Maternal exposure to outdoor air pollution and congenital limb deficiencies in the National Birth Defects Prevention Study

Background: Congenital limb deficiencies (CLDs) are a relatively common group of birth defects whose etiology is mostly unknown. Recent studies suggest maternal air pollution exposure as a potential risk factor. Aim: To investigate the relationship between ambient air pollution exposure during early pregnancy and offspring CLDs. Methods: The study population was identified from the National Birth Defects Prevention Study, a population-based multi-center case-control study, and consisted of 615 CLD cases and 5,701 controls with due dates during 1997 through 2006. Daily averages and/or maxima of six criteria air pollutants (particulate matter <2.5 μm [PM2.5], particulate matter <10 μm [PM10], nitrogen dioxide [NO2], sulfur dioxide [SO2], carbon monoxide [CO], and ozone [O3]) were averaged over gestational weeks 2–8, as well as for individual weeks during this period, using data from EPA air monitors nearest to the maternal address. Logistic regression was used to estimate odds ratios (aORs) and 95% confidence intervals (CIs) adjusted for maternal age, race/ethnicity, education, and study center. We estimated aORs for any CLD and CLD subtypes (i.e., transverse, longitudinal, and preaxial). Potential confounding by co-pollutant was assessed by adjusting for one additional air pollutant. Using the single pollutant model, we further investigated effect measure modification by body mass index, cigarette smoking, and folic acid use. Sensitivity analyses were conducted restricting to those with a residence closer to an air monitor. Results: We observed near-null aORs for CLDs per interquartile range (IQR) increase in PM10, PM2.5, and O3. However, weekly averages of the daily average NO2 and SO2, and daily max NO2, SO2, and CO concentrations were associated with increased odds of CLDs. The crude ORs ranged from 1.03 to 1.12 per IQR increase in these air pollution concentrations, and consistently elevated aORs were observed for CO. Stronger associations were observed for SO2 and O3 in subtype analysis (preaxial). In co-pollutant adjusted models, associations with CO remained elevated (aORs: 1.02–1.30); but aORs for SO2 and NO2 became near-null. The aORs for CO remained elevated among mothers who lived within 20 km of an air monitor. The aORs varied by maternal BMI, smoking status, and folic acid use. Conclusion: We observed modest associations between CLDs and air pollution exposures during pregnancy, including CO, SO2, and NO2, though replication through further epidemiologic research is warranted

Inter-Individual Variation in Response to Estrogen in Human Breast Explants

Exposure to estrogen is strongly associated with increased breast cancer risk. While all women are exposed to estrogen, only 12% are expected to develop breast cancer during their lifetime. These women may be more sensitive to estrogen, as rodent models have demonstrated variability in estrogen sensitivity. Our objective was to determine individual variation in expression of estrogen receptor (ER) and estrogen-induced responses in the normal human breast. Human breast tissue from female donors undergoing reduction mammoplasty surgery were collected for microarray analysis of ER expression. To examine estrogen-induced responses, breast tissue from 23 female donors were cultured ex- vivo in basal or 10 nM 17β-estradiol (E2) media for 4 days. Expression of ER genes (ESR1 and ESR2) increased significantly with age. E2 induced consistent increases in global gene transcription, but expression of target genes AREG, PGR, and TGFβ2 increased significantly only in explants from nulliparous women. E2-treatment did not induce consistent changes in proliferation or radiation induced apoptosis. Responses to estrogen are highly variable among women and not associated with levels of ER expression, suggesting differences in intracellular signaling among individuals. The differences in sensitivity to E2-stimulated responses may contribute to variation in risk of breast cancer

Paternal genetic variants and risk of obstructive heart defects: A parent-of-origin approach

Previous research on risk factors for obstructive heart defects (OHDs) focused on maternal and infant genetic variants, prenatal environmental exposures, and their potential interaction effects. Less is known about the role of paternal genetic variants or environmental exposures and risk of OHDs. We examined parent-of-origin effects in transmission of alleles in the folate, homocysteine, or transsulfuration pathway genes on OHD occurrence in offspring. We used data on 569 families of liveborn infants with OHDs born between October 1997 and August 2008 from the National Birth Defects Prevention Study to conduct a family-based case-only study. Maternal, paternal, and infant DNA were genotyped using an Illumina Golden Gate custom single nucleotide polymorphism (SNP) panel. Relative risks (RR), 95% confidence interval (CI), and likelihood ratio tests from log-linear models were used to estimate the parent-of-origin effect of 877 SNPs in 60 candidate genes in the folate, homocysteine, and transsulfuration pathways on the risk of OHDs. Bonferroni correction was applied for multiple testing. We identified 3 SNPs in the transsulfuration pathway and 1 SNP in the folate pathway that were statistically significant after Bonferroni correction. Among infants who inherited paternally-derived copies of the G allele for rs6812588 in the RFC1 gene, the G allele for rs1762430 in the MGMT gene, and the A allele for rs9296695 and rs4712023 in the GSTA3 gene, RRs for OHD were 0.11 (95% CI: 0.04, 0.29, P = 9.16x10-7), 0.30 (95% CI: 0.17, 0.53, P = 9.80x10-6), 0.34 (95% CI: 0.20, 0.57, P = 2.28x10-5), and 0.34 (95% CI: 0.20, 0.58, P = 3.77x10-5), respectively, compared to infants who inherited maternally-derived copies of the same alleles. We observed statistically significant decreased risk of OHDs among infants who inherited paternal gene variants involved in folate and transsulfuration pathways

A genome-wide association study of obstructive heart defects among participants in the National Birth Defects Prevention Study

Obstructive heart defects (OHDs) share common structural lesions in arteries and cardiac valves, accounting for ~25% of all congenital heart defects. OHDs are highly heritable, resulting from interplay among maternal exposures, genetic susceptibilities, and epigenetic phenomena. A genome-wide association study was conducted in National Birth Defects Prevention Study participants (Ndiscovery = 3978; Nreplication = 2507), investigating the genetic architecture of OHDs using transmission/disequilibrium tests (TDT) in complete case-parental trios (Ndiscovery_TDT = 440; Nreplication_TDT = 275) and case–control analyses separately in infants (Ndiscovery_CCI = 1635; Nreplication_CCI = 990) and mothers (case status defined by infant; Ndiscovery_CCM = 1703; Nreplication_CCM = 1078). In the TDT analysis, the SLC44A2 single nucleotide polymorphism (SNP) rs2360743 was significantly associated with OHD (pdiscovery = 4.08 × 10−9; preplication = 2.44 × 10−4). A CAPN11 SNP (rs55877192) was suggestively associated with OHD (pdiscovery = 1.61 × 10−7; preplication = 0.0016). Two other SNPs were suggestively associated (p < 1 × 10−6) with OHD in only the discovery sample. In the case–control analyses, no SNPs were genome-wide significant, and, even with relaxed thresholds (× discovery < 1 × 10−5 and preplication < 0.05), only one SNP (rs188255766) in the infant analysis was associated with OHDs (pdiscovery = 1.42 × 10−6; preplication = 0.04). Additional SNPs with pdiscovery < 1 × 10−5 were in loci supporting previous findings but did not replicate. Overall, there was modest evidence of an association between rs2360743 and rs55877192 and OHD and some evidence validating previously published findings

Handgrip strength cannot be assumed a proxy for overall muscle strength

Objectives: Dynapenia, low muscle strength, is predictive for negative health outcomes and is usually expressed as handgrip strength (HGS). Whether HGS can be a proxy for overall muscle strength and whether this depends on age and health status is controversial. This study assessed the agreement between HGS and knee extension strength (KES) in populations differing in age and health status. Design: Data were retrieved from 5 cohorts. Setting and Participants: Community, geriatric outpatient clinics, and a hospital. Five cohorts (960 individuals, 49.8% male) encompassing healthy young and older individuals, geriatric outpatients, and older individuals post hip fracture were included. Measures: HGS and KES were measured according to the protocol of each cohort. Pearson correlation was performed to analyze the association between HGS and KES, stratified by sex. HGS and KES were standardized into sex-specific z scores. The agreement between standardized HGS and standardized KES at population level and individual level were assessed by intraclass correlation coefficients (ICC) and Bland-Altman analysis. Results: Pearson correlation coefficients were low in healthy young (male: 0.36 to 0.45, female: 0.45) and healthy older individuals (male: 0.35 to 0.37, female: 0.44), and moderate in geriatric outpatients (male and female: 0.54) and older individuals post hip fracture (male: 0.44, female: 0.57) (P<.05, except for male older individuals post hip fracture [P¼.07]). Intraclass correlation coefficient values were poor to moderate in all populations (ie, healthy young individuals [0.41, 0.45], healthy older individuals [0.37, 0.41, 0.44], geriatric outpatients [0.54], and older individuals post hip fracture [0.54]). Bland-Altman analysis showed that within the same population of age and health status, agreement between HGS and KES varied on individual level

Exome sequencing identifies variants in infants with sacral agenesis

Background: Sacral agenesis (SA) consists of partial or complete absence of the caudal end of the spine and often presents with additional birth defects. Several studies have examined gene variants for syndromic forms of SA, but only one has examined exomes of children with non-syndromic SA. Methods: Using buccal cell specimens from families of children with non-syndromic SA, exomes of 28 child–parent trios (eight with and 20 without a maternal diagnosis of pregestational diabetes) and two child–father duos (neither with diagnosis of maternal pregestational diabetes) were exome sequenced. Results: Three children had heterozygous missense variants in ID1 (Inhibitor of DNA Binding 1), with CADD scores >20 (top 1% of deleterious variants in the genome); two children inherited the variant from their fathers and one from the child's mother. Rare missense variants were also detected in PDZD2 (PDZ Domain Containing 2; N = 1) and SPTBN5 (Spectrin Beta, Non-erythrocytic 5; N = 2), two genes previously suggested to be associated with SA etiology. Examination of variants with autosomal recessive and X-linked recessive inheritance identified five and two missense variants, respectively. Compound heterozygous variants were identified in several genes. In addition, 12 de novo variants were identified, all in different genes in different children. Conclusions: To our knowledge, this is the first study reporting a possible association between ID1 and non-syndromic SA. Although maternal pregestational diabetes has been strongly associated with SA, the missense variants in ID1 identified in two of three children were paternally inherited. These findings add to the knowledge of gene variants associated with non-syndromic SA and provide data for future studies

Exome sequencing identifies genetic variants in anophthalmia and microphthalmia

Anophthalmia and microphthalmia (A/M) are rare birth defects affecting up to 2 per 10,000 live births. These conditions are manifested by the absence of an eye or reduced eye volumes within the orbit leading to vision loss. Although clinical case series suggest a strong genetic component in A/M, few systematic investigations have been conducted on potential genetic contributions owing to low population prevalence. To overcome this challenge, we utilized DNA samples and data collected as part of the National Birth Defects Prevention Study (NBDPS). The NBDPS employed multi-center ascertainment of infants affected by A/M. We performed exome sequencing on 67 family trios and identified numerous genes affected by rare deleterious nonsense and missense variants in this cohort, including de novo variants. We identified 9 nonsense changes and 86 missense variants that are absent from the reference human population (Genome Aggregation Database), and we suggest that these are high priority candidate genes for A/M. We also performed literature curation, single cell transcriptome comparisons, and molecular pathway analysis on the candidate genes and performed protein structure modeling to determine the potential pathogenic variant consequences on PAX6 in this disease

A muon-track reconstruction exploiting stochastic losses for large-scale Cherenkov detectors

IceCube is a cubic-kilometer Cherenkov telescope operating at the South Pole. The main goal of IceCube is the detection of astrophysical neutrinos and the identification of their sources. High-energy muon neutrinos are observed via the secondary muons produced in charge current interactions with nuclei in the ice. Currently, the best performing muon track directional reconstruction is based on a maximum likelihood method using the arrival time distribution of Cherenkov photons registered by the experiment\u27s photomultipliers. A known systematic shortcoming of the prevailing method is to assume a continuous energy loss along the muon track. However at energies >1 TeV the light yield from muons is dominated by stochastic showers. This paper discusses a generalized ansatz where the expected arrival time distribution is parametrized by a stochastic muon energy loss pattern. This more realistic parametrization of the loss profile leads to an improvement of the muon angular resolution of up to 20% for through-going tracks and up to a factor 2 for starting tracks over existing algorithms. Additionally, the procedure to estimate the directional reconstruction uncertainty has been improved to be more robust against numerical errors

Exome-wide assessment of isolated biliary atresia: A report from the National Birth Defects Prevention Study using child–parent trios and a case–control design to identify novel rare variants

The etiology of biliary atresia (BA) is unknown, but recent studies suggest a role for rare protein-altering variants (PAVs). Exome sequencing data from the National Birth Defects Prevention Study on 54 child–parent trios, one child–mother duo, and 1513 parents of children with other birth defects were analyzed. Most (91%) cases were isolated BA. We performed (1) a trio-based analysis to identify rare de novo, homozygous, and compound heterozygous PAVs and (2) a case–control analysis using a sequence kernel-based association test to identify genes enriched with rare PAVs. While we replicated previous findings on PKD1L1, our results do not suggest that recurrent de novo PAVs play important roles in BA susceptibility. In fact, our finding in NOTCH2, a disease gene associated with Alagille syndrome, highlights the difficulty in BA diagnosis. Notably, IFRD2 has been implicated in other gastrointestinal conditions and warrants additional study. Overall, our findings strengthen the hypothesis that the etiology of BA is complex