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201. Maternal vitamin D status modifies the effects of early life tobacco exposure on child lung function

Author

Knihtilä, Hanna M., primary, Huang, Mengna, additional, Prince, Nicole, additional, Stubbs, Benjamin J., additional, Carey, Vincent J., additional, Laranjo, Nancy, additional, Mirzakhani, Hooman, additional, Zeiger, Robert S., additional, Bacharier, Leonard B., additional, O’Connor, George T., additional, Litonjua, Augusto A., additional, Weiss, Scott T., additional, and Lasky-Su, Jessica, additional

Published
2022
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202. The Association of Prenatal C-Reactive Protein and Interleukin-8 Levels with Maternal Characteristics and Preterm Birth

Author

Litonjua, Augusto A., primary, Lee-Sarwar, Kathleen A., primary, Chen, Yih-Chieh S., additional, Mirzakhani, Hooman, additional, Knihtilä, Hanna, additional, Fichorova, Raina N., additional, Luu, Ngan, additional, Laranjo, Nancy, additional, Jha, Anjali, additional, Kelly, Rachel S., additional, and Weiss, Scott T., additional

Published
2022
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203. The maternal prenatal and offspring early‐life gut microbiome of childhood asthma phenotypes

Author

Lee‐Sarwar, Kathleen A., primary, Chen, Yih‐Chieh, additional, Chen, Yuan Yao, additional, Kozyrskyj, Anita L., additional, Mandhane, Piush J., additional, Turvey, Stuart E., additional, Subbarao, Padmaja, additional, Bisgaard, Hans, additional, Stokholm, Jakob, additional, Chawes, Bo, additional, Sørensen, Søren J., additional, Kelly, Rachel S., additional, Lasky‐Su, Jessica, additional, Zeiger, Robert S., additional, O'Connor, George T., additional, Sandel, Megan T., additional, Bacharier, Leonard B., additional, Beigelman, Avraham, additional, Carey, Vincent J., additional, Harshfield, Benjamin J., additional, Laranjo, Nancy, additional, Gold, Diane R., additional, Weiss, Scott T., additional, and Litonjua, Augusto A., additional

Published
2022
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208. Gene expression analysis uncovers novel hedgehog interacting protein (HHIP) effects in human bronchial epithelial cells

Author

Zhou, Xiaobo, Qiu, Weiliang, Sathirapongsasuti, J. Fah, Cho, Michael H., Mancini, John D., Lao, Taotao, Thibault, Derek M., Litonjua, Augusto A., Bakke, Per S., Gulsvik, Amund, Lomas, David A., Beaty, Terri H., Hersh, Craig P., Anderson, Christopher, Geigenmuller, Ute, Raby, Benjamin A., Rennard, Stephen I., Perrella, Mark A., Choi, Augustine M.K., Quackenbush, John, and Silverman, Edwin K.

Published
2013
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209. Characteristics and Mechanisms of a Sphingolipid-associated Childhood Asthma Endotype

Author

Hanna M. Knihtilä, Kathleen Lee-Sarwar, Morten Arendt Rasmussen, Hans Bisgaard, Casper-Emil T. Pedersen, Craig E. Wheelock, Klaus Bønnelykke, Mengna Huang, Daniela Rago, Jessica Lasky-Su, Nicklas Brustad, Bo L. Chawes, Scott T. Weiss, Gözde Gürdeniz, Jakob Stokholm, Rachel S. Kelly, Andréanne Morin, and Augusto A. Litonjua

Subjects
Pulmonary and Respiratory Medicine, Endotype, Childhood asthma, business.industry, Genetic variants, Critical Care and Intensive Care Medicine, medicine.disease, Sphingolipid, respiratory tract diseases, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, immune system diseases, Immunology, Medicine, 030212 general & internal medicine, business, Lung function, Asthma
Abstract

Rationale: A link among sphingolipids, 17q21 genetic variants, and childhood asthma has been suggested, but the underlying mechanisms and characteristics of such an asthma endotype remain to be elu...

Published
2021
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216. The maternal prenatal and offspring early-life gut microbiome of childhood asthma phenotypes

Author

Kathleen A. Lee‐Sarwar, Yih‐Chieh Chen, Yuan Yao Chen, Anita L. Kozyrskyj, Piush J. Mandhane, Stuart E. Turvey, Padmaja Subbarao, Hans Bisgaard, Jakob Stokholm, Bo Chawes, Søren J. Sørensen, Rachel S. Kelly, Jessica Lasky‐Su, Robert S. Zeiger, George T. O'Connor, Megan T. Sandel, Leonard B. Bacharier, Avraham Beigelman, Vincent J. Carey, Benjamin J. Harshfield, Nancy Laranjo, Diane R. Gold, Scott T. Weiss, and Augusto A. Litonjua

Subjects
Immunology, Immunology and Allergy
Abstract

The infant fecal microbiome is known to impact subsequent asthma risk, but the environmental exposures impacting this association, the role of the maternal microbiome, and how the microbiome impacts different childhood asthma phenotypes are unknown.Our objective was to identify associations between features of the prenatal and early-life fecal microbiomes and child asthma phenotypes. We analyzed fecal 16 s rRNA microbiome profiling and fecal metabolomic profiling from stool samples collected from mothers during the third trimester of pregnancy (n = 120) and offspring at ages 3-6 months (n = 265), 1 (n = 436) and 3 years (n = 506) in a total of 657 mother-child pairs participating in the Vitamin D Antenatal Asthma Reduction Trial. We used clinical data from birth to age 6 years to characterize subjects with asthma as having early, transient or active asthma phenotypes. In addition to identifying specific genera that were robustly associated with asthma phenotypes in multiple covariate-adjusted models, we clustered subjects by their longitudinal microbiome composition and sought associations between fecal metabolites and relevant microbiome and clinical features.Seven maternal and two infant fecal microbial taxa were robustly associated with at least one asthma phenotype, and a longitudinal gut microenvironment profile was associated with early asthma (Fisher exact test p = .03). Though mode of delivery was not directly associated with asthma, we found substantial evidence for a pathway whereby cesarean section reduces fecal Bacteroides and microbial sphingolipids, increasing susceptibility to early asthma.Overall, our results suggest that the early-life, including prenatal, fecal microbiome modifies risk of asthma, especially asthma with onset by age 3 years.

Published
2022

224. African ancestry and lung function in Puerto Rican children

Author

Brehm, John M., Acosta-Pérez, Edna, Klei, Lambertus, Roeder, Kathryn, Barmada, Michael M., Boutaoui, Nadia, Forno, Erick, Cloutier, Michelle M., Datta, Soma, Kelly, Roxanne, Paul, Kathryn, Sylvia, Jody, Calvert, Deanna, Thornton-Thompson, Sherell, Wakefield, Dorothy, Litonjua, Augusto A., Alvarez, María, Colón-Semidey, Angel, Canino, Glorisa, and Celedón, Juan C.

Published
2012
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225. Prenatal vitamin D supplementation reduces risk of asthma/recurrent wheeze in early childhood: A combined analysis of two randomized controlled trials.

Author

Helene M Wolsk, Bo L Chawes, Augusto A Litonjua, Bruce W Hollis, Johannes Waage, Jakob Stokholm, Klaus Bønnelykke, Hans Bisgaard, and Scott T Weiss

Subjects
Medicine, Science
Abstract

BACKGROUND:We recently published two independent randomized controlled trials of vitamin D supplementation during pregnancy, both indicating a >20% reduced risk of asthma/recurrent wheeze in the offspring by 3 years of age. However, neither reached statistical significance. OBJECTIVE:To perform a combined analysis of the two trials and investigate whether maternal 25-hydroxy-vitamin D (25(OH)D) level at trial entry modified the intervention effect. METHODS:VDAART (N = 806) and COPSAC2010. (N = 581) randomized pregnant women to daily high-dose vitamin D3 (4,000 IU/d and 2,400 IU/d, respectively) or placebo. All women also received a prenatal vitamin containing 400 IU/d vitamin D3. The primary outcome was asthma/recurrent wheeze from 0-3yrs. Secondary end-points were specific IgE, total IgE, eczema and lower respiratory tract infections (LRTI). We conducted random effects combined analyses of the treatment effect, individual patient data (IPD) meta-analyses, and analyses stratified by 25(OH)D level at study entry. RESULTS:The analysis showed a 25% reduced risk of asthma/recurrent wheeze at 0-3yrs: adjusted odds ratio (aOR) = 0.74 (95% CI, 0.57-0.96), p = 0.02. The effect was strongest among women with 25(OH)D level ≥30ng/ml at study entry: aOR = 0.54 (0.33-0.88), p = 0.01, whereas no significant effect was observed among women with 25(OH)D level

Published
2017
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229. Vitamin D constrains inflammation by modulating the expression of key genes on Chr17q12-21.1

Author

Ayşe Kılıç, Arda Halu, Margherita De Marzio, Enrico Maiorino, Melody G. Duvall, Thayse Brueggemann, Joselyn J. Rojas Quintero, Robert Chase, Hooman Mirzakhani, Ayse Özge Sungur, Janine Koepke, Taiji Nakano, Hong Yong Peh, Nandini Krishnamoorthy, Raja-Elie Abdulnour, Katia Georgopoulos, Augusto A. Litonjua, Marie B. Demay, Harald Renz, Bruce D. Levy, and Scott. T Weiss

Abstract

Vitamin D possesses immunomodulatory functions and vitamin D deficiency has been associated with the rise in chronic inflammatory diseases, including asthma (1). Vitamin D supplementation studies do not provide insight into the molecular genetic mechanisms of vitamin D mediated immunoregulation. Here we provide evidence for vitamin D regulation of two human chromosomal loci, Chr17q12-21.1 and Chr17q21.2, reliably associated with autoimmune and chronic inflammatory diseases (2–4). We demonstrate increased vitamin D receptor (VDR) expression in mouse lung CD4+ Th2 cells, differential expression of Chr17q12-21.1 and Chr17q21.2 genes in Th2 cells based on vitamin D status and identify the IL-2/Stat5 pathway as a target of vitamin D signaling. Vitamin D deficiency caused severe lung inflammation after allergen challenge in mice that was prevented by long term prenatal vitamin D supplementation. Mechanistically, vitamin D induced the expression of theIkzf3encoded protein Aiolos to suppress IL-2-signaling and ameliorate cytokine production in Th2 cells. These translational findings demonstrate mechanisms for the immune protective effect of vitamin D in allergic lung inflammation with a strong molecular genetic link to the regulation of both Chr17q12-21.1 and Chr17q21.2 genes and suggest further functional studies and interventional strategies for long-term prevention of asthma and other autoimmune disorders.One Sentence SummaryVitamin D regulates two human chromosomal loci, Chr17q12-21.1 and Chr17q21.2, that are associated with autoimmune and chronic inflammatory diseases.

Published
2022
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232. Omega-3 Fatty Acids Interact with DPP10 Region Genotype in Association with Childhood Atopy

Author

Kathleen A. Lee-Sarwar, Kasper Fischer-Rasmussen, Klaus Bønnelykke, Hans Bisgaard, Bo Chawes, Rachel S. Kelly, Jessica Lasky-Su, Robert S. Zeiger, George T. O’Connor, Leonard B. Bacharier, Vincent J. Carey, Nancy Laranjo, Augusto A. Litonjua, and Scott T. Weiss

Subjects
Nutrition and Dietetics, omega-3, polyunsaturated fatty acids, asthma, allergy, genotype, Food Science
Abstract

Associations of omega-3 fatty acids (n-3) with allergic diseases are inconsistent, perhaps in part due to genetic variation. We sought to identify and validate genetic variants that modify associations of n-3 with childhood asthma or atopy in participants in the Vitamin D Antenatal Asthma Reduction Trial (VDAART) and the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC). Dietary n-3 was derived from food frequency questionnaires and plasma n-3 was measured via untargeted mass spectrometry in early childhood and children aged 6 years old. Interactions of genotype with n-3 in association with asthma or atopy at age 6 years were sought for six candidate genes/gene regions and genome-wide. Two SNPs in the region of DPP10 (rs958457 and rs1516311) interacted with plasma n-3 at age 3 years in VDAART (p = 0.007 and 0.003, respectively) and with plasma n-3 at age 18 months in COPSAC (p = 0.01 and 0.02, respectively) in associationwith atopy. Another DPP10 region SNP, rs1367180, interacted with dietary n-3 at age 6 years in VDAART (p = 0.009) and with plasma n-3 at age 6 years in COPSAC (p = 0.004) in association with atopy. No replicated interactions were identified for asthma. The effect of n-3 on reducing childhood allergic disease may differ by individual factors, including genetic variation in the DPP10 region.

Published
2023
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233. Association of Vitamin D Level and Maternal Gut Microbiome during Pregnancy: Findings from a Randomized Controlled Trial of Antenatal Vitamin D Supplementation

Author

Andrea Aparicio, Diane R. Gold, Scott T. Weiss, Augusto A. Litonjua, Kathleen Lee-Sarwar, and Yang-Yu Liu

Subjects
Nutrition and Dietetics, vitamin D supplementation, pregnancy, maternal gut microbiome, Article, Food Science
Abstract

Shifts in the maternal gut microbiome and vitamin D deficiency during pregnancy have been associated, separately, with health problems for both the mother and the child. Yet, they have rarely been studied simultaneously. Here, we analyzed gut microbiome (from stool samples obtained in late pregnancy) and vitamin D level (from blood samples obtained both in early and late pregnancy) data of pregnant women in the Vitamin D Antenatal Asthma Reduction Trial (VDAART), a randomized controlled trial of vitamin D supplementation during pregnancy, to investigate the association of vitamin D status on the pregnant women’s microbiome. To find associations we ran linear regressions on alpha diversity measures, PERMANOVA tests on beta diversity distances, and used the ANCOM-BS and Maaslin2 algorithms to find differentially abundant taxa. Analyses were deemed significant using a cut-off p-value of 0.05. We found that gut microbiome composition is associated with the vitamin D level in early pregnancy (baseline), the maternal gut microbiome does not show a shift in response to vitamin D supplementation during pregnancy, and that the genusDesulfovibriois enriched in women without a substantial increase in vitamin D level between the first and the third trimesters of pregnancy. We conclude that increasing the vitamin D level during pregnancy could be protective against the growth of sulfate-reducing bacteria such asDesulfovibrio, which has been associated with chronic intestinal inflammatory disorders. More in-depth investigations are needed to confirm this hypothesis.

Published
2023
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234. Changes in Body Mass Index Among School-Aged Youths Following Implementation of the Healthy, Hunger-Free Kids Act of 2010

Author

Aruna Chandran, Mohamad Burjak, Joshua Petimar, Ghassan Hamra, Melissa M. Melough, Anne L. Dunlop, Brittney M. Snyder, Augusto A. Litonjua, Tina Hartert, James Gern, Akram N. Alshawabkeh, Judy Aschner, Carlos A. Camargo, Dana Dabelea, Cristiane S. Duarte, Assiamira Ferrara, Jody M. Ganiban, Frank Gilliland, Diane R. Gold, Monique Hedderson, Julie B. Herbstman, Christine Hockett, Margaret R. Karagas, Jean M. Kerver, Kathleen A. Lee-Sarwar, Barry Lester, Cindy T. McEvoy, Zhongzheng Niu, Joseph B. Stanford, Rosalind Wright, Emily Zimmerman, Shohreh Farzan, Zhumin Zhang, and Emily Knapp

Subjects
Pediatrics, Perinatology and Child Health
Abstract

ImportanceThe prevalence of obesity among youths 2 to 19 years of age in the US from 2017 to 2018 was 19.3%; previous studies suggested that school lunch consumption was associated with increased obesity. The Healthy, Hunger-Free Kids Act of 2010 (HHFKA) strengthened nutritional standards of school-based meals.ObjectiveTo evaluate the association between the HHFKA and youth body mass index (BMI).Design, Setting, and ParticipantsThis cohort study was conducted using data from the Environmental Influences on Child Health Outcomes program, a nationwide consortium of child cohort studies, between January 2005 and March 2020. Cohorts in the US of youths aged 5 to 18 years with reported height and weight measurements were included.ExposuresFull implementation of the HHFKA.Main Outcomes and MeasuresThe main outcome was annual BMI z-score (BMIz) trends before (January 2005 to August 2016) and after (September 2016 to March 2020) implementation of the HHFKA, adjusted for self-reported race, ethnicity, maternal education, and cohort group. An interrupted time-series analysis design was used to fit generalized estimating equation regression models.ResultsA total of 14 121 school-aged youths (7237 [51.3%] male; mean [SD] age at first measurement, 8.8 [3.6] years) contributing 26 205 BMI measurements were included in the study. Overall, a significant decrease was observed in the annual BMIz in the period following implementation of the HHFKA compared with prior to implementation (−0.041; 95% CI, −0.066 to −0.016). In interaction models to evaluate subgroup associations, similar trends were observed among youths 12 to 18 years of age (−0.045; 95% CI, −0.071 to −0.018) and among youths living in households with a lower annual income (−0.038; 95% CI, −0.063 to −0.013).Conclusions and RelevanceIn this cohort study, HHFKA implementation was associated with a significant decrease in BMIz among school-aged youths in the US. The findings suggest that school meal programs represent a key opportunity for interventions to combat the childhood obesity epidemic given the high rates of program participation and the proportion of total calories consumed through school-based meals.

Published
2023
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241. Meta-analysis of epigenome-wide association studies in newborns and children show widespread sex differences in blood DNA methylation.

Author

Solomon, O, Huen, K, Yousefi, P, Küpers, LK, González, JR, Suderman, M, Reese, SE, Page, CM, Gruzieva, O, Rzehak, P, Gao, L, Bakulski, KM, Novoloaca, A, Allard, C, Pappa, I, Llambrich, M, Vives, M, Jima, DD, Kvist, T, Baccarelli, A, White, C, Rezwan, FI, Sharp, GC, Tindula, G, Bergström, A, Grote, V, Dou, JF, Isaevska, E, Magnus, MC, Corpeleijn, E, Perron, P, Jaddoe, VWV, Nohr, EA, Maitre, L, Foraster, M, Hoyo, C, Håberg, SE, Lahti, J, DeMeo, DL, Zhang, H, Karmaus, W, Kull, I, Koletzko, B, Feinberg, JI, Gagliardi, L, Bouchard, L, Ramlau-Hansen, CH, Tiemeier, H, Santorelli, G, Maguire, RL, Czamara, D, Litonjua, AA, Langhendries, J-P, Plusquin, M, Lepeule, J, Binder, EB, Verduci, E, Dwyer, T, Carracedo, Á, Ferre, N, Eskenazi, B, Kogevinas, M, Nawrot, TS, Munthe-Kaas, MC, Herceg, Z, Relton, C, Melén, E, Gruszfeld, D, Breton, C, Fallin, MD, Ghantous, A, Nystad, W, Heude, B, Snieder, H, Hivert, M-F, Felix, JF, Sørensen, TIA, Bustamante, M, Murphy, SK, Raikkönen, K, Oken, E, Holloway, JW, Arshad, SH, London, SJ, Holland, N, Solomon, O, Huen, K, Yousefi, P, Küpers, LK, González, JR, Suderman, M, Reese, SE, Page, CM, Gruzieva, O, Rzehak, P, Gao, L, Bakulski, KM, Novoloaca, A, Allard, C, Pappa, I, Llambrich, M, Vives, M, Jima, DD, Kvist, T, Baccarelli, A, White, C, Rezwan, FI, Sharp, GC, Tindula, G, Bergström, A, Grote, V, Dou, JF, Isaevska, E, Magnus, MC, Corpeleijn, E, Perron, P, Jaddoe, VWV, Nohr, EA, Maitre, L, Foraster, M, Hoyo, C, Håberg, SE, Lahti, J, DeMeo, DL, Zhang, H, Karmaus, W, Kull, I, Koletzko, B, Feinberg, JI, Gagliardi, L, Bouchard, L, Ramlau-Hansen, CH, Tiemeier, H, Santorelli, G, Maguire, RL, Czamara, D, Litonjua, AA, Langhendries, J-P, Plusquin, M, Lepeule, J, Binder, EB, Verduci, E, Dwyer, T, Carracedo, Á, Ferre, N, Eskenazi, B, Kogevinas, M, Nawrot, TS, Munthe-Kaas, MC, Herceg, Z, Relton, C, Melén, E, Gruszfeld, D, Breton, C, Fallin, MD, Ghantous, A, Nystad, W, Heude, B, Snieder, H, Hivert, M-F, Felix, JF, Sørensen, TIA, Bustamante, M, Murphy, SK, Raikkönen, K, Oken, E, Holloway, JW, Arshad, SH, London, SJ, and Holland, N

Abstract

BACKGROUND: Among children, sex-specific differences in disease prevalence, age of onset, and susceptibility have been observed in health conditions including asthma, immune response, metabolic health, some pediatric and adult cancers, and psychiatric disorders. Epigenetic modifications such as DNA methylation may play a role in the sexual differences observed in diseases and other physiological traits. METHODS: We performed a meta-analysis of the association of sex and cord blood DNA methylation at over 450,000 CpG sites in 8438 newborns from 17 cohorts participating in the Pregnancy And Childhood Epigenetics (PACE) Consortium. We also examined associations of child sex with DNA methylation in older children ages 5.5-10 years from 8 cohorts (n = 4268). RESULTS: In newborn blood, sex was associated at Bonferroni level significance with differences in DNA methylation at 46,979 autosomal CpG sites (p < 1.3 × 10-7) after adjusting for white blood cell proportions and batch. Most of those sites had lower methylation levels in males than in females. Of the differentially methylated CpG sites identified in newborn blood, 68% (31,727) met look-up level significance (p < 1.1 × 10-6) in older children and had methylation differences in the same direction. CONCLUSIONS: This is a large-scale meta-analysis examining sex differences in DNA methylation in newborns and older children. Expanding upon previous studies, we replicated previous findings and identified additional autosomal sites with sex-specific differences in DNA methylation. Differentially methylated sites were enriched in genes involved in cancer, psychiatric disorders, and cardiovascular phenotypes.

Published
2022

242. The Role of Childhood Asthma in Obesity Development: A Nationwide US Multicohort Study.

Author

Stratakis, Nikos, Stratakis, Nikos, Garcia, Erika, Chandran, Aruna, Hsu, Tingju, Alshawabkeh, Akram, Aris, Izzuddin M, Aschner, Judy L, Breton, Carrie, Burbank, Allison, Camargo, Carlos A, Carroll, Kecia N, Chen, Zhanghua, Claud, Erika C, Dabelea, Dana, Dunlop, Anne L, Elliott, Amy J, Ferrara, Assiamira, Ganiban, Jody M, Gern, James E, Gold, Diane R, Gower, William A, Hertz-Picciotto, Irva, Karagas, Margaret R, Karr, Catherine J, Lester, Barry, Leve, Leslie D, Litonjua, Augusto A, Ludena, Yunin, McEvoy, Cindy T, Miller, Rachel L, Mueller, Noel T, O'Connor, Thomas G, Oken, Emily, O'Shea, T Michael, Perera, Frederica, Stanford, Joseph B, Rivera-Spoljaric, Katherine, Rundle, Andrew, Trasande, Leonardo, Wright, Rosalind J, Zhang, Yue, Zhu, Yeyi, Berhane, Kiros, Gilliland, Frank, Chatzi, Lida, program collaborators for Environmental Influences on Child Health Outcomes, Stratakis, Nikos, Stratakis, Nikos, Garcia, Erika, Chandran, Aruna, Hsu, Tingju, Alshawabkeh, Akram, Aris, Izzuddin M, Aschner, Judy L, Breton, Carrie, Burbank, Allison, Camargo, Carlos A, Carroll, Kecia N, Chen, Zhanghua, Claud, Erika C, Dabelea, Dana, Dunlop, Anne L, Elliott, Amy J, Ferrara, Assiamira, Ganiban, Jody M, Gern, James E, Gold, Diane R, Gower, William A, Hertz-Picciotto, Irva, Karagas, Margaret R, Karr, Catherine J, Lester, Barry, Leve, Leslie D, Litonjua, Augusto A, Ludena, Yunin, McEvoy, Cindy T, Miller, Rachel L, Mueller, Noel T, O'Connor, Thomas G, Oken, Emily, O'Shea, T Michael, Perera, Frederica, Stanford, Joseph B, Rivera-Spoljaric, Katherine, Rundle, Andrew, Trasande, Leonardo, Wright, Rosalind J, Zhang, Yue, Zhu, Yeyi, Berhane, Kiros, Gilliland, Frank, Chatzi, Lida, and program collaborators for Environmental Influences on Child Health Outcomes

Abstract

RationaleAsthma and obesity often co-occur. It has been hypothesized that asthma may contribute to childhood obesity onset.ObjectivesTo determine if childhood asthma is associated with incident obesity and examine the role of asthma medication in this association.MethodsWe studied 8,716 children between ages 6 and 18.5 years who were nonobese at study entry participating in 18 US cohorts of the Environmental influences on Child Health Outcomes program (among 7,299 children with complete covariate data mean [SD] study entry age = 7.2 [1.6] years and follow up = 5.3 [3.1] years).Measurements and main resultsWe defined asthma based on caregiver report of provider diagnosis. Incident obesity was defined as the first documented body mass index ≥95th percentile for age and sex following asthma status ascertainment. Over the study period, 26% of children had an asthma diagnosis and 11% developed obesity. Cox proportional hazards models with sex-specific baseline hazards were fitted to assess the association of asthma diagnosis with obesity incidence. Children with asthma had a 23% (95% confidence intervals [CI] = 4, 44) higher risk for subsequently developing obesity compared with those without asthma. A novel mediation analysis was also conducted to decompose the total asthma effect on obesity into pathways mediated and not mediated by asthma medication use. Use of asthma medication attenuated the total estimated effect of asthma on obesity by 64% (excess hazard ratios = 0.64; 95% CI = -1.05, -0.23).ConclusionsThis nationwide study supports the hypothesis that childhood asthma is associated with later risk of obesity. Asthma medication may reduce this association and merits further investigation as a potential strategy for obesity prevention among children with asthma.

Published
2022

243. Reduced Steroid Metabolites Identify Infection-Prone Children in Two Independent Pre-Birth Cohorts

Author

Prince, Nicole, Kim, Min, Kelly, Rachel S., Diray-Arce, Joann, Bonnelykke, Klaus, Chawes, Bo L., Huang, Mengna, Levy, Ofer, Litonjua, Augusto A., Stokholm, Jakob, Wheelock, Craig E., Bisgaard, Hans, Weiss, Scott T., Lasky-Su, Jessica A., Prince, Nicole, Kim, Min, Kelly, Rachel S., Diray-Arce, Joann, Bonnelykke, Klaus, Chawes, Bo L., Huang, Mengna, Levy, Ofer, Litonjua, Augusto A., Stokholm, Jakob, Wheelock, Craig E., Bisgaard, Hans, Weiss, Scott T., and Lasky-Su, Jessica A.

Abstract

Recurrent respiratory infections are a leading cause of morbidity and mortality in early life, but there is no broadly accepted means to identify infection-prone children during this highly vulnerable period. In this study, we investigated associations between steroid metabolites and incident respiratory infections in two pre-birth cohorts to identify novel metabolomic signatures of early infection proneness. Children from the Vitamin D Antenatal Asthma Reduction Trial and the Copenhagen Prospective Studies on Asthma in Childhood were included, and profiling was performed on plasma samples collected at ages 1 and 6 years. Both cohorts recorded incidence of lower respiratory infections, upper respiratory infections, ear infections, and colds. Poisson regression analysis assessed the associations between 18 steroid metabolites and the total number of respiratory infections that occurred in offspring during follow-up. We found that steroid metabolites across androgenic, corticosteroid, pregnenolone, and progestin classes were reduced in children that suffered more infections, and these patterns persisted at age 6 years, generally reflecting consistency in direction of effect and significance. Our analysis suggested steroid metabolite measurement may be useful in screening for infection proneness during this critical developmental period. Future studies should clinically evaluate their potential utility as a clinical screening tool.

Published
2022

244. Meta-analysis of epigenome-wide association studies in newborns and children show widespread sex differences in blood DNA methylation

Author

Solomon, Olivia, Huen, Karen, Yousefi, Paul, Küpers, Leanne K., González, Juan R., Suderman, Matthew, Reese, Sarah E., Page, Christian M., Gruzieva, Olena, Rzehak, Peter, Gao, Lu, Bakulski, Kelly M., Novoloaca, Alexei, Allard, Catherine, Pappa, Irene, Llambrich, Maria, Vives, Marta, Jima, Dereje D., Kvist, Tuomas, Baccarelli, Andrea, White, Cory, Rezwan, Faisal I., Sharp, Gemma C., Tindula, Gwen, Bergström, Anna, Grote, Veit, Dou, John F., Isaevska, Elena, Magnus, Maria C., Corpeleijn, Eva, Perron, Patrice, Jaddoe, Vincent W.V., Nohr, Ellen A., Maitre, Lea, Foraster, Maria, Hoyo, Cathrine, Håberg, Siri E., Lahti, Jari, DeMeo, Dawn L., Zhang, Hongmei, Karmaus, Wilfried, Kull, Inger, Koletzko, Berthold, Feinberg, Jason I., Gagliardi, Luigi, Bouchard, Luigi, Ramlau-Hansen, Cecilia Høst, Tiemeier, Henning, Santorelli, Gillian, Maguire, Rachel L., Czamara, Darina, Litonjua, Augusto A., Langhendries, Jean Paul, Plusquin, Michelle, Lepeule, Johanna, Binder, Elisabeth B., Verduci, Elvira, Dwyer, Terence, Carracedo, Ángel, Ferre, Natalia, Eskenazi, Brenda, Kogevinas, Manolis, Nawrot, Tim S., Munthe-Kaas, Monica C., Herceg, Zdenko, Relton, Caroline, Melén, Erik, Gruszfeld, Dariusz, Breton, Carrie, Fallin, M. D., Ghantous, Akram, Nystad, Wenche, Heude, Barbara, Snieder, Harold, Hivert, Marie France, Felix, Janine F., Sørensen, Thorkild I.A., Bustamante, Mariona, Murphy, Susan K., Raikkönen, Katri, Oken, Emily, Holloway, John W., Arshad, Syed Hasan, London, Stephanie J., Holland, Nina, Solomon, Olivia, Huen, Karen, Yousefi, Paul, Küpers, Leanne K., González, Juan R., Suderman, Matthew, Reese, Sarah E., Page, Christian M., Gruzieva, Olena, Rzehak, Peter, Gao, Lu, Bakulski, Kelly M., Novoloaca, Alexei, Allard, Catherine, Pappa, Irene, Llambrich, Maria, Vives, Marta, Jima, Dereje D., Kvist, Tuomas, Baccarelli, Andrea, White, Cory, Rezwan, Faisal I., Sharp, Gemma C., Tindula, Gwen, Bergström, Anna, Grote, Veit, Dou, John F., Isaevska, Elena, Magnus, Maria C., Corpeleijn, Eva, Perron, Patrice, Jaddoe, Vincent W.V., Nohr, Ellen A., Maitre, Lea, Foraster, Maria, Hoyo, Cathrine, Håberg, Siri E., Lahti, Jari, DeMeo, Dawn L., Zhang, Hongmei, Karmaus, Wilfried, Kull, Inger, Koletzko, Berthold, Feinberg, Jason I., Gagliardi, Luigi, Bouchard, Luigi, Ramlau-Hansen, Cecilia Høst, Tiemeier, Henning, Santorelli, Gillian, Maguire, Rachel L., Czamara, Darina, Litonjua, Augusto A., Langhendries, Jean Paul, Plusquin, Michelle, Lepeule, Johanna, Binder, Elisabeth B., Verduci, Elvira, Dwyer, Terence, Carracedo, Ángel, Ferre, Natalia, Eskenazi, Brenda, Kogevinas, Manolis, Nawrot, Tim S., Munthe-Kaas, Monica C., Herceg, Zdenko, Relton, Caroline, Melén, Erik, Gruszfeld, Dariusz, Breton, Carrie, Fallin, M. D., Ghantous, Akram, Nystad, Wenche, Heude, Barbara, Snieder, Harold, Hivert, Marie France, Felix, Janine F., Sørensen, Thorkild I.A., Bustamante, Mariona, Murphy, Susan K., Raikkönen, Katri, Oken, Emily, Holloway, John W., Arshad, Syed Hasan, London, Stephanie J., and Holland, Nina

Abstract

Background: Among children, sex-specific differences in disease prevalence, age of onset, and susceptibility have been observed in health conditions including asthma, immune response, metabolic health, some pediatric and adult cancers, and psychiatric disorders. Epigenetic modifications such as DNA methylation may play a role in the sexual differences observed in diseases and other physiological traits. Methods: We performed a meta-analysis of the association of sex and cord blood DNA methylation at over 450,000 CpG sites in 8438 newborns from 17 cohorts participating in the Pregnancy And Childhood Epigenetics (PACE) Consortium. We also examined associations of child sex with DNA methylation in older children ages 5.5–10 years from 8 cohorts (n = 4268). Results: In newborn blood, sex was associated at Bonferroni level significance with differences in DNA methylation at 46,979 autosomal CpG sites (p < 1.3 × 10−7) after adjusting for white blood cell proportions and batch. Most of those sites had lower methylation levels in males than in females. Of the differentially methylated CpG sites identified in newborn blood, 68% (31,727) met look-up level significance (p < 1.1 × 10−6) in older children and had methylation differences in the same direction. Conclusions: This is a large-scale meta-analysis examining sex differences in DNA methylation in newborns and older children. Expanding upon previous studies, we replicated previous findings and identified additional autosomal sites with sex-specific differences in DNA methylation. Differentially methylated sites were enriched in genes involved in cancer, psychiatric disorders, and cardiovascular phenotypes.

Published
2022

245. Meta-analysis of epigenome-wide association studies in newborns and children show widespread sex differences in blood DNA methylation

Author

Universitat Rovira i Virgili, Solomon, O; Huen, K; Yousefi, P; Küpers, LK; González, JR; Suderman, M; Reese, SE; Page, CM; Gruzieva, O; Rzehak, P; Gao, L; Bakulski, KM; Novoloaca, A; Allard, C; Pappa, I; Llambrich, M; Vives, M; Jima, DD; Kvist, T; Baccarelli, A; White, C; Rezwan, FI; Sharp, GC; Tindula, G; Bergström, A; Grote, V; Dou, JF; Isaevska, E; Magnus, MC; Corpeleijn, E; Perron, P; Jaddoe, VWV; Nohr, EA; Maitre, L; Foraster, M; Hoyo, C; Håberg, SE; Lahti, J; DeMeo, DL; Zhang, HM; Karmaus, W; Kull, I; Koletzko, B; Feinberg, JI; Gagliardi, L; Bouchard, L; Ramlau-Hansen, CH; Tiemeier, H; Santorelli, G; Maguire, RL; Czamara, D; Litonjua, AA; Langhendries, JP; Plusquin, M; Lepeule, J; Binder, EB; Verduci, E; Dwyer, T; Carracedo, A; Ferre, N; Eskenazi, B; Kogevinas, M; Nawrot, TS; Munthe-Kaas, MC; Herceg, Z; Relton, C; Melén, E; Gruszfeld, D; Breton, C; Fallin, MD; Ghantous, A; Nystad, W; Heude, B; Snieder, H; Hivert, MF; Felix, JF; Sorensen, TIA; Bustamante, M; Murphy, SK; Raikkönen, K; Oken, E; Holloway, JW; Arshad, SH; London, SJ; Holland, N, Universitat Rovira i Virgili, and Solomon, O; Huen, K; Yousefi, P; Küpers, LK; González, JR; Suderman, M; Reese, SE; Page, CM; Gruzieva, O; Rzehak, P; Gao, L; Bakulski, KM; Novoloaca, A; Allard, C; Pappa, I; Llambrich, M; Vives, M; Jima, DD; Kvist, T; Baccarelli, A; White, C; Rezwan, FI; Sharp, GC; Tindula, G; Bergström, A; Grote, V; Dou, JF; Isaevska, E; Magnus, MC; Corpeleijn, E; Perron, P; Jaddoe, VWV; Nohr, EA; Maitre, L; Foraster, M; Hoyo, C; Håberg, SE; Lahti, J; DeMeo, DL; Zhang, HM; Karmaus, W; Kull, I; Koletzko, B; Feinberg, JI; Gagliardi, L; Bouchard, L; Ramlau-Hansen, CH; Tiemeier, H; Santorelli, G; Maguire, RL; Czamara, D; Litonjua, AA; Langhendries, JP; Plusquin, M; Lepeule, J; Binder, EB; Verduci, E; Dwyer, T; Carracedo, A; Ferre, N; Eskenazi, B; Kogevinas, M; Nawrot, TS; Munthe-Kaas, MC; Herceg, Z; Relton, C; Melén, E; Gruszfeld, D; Breton, C; Fallin, MD; Ghantous, A; Nystad, W; Heude, B; Snieder, H; Hivert, MF; Felix, JF; Sorensen, TIA; Bustamante, M; Murphy, SK; Raikkönen, K; Oken, E; Holloway, JW; Arshad, SH; London, SJ; Holland, N

Abstract

Background: Among children, sex-specific differences in disease prevalence, age of onset, and susceptibility have been observed in health conditions including asthma, immune response, metabolic health, some pediatric and adult cancers, and psychiatric disorders. Epigenetic modifications such as DNA methylation may play a role in the sexual differences observed in diseases and other physiological traits. Methods: We performed a meta-analysis of the association of sex and cord blood DNA methylation at over 450,000 CpG sites in 8438 newborns from 17 cohorts participating in the Pregnancy And Childhood Epigenetics (PACE) Consortium. We also examined associations of child sex with DNA methylation in older children ages 5.5–10 years from 8 cohorts (n = 4268). Results: In newborn blood, sex was associated at Bonferroni level significance with differences in DNA methylation at 46,979 autosomal CpG sites (p < 1.3 × 10−7) after adjusting for white blood cell proportions and batch. Most of those sites had lower methylation levels in males than in females. Of the differentially methylated CpG sites identified in newborn blood, 68% (31,727) met look-up level significance (p < 1.1 × 10−6) in older children and had methylation differences in the same direction. Conclusions: This is a large-scale meta-analysis examining sex differences in DNA methylation in newborns and older children. Expanding upon previous studies, we replicated previous findings and identified additional autosomal sites with sex-specific differences in DNA methylation. Differentially methylated sites were enriched in genes involved in cancer, psychiatric disorders, and cardiovascular phenotypes.

Published
2022

247. Partial Least Squares Discriminant Analysis and Bayesian Networks for Metabolomic Prediction of Childhood Asthma

Author

Rachel S. Kelly, Michael J. McGeachie, Kathleen A. Lee-Sarwar, Priyadarshini Kachroo, Su H. Chu, Yamini V. Virkud, Mengna Huang, Augusto A. Litonjua, Scott T. Weiss, and Jessica Lasky-Su

Subjects
Partial Least-Squares Discriminant analysis, Bayesian networks, asthma, arginine metabolism, overfitting, Microbiology, QR1-502
Abstract

To explore novel methods for the analysis of metabolomics data, we compared the ability of Partial Least Squares Discriminant Analysis (PLS-DA) and Bayesian networks (BN) to build predictive plasma metabolite models of age three asthma status in 411 three year olds (n = 59 cases and 352 controls) from the Vitamin D Antenatal Asthma Reduction Trial (VDAART) study. The standard PLS-DA approach had impressive accuracy for the prediction of age three asthma with an Area Under the Curve Convex Hull (AUCCH) of 81%. However, a permutation test indicated the possibility of overfitting. In contrast, a predictive Bayesian network including 42 metabolites had a significantly higher AUCCH of 92.1% (p for difference < 0.001), with no evidence that this accuracy was due to overfitting. Both models provided biologically informative insights into asthma; in particular, a role for dysregulated arginine metabolism and several exogenous metabolites that deserve further investigation as potential causative agents. As the BN model outperformed the PLS-DA model in both accuracy and decreased risk of overfitting, it may therefore represent a viable alternative to typical analytical approaches for the investigation of metabolomics data.

Published
2018
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