations between childhood food allergy and asthma with hygiene factors.
Of the 1359 children, 832 (61.2%) had food allergy, and 406 (30%) had asthma. In the adjusted analysis, the prevalence of food allergy was increased if there was a history of skin infection (prevalence ratio [RRR] 1.12 [95% confidence interval {CI}, 1.01–1.24]) or eczema (RRR 1.89 [95% CI, 1.70–2.10]). The prevalence of asthma was increased with a history of respiratory syncytial virus infection (RRR 1.60 [95% CI, 1.34–1.90]) or eczema (RRR 1.54 [95% CI, 1.27–1.86]). A greater number of siblings were associated with a decreased prevalence of food allergy (RRR 0.79 [95% CI, 0.75–0.84]) and asthma (RRR 0.82 [95% CI, 0.74–0.91]).
Our findings supported the accumulating evidence of an association between skin infections and eczema with food allergy. Because these results could be subject to recall bias, additional prospective studies are needed to substantiate these findings.
PMCID: PMC5080537
Hygiene factors; pediatric; food allergy; asthma; cohort; hygiene hypothesis; eczema; skin infections; siblings; respiratory syncytial virus.
3.  MLL1 promotes cervical carcinoma cell tumorigenesis and metastasis through interaction with β-catenin 
OncoTargets and therapy  2016;9:6631-6640.
MLL protein genes encode a family of crucial transcription factors that play a key role in multiple cancer development. The functions of different MLL proteins have not been definitively studied. MLL1 is a histone methyltransferase that mediates histone H3 lysine 4, and it has been found to have aberrant expression in several tumors. However, the function of MLL1 in cervical carcinoma is little known. We used tissue analysis, cell culture experiments, and molecular profiling to investigate the mechanism of MLL1 in cervical carcinoma development. We report here that MLL1 is overexpressed in cervical carcinoma tissues and cell lines, and its overexpression is correlated with the tumor grade. Through FACScan flow cytometry assay, we found that MLL1 promotes cell proliferation by promoting the G1/S transition through transcriptional activation of CCND1 in cervical carcinoma cells. Furthermore, we utilized co-immunoprecipitation and glutathione S-transferase pull-down assays to identify β-catenin as the transcription partner for MLL1 and demonstrated that MLL1 and β-catenin act in synergy in the transcriptional activation of CCND1 in cervical carcinoma cells. In addition, transwell assay and anchorage-independent cell growth assay also revealed that MLL1 promotes metastasis of cervical carcinoma cells through interaction with β-catenin. Our study not only demonstrated a role for MLL1 in the proliferation and metastasis of cervical carcinoma cells but also revealed the interaction of MLL1 with β-catenin to play a different role.
PMCID: PMC5098588  PMID: 27843326
MLL1; cell cycle; β-catenin; metastasis
4.  Whole-genome resequencing of 100 healthy individuals using DNA pooling 
With the advent of next-generation sequencing technology, the cost of sequencing has significantly decreased. However, sequencing costs remain high for large-scale studies. In the present study, DNA pooling was applied as a cost-effective strategy for sequencing. The sequencing results for 100 healthy individuals obtained via whole-genome resequencing and using DNA pooling are presented in the present study. In order to minimise the likelihood of systematic bias in sampling, paired-end libraries with an insert size of 500 bp were prepared for all samples and then subjected to whole-genome sequencing using four lanes for each library and resulting in at least a 30-fold haploid coverage for each sample. The NCBI human genome build37 (hg19) was used as a reference genome for the present study and the short reads were aligned to the reference genome achieving 99.84% coverage. In addition, the average sequencing depth was 32.76. In total, ~3 million single-nucleotide polymorphisms were identified, of which 99.88% were in the NCBI dbSNP database. Furthermore, ~600,000 small insertion/deletions, 500,000 structure variants, 5,000 copy number variations and 13,000 single nucleotide variants were identified. According to the present study, the whole genome has been sequenced for a small sample subjects from southern China for the first time. Furthermore, new variation sites were identified by comparing with the reference sequence, and new knowledge of the human genome variation was added to the human genomic databases. Furthermore, the particular distribution regions of variation were illustrated by analyzing various sites of variation, such as single-nucleotide polymorphisms.
PMCID: PMC5103757  PMID: 27882129
DNA pooling; whole-genome resequencing; genetic variation; single nucleotide polymorphism; variation site
5.  Intrauterine Inflammation and Maternal Exposure to Ambient PM2.5 during Preconception and Specific Periods of Pregnancy: The Boston Birth Cohort 
Environmental Health Perspectives  2016;124(10):1608-1615.
Prenatal exposure to ambient PM2.5, (i.e., fine particulate matter, aerodynamic diameter ≤ 2.5 μm) has been associated with preterm birth and low birth weight. The association between prenatal PM2.5 exposure and intrauterine inflammation (IUI), an important risk factor for preterm birth and neurodevelopmental outcomes, has not been evaluated.
We aimed to investigate the association between maternal exposure to PM2.5 and IUI in the Boston Birth Cohort, a predominantly urban low-income minority population.
This analysis included 5,059 mother–infant pairs in the Boston Birth Cohort. IUI was assessed based on intrapartum fever and placenta pathology. PM2.5 exposure was assigned using data from the U.S. EPA’s Air Quality System. Odds ratios (OR) and 95% confidence intervals (CI) quantified the association of maternal PM2.5 exposure during preconception and various periods of pregnancy with IUI.
Comparing the highest with the lowest PM2.5 exposure quartiles, the multi-adjusted association with IUI was significant for all exposure periods considered, including 3 months before conception (OR = 1.52; 95% CI: 1.22, 1.89), first trimester (OR = 1.93; 95% CI: 1.55, 2.40), second trimester (OR = 1.67; 95% CI: 1.35, 2.08), third trimester (OR = 1.53; 95% CI: 1.24, 1.90), and whole pregnancy (OR = 1.92; 95% CI: 1.55, 2.37).
Despite relatively low exposures, our results suggest a monotonic positive relationship between PM2.5 exposure during preconception and pregnancy and IUI. IUI may be a sensitive biomarker for assessing early biological effect of PM2.5 exposure on the developing fetus.
Nachman RM, Mao G, Zhang X, Hong X, Chen Z, Soria CS, He H, Wang G, Caruso D, Pearson C, Biswal S, Zuckerman B, Wills-Karp M, Wang X. 2016. Intrauterine inflammation and maternal exposure to ambient PM2.5 during preconception and specific periods of pregnancy: the Boston Birth Cohort. Environ Health Perspect 124:1608–1615;
PMCID: PMC5047781  PMID: 27120296
6.  Stable nuclear expression of ATP8 and ATP6 genes rescues a mtDNA Complex V null mutant 
Nucleic Acids Research  2016;44(19):9342-9357.
We explore the possibility of re-engineering mitochondrial genes and expressing them from the nucleus as an approach to rescue defects arising from mitochondrial DNA mutations. We have used a patient cybrid cell line with a single point mutation in the overlap region of the ATP8 and ATP6 genes of the human mitochondrial genome. These cells are null for the ATP8 protein, have significantly lowered ATP6 protein levels and no Complex V function. Nuclear expression of only the ATP8 gene with the ATP5G1 mitochondrial targeting sequence appended restored viability on Krebs cycle substrates and ATP synthesis capabilities but, failed to restore ATP hydrolysis and was insensitive to various inhibitors of oxidative phosphorylation. Co-expressing both ATP8 and ATP6 genes under similar conditions resulted in stable protein expression leading to successful integration into Complex V of the oxidative phosphorylation machinery. Tests for ATP hydrolysis / synthesis, oxygen consumption, glycolytic metabolism and viability all indicate a significant functional rescue of the mutant phenotype (including re-assembly of Complex V) following stable co-expression of ATP8 and ATP6. Thus, we report the stable allotopic expression, import and function of two mitochondria encoded genes, ATP8 and ATP6, resulting in simultaneous rescue of the loss of both mitochondrial proteins.
PMCID: PMC5100594  PMID: 27596602
7.  Cord Blood Biomarkers of the Fetal Inflammatory Response 
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. 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. Among 506 births (GA 23-42wks), IL-1β increased with FIR among preterm subgroups (P=0.0001 for <32wks; P=0.0009 for 33-36wks). 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. 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.
PMCID: PMC5001950  PMID: 19529994
Placenta; chorioamnionitis; cytokines; intrauterine infection
8.  The joint associations between F5 gene polymorphisms and maternal smoking during pregnancy on preterm delivery 
Human genetics  2008;124(6):659-668.
Factor V (F5) genetic variants and maternal smoking during pregnancy individually has been associated with increased risk of preterm delivery (PTD). We hypothesize that F5 gene and maternal smoking may synergistically increase the risk of PTD. Three single nucleotide polymorphisms (SNPs) in F5 gene (rs6019, rs2213869 and rs6022) were genotyped in 542 mothers with PTD and 1,141 mothers with term deliveries at the Boston Medical Center. The individual and interactive effects of F5 SNPs and maternal smoking on PTD and gestational age were examined, respectively. The results suggested that maternal smoking, three F5 SNPs and F5 haplotype were individually associated with PTD and gestational age. More importantly, we found significant interactions between the two F5 SNPs (rs6019 and rs6022) and maternal smoking on PTD and gestational age. Compared with non-smoking mothers carrying rs6019 GG genotype, persistently smoking mothers carrying genotypes GC or CC were associated with significantly increased risk of PTD (OR(95%CI): 2.1(1.2–3.6) for GC; 5.7(2.1–15.0) for CC; p-interaction=0.02). A significant interaction was also observed for gestational age. Similar pattern of interactions was found between rs6022 and maternal smoking on PTD. In summary, our data indicated that F5 gene variants and maternal smoking may synergistically increase the risk of PTD.
PMCID: PMC4986615  PMID: 19020903
10.  rDNA Copy Number Variants Are Frequent Passenger Mutations in Saccharomyces cerevisiae Deletion Collections and de Novo Transformants 
G3: Genes|Genomes|Genetics  2016;6(9):2829-2838.
The Saccharomyces cerevisiae ribosomal DNA (rDNA) locus is known to exhibit greater instability relative to the rest of the genome. However, wild-type cells preferentially maintain a stable number of rDNA copies, suggesting underlying genetic control of the size of this locus. We performed a screen of a subset of the Yeast Knock-Out (YKO) single gene deletion collection to identify genetic regulators of this locus and to determine if rDNA copy number correlates with yeast replicative lifespan. While we found no correlation between replicative lifespan and rDNA size, we identified 64 candidate strains with significant rDNA copy number differences. However, in the process of validating candidate rDNA variants, we observed that independent isolates of our de novo gene deletion strains had unsolicited but significant changes in rDNA copy number. Moreover, we were not able to recapitulate rDNA phenotypes from the YKO yeast deletion collection. Instead, we found that the standard lithium acetate transformation protocol is a significant source of rDNA copy number variation, with lithium acetate exposure being the treatment causing variable rDNA copy number events after transformation. As the effects of variable rDNA copy number are being increasingly reported, our finding that rDNA is affected by lithium acetate exposure suggested that rDNA copy number variants may be influential passenger mutations in standard strain construction in S. cerevisiae.
PMCID: PMC5015940  PMID: 27449518
rDNA; CNV; lithium; transformation; Saccharomyces cerevisiae
11.  Weight Gain in Infancy and Overweight or Obesity in Childhood across the Gestational Spectrum: a Prospective Birth Cohort Study 
Scientific Reports  2016;6:29867.
This study aimed to investigate the optimal degree of weight gain across the gestational spectrum in 1971 children enrolled at birth and followed up to age 7 years. Weight gain in infancy was categorized into four groups based on weight gain z-scores: slow (<−0.67), on track (−0.67 to 0.67), rapid (0.67 to 1.28), and extremely rapid (>1.28). Underweight and overweight or obesity (OWO) were defined as a body mass index ≤5th and ≥85th percentile, respectively, for age and gender. In our population, OWO was far more common than underweight (39.7% vs. 3.6%). Weight gain tracked strongly from age 4 to 24 months, and was positively associated with OWO and an unfavorable pattern of metabolic biomarkers, although the degree of weight gain for the risk was different across gestational categories. Extremely rapid weight gain led to a particularly high risk of OWO among children born early term and late preterm: odds ratio: 3.3 (95% confidence interval: 1.9 to 5.5) and 3.7 (1.8 to 7.5), respectively, as compared to those with on track weight gain. Our findings suggest that monitoring and ensuring optimal weight gain across the entire gestational spectrum beginning from birth represents a first step towards primary prevention of childhood obesity.
PMCID: PMC4945912  PMID: 27417566
12.  Cardiovascular Risk Factors in Parents of Food-Allergic Children 
Medicine  2016;95(15):e3156.
Previous studies suggest that chronic stress may induce immune system malfunction and a broad range of adverse health outcomes; however, the underlying pathways for this relationship are unclear.
Our study aimed to elucidate this question by examining the relationship between parental cardiovascular risk factors including systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), and waist-to-hip ratio (WHR) and maternal psychological stress score (MPSS) relative to the severity of the child's food allergy (FA) and number of affected children.
SBP, DBP, BMI, and WHR were measured and calculated at the time of recruitment by trained nurses. MPSS was obtained based on self-report questionnaires covering lifestyle adjustments, perceived chronic stress, and quality of life. General linear models examined whether caregiver chronic stress was associated with FA.
For mothers with children under age 5 years, SBP, DBP and number of affected children had strong and graded relationships with severity of the child's FA. MPSS was also significantly and positively associated with child FA severity (P < 0.001). However, no relationships were found between FA severity, BMI, or WHR for either parent. This was also the case for paternal SBP, DBP, and number of affected children of any age.
There is a strong and graded link between cardiovascular risk and perceived stress in mothers of food-allergic children under age 5. Findings may have important implications for family-centered care of FA, may generalize to caregivers of children with chronic conditions, and extend the literature on allostatic load.
PMCID: PMC4839798  PMID: 27082554
13.  Proteinuria Is an Independent Risk Factor for First Incident Stroke in Adults Under Treatment for Hypertension in China 
Conflicting evidence exists regarding whether reduced estimated glomerular filtration rate (eGFR) and proteinuria are independent risk factors for stroke and its subtypes in hypertensive patients. This study investigated the association of these renal measures with first incident stroke in adults under treatment for hypertension in China.
Methods and Results
The study included 19 599 adults aged 45 to 75 years who participated in the China Stroke Primary Prevention Trial. Baseline eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration creatinine equation. Proteinuria was assessed by qualitative dipstick urinalysis and in a subset by the quantitative albumin–creatinine ratio method. Cox regression analysis was used to examine the effects of eGFR and proteinuria on the risk of first incident stroke. During a median of 4.5 years of follow‐up, a total of 585 first strokes (472 ischemic strokes) were identified. Compared to participants without proteinuria, participants with proteinuria (trace or more by dipstick) had a 35% increased risk of first stroke: the adjusted hazard ratio (HR) (95% CI) was 1.35 (1.09–1.66, P=0.005). The results were robust in subgroup analyses. In a subset with data on proteinuria measured by quantitative albumin–creatinine ratio, a similar association was found. In both independent and combined analyses with proteinuria, eGFR was not significantly associated with stroke.
In adults under treatment for hypertension in China, baseline proteinuria measured by dipstick or quantitative albumin–creatinine ratio, but not reduced eGFR, was found to be an independent risk factor for first incident stroke and ischemic stroke.
PMCID: PMC4845256  PMID: 26683219
albumin–creatinine ratio; Chinese hypertensive adults; estimated glomerular filtration rate; first incident stroke; proteinuria; Cerebrovascular Disease/Stroke; Epidemiology; Clinical Studies
14.  Hyperhomocysteinemia predicts renal function decline: a prospective study in hypertensive adults 
Scientific Reports  2015;5:16268.
Hyper-homocysteinemia (HHcy) is associated with microalbuminuria and glomerular injury in general and diabetic populations. However, HHcy’s role in hypertensive patients was not studied. We investigated whether HHcy is an independent risk factor for renal function decline and development of chronic kidney disease (CKD) in hypertensive men and women. This was a community-based prospective cohort study of 2,387 hypertensive adults without CKD at baseline, with a mean follow-up of 4.4 years. Baseline and follow-up levels of plasma Hcy, folate, vitamin B12, blood pressure and other pertinent covariables were obtained. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/per 1.73 m2 and an eGFR decline rate >1 ml/min/per 1.73 m2/year. There was a graded association between Hcy tertiles and eGFR decline. Subjects in the 3rd tertile of Hcy levels had an accelerated rate of eGFR decline and an increased risk of incident CKD, as compared with those in the 1st tertile, after adjusting for age, gender, baseline diabetes, SBP, BMI, smoking, dyslipidemia, eGFR, folate and vitamin B12 levels. In conclusion, in this prospective cohort of Chinese hypertensive adults, elevated baseline plasma Hcy can serve as an independent biomarker to predict renal function decline and incident CKD.
PMCID: PMC4639775  PMID: 26553372
15.  Aberrant 5’-CpG Methylation of Cord Blood TNFα Associated with Maternal Exposure to Polybrominated Diphenyl Ethers 
PLoS ONE  2015;10(9):e0138815.
Growing evidence suggests that maternal exposures to endocrine disrupting chemicals during pregnancy may lead to poor pregnancy outcomes and increased fetal susceptibility to adult diseases. Polybrominated diphenyl ethers (PBDEs), which are ubiquitously used flame-retardants, could leach into the environment; and become persistent organic pollutants via bioaccumulation. In the United States, blood PBDE levels in adults range from 30–100 ng/g- lipid but the alarming health concern revolves around children who have reported blood PBDE levels 3 to 9-fold higher than adults. PBDEs disrupt endocrine, immune, reproductive and nervous systems. However, the mechanism underlying its adverse health effect is not fully understood. Epigenetics is a possible biological mechanism underlying maternal exposure-child health outcomes by regulating gene expression without changes in the DNA sequence. We sought to examine the relationship between maternal exposure to environmental PBDEs and promoter methylation of a proinflammatory gene, tumor necrosis factor alpha (TNFα). We measured the maternal blood PBDE levels and cord blood TNFα promoter methylation levels on 46 paired samples of maternal and cord blood from the Boston Birth Cohort (BBC). We showed that decreased cord blood TNFα methylation associated with high maternal PBDE47 exposure. CpG site-specific methylation showed significantly hypomethylation in the girl whose mother has a high blood PBDE47 level. Consistently, decreased TNFα methylation associated with an increase in TNFα protein level in cord blood. In conclusion, our finding provided evidence that in utero exposure to PBDEs may epigenetically reprogram the offspring’s immunological response through promoter methylation of a proinflammatory gene.
PMCID: PMC4583495  PMID: 26406892
16.  Genome-wide Association Study Identifies Peanut Allergy-Specific Loci and Evidence of Epigenetic Mediation in U.S. Children 
Nature communications  2015;6:6304.
Food allergy (FA) affects 2–10% of U.S. children and is a growing clinical and public health problem. Here we conduct the first genome-wide association study of well-defined FA, including specific subtypes (peanut, milk, and egg) in 2,759 U.S. participants (1,315 children; 1,444 parents) from the Chicago Food Allergy Study; and identify peanut allergy (PA)-specific loci in the HLA-DR and -DQ gene region at 6p21.32, tagged by rs7192 (p=5.5×10−8) and rs9275596 (p=6.8×10−10), in 2,197 participants of European ancestry. We replicate these associations in an independent sample of European ancestry. These associations are further supported by meta-analyses across the discovery and replication samples. Both single-nucleotide polymorphisms (SNPs) are associated with differential DNA methylation levels at multiple CpG sites (p<5×10−8); and differential DNA methylation of the HLA-DQB1 and HLA-DRB1 genes partially mediate the identified SNP-PA associations. This study suggests that the HLA-DR and -DQ gene region likely poses significant genetic risk for PA.
PMCID: PMC4340086  PMID: 25710614
17.  Associations between gene polymorphisms in fatty acid metabolism pathway and preterm delivery in a US urban black population 
Human genetics  2011;131(3):341-351.
There is increasing evidence suggesting that higher intakes of fish or n-3 polyunsaturated fatty acids supplements may decrease the risk of preterm delivery (PTD). We hypothesized that genetic variants of the enzymes critical to fatty acids biosynthesis and metabolism may be associated with PTD. We genotyped 231 potentially functional single nucleotide polymorphisms (SNPs) and tagSNPs in 9 genes (FADS1, FADS2, PTGS1, PTGS2, ALOX5, ALOX5AP, PTGES, PTGES2, and PTGES3) among 1,110 black mothers, including 542 mothers who delivered preterm (<37 weeks gestation) and 568 mothers who delivered full-term babies (≥37 weeks gestation) at Boston Medical Center. After excluding SNPs that are in complete linkage disequilibrium or have lower minor allele frequency (<1%) or call rate (<90%), we examined the association of 206 SNPs with PTD using multiple logistic regression models. We also imputed 190 HapMap SNPs via program MACH and examined their associations with PTD. Finally, we explored gene-level and pathway-level associations with PTD using the adaptive rank truncated product (ARTP) methods. A total of 21 SNPs were associated with PTD (p value ranging from 0.003 to 0.05), including 3 imputed SNPs. Gene-level ARTP statistics indicated that the gene PTGES2 was significantly associated with PTD with a gene-based p value equal to 0.01. No pathway-based association was found. In this large and comprehensive candidate gene study, we found a modest association of genes in fatty acid metabolism pathway with PTD. Further investigation of these gene polymorphisms jointly with fatty acid measures and other genetic factors would help better understand the pathogenesis of PTD.
PMCID: PMC4547931  PMID: 21847588
18.  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.
PMCID: PMC4547934  PMID: 24243566
maternal BMI; cord blood; DNA methylation; early life origins of disease
19.  Unexpected pro-injury effect of propofol on vascular smooth muscle cells with increased oxidative stress* 
Critical care medicine  2011;39(4):738-745.
Propofol is a widely used intravenous anesthetic agent with antioxidant properties. However, the effect of propofol on reactive oxygen species-induced injury in vascular smooth muscle cells is still unknown. In this study, the authors determined the effect of propofol on hydrogen peroxide-induced injury in vascular smooth muscle cells and the potential molecular mechanisms involved.
Prospective cell and animal study.
University research laboratory.
Sprague-Dawley rats.
For the in vitro study, rat vascular smooth muscle cells pretreated with vehicle or hydrogen peroxide (200 μM) were exposed to vehicle or increasing concentrations of propofol (10–50 μM). For the in vivo study, propofol (12 mg kg–1/hr–1, intravenous) or vehicle was administrated into rats after carotid artery angioplasty.
Measurements and Main Results
The cell survival and cell death were measured by MTT and trypan blue exclusion. Cell apoptosis was evaluated by terminal deoxynucleotide transferase dUTP nick end labeling staining and cleaved caspase-3 expression. To further elucidate the molecular mechanisms in propofol-mediated cellular effect, the expression of programmed cell death 4 and microRNA-21 were measured. Unexpectedly, propofol exacerbated hydrogen peroxide-induced injury responses in vascular smooth muscle cells as demonstrated by a decrease in cell viability and an increase in trypan blue-stained cells, cell apoptosis, and cleaved caspase-3 expression. In addition, propofol inhibited hydrogen peroxide-induced up-regulation of microRNA-21 and increased its target gene programmed cell death 4. Propofol-mediated injury was attenuated by restoration of microRNA-21 expression. Finally, the pro-injury effect of propofol on vascular cells with increased reactive oxygen species was illustrated in vivo in rat carotid arteries after angioplasty.
The results revealed that propofol exacerbates cell injury in vascular smooth muscle cells with increased reactive oxygen species, at least in part, through microRNA-21 and its target gene, programmed cell death 4. Because increased reactive oxygen species is a common pathologic component in many vascular diseases, the novel findings in the current study suggest that propofol might have some application limitations.
PMCID: PMC4527164  PMID: 21263323
propofol; oxidative stress; vascular smooth muscle cells; vascular disease; apoptosis; microRNA; reactive oxygen species; free radicals; ischemia-reperfusion
20.  Do Static and Dynamic Insulin Resistance Indices Perform Similarly in Predicting Pre-diabetes and Type 2 Diabetes? 
We designed a study to compare the predictive power of static and dynamic insulin resistance indices for categorized pre-diabetes (PDM) / type 2 diabetes (DM).
Participants included 1,134 adults aged 18-60 years old with normal glucose at baseline who completed both baseline and 6-years later follow-up surveys. Insulin resistance indices from baseline data were used to predict risk of PDM or DM at follow-up. Two static indices and two dynamic indices were calculated from oral glucose tolerance test results (OGTT) at baseline. Area under the receiver operating characteristic curve (AROC) analysis was used to estimate the predictive ability of candidate indices to predict PDM/DM. A general estimation equation (GEE) model was applied to assess the magnitude of association of each index at baseline with the risk of PDM/DM at follow-up.
The dynamic indices displayed the largest and statistically predictive AROC for PDM/DM diagnosed either by fasting glucose or by postprandial glucose. The bottom quartiles of the dynamic indices were associated with an elevated risk of PDM/DM vs. the top three quartiles. However, the static indices only performed significantly to PDM/DM diagnosed by fasting glucose.
Dynamic insulin resistance indices are stronger predictors of future PDM/DM than static indices. This may be because dynamic indices better reflect the full range of physiologic disturbances in PDM/DM.
PMCID: PMC4138243  PMID: 24882014
insulin resistance indices; predict; pre-diabetes; type 2 diabetes; Chinese; twin; adult
21.  Human papillomavirus infection and cervical dysplasia in female sex workers in Northeast China: an observational study 
BMC Public Health  2015;15:695.
Women having multiple sex partners are reportedly at an increased risk of HPV infection. However, the prevalence and risk factors of HPV infection in female sex workers (FSWs) vary considerably across racial/ethnic, socioeconomic, and geographic groups. This study aimed to determine the prevalence and risk factors of HPV infection in FSWs in Northeast China.
A total of 309 FSWs identified and approached through a local police office and 1000 healthy subjects from a single factor undergoing annual gynecological examinations in Shenyang were recruited. A liquid-based ThinPrep Pap test and the Hybrid Capture II-based high-risk HPV DNA test, with or without a colposcopic examination, were performed on both FSWs and control subjects. Data on HPV infection and histological and cytological lesions of the cervix were obtained and analyzed. A questionnaire survey was administered to all 309 FSWs with their socio-demographic and behavioral information collected. The association of various socio-demographic and behavioral variables with HPV infection was assessed.
HPV was significantly more prevalent in FSWs (61.90 %) than in healthy control subjects (21.00 %) (P < 0.01), so were cervical lesions (P < 0.01). HPV prevalence in our sample of FSWs fell in the upper range of reported values in FSWs across different countries, and was similar to that for FSWs in the southeast Chinese city of Huzhou but higher than that for FSWs in southwest China, Guangxi, as compared with data from other studies within China. HPV infection in FSWs was significantly associated with the age at first sexual intercourse (OR 0.699, 95 % CI 0.492–0.992) and post-menopause (OR 2.928, 95 % CI 1.099–7.800) (P < 0.05).
FSWs are at a substantially high risk of HPV infection and cervical dysplasia development as compared with healthy control subjects in Shenyang, China. Age of first sexual intercourse and post-menopause are two independent risk factors for HPV infection in this special group of population. Intensified and coordinated efforts from government, public health sector, communities and families are needed to reduce the risk of HPV infection in this specific group of population.
PMCID: PMC4512111  PMID: 26202513
Female sex workers; Human papillomavirus (HPV); Cervical dysplasia; Risk factors; Shenyang; China
22.  A translational study of urine miRNAs in acute myocardial infarction 
The currently used biomarkers for acute myocardial infarction (AMI) are blood creatinine phosphokinase-muscle band (CPK-MB), troponin-T (TnT), and troponin I (TnI). However, no good biomarkers are identified in urine after AMI, because these blood protein biomarkers are difficult to be filtered into urine. In this study, the role of urine microRNAs in the diagnosis of AMI and the mechanism involved were determined. We found that urine miR-1 was quickly increased in rats after AMI with peak at 24 h after AMI, in which an over 50-fold increase was demonstrated. At 7 days after AMI, the urine miR-1 level was returned to the basal level. No miR-208 was found in normal urine. In urine from rats with AMI, miR-208 was easily detected. To determine the mechanism involved, we determined the levels of heart-released miR-1 in the liver, spleen and kidney after AMI in rats and found that the kidney was an important metabolic organ. To determine the renal elimination of blood miRNAs, we isolated serum exosomes from rats after AMI and injected these exosomes into the circulating blood of normal rats. We found that the urine miR-1 was significantly increased in exosome-injected animals. Moreover, PKH67-labeled exosomes injected into circulating blood could enter into the kidney tissues and cells, as well as urine. Furthermore, the levels of urine miR-1 were significantly increased in patients with AMI. The results suggest that urine miRNAs such as miR-1 could be novel urine biomarkers for AMI.
PMCID: PMC4492106  PMID: 22921780
Acute myocardial infarction; microRNA; miR-1; miR-208; Urine; Biomarker
23.  Preterm Birth and Random Plasma Insulin Levels at Birth and in Early Childhood 
JAMA  2014;311(6):587-596.
Although previous reports have linked preterm birth with insulin resistance in children and adults, it is not known whether altered insulin homeostasis is detectable at birth and tracks from birth onwards.
To investigate whether preterm birth is associated with elevated plasma insulin levels at birth and whether this association persists into early childhood.
Design, Setting, and Participation
A prospective birth cohort of 1358 children recruited at birth from 1998 to 2010 and followed prospectively from 2005 to 2012 at the Boston Medical Center, Boston, MA.
Main Outcome Measures
Random plasma insulin levels were measured at two time points: at birth (cord blood) and in early childhood (venous blood) (median age (25th–75th percentile): 1.4 (0.8–3.3) years) among four gestational age groups: term (≥37 weeks), and further grouped into full term (≥39 weeks) and early term (37–38 weeks); preterm (<37 weeks), and further grouped into late preterm (34–36 weeks) and early preterm (<34 weeks).
The geometric mean (95% confidence interval(CI)) of insulin levels for full term, early term, late preterm and early preterm births was 9.2(8.4–10.0), 10.3(9.3–11.5), 13.2(11.8–14.8) and 18.9(16.6–21.4) µU/ml, respectively at birth, and 11.2(10.3–12.0), 12.4(11.3–13.6), 13.3(11.9–14.8) and 14.6(12.6–16.9) µU/ml, respectively in early childhood. At birth, insulin levels were 1.13(95% CI: 0.97–1.28), 1.45(95%CI: 1.25–1.65) and 2.05(95%CI: 1.69–2.42) folds higher for early term, late preterm and early preterm, respectively, than those born full term. In early childhood, plasma random insulin levels in those born early term, late preterm and early preterm were 1.12(95%CI: 0.99–1.25), 1.19(95%CI: 1.02–1.35), and 1.31(95%CI: 1.10–1.52) folds higher, respectively, than those born full term. The association was attenuated after adjustment for postnatal weight gain and was not significant after adjustment for insulin levels at birth. Children ranked in the top insulin tertile at birth were more likely to remain in the top tertile in early childhood relative to children ranked in the lowest tertile (41.2% vs. 28.6%).
Conclusion and Relevance
There was an inverse association between gestational age and elevated plasma insulin levels at birth and in early childhood. The implications for future development of insulin resistance and type 2 diabetes warrant further investigation.
PMCID: PMC4392841  PMID: 24519298
24.  Identification of Differential MicroRNAs in Cerebrospinal Fluid and Serum of Patients with Major Depressive Disorder 
PLoS ONE  2015;10(3):e0121975.
Major depression is a debilitating disease. To date, the development of biomarkers of major depressive disorder (MDD) remains a challenge. Recently, alterations in the expression of microRNAs (miRNAs) from post-mortem brain tissue and peripheral blood have been linked to MDD. The goals of this study were to detect the differential miRNAs in cerebrospinal fluid (CSF) and serum of MDD patients. First, the relative expression levels of 179 miRNAs (relative high levels in serum) were analyzed by miRNA PCR Panel in the CSF of MDD patients. Then, the differentially altered miRNAs from CSF were further assessed by qRT-PCR in the serum of the same patients. Finally, the serum differentially altered miRNAs were further validated by qRT-PCR in the serum of another MDD patients. The CSF-results indicated that 11 miRNAs in MDD patients were significantly higher than these in control subjects, and 5 miRNAs were significantly lower than these in control subjects. The serum-results from the same patients showed that 3 miRNAs (miR-221-3p, miR-34a-5p, and let-7d-3p) of the 11 miRNAs were significantly higher than these in control subjects, and 1 miRNA (miR-451a) of 5 miRNAs was significantly lower than these in control subjects. The up-regulation of miR-221-3p, miR-34a-5p, let-7d-3p and down-regulation of miR-451a was further validated in another 32 MDD patients. ROC analysis showed that the area under curve of let-7d-3p, miR-34a-5p, miR-221-3p and miR-451a was 0.94, 0.98, 0.97 and 0.94, with specificity of 90.48%, 95.24%, 90.48% and 90.48%, and sensitivity of 93.75%, 96.88%, 90.63% and 84.85%, respectively. In addition, target gene prediction found that the altered miRNAs are involved in affecting some important genes and pathway related to MDD. Our results suggested that differentially altered miRNAs in CSF might be involved in MDD, and serum miR-221-3p, miR-34a-5p, let-7d-3p, and miR-451a might be able to serve as biomarkers for MDD.
PMCID: PMC4357380  PMID: 25763923
25.  Early Life Origins of Metabolic Syndrome: The Role of Environmental Toxicants 
Metabolic syndrome (MetS) affects more than 47 million people in the U.S. Even more alarming, MetS, once regarded as an “adult problem”, has become increasingly common in children. To date, most related research and intervention efforts have occurred in the adult medicine arena, with limited understanding of the root causes and lengthy latency of MetS. This review highlights new science on the early life origins of MetS, with a particular focus on exposure to two groups of environmental toxicants: endocrine disrupting chemicals (EDCs) and metals during the prenatal and early postnatal periods, and their specific effects and important differences in the development of MetS. It also summarizes available data on epigenetic effects, including the role of EDCs in the androgen/estrogen pathways. Emerging evidence supports the link between exposures to environmental toxicants during early life and the development of MetS later in life. Additional research is needed to address important research gaps in this area, including prospective birth cohort studies to delineate temporal and dose-response relationships, important differences in the effects of various environmental toxicants and their joint effects on MetS, as well as epigenetic mechanisms underlying the effects of specific toxicants such as EDCs and metals.
PMCID: PMC4037145  PMID: 24883264
diabetes; environmental toxicants; metabolic syndrome; obesity; prenatal exposure

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