HOLBROOK JOANNA DAWN
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bchhjd@nus.edu.sg
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YONG LOO LIN SCH OF MEDICINE
faculty
BIOCHEMISTRY
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Publication Association of maternal Vitamin D status with glucose tolerance and caesarean section in a multi-ethnic Asian cohort: the growing up in Singapore towards healthy outcomes study(Public Library of Science, 2015-11-01) Loy, See Ling; Lek, Ngee; Yap, Kok Peng Fabian; Soh, Shu E.; Natarajan, Padmapriya; Tan, Kok Lian; Biswas, Arijit; Yeo, George S. H.; Kwek, Yung Chiang Kenneth; Gluckman, Peter David; Saw, Seang Mei; Chong, Foong Fong Mary; Chan, Kok Yen Jerry; Chinnadurai, Amutha; Qiu, Anqi; Lee, Bee Wah; Broekman, Birit Froukje Philippien; Shuter, Borys; Hsu, Chin-Ying Stephen; Chee, Yin Ing Cornelia; Van Bever, Hugo P.S.; Holbrook, Joanna Dawn; Gooley, Joshua J.; Niduvaje, Krishnamoorthy; Singh, Leher; Su, Lin Lin; Shek, Pe-Chi Lynette; RAUFF HOW JING,MARY; Chua, Mei Chien; Tint, Mya Thway; Teoh, Oon Hoe; Wong, Peng Cheang; Rob Martinus, van Dam; Rebello, Salome Antonette; Chong, Shang Chee; Cai, Shirong; Rajadurai, Victor Samuel; Pang, Wei Wei; Goh, Yam Thiam Daniel; Cheung, Yin Bun; Chan, Yiong Huak; Lee, Yung Seng; DIAGNOSTIC RADIOLOGY; PSYCHOLOGY; PREVENTIVE DENTISTRY; DUKE-NUS GRADUATE MEDICAL SCHOOL S'PORE; EPIDEMIOLOGY & PUBLIC HEALTH; PSYCHOLOGICAL MEDICINE; DIVISION OF BIOENGINEERING; PAEDIATRICS; BIOCHEMISTRY; OBSTETRICS & GYNAECOLOGYObjective Epidemiological studies relating maternal 25-hydroxyvitamin D (25OHD) with gestational diabetes mellitus (GDM) and mode of delivery have shown controversial results. We examined if maternal 25OHD status was associated with plasma glucose concentrations, risks of GDM and caesarean section in the Growing Up in Singapore Towards healthy Outcomes (GUSTO) study. Methods Plasma 25OHD concentrations, fasting glucose (FG) and 2-hour postprandial glucose (2HPPG) concentrations were measured in 940 women from a Singapore mother-offspring cohort study at 26-28 weeks' gestation. 25OHD inadequacy and adequacy were defined based on concentrations of 25OHD ≤75nmol/l and >75nmol/l respectively. Mode of delivery was obtained from hospital records. Multiple linear regression was performed to examine the association between 25OHD status and glucose concentrations, while multiple logistic regression was performed to examine the association of 25OHD status with risks of GDM and caesarean section. Results In total, 388 (41.3%) women had 25OHD inadequacy. Of these, 131 (33.8%), 155 (39.9%) and 102 (26.3%) were Chinese, Malay and Indian respectively. After adjustment for confounders, maternal 25OHD inadequacy was associated with higher FG concentrations (β = 0.08mmol/l, 95% Confidence Interval (CI) = 0.01, 0.14), but not 2HPPG concentrations and risk of GDM. A trend between 25OHD inadequacy and higher likelihood of emergency caesarean section (Odds Ratio (OR) = 1.39, 95% CI = 0.95, 2.05) was observed. On stratification by ethnicity, the association with higher FG concentrations was significant in Malay women (β = 0.19mmol/l, 95% CI = 0.04, 0.33), while risk of emergency caesarean section was greater in Chinese (OR = 1.90, 95% CI = 1.06, 3.43) and Indian women (OR = 2.41, 95% CI = 1.01, 5.73). Conclusions 25OHD inadequacy is prevalent in pregnant Singaporean women, particularly among the Malay and Indian women. This is associated with higher FG concentrations in Malay women, and increased risk of emergency caesarean section in Chinese and Indian women. © 2015 Loy et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Publication ACSL1 is associated with fetal programming of insulin sensitivity and cellular lipid content(Endocrine Society, 2015-06) Joseph, Roy; Poschmann, Jeremie; Sukarieh, Rami; Too, Peh Gek; Julien, Sofi G.; Xu, Feng; Teh, Ai Ling; Holbrook, Joanna D; Ng, Kai Lyn; Chong, Yap Seng; Gluckman, Peter D.; Prabhakar, Shyam; Stünkel, Walter; PAEDIATRICS; BIOCHEMISTRYPublication Insights from the growing up in singapore towards healthy outcomes (GUSTO) cohort study(S. Karger AG, 2014) Soh S.-E.; Chong Y.-S.; Kwek K.; Saw S.-M.; Meaney M.J.; Gluckman P.D.; Holbrook J.D.; Godfrey K.M.; The GUSTO Study Group; SAW SWEE HOCK SCHOOL OF PUBLIC HEALTH; DUKE-NUS MEDICAL SCHOOL; PAEDIATRICS; BIOCHEMISTRY; OBSTETRICS & GYNAECOLOGYBackground: The dramatic emergence of noncommunicable diseases (NCD) in Asia, albeit with ethnic variation, has coincided with the rapid socioeconomic and nutritional transition taking place in the region, with the prevalence of diabetes rising 5-fold in Singapore in less than 4 decades. The Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort study recruited 1,247 expectant mothers of Chinese, Malay, or Indian ethnicity in their first trimester, with detailed longitudinal tracking - through the antenatal period, birth, and the child's first 4 years of life - to examine the potential roles of fetal, developmental, and epigenetic factors in early pathways to metabolic and neurodevelopmental outcomes. Key Messages: A number of findings with a translational and clinical focus have already emerged. In the mothers, we found that changes and differences in food consumption varied across ethnic groups, with persistence of traditional beliefs, during pregnancy and the postpartum period. During pregnancy, higher maternal glucose levels, even in the absence of gestational diabetes mellitus, had graded relations with infant adiposity. Relations between maternal emotional health and birth outcomes and neurodevelopment have been identified. Genotype (25%) and in particular gene × environment interactions (75%) shape interindividual variations in the DNA methylome at birth. The complex effects of fixed genetic variations and different in utero environments can influence the epigenetic status at birth and the later-life phenotype. Conclusions: The richness of the clinical data in 3 ethnicities, the extent of the biospecimen collection, and the extensive infancy and preschool follow-up have allowed us to study the biological pathways that link fetal development to health outcomes. In the coming years, more sophisticated analyses of epigenotype-phenotype relationships will become possible as the children grow and develop. Our studies will lead to the development of clinical and population-based interventions to reduce the burden of NCD. © 2014 S. Karger AG, Basel.Publication ST3GAL1-Associated Transcriptomic Program in Glioblastoma Tumor Growth, Invasion, and Prognosis(Oxford University Press, 2016) Chong Y.K.; Sandanaraj E.; Koh L.W.H.; Thangaveloo M.; Tan M.S.Y.; Koh G.R.H.; Toh T.B.; Lim G.G.Y.; Holbrook J.D.; Kon O.L.; Nadarajah M.; Ng I.; Ng W.H.; Tan N.S.; Lim K.L.; Tang Soo Leng Carol; Ang B.T.; PHYSIOLOGY; CANCER SCIENCE INSTITUTE OF SINGAPORE; BIOLOGICAL SCIENCES; DUKE-NUS MEDICAL SCHOOL; BIOCHEMISTRYBackground: Cell surface sialylation is associated with tumor cell invasiveness in many cancers. Glioblastoma is the most malignant primary brain tumor and is highly infiltrative. ST3GAL1 sialyltransferase gene is amplified in a subclass of glioblastomas, and its role in tumor cell self-renewal remains unexplored. Methods: Self-renewal of patient glioma cells was evaluated using clonogenic, viability, and invasiveness assays. ST3GAL1 was identified from differentially expressed genes in Peanut Agglutinin-stained cells and validated in REMBRANDT (n = 390) and Gravendeel (n = 276) clinical databases. Gene set enrichment analysis revealed upstream processes. TGF? signaling on ST3GAL1 transcription was assessed using chromatin immunoprecipitation. Transcriptome analysis of ST3GAL1 knockdown cells was done to identify downstream pathways. A constitutively active FoxM1 mutant lacking critical anaphase-promoting complex/cyclosome ([APC/C]-Cdh1) binding sites was used to evaluate ST3Gal1-mediated regulation of FoxM1 protein. Finally, the prognostic role of ST3Gal1 was determined using an orthotopic xenograft model (3 mice groups comprising nontargeting and 2 clones of ST3GAL1 knockdown in NNI-11 [8 per group] and NNI-21 [6 per group]), and the correlation with patient clinical information. All statistical tests on patients' data were two-sided; other P values below are one-sided. Results: High ST3GAL1 expression defines an invasive subfraction with self-renewal capacity; its loss of function prolongs survival in a mouse model established from mesenchymal NNI-11 (P <. 001; groups of 8 in 3 arms: nontargeting, C1, and C2 clones of ST3GAL1 knockdown). ST3GAL1 transcriptomic program stratifies patient survival (hazard ratio [HR] = 2.47, 95% confidence interval [CI] = 1.72 to 3.55, REMBRANDT P = 1.92x10-8; HR = 2.89, 95% CI = 1.94 to 4.30, Gravendeel P = 1.05x10-11), independent of age and histology, and associates with higher tumor grade and T2 volume (P = 1.46x10-4). TGF? signaling, elevated in mesenchymal patients, correlates with high ST3GAL1 (REMBRANDT gliomacor = 0.31, P = 2.29x10-10; Gravendeel gliomacor = 0.50, P = 3.63x10-20). The transcriptomic program upon ST3GAL1 knockdown enriches for mitotic cell cycle processes. FoxM1 was identified as a statistically significantly modulated gene (P = 2.25x10-5) and mediates ST3Gal1 signaling via the (APC/C)-Cdh1 complex. Conclusions: The ST3GAL1-associated transcriptomic program portends poor prognosis in glioma patients and enriches for higher tumor grades of the mesenchymal molecular classification. We show that ST3Gal1-regulated self-renewal traits are crucial to the sustenance of glioblastoma multiforme growth. © 2015 The Author 2015.Publication Neonatal amygdalae and hippocampi are influenced by genotype and prenatal environment, and reflected in the neonatal DNA methylome(Blackwell Publishing Ltd, 2019) Ong M.-L.; Tuan T.A.; Poh J.; Teh A.L.; Chen L.; Pan H.; MacIsaac J.L.; Kobor M.S.; Chong Y.S.; Kwek K.; Saw S.M.; Godfrey K.M.; Gluckman P.D.; Fortier M.V.; Karnani N.; Meaney M.J.; Qiu A.; Holbrook J.D.; BIOMEDICAL ENGINEERING; BIOENGINEERING; SAW SWEE HOCK SCHOOL OF PUBLIC HEALTH; DUKE-NUS MEDICAL SCHOOL; PAEDIATRICS; BIOCHEMISTRY; OBSTETRICS & GYNAECOLOGYThe amygdala and hippocampus undergo rapid development in early life. The relative contribution of genetic and environmental factors to the establishment of their developmental trajectories has yet to be examined. We performed imaging on neonates and examined how the observed variation in volume and microstructure of the amygdala and hippocampus varied by genotype, and compared with prenatal maternal mental health and socioeconomic status. Gene × Environment models outcompeted models containing genotype or environment only to best explain the majority of measures but some, especially of the amygdaloid microstructure, were best explained by genotype only. Models including DNA methylation measured in the neonate umbilical cords outcompeted the Gene and Gene × Environment models for the majority of amygdaloid measures and minority of hippocampal measures. This study identified brain region-specific gene networks associated with individual differences in fetal brain development. In particular, genetic and epigenetic variation within CUX1 was highlighted. © 2019 John Wiley & Sons Ltd and International Behavioural and Neural Genetics SocietyPublication Toxoplasma gondii superinfection and virulence during secondary infection correlate with the exact ROP5/ROP18 allelic combination(American Society for Microbiology, 2015) Dogra S.; Sakwinska O.; Soh S.-E.; Ngom-Bru C.; Bruck W.M.; Berger B.; Brussow H.; Lee Y.S.; Yap F.; Chong Y.-S.; Godfrey K.M.; Holbrook J.D.; MICROBIOLOGYPublication Effects of prenatal environment, genotype and DNA methylation on birth weight and subsequent postnatal outcomes: findings from GUSTO, an Asian birth cohort(BMC, 2016-05-26) Lin, X; Lim, IY; Wu, Y; Teh, AL; Chen, L; Aris, IM; Soh, SE; Tint, MT; MacIsaac, JL; Yap, F; Kwek, K; Saw, SM; Kobor, MS; Meaney, MJ; Godfrey, KM; Chong, YS; Holbrook, JD; Lee, YS; Gluckman, PD; Karnani, N; Dr Shu Qin Ooi; DEAN'S OFFICE (MEDICINE); DUKE-NUS MEDICAL SCHOOL; PAEDIATRICS; BIOCHEMISTRY; OBSTETRICS & GYNAECOLOGYPublication Cohort profile: Growing up in Singapore towards healthy outcomes (GUSTO) birth cohort study(Oxford University Press, 2014) Soh S.-E.; Saw S.M.; Tint M.T.; Chong Y.-S.; Gluckman P.D.; Rifkin-Graboi A.; Stünkel W.; Holbrook J.D.; Godfrey K.M.; Chan Y.H.; Kwek K.; Sheppard A.; Chinnadurai A.; Ferguson-Smith A.; Biswas A.; Chia U.; Leutscher-Broekman B.; Shuter B.; Cai S.; Ngo C.; Chng C.K.; Chong S.C.; Henry C.J.; Chu M.C.; Chee C.Y.I.; Goh Y.T.D.; Bier D.; Ding C.M.; Fok D.; Finkelstein E.A.; Peng Yap F.K.; Yeo G.S.H.; Meng Han W.; Chen H.; Van Bever H.P.S.; Inskip H.; Magiati I.; Kapur J.; Richmond J.L.; Gooley J.J.; Niduvaje K.; Lee B.W.; Lee Y.S.; Singh L.; Lim S.B.; Daniel L.M.; Loh S.F.; Low Y.-L.; Fortier M.; Hanson M.; Chong M.F.-F.; Meaney M.; Morton S.; Pang W.W.; Agarwal P.; Qiu A.; Quah B.L.; van Dam R.M.; Stringer D.; Rebello S.A.; So W.C.; Hsu C.-Y.; Su L.L.; Tang J.; Tan K.H.; Tan S.H.; Teoh O.H.; Rajadurai V.S.; Wong P.C.; Venkatesh S.K.; The GUSTO Study Group; Anne Eng Neo Goh; Jerry Kok Yen Chan; Inez Bik Yun Wong; Pei-Chi Lynette Shek; DEAN'S OFFICE (MEDICINE); DIAGNOSTIC RADIOLOGY; BIOMEDICAL ENGINEERING; DEAN'S OFFICE (DENTISTRY); PSYCHOLOGY; SAW SWEE HOCK SCHOOL OF PUBLIC HEALTH; PSYCHOLOGICAL MEDICINE; DUKE-NUS MEDICAL SCHOOL; PAEDIATRICS; BIOCHEMISTRY; OPHTHALMOLOGY; OBSTETRICS & GYNAECOLOGYPublication HIF3A association with adiposity: The story begins before birth(Future Medicine Ltd., 2015) Pan H.; Lin X.; Wu Y.; Chen L.; Teh A.L.; Soh S.E.; Lee Y.S.; Tint M.T.; Macisaac J.L.; Morin A.M.; Tan K.H.; Yap F.; Saw S.M.; Kobor M.S.; Meaney M.J.; Godfrey K.M.; Chong Y.-S.; Gluckman P.D.; Karnani N.; Holbrook J.D.; BIOMEDICAL ENGINEERING; LIFE SCIENCES INSTITUTE; SAW SWEE HOCK SCHOOL OF PUBLIC HEALTH; DUKE-NUS MEDICAL SCHOOL; PAEDIATRICS; BIOCHEMISTRY; OBSTETRICS & GYNAECOLOGYAim: Determine if the association of HIF3A DNA methylation with weight and adiposity is detectable early in life. Material & methods: We determined HIF3A genotype and DNA methylation patterns (on hybridization arrays) in DNA extracted from umbilical cords of 991 infants. Methylation levels at three CpGs in the HIF3A first intron were related to neonatal and infant anthropometry and to genotype at nearby polymorphic sites. Results & conclusion: Higher methylation levels at three previously described HIF3A CpGs were associated with greater infant weight and adiposity. The effect sizes were slightly smaller than those reported for adult BMI. There was also an interaction within cis-genotype. The association between higher DNA methylation at HIF3A and increased adiposity is present in neonates. In this study, no particular prenatal factor strongly influenced HIF3A hypermethylation. Our data nonetheless suggest shared prenatal influences on HIF3A methylation and adiposity. © JD Holbrook.Publication Choice of surrogate tissue influences neonatal EWAS findings(BioMed Central Ltd., 2017) Lin X.; Teh A.L.; Chen L.; Lim I.Y.; Tan P.F.; MacIsaac J.L.; Morin A.M.; Yap F.; Tan K.H.; Saw S.M.; Lee Y.S.; Holbrook J.D.; Godfrey K.M.; Meaney M.J.; Kobor M.S.; Chong Y.S.; Gluckman P.D.; Karnani N.; MEDICINE; PHYSIOLOGY; SAW SWEE HOCK SCHOOL OF PUBLIC HEALTH; DUKE-NUS MEDICAL SCHOOL; PAEDIATRICS; BIOCHEMISTRY; OBSTETRICS & GYNAECOLOGYBackground: Epigenomes are tissue specific and thus the choice of surrogate tissue can play a critical role in interpreting neonatal epigenome-wide association studies (EWAS) and in their extrapolation to target tissue. To develop a better understanding of the link between tissue specificity and neonatal EWAS, and the contributions of genotype and prenatal factors, we compared genome-wide DNA methylation of cord tissue and cord blood, two of the most accessible surrogate tissues at birth. Methods: In 295 neonates, DNA methylation was profiled using Infinium HumanMethylation450 beadchip arrays. Sites of inter-individual variability in DNA methylation were mapped and compared across the two surrogate tissues at birth, i.e., cord tissue and cord blood. To ascertain the similarity to target tissues, DNA methylation profiles of surrogate tissues were compared to 25 primary tissues/cell types mapped under the Epigenome Roadmap project. Tissue-specific influences of genotype on the variable CpGs were also analyzed. Finally, to interrogate the impact of the in utero environment, EWAS on 45 prenatal factors were performed and compared across the surrogate tissues. Results: Neonatal EWAS results were tissue specific. In comparison to cord blood, cord tissue showed higher inter-individual variability in the epigenome, with a lower proportion of CpGs influenced by genotype. Both neonatal tissues were good surrogates for target tissues of mesodermal origin. They also showed distinct phenotypic associations, with effect sizes of the overlapping CpGs being in the same order of magnitude. Conclusions: The inter-relationship between genetics, prenatal factors and epigenetics is tissue specific, and requires careful consideration in designing and interpreting future neonatal EWAS. Trial registration: This birth cohort is a prospective observational study, designed to study the developmental origins of health and disease, and was retrospectively registered on 1 July 2010 under the identifier NCT01174875. © 2017 The Author(s).