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We investigate 71 single nucleotide polymorphisms (SNPs) identified in meta-analytic studies of genome-wide association studies (GWAS) of breast cancer, the majority of which are located in intergenic or intronic regions. To explore regulatory impacts of these variants we conducted expression quantitative loci (eQTL) analyses on tissue samples from 376 invasive postmenopausal breast cancer cases in the Nurses’ Health Study (NHS) diagnosed from 1990–2004. Expression analysis was conducted on all formalin-fixed paraffin-embedded (FFPE) tissue samples (and on 264 adjacent normal samples) using the Affymetrix Human Transcriptome Array. Significance and ranking of associations between tumor receptor status and expression variation was preserved between NHS FFPE and TCGA fresh-frozen sample sets (Spearman r = 0.85, p<10^-10 for 17 of the 21 Oncotype DX recurrence signature genes). At an FDR threshold of 10%, we identified 27 trans-eQTLs associated with expression variation in 217 distinct genes. SNP-gene associations can be explored using an open-source interactive browser distributed in a Bioconductor package. Using a new a procedure for testing hypotheses relating SNP content to expression patterns in gene sets, defined as molecular function pathways, we find that loci on 6q14 and 6q25 affect various gene sets and molecular pathways (FDR < 10%). Although the ultimate biological interpretation of the GWAS-identified variants remains to be uncovered, this study validates the utility of expression analysis of this FFPE expression set for more detailed integrative analyses. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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. Results: 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. Conclusion: Overall, our results suggest that the early‐life, including prenatal, fecal microbiome modifies risk of asthma, especially asthma with onset by age 3 years. [ABSTRACT FROM AUTHOR]

Importance: Asthma and wheezing begin early in life, and prenatal vitamin D deficiency has been variably associated with these disorders in offspring.Objective: To determine whether prenatal vitamin D (cholecalciferol) supplementation can prevent asthma or recurrent wheeze in early childhood.Design, Setting, and Participants: The Vitamin D Antenatal Asthma Reduction Trial was a randomized, double-blind, placebo-controlled trial conducted in 3 centers across the United States. Enrollment began in October 2009 and completed follow-up in January 2015. Eight hundred eighty-one pregnant women between the ages of 18 and 39 years at high risk of having children with asthma were randomized at 10 to 18 weeks' gestation. Five participants were deemed ineligible shortly after randomization and were discontinued.Interventions: Four hundred forty women were randomized to receive daily 4000 IU vitamin D plus a prenatal vitamin containing 400 IU vitamin D, and 436 women were randomized to receive a placebo plus a prenatal vitamin containing 400 IU vitamin D.Main Outcomes and Measures: Coprimary outcomes of (1) parental report of physician-diagnosed asthma or recurrent wheezing through 3 years of age and (2) third trimester maternal 25-hydroxyvitamin D levels.Results: Eight hundred ten infants were born in the study, and 806 were included in the analyses for the 3-year outcomes. Two hundred eighteen children developed asthma or recurrent wheeze: 98 of 405 (24.3%; 95% CI, 18.7%-28.5%) in the 4400-IU group vs 120 of 401 (30.4%, 95% CI, 25.7%-73.1%) in the 400-IU group (hazard ratio, 0.8; 95% CI, 0.6-1.0; P = .051). Of the women in the 4400-IU group whose blood levels were checked, 289 (74.9%) had 25-hydroxyvitamin D levels of 30 ng/mL or higher by the third trimester of pregnancy compared with 133 of 391 (34.0%) in the 400-IU group (difference, 40.9%; 95% CI, 34.2%-47.5%, P < .001).Conclusions and Relevance: In pregnant women at risk of having a child with asthma, supplementation with 4400 IU/d of vitamin D compared with 400 IU/d significantly increased vitamin D levels in the women. The incidence of asthma and recurrent wheezing in their children at age 3 years was lower by 6.1%, but this did not meet statistical significance; however, the study may have been underpowered. Longer follow-up of the children is ongoing to determine whether the difference is clinically important.Trial Registration: clinicaltrials.gov Identifier: NCT00920621. [ABSTRACT FROM AUTHOR]

IMPORTANCE Foods that have similar carbohydrate content can differ in the amount they raise blood glucose. The effects of this property, called the glycemic index, on risk factors for cardiovascular disease and diabetes are not well understood. OBJECTIVE To determine the effect of glycemic index and amount of total dietary carbohydrate on risk factors for cardiovascular disease and diabetes. DESIGN, SETTING, AND PARTICIPANTS Randomized crossover-controlled feeding trial conducted in research units in academic medical centers, in which 163 overweight adults (systolic blood pressure, 120-159mmHg) were given 4 complete diets that contained all of their meals, snacks, and calorie-containing beverages, each for 5 weeks, and completed at least 2 study diets. The first participant was enrolled April 1, 2008; the last participant finished December 22, 2010. For any pair of the 4 diets, there were 135 to 150 participants contributing at least 1 primary outcome measure. INTERVENTIONS (1) A high-glycemic index (65%on the glucose scale), high-carbohydrate diet (58%energy); (2) a low-glycemic index (40%), high-carbohydrate diet; (3) a high-glycemic index, low-carbohydrate diet (40% energy); and (4) a low-glycemic index, low-carbohydrate diet. Each diet was based on a healthful DASH-type diet. MAIN OUTCOMES AND MEASURES The 5 primary outcomeswere insulin sensitivity, determined from the areas under the curves of glucose and insulin levels during an oral glucose tolerance test; levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides; and systolic blood pressure. RESULTS At high dietary carbohydrate content, the low-compared with high-glycemic index level decreased insulin sensitivity from 8.9 to 7.1 units (-20%, P = .002); increased LDL cholesterol from 139 to 147mg/dL (6%, P ≤ .001); and did not affect levels of HDL cholesterol, triglycerides, or blood pressure. At low carbohydrate content, the low- compared with high-glycemic index level did not affect the outcomes except for decreasing triglycerides from 91 to 86mg/dL (-5%, P = .02). In the primary diet contrast, the low-glycemic index, low-carbohydrate diet, compared with the high-glycemic index, high-carbohydrate diet, did not affect insulin sensitivity, systolic blood pressure, LDL cholesterol, or HDL cholesterol but did lower triglycerides from 111 to 86mg/dL (-23%, P ≤ .001). CONCLUSIONS AND RELEVANCE In this 5-week controlled feeding study, diets with low glycemic index of dietary carbohydrate, compared with high glycemic index of dietary carbohydrate, did not result in improvements in insulin sensitivity, lipid levels, or systolic blood pressure. In the context of an overall DASH-type diet, using glycemic index to select specific foods may not improve cardiovascular risk factors or insulin resistance. [ABSTRACT FROM AUTHOR]

Importance: Foods that have similar carbohydrate content can differ in the amount they raise blood glucose. The effects of this property, called the glycemic index, on risk factors for cardiovascular disease and diabetes are not well understood.Objective: To determine the effect of glycemic index and amount of total dietary carbohydrate on risk factors for cardiovascular disease and diabetes.Design, Setting, and Participants: Randomized crossover-controlled feeding trial conducted in research units in academic medical centers, in which 163 overweight adults (systolic blood pressure, 120-159 mm Hg) were given 4 complete diets that contained all of their meals, snacks, and calorie-containing beverages, each for 5 weeks, and completed at least 2 study diets. The first participant was enrolled April 1, 2008; the last participant finished December 22, 2010. For any pair of the 4 diets, there were 135 to 150 participants contributing at least 1 primary outcome measure.Interventions: (1) A high-glycemic index (65% on the glucose scale), high-carbohydrate diet (58% energy); (2) a low-glycemic index (40%), high-carbohydrate diet; (3) a high-glycemic index, low-carbohydrate diet (40% energy); and (4) a low-glycemic index, low-carbohydrate diet. Each diet was based on a healthful DASH-type diet.Main Outcomes and Measures: The 5 primary outcomes were insulin sensitivity, determined from the areas under the curves of glucose and insulin levels during an oral glucose tolerance test; levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides; and systolic blood pressure.Results: At high dietary carbohydrate content, the low- compared with high-glycemic index level decreased insulin sensitivity from 8.9 to 7.1 units (-20%, P = .002); increased LDL cholesterol from 139 to 147 mg/dL (6%, P ≤ .001); and did not affect levels of HDL cholesterol, triglycerides, or blood pressure. At low carbohydrate content, the low- compared with high-glycemic index level did not affect the outcomes except for decreasing triglycerides from 91 to 86 mg/dL (-5%, P = .02). In the primary diet contrast, the low-glycemic index, low-carbohydrate diet, compared with the high-glycemic index, high-carbohydrate diet, did not affect insulin sensitivity, systolic blood pressure, LDL cholesterol, or HDL cholesterol but did lower triglycerides from 111 to 86 mg/dL (-23%, P ≤ .001).Conclusions and Relevance: In this 5-week controlled feeding study, diets with low glycemic index of dietary carbohydrate, compared with high glycemic index of dietary carbohydrate, did not result in improvements in insulin sensitivity, lipid levels, or systolic blood pressure. In the context of an overall DASH-type diet, using glycemic index to select specific foods may not improve cardiovascular risk factors or insulin resistance.Trial Registration: clinicaltrials.gov Identifier: NCT00608049. [ABSTRACT FROM AUTHOR]

Abstract: 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 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 4000IU/day of vitamin D3 plus a daily multivitamin that contained 400IU of vitamin D3 or the placebo arm of placebo plus a multivitamin that contained 400IU daily of vitamin D3. Women who were between the gestational ages of 10 and 18weeks 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. [Copyright &y& Elsevier]

To determine the relative contributions of triglycerides (TGs) and high-density lipoprotein (HDL) cholesterol in the residual risk of coronary heart disease (CHD) after the reduction of low-density lipoprotein (LDL) cholesterol to guideline-recommended levels, we conducted a hospital-based, case-control study with optimal matching in the strata of LDL cholesterol, gender, ethnicity, and age. The 170 cases and 175 controls were patients at Brigham and Women''s Hospital (Boston, Massachusetts) from 2005 to 2008 who had an LDL cholesterol level <130 mg/dl. The cases had incident CHD, and the controls had diagnoses unrelated to CHD. The 170 cases and 175 controls had a mean LDL cholesterol level of 73 and 87 mg/dl, respectively. The association between TG and HDL cholesterol levels and CHD risk was assessed using conditional and unconditional logistic regression analysis. The models investigated accommodated the possibility of an interaction between lipid factors. The odds of CHD increased by approximately 20% per 23-mg/dl increase in TGs and decreased by approximately 40% per 7.5-mg/dl decrease in HDL cholesterol. High TGs and low HDL cholesterol interacted synergistically to increase the odds ratio to 10 for the combined greatest TG (≥190 mg/dl) and lowest HDL cholesterol quintiles (<30 mg/dl). High TG levels were more strongly associated with CHD when the HDL cholesterol was low than average or high; and low HDL cholesterol levels were more strongly associated with CHD when the TGs were high. TGs and HDL cholesterol were associated with CHD in patients with a LDL cholesterol level of ≤70 mg/dl, with a risk similar to, or greater than, those in the total group. In conclusion, high TG and low HDL cholesterol levels contribute strongly and synergistically to CHD when LDL cholesterol is well controlled. Thus, high TGs might have greater importance in patients with optimal rather than greater LDL cholesterol concentrations. [Copyright &y& Elsevier]