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2.  Genome-Wide Expression Profiles Identify Potential Targets for Gene by Environment Interactions in Asthma Severity 
Gene by environment interaction (G × E) studies utilizing GWAS data are often underpowered after adjustment for multiple comparisons. Differential gene expression, in response to the exposure of interest, may capture the most biologically relevant genes at the genome-wide level.
We used differential genome-wide expression profiles from the Home Allergens and Asthma Birth cohort in response to Der f 1 allergen (sensitized vs. non-sensitized) to inform a G × E study of dust mite exposure and asthma severity. Polymorphisms in differentially expressed genes were identified in GWAS data from CAMP, a clinical trial in childhood asthmatics. Home dust mite allergen (< or ≥ 10µg/g dust) was assessed at baseline, and (≥ 1) severe asthma exacerbation (emergency room (ER) visit or hospitalization for asthma in the first trial year) served as the disease severity outcome. The Genetics of Asthma in Costa Rica (GACRS) study, and a Puerto Rico/Connecticut asthma cohortwere used for replication.
IL-9, IL-5 and PRG2 expression was up-regulated in Der f 1 stimulated PBMCs from dust mite sensitized individuals (adj. p value <0.04). IL-9 polymorphisms (rs11741137, rs2069885, rs1859430) showed evidence for interaction with dust mite in CAMP (p=0.02 to 0.03), with replication in GACRS (p=0.04). Subjects with the dominant genotype for these IL-9 polymorphisms were more likely to report a severe asthma exacerbation if exposed to elevated dust mite.
Genome-wide differential gene expression in response to dust mite allergen identified IL-9, a biologically plausible gene target that may interact with environmental dust mite to increase severe asthma exacerbations in children.
PMCID: PMC4763940  PMID: 25913104
3.  Longitudinal Prediction of the Infant Gut Microbiome with Dynamic Bayesian Networks 
Scientific Reports  2016;6:20359.
Sequencing of the 16S rRNA gene allows comprehensive assessment of bacterial community composition from human body sites. Previously published and publicly accessible data on 58 preterm infants in the Neonatal Intensive Care Unit who underwent frequent stool collection was used. We constructed Dynamic Bayesian Networks from the data and analyzed predictive performance and network characteristics. We constructed a DBN model of the infant gut microbial ecosystem, which explicitly captured specific relationships and general trends in the data: increasing amounts of Clostridia, residual amounts of Bacilli, and increasing amounts of Gammaproteobacteria that then give way to Clostridia. Prediction performance of DBNs with fewer edges were overall more accurate, although less so on harder-to-predict subjects (p = 0.045). DBNs provided quantitative likelihood estimates for rare abruptions events. Iterative prediction was less accurate (p < 0.001), but showed remarkable insensitivity to initial conditions and predicted convergence to a mix of Clostridia, Gammaproteobacteria, and Bacilli. DBNs were able to identify important relationships between microbiome taxa and predict future changes in microbiome composition from measured or synthetic initial conditions. DBNs also provided likelihood estimates for sudden, dramatic shifts in microbiome composition, which may be useful in guiding further analysis of those samples.
PMCID: PMC4745046  PMID: 26853461
4.  Prenatal and Infant Exposure to Acetaminophen and Ibuprofen and the Risk for Wheeze and Asthma in Children 
Several studies have reported an association between use of over-the-counter antipyretics during pregnancy or infancy and increased asthma risk. An important potential limitation of these observational studies is confounding by indication.
We investigated the association of antipyretic intake, 1) during pregnancy and 2) during the first year of life (infancy), with asthma-related outcomes, before and after controlling for early life respiratory infections.
We included 1490 mother-child pairs in Project Viva, a longitudinal pre-birth cohort study. We categorized prenatal acetaminophen exposure as the maximum intake (never, 1–9 or ≥ 10 times) in early or mid-pregnancy, and ibuprofen intake as presence or absence in early pregnancy. We expressed intakes of antipyretics in infancy as never, 1–5, 6–10, or >10 times. We examined the associations of acetaminophen and ibuprofen (per unit increase in exposure category) during pregnancy and infancy with wheeze, asthma and allergen sensitization in early (3–5 y) (n= 1419) and mid-childhood (7–10 y) (n= 1220).
Unadjusted models showed an elevated asthma risk in early childhood for higher infant acetaminophen (OR 1.21, 95% CI 1.04, 1.41) and ibuprofen (OR 1.35, 95% CI 1.19, 1.52) intake. Controlling for respiratory infections attenuated estimates for acetaminophen (OR 1.03, 95% CI 0.88, 1.22) and ibuprofen (OR 1.19, 95% CI 1.05, 1.36). Prenatal acetaminophen was associated with increased asthma (OR 1.26, 95% CI 1.02, 1.58) in early but not mid-childhood.
Adjustment for respiratory infections in early life substantially diminished associations between infant antipyretics and early childhood asthma. Respiratory infections should be accounted for in studies of antipyretics and asthma, to mitigate bias due to confounding by indication.
PMCID: PMC4323723  PMID: 25441647
Asthma; antipyretic; analgesic; respiratory infection
5.  Cohort Profile: Project Viva 
We established Project Viva to examine prenatal diet and other factors in relation to maternal and child health. We recruited pregnant women at their initial prenatal visit in eastern Massachusetts between 1999 and 2002. Exclusion criteria included multiple gestation, inability to answer questions in English, gestational age ≥22 weeks at recruitment and plans to move away before delivery. We completed in-person visits with mothers during pregnancy in the late first (median 9.9 weeks of gestation) and second (median 27.9 weeks) trimesters. We saw mothers and children in the hospital during the delivery admission and during infancy (median age 6.3 months), early childhood (median 3.2 years) and mid-childhood (median 7.7 years). We collected information from mothers via interviews and questionnaires, performed anthropometric and neurodevelopmental assessments and collected biosamples. We have collected additional information from medical records and from mailed questionnaires sent annually to mothers between in-person visits and to children beginning at age 9 years. From 2341 eligible women, there were 2128 live births; 1279 mother-child pairs provided data at the mid-childhood visit. Primary study outcomes include pregnancy outcomes, maternal mental and cardiometabolic health and child neurodevelopment, asthma/atopy and obesity/cardiometabolic health. Investigators interested in learning more about how to obtain Project Viva data can contact
PMCID: PMC4339753  PMID: 24639442
Pregnancy; cohort; obesity; nutrition; childhood
6.  Dietary anthocyanin intake and age-related decline in lung function: longitudinal findings from the VA Normative Aging Study123 
Background: It is unknown whether habitual intake of dietary flavonoids, known for their antioxidative and anti-inflammatory properties, affects longitudinal change in lung function.
Objective: We investigated whether different flavonoid subclasses present in the habitual diet were associated with beneficial changes in lung function over time in the elderly.
Design: This longitudinal analysis included 839 participants from the VA (Veterans Affairs) Normative Aging Study whose lung function [forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC)] was measured at 2 and up to 5 visits between 1992 and 2008 (n = 2623 measurements). Yearly average intake of major flavonoid subclasses (anthocyanins, flavanones, flavan-3-ols, flavonols, flavones, and polymers) was calculated from food-frequency questionnaires at each visit. We estimated adjusted differences in annual change in lung function associated with each flavonoid subclass, categorized into quartiles, in linear mixed-effects regression models after adjustment for lifestyle and dietary confounders.
Results: Strong inverse associations were found between anthocyanin intake and age-related decline in lung function. Independent of dietary and nondietary risk factors, slower rates of FEV1 and FVC decline by 23.6 (95% CI: 16.6, 30.7) and 37.3 (95% CI: 27.8, 46.8) mL/y, respectively, were observed in participants in the fourth quartile of intake compared with participants in the first quartile (P-trend < 0.0001). The protective associations observed for anthocyanin intake were present in both current/former and never smokers. Compared with no or very low intakes, an intake of ≥2 servings of anthocyanin-rich blueberries/wk was associated with slower decline in FEV1 and FVC by 22.5 (95% CI: 10.8, 34.2) and 37.9 (95% CI: 22.1, 53.7) mL/y, respectively. To a lesser extent, higher flavan-3-ol intake was also associated with slower lung function decline.
Conclusions: An attenuation of age-related lung function decline was associated with higher dietary anthocyanin intake in this longitudinal sample of predominantly elderly men. Further prospective studies are needed to confirm these novel associations.
PMCID: PMC4733262  PMID: 26791184
anthocyanins; clinical epidemiology; diet; flavonoids; lung function tests
7.  Vitamin D and the development of allergic disease: how important is it? 
Vitamin D has known effects on lung development and the immune system that may be important in the development, severity and course of allergic diseases (asthma, eczema and food allergy). Vitamin D deficiency is prevalent worldwide and may partly explain the increases in asthma and allergic diseases that have occurred over the last 50–60 years. In this review we explore past and current knowledge on the effect of vitamin D on lung development and immunomodulation and present the evidence of its role in allergic conditions. While there is growing observational and experimental evidence for the role of vitamin D, well-designed and well-powered clinical trials are needed to determine whether supplementation of vitamin D should be recommended in these disorders.
PMCID: PMC4369152  PMID: 25307157
Vitamin D; Immunomodulation; Development; Asthma and Allergy
8.  Association Between Prehospital Vitamin D Status and Hospital-Acquired Clostridium difficile Infections 
To investigate whether preadmission 25-hydroxyvitamin D (25(OH)D) levels are associated with the risk of hospital-acquired Clostridium difficile infection (HACDI).
Materials and Methods
Our retrospective cohort study focused on 568 adult patients from 2 Boston teaching hospitals between August 1993 and November 2006. All patients had 25(OH)D levels measured before hospitalization and were at risk for HACDI (defined as the presence of C difficile toxin A or B in stool samples obtained >48 hours after hospitalization). We performed multivariable regression analyses to test the association of prehospital 25(OH)D levels with HACDI while adjusting for clinically relevant covariates.
In these 568 patients, mean (SD) 25(OH)D level was 19 (12) ng/mL, and 11% of patients met criteria for incident HACDI. Following adjustment for age, sex, race (nonwhite vs white), patient type (medical vs surgical), and Deyo-Charlson index, patients with 25(OH)D levels <10 ng/mL had higher odds of HACDI (odds ratio [OR], 2.90; 95% confidence interval [CI], 1.01–8.34) compared with patients with 25(OH)D levels ≥30 ng/mL. When patients with HACDI were analyzed relative to a larger patient cohort without HACDI (n = 5047), those with 25(OH)D levels <10 ng/mL (OR, 4.96; 95% CI, 1.84–13.38) and 10–19.9 ng/mL (OR, 3.36; 95% CI, 1.28–8.85) had higher adjusted odds of HACDI compared with patients with 25(OH)D levels ≥30 ng/mL.
In our cohort of adult patients, vitamin D status before hospital admission was inversely associated with the risk of developing HACDI. These data support the need for randomized, controlled trials to test the role of vitamin D supplementation to prevent HACDI.
PMCID: PMC4402285  PMID: 24492311
vitamin D; 25-hydroxyvitamin D; Clostridium difficile; hospital-acquired infection; nosocomial infection
9.  Exposure to Traffic and Early Life Respiratory Infection: A Cohort Study 
Pediatric pulmonology  2014;10.1002/ppul.23029.
We examined whether proximity to a major roadway and traffic density around the home during pregnancy are associated with risk of early life respiratory infection in a pre-birth cohort in the Boston area. We geocoded addresses for 1,263 mother-child pairs enrolled during the first trimester of pregnancy in Project Viva during 1999-2002. We calculated distance from home to nearest major roadway and traffic density in a 100 m buffer around the home. We defined respiratory infection as maternal report of >1 doctor-diagnosed pneumonia, bronchiolitis, croup or other respiratory infection from birth until the early childhood visit (median age 3.3). We used relative risk regression models adjusting for potential confounders to estimate associations between traffic exposures and risk of respiratory infection. Distance to roadway during pregnancy was associated with risk of respiratory infection. In fully adjusted models, relative risks (95% CI) for respiratory infection were: 1.30 (1.08, 1.55) for <100 m, 1.15 (0.93, 1.41) for 100 to <200 m, and 0.95 (0.84, 1.07) for 200 to <1000 m compared with living ≥1000 m away from a major roadway. Each interquartile range increase in distance to roadway was associated with an 8% (95% CI 0.87, 0.98) lower risk, and each interquartile range increase in traffic density was associated with a 5% (95% CI 0.98, 1.13) higher risk of respiratory infection. Our findings suggest that living close to a major roadway during pregnancy may predispose the developing lung to infection in early life.
PMCID: PMC4177521  PMID: 24678045
Epidemiology; Environmental Lung Disease; Air pollution; Traffic; Prenatal exposures; Respiratory Infection
10.  Long-Term Effects of Traffic Particles on Lung Function Decline in the Elderly 
Rationale: Few studies have been performed on air pollution effects on lung function in the elderly, a vulnerable population with low reserve capacity, and even fewer have looked at changes in the rate of lung function decline.
Objectives: We evaluated the effect of long-term exposure to black carbon on levels and rates of decline in lung function in the elderly.
Methods: FVC and FEV1 were measured one to six times during the period 1995–2011 in 858 men participating in the Normative Aging Study. Exposure to black carbon, a tracer of traffic emissions, was estimated by a spatiotemporal land use regression model. We investigated the effects of moving averages of black carbon of 1–5 years before the lung function measurement using linear mixed models.
Measurements and Main Results: A 0.5 μg/m3 increase in long-term exposure to black carbon was associated with an additional rate of decline in FVC and FEV1 of between 0.5% and 0.9% per year, respectively, depending on the averaging time. In addition, black carbon exposure before the baseline visit was associated with lower levels of both FVC and FEV1, with effect estimates increasing up to 6–7% with a 5-year average exposure.
Conclusions: Our results support adverse effects of long-term exposure to traffic particles on lung function level and rate of decline in the elderly and suggest that functionally significant differences in health and risk of disability occur below the annual Environmental Protection Agency National Air Quality Standards.
PMCID: PMC4214085  PMID: 25028775
air pollution; black carbon; FEV1
11.  Peanut allergy prevalence among school-age children in a US cohort not selected for any disease 
PMCID: PMC4149917  PMID: 25086866
peanut allergy; prevalence; children; United States; food allergy
12.  Vitamin D Modulates Expression of the Airway Smooth Muscle Transcriptome in Fatal Asthma 
PLoS ONE  2015;10(7):e0134057.
Globally, asthma is a chronic inflammatory respiratory disease affecting over 300 million people. Some asthma patients remain poorly controlled by conventional therapies and experience more life-threatening exacerbations. Vitamin D, as an adjunct therapy, may improve disease control in severe asthma patients since vitamin D enhances glucocorticoid responsiveness and mitigates airway smooth muscle (ASM) hyperplasia. We sought to characterize differences in transcriptome responsiveness to vitamin D between fatal asthma- and non-asthma-derived ASM by using RNA-Seq to measure ASM transcript expression in five donors with fatal asthma and ten non-asthma-derived donors at baseline and with vitamin D treatment. Based on a Benjamini-Hochberg corrected p-value <0.05, 838 genes were differentially expressed in fatal asthma vs. non-asthma-derived ASM at baseline, and vitamin D treatment compared to baseline conditions induced differential expression of 711 and 867 genes in fatal asthma- and non-asthma-derived ASM, respectively. Functional gene categories that were highly represented in all groups included extracellular matrix, and responses to steroid hormone stimuli and wounding. Genes differentially expressed by vitamin D also included cytokine and chemokine activity categories. Follow-up qPCR and individual analyte ELISA experiments were conducted for four cytokines (i.e. CCL2, CCL13, CXCL12, IL8) to measure TNFα-induced changes by asthma status and vitamin D treatment. Vitamin D inhibited TNFα-induced IL8 protein secretion levels to a comparable degree in fatal asthma- and non-asthma-derived ASM even though IL8 had significantly higher baseline levels in fatal asthma-derived ASM. Our findings identify vitamin D-specific gene targets and provide transcriptomic data to explore differences in the ASM of fatal asthma- and non-asthma-derived donors.
PMCID: PMC4514847  PMID: 26207385
13.  Variants of Asthma and Chronic Obstructive Pulmonary Disease Genes and Lung Function Decline in Aging 
A substantial proportion of the general population has low lung function, and lung function is known to decrease as we age. Low lung function is a feature of several pulmonary disorders, such as uncontrolled asthma and chronic obstructive pulmonary disease. The objective of this study is to investigate the association of polymorphisms in asthma and chronic obstructive pulmonary disease candidate genes with rates of lung function decline in a general population sample of aging men.
We analyzed data from a cohort of 1,047 Caucasian men without known lung disease, who had a mean of 25 years of lung function data, and on whom DNA was available. The cohort was randomly divided into two groups, and we tested a total of 940 single-nucleotide polymorphisms in 44 asthma and chronic obstructive pulmonary disease candidate genes in the first group (testing cohort, n = 545) for association with change in forced expiratory volume in 1 second over time.
One hundred nineteen single-nucleotide polymorphisms that showed nominal associations in the testing cohort were then genotyped and tested in the second group (replication cohort, n = 502). Evidence for association from the testing and replication cohorts were combined, and after adjustment for multiple testing, seven variants of three genes (DPP10, NPSR1, and ADAM33) remained significantly associated with change in forced expiratory volume in 1 second over time.
Our findings that genetic variants of genes involved in asthma and chronic obstructive pulmonary disease are associated with lung function decline in normal aging participants suggest that similar genetic mechanisms may underlie lung function decline in both disease and normal aging processes.
PMCID: PMC4111635  PMID: 24253534
Genetics; Pulmonary; Normative aging; Successful aging.
14.  Genome-Wide Association Study Identifies Novel Pharmacogenomic Loci For Therapeutic Response to Montelukast in Asthma 
PLoS ONE  2015;10(6):e0129385.
Genome-wide association study (GWAS) is a powerful tool to identify novel pharmacogenetic single nucleotide polymorphisms (SNPs). Leukotriene receptor antagonists (LTRAs) are a major class of asthma medications, and genetic factors contribute to variable responses to these drugs. We used GWAS to identify novel SNPs associated with the response to the LTRA, montelukast, in asthmatics.
Using genome-wide genotype and phenotypic data available from American Lung Association - Asthma Clinical Research Center (ALA-ACRC) cohorts, we evaluated 8-week change in FEV1 related to montelukast administration in a discovery population of 133 asthmatics. The top 200 SNPs from the discovery GWAS were then tested in 184 additional samples from two independent cohorts.
Twenty-eight SNP associations from the discovery GWAS were replicated. Of these, rs6475448 achieved genome-wide significance (combined P = 1.97 x 10-09), and subjects from all four studies who were homozygous for rs6475448 showed increased ΔFEV1 from baseline in response to montelukast.
Through GWAS, we identified a novel pharmacogenomic locus related to improved montelukast response in asthmatics.
PMCID: PMC4470685  PMID: 26083242
15.  Association between prehospital vitamin D status and incident acute respiratory failure in critically ill patients: a retrospective cohort study 
BMJ Open Respiratory Research  2015;2(1):e000074.
We hypothesise that low 25-hydroxyvitamin D (25(OH)D) levels before hospitalisation are associated with increased risk of acute respiratory failure.
Retrospective cohort study.
Medical and Surgical Intensive care units of two Boston teaching hospitals.
1985 critically ill adults admitted between 1998 and 2011.
Measurements and main results
The exposure of interest was prehospital serum 25(OH)D categorised as ≤10 ng/mL, 11–19.9 ng/mL, 20–29.9 ng/mL and ≥30 ng/mL. The primary outcome was acute respiratory failure excluding congestive heart failure determined by International Classification of Diseases Ninth Edition (ICD-9) coding and validated against the Berlin Definition of acute respiratory sistress syndrome. Association between 25(OH)D and acute respiratory failure was assessed using logistic regression, while adjusting for age, race, sex, Deyo-Charlson Index and patient type (medical vs surgical).
In the cohort, the mean age was 63 years, 45% were male and 80% were white; 25(OH)D was ≤10 ng/mL in 8% of patients, 11–19.9 ng/mL in 24%, 20–29.9 ng/mL in 24% and ≥30 ng/mL in 44% of patients. Eighteen per cent (n=351) were diagnosed with acute respiratory failure. Compared to patients with 25(OH)D ≥30 ng/mL, patients with lower 25(OH)D levels had significantly higher adjusted odds of acute respiratory failure (≤10 ng/mL, OR=1.84 (95% CI 1.22 to 2.77); 11–19.9 ng/mL, OR=1.60 (95% CI 1.19 to 2.15); 20–29.9 ng/mL, OR=1.37 (95% CI 1.01 to 1.86)).
Prehospital 25(OH)D was associated with the risk of acute respiratory failure in our critically ill patient cohort.
PMCID: PMC4477148  PMID: 26113982
ARDS; Clinical Epidemiology
16.  Low serum 25-hydroxyvitamin D at critical care initiation is associated with increased mortality 
Critical care medicine  2012;40(1):63-72.
We hypothesized that deficiency in 25-hydroxy vitamin D at critical care initiation would be associated with all cause mortality.
Two-center observational study.
Two teaching hospitals in Boston, Massachusetts
1,325 patients, age ≥ 18 years, in whom 25-hydroxy vitamin D was measured 7 days prior to or after critical care initiation between 1998 and 2009.
25-hydroxy vitamin D was categorized as deficiency in 25-hydroxy vitamin D (≤15 ng/mL), insufficiency (16–29 ng/mL) and sufficiency (≥30 ng/mL). Logistic regression examined death by days 30, 90 and 365 post-critical care initiation and in hospital mortality. Adjusted odds ratios were estimated by multivariable logistic regression models.
Key Results
25-hydroxy vitamin D deficiency is predictive for short term and long term mortality. 30 days following critical care initiation, patients with 25-hydroxy vitamin D deficiency have an OR for mortality of 1.85 (95% CI, 1.15–2.98;P=0.01) relative to patients with 25-hydroxy vitamin D sufficiency. 25-hydroxy vitamin D deficiency remains a significant predictor of mortality at 30 days following critical care initiation following multivariable adjustment for age, gender, race, Deyo-Charlson index, sepsis, season, and surgical versus medical patient type (adjusted OR 1.94; 95% CI, 1.18–3.20;P=0.01). Results were similarly significant at 90 and 365 days following critical care initiation and for in hospital mortality. The association between vitamin D and mortality was not modified by sepsis, race, or Neighborhood poverty rate, a proxy for socioeconomic status.
Deficiency of 25-hydroxy vitamin D at the time of critical care initiation is a significant predictor of all cause patient mortality in a critically ill patient population.
PMCID: PMC4427350  PMID: 21926604
17.  Asthma, Allergy, and Responses to Methyl Donor Supplements and Nutrients 
After a brief period of stabilization, recent data has shown that the prevalence of asthma and allergic diseases continue to increase. Atopic diseases are major public health problems resulting in significant disability and resource utilization globally. While environmental factors influence the development of atopic disease, dietary changes may partially explain the high burden of atopic disease. One mechanism by which diet is suspected to impact asthma and allergy susceptibility is through epigenetic mechanisms including DNA methylation. Dietary methyl donors are important in the one-carbon metabolism pathway that is essential for DNA methylation. Findings from both observational studies and interventional trials of dietary methyl donor supplementation on the development and treatment of asthma and allergy have produced mixed results. While issues related to the differences in study design partially explain the heterogeneous results, two other issues have been largely overlooked in these studies. Firstly, these nutrients affect one of many pathways and occur in many of the same foods. Secondly, it is now becoming clear that the human intestinal microbiome is involved in the metabolism and production of the B vitamins and other methyl donor nutrients. Future studies will need to account for both the interrelationships between these nutrients and the effects of the microbiome.
PMCID: PMC4004707  PMID: 24360248
Allergy; Asthma; Betaine; Choline; Vitamin B2; Vitamin B6; Vitamin B12; Folate; Methyl Donor; Microbiome
18.  Peanut, milk, and wheat intake during pregnancy is associated with reduced allergy and asthma in children 
Maternal diet during pregnancy may influence childhood allergy and asthma.
To examine the associations between maternal intake of common childhood food allergens during early pregnancy and childhood allergy and asthma.
We studied 1277 mother-child pairs from a United States pre-birth cohort unselected for any disease. Using food frequency questionnaires administered during the first and second trimesters, we assessed maternal intake of common childhood food allergens during pregnancy. In mid-childhood (mean age 7.9 years), we assessed food allergy, asthma, allergic rhinitis, and atopic dermatitis by questionnaire and serum specific IgE levels. We examined the associations between maternal diet during pregnancy and childhood allergy and asthma. We also examined the cross-sectional associations between specific food allergies, asthma, and atopic conditions in mid-childhood.
Food allergy was common (5.6%) in mid-childhood, as was sensitization to at least one food allergen (28.0%). Higher maternal peanut intake (each additional z-score) during the first trimester was associated with 47% reduced odds of peanut allergic reaction (OR 0.53, 95%CI 0.30–0.94). Higher milk intake during the first trimester was associated with reduced asthma (OR 0.83, 95%CI 0.69–0.99) and allergic rhinitis (OR 0.85, 95%CI 0.74–0.97). Higher maternal wheat intake during the second trimester was associated with reduced atopic dermatitis (OR 0.64, 95%CI 0.46–0.90). Peanut, wheat, and soy allergy were each cross-sectionally associated with increased childhood asthma, atopic dermatitis, and allergic rhinitis (ORs 3.6 to 8.1).
Higher maternal intake of peanut, milk, and wheat during early pregnancy was associated with reduced odds of mid-childhood allergy and asthma.
PMCID: PMC4004710  PMID: 24522094
maternal diet; pregnancy; food allergy; sensitization; asthma; allergic rhinitis; peanut; milk; wheat; childhood
20.  Vitamin D Status and Hypertensive Disorders in Pregnancy 
Annals of epidemiology  2014;24(5):399-403.e1.
Several studies have reported increased risk of preeclampsia when 25-hyrdoxyvitamin D (25[OH]D) levels are low. The extent to which 25(OH)D may lower risk for hypertensive disorder during pregnancy remains unclear.
Among women enrolled in the Project Viva prenatal cohort in Massachusetts, we examined associations of 25(OH)D levels obtained at 16.4 –36.9 weeks of gestation (mean 27.9 weeks) with hypertensive disorders of pregnancy, including preeclampsia (56/1591, 3.5%) and gestational hypertension (109/1591, 6.9%).
We did not detect an association between plasma 25(OH)D concentration (mean 58, SD 22 nmol/L) and preeclampsia. For each 25 nmol/L increase in 25(OH)D, the adjusted odds ratio for preeclampsia was 1.14 (95% confidence interval: 0.77, 1.67). By contrast and contrary to hypothesis, higher 25(OH)D concentrations were associated with higher odds of gestational hypertension: adjusted odds ratio for gestational hypertension was 1.32 (95% confidence interval: 1.01, 1.72) per each 25nmol/L increment in 25(OH)D. Vitamin D intake patterns suggest this association was not because of reverse causation. While the elevated hypertension risk may be due to chance, randomized trials of vitamin D supplementation during pregnancy should monitor for gestational hypertension.
These data do not support the hypothesis that higher 25(OH)D levels lower the overall risk of hypertensive disorders of pregnancy.
PMCID: PMC4011985  PMID: 24631523
Pregnancy; Pre-Eclampsia; Hypertension; Pregnancy-Induced; Vitamin D; 25-hydroxyvitamin D
21.  The Vitamin D Antenatal Asthma Reduction Trial (VDAART): Rationale, design, and methods of a randomized, controlled trial of vitamin D supplementation in pregnancy for the primary prevention of asthma and allergies in children 
Contemporary clinical trials  2014;38(1):37-50.
There is intense interest in the role of vitamin D in the development of asthma and allergies. However, studies differ on whether a higher vitamin D intake or status in pregnancy or at birth is protective against asthma and allergies. To address this uncertainty, the Vitamin D Antenatal Asthma Reduction Trial (VDAART) was developed. VDAART is a randomized, double-blind, placebo-controlled trial of vitamin D supplementation in pregnant women to determine whether prenatal supplementation can prevent the development of asthma and allergies in the women’s offspring. A secondary aim is to determine whether vitamin D supplementation can prevent the development of pregnancy complications, such as preeclampsia, preterm birth, and gestational diabetes. Women were randomized to the treatment arm of 4,000 IU/day of vitamin D3 plus a daily multivitamin that contained 400 IU of vitamin D3 or the placebo arm of placebo plus a multivitamin that contained 400 IU daily of vitamin D3. Women who were between the gestational ages of 10–18 weeks were randomized from three clinical centers across the United States – Boston Medical Center, Washington University in St. Louis, and Kaiser Permanente Southern California Region (San Diego, CA). Supplementation took place throughout pregnancy. Monthly monitoring of urinary calcium to creatinine ratio was performed in addition to medical record review for adverse events. Offspring are being evaluated quarterly through questionnaires and yearly during in-person visits until the 3rd birthday of the child. Ancillary studies will investigate neonatal T-regulatory cell function, maternal vaginal flora, and maternal and child intestinal flora.
PMCID: PMC4086903  PMID: 24614387
Vitamin D; asthma; allergy; randomized controlled trial; Deveopmental Origins; prenatal
22.  Maternal intake of vitamin D during pregnancy and risk of recurrent wheeze in children at 3 y of age1–3 
Vitamin D deficiency and asthma are common at higher latitudes. Although vitamin D has important immunologic effects, its relation with asthma is unknown.
We hypothesized that a higher maternal intake of vitamin D during pregnancy is associated with a lower risk of recurrent wheeze in children at 3 y of age.
The participants were 1194 mother-child pairs in Project Viva—a prospective prebirth cohort study in Massachusetts. We assessed the maternal intake of vitamin D during pregnancy from a validated food-frequency questionnaire. The primary outcome was recurrent wheeze, ie, a positive asthma predictive index (≥2 wheezing attacks among children with a personal diagnosis of eczema or a parental history of asthma).
The mean (±SD) total vitamin D intake during pregnancy was 548 ± 167 IU/d. By age 3 y, 186 children (16%) had recurrent wheeze. Compared with mothers in the lowest quartile of daily intake (median: 356 IU), those in the highest quartile (724 IU) had a lower risk of having a child with recurrent wheeze [odds ratio (OR): 0.39; 95% CI: 0.25, 0.62; P for trend <0.001]. A 100-IU increase in vitamin D intake was associated with lower risk (OR: 0.81; 95% CI: 0.74, 0.89), regardless of whether vitamin D was from the diet (OR: 0.81; 95% CI: 0.69, 0.96) or supplements (OR: 0.82; 95% CI: 0.73, 0.92). Adjustment for 12 potential confounders, including maternal intake of other dietary factors, did not change the results.
In the northeastern United States, a higher maternal intake of vitamin D during pregnancy may decrease the risk of recurrent wheeze in early childhood.
PMCID: PMC4406411  PMID: 17344501
Vitamin D; pregnancy; dietary intake; childhood wheeze; asthma
23.  Vitamin D status among preterm and full-term infants at birth 
Pediatric research  2013;75(0):75-80.
Risk factors for maternal vitamin D deficiency and preterm birth overlap but the distribution of 25-hydroxyvitamin D (25(OH)D) levels among preterm infants is not known. We aimed to determine associations between 25(OH)D levels and gestational age.
We measured umbilical cord plasma levels of 25(OH)D from 471 infants born at Brigham and Women’s Hospital in Boston. We used generalized estimating equations to determine whether preterm (<37 weeks’ gestation) or very preterm (<32 weeks’ gestation) infants had greater odds of 25(OH)D levels < 20 ng/ml than more mature infants. We adjusted for potential confounding by season of birth, maternal age, race, marital status and singleton or multiple gestation.
Mean cord plasma 25(OH)D level was 34.0 ng/ml (range 4.1 to 95.3, and SD 14.1). Infants born before 32 weeks’ gestation had increased odds of 25(OH)D levels < 20 ng/ml in unadjusted (OR 2.2, 95% CI 1.1, 4.3) and adjusted models (OR 2.4, 95% CI 1.2, 5.3) compared to more mature infants.
Infants born < 32 weeks’ gestation are at higher risk than more mature infants for low 25(OH)D levels. Further investigation of the relationships between low 25(OH)D levels and preterm birth and its sequelae is thus warranted.
PMCID: PMC4349515  PMID: 24121425
24.  Inhaled corticosteroid treatment modulates ZNF432 gene variant's effect on bronchodilator response in asthmatics 
Single nucleotide polymorphisms (SNPs) influence a patient's response to inhaled corticosteroids and β2-agonists, and the effect of treatment with inhaled corticosteroids is synergistic with the effect of β2-agonists. We hypothesized that use of inhaled corticosteroids could influence the effect of SNPs associated with bronchodilator response.
To assess whether, among asthma subjects, the association of SNPs with bronchodilator response is different between those treated with inhaled corticosteroids vs. those on placebo.
A genome-wide association analysis was conducted using 581 white subjects from the Childhood Asthma Management Program (CAMP). Using data for 449,540 SNPs, we conducted a gene by environment analysis in PLINK with inhaled corticosteroid treatment as the environmental exposure and bronchodilator response as the outcome measure. We attempted to replicate the top 12 SNPs in the Leukotriene Modifier Or Corticosteroid or Corticosteroid-Salmeterol (LOCCS) Trial.
The combined P-value for the CAMP and LOCCS populations was 4.81E-08 for rs3752120, which is located in the zinc finger protein gene ZNF432, and has unknown function.
Inhaled corticosteroids appear to modulate the association of bronchodilator response with variant(s) in the ZNF432 gene among adults and children with asthma.
Clinical Implications
Clinicians who treat asthma patients with inhaled corticosteroids should be aware that the patient's genetic makeup likely influences response as measured in lung function.
Capsule Summary
Our study suggests that inhaled corticosteroids could influence the effect of multiple SNPs associated with bronchodilator response across the genome.
PMCID: PMC3943570  PMID: 24280104
asthma; bronchodilator response; lung function; inhaled corticosteroids; single nucleotide polymorphisms; zinc finger proteins; ZNF432
25.  Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis 
The Lancet. Respiratory medicine  2014;2(3):214-225.
The genetic risk factors for susceptibility to chronic obstructive pulmonary disease (COPD) are still largely unknown. Additional genetic variants are likely to be identified by genome-wide association studies in larger cohorts or specific subgroups.
Genome-wide association analysis in COPDGene (non-Hispanic whites and African-Americans) was combined with existing data from the ECLIPSE, NETT/NAS, and GenKOLS (Norway) studies. Analyses were performed both using all moderate-to-severe cases and the subset of severe cases. Top loci not previously described as genome-wide significant were genotyped in the ICGN study, and results combined in a joint meta-analysis.
Analysis of a total of 6,633 moderate-to-severe cases and 5,704 controls confirmed association at three known loci: CHRNA3/CHRNA5/IREB2, FAM13A, and HHIP (10−12 < P < 10−14), and also showed significant evidence of association at a novel locus near RIN3 (overall P, including ICGN = 5•4×10−9). In the severe COPD analysis (n=3,497), the effects at two of three previously described loci were significantly stronger; we also identified two additional loci previously reported to affect gene expression of MMP12 and TGFB2 (overall P = 2•6x10−9 and 8•3×10−9). RIN3 and TGFB2 expression levels were reduced in a set of Lung Tissue Research Consortium COPD lung tissue samples compared with controls.
In a genome-wide study of COPD, we confirmed associations at three known loci and found additional genome-wide significant associations with moderate-to-severe COPD near RIN3 and with severe COPD near MMP12 and TGFB2. Genetic variants, apart from alpha-1 antitrypsin deficiency, increase the risk of COPD. Our analysis of severe COPD suggests additional genetic variants may be identified by focusing on this subgroup.
National Heart, Lung, and Blood Institute; the COPD Foundation through contributions from AstraZeneca, Boehringer Ingelheim, Novartis, and Sepracor; GlaxoSmithKline; Centers for Medicare and Medicaid Services; Agency for Healthcare Research and Quality; US Department of Veterans Affairs.
PMCID: PMC4176924  PMID: 24621683

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