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BackgroundPolycyclic aromatic hydrocarbons (PAHs) are ubiquitous pollutants originating from petrogenic and pyrogenic sources. PAH compounds can cross the placenta, and prenatal PAH exposure is linked to adverse infant and childhood health outcomes.ObjectiveIn this first human transcriptomic assessment of PAHs in the placenta, we examined associations between prenatal PAH exposure and placental gene expression to gain insight into mechanisms by which PAHs may disrupt placental function.MethodsThe ECHO PATHWAYS Consortium quantified prenatal PAH exposure and the placental transcriptome from 629 pregnant participants enrolled in the CANDLE study. Concentrations of 12 monohydroxy-PAH (OH-PAH) metabolites were measured in mid-pregnancy urine using high performance liquid chromatography tandem mass spectrometry. Placental transcriptomic data were obtained using paired-end RNA sequencing. Linear models were fitted to estimate covariate-adjusted associations between maternal urinary OH-PAHs and placental gene expression. We performed sex-stratified analyses to evaluate whether associations varied by fetal sex. Selected PAH/gene expression analyses were validated by treating HTR-8/SVneo cells with phenanthrene, and quantifying expression via qPCR.ResultsUrinary concentrations of 6 OH-PAHs were associated with placental expression of 8 genes. Three biological pathways were associated with 4 OH-PAHs. Placental expression of SGF29 and TRIP13 as well as the vitamin digestion and absorption pathway were positively associated with multiple metabolites. HTR-8/SVneo cells treated with phenanthrene also exhibited 23 % increased TRIP13 expression compared to vehicle controls (p = 0.04). Fetal sex may modify the relationship between prenatal OH-PAHs and placental gene expression, as more associations were identified in females than males (45 vs 28 associations).DiscussionOur study highlights novel genes whose placental expression may be disrupted by OH-PAHs. Increased expression of DNA damage repair gene TRIP13 may represent a response to double-stranded DNA breaks. Increased expression of genes involved in vitamin digestion and metabolism may reflect dietary exposures or represent a compensatory mechanism to combat damage related to OH-PAH toxicity. Further work is needed to study the role of these genes in placental function and their links to perinatal outcomes and lifelong health.

BACKGROUND: Spontaneous preterm birth accounts for most preterm births and leads to significant morbidity in the newborn and childhood period. This subtype of preterm birth represents an increasing proportion of all preterm births when compared with medically indicated preterm birth, yet it is understudied in omics analyses. The placenta is a key regulator of fetal and newborn health, and the placental transcriptome can provide insight into pathologic changes that lead to spontaneous preterm birth. OBJECTIVE: This analysis aimed to identify genes for which placental expression was associated with spontaneous preterm birth (including early preterm and late preterm birth). STUDY DESIGN: The ECHO PATHWAYS consortium extracted RNA from placental samples collected from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood and the Global Alliance to Prevent Prematurity and Stillbirth studies. Placental transcriptomic data were obtained by RNA sequencing. Linear models were fit to estimate differences in placental gene expression between term birth and spontaneous preterm birth (including gestational age subgroups defined by the American College of Obstetricians and Gynecologists). Models were adjusted for numerous confounding variables, including labor status, cohort, and RNA sequencing batch. This analysis excluded patients with induced labor, chorioamnionitis, multifetal gestations, or medical indications for preterm birth. Our combined cohort contained gene expression data for 14,023 genes in 48 preterm and 540 term samples. Genes and pathways were considered statistically significantly different at false discovery rate-adjusted P value of

BackgroundMaternal exposure to air pollution has been associated with birth outcomes; however, few studies examined biologically critical exposure windows shorter than trimesters or potential effect modifiers.ObjectivesTo examine associations of prenatal fine particulate matter (PM2.5), by trimester and in biologically critical windows, with birth outcomes and assess potential effect modifiers.MethodsThis study used two pregnancy cohorts (CANDLE and TIDES; N = 2099) in the ECHO PATHWAYS Consortium. PM2.5 was estimated at the maternal residence using a fine-scale spatiotemporal model, averaged over pregnancy, trimesters, and critical windows (0-2 weeks, 10-12 weeks, and last month of pregnancy). Outcomes were preterm birth (PTB,

BackgroundWhile strong evidence supports adverse maternal and offspring consequences of air pollution, mechanisms that involve the placenta, a key part of the intrauterine environment, are largely unknown. Previous studies of air pollution and placental gene expression were small candidate gene studies that rarely considered prenatal windows of exposure or the potential role of offspring sex. We examined overall and sex-specific associations of prenatal exposure to fine particulate matter (PM2.5) with genome-wide placental gene expression.MethodsParticipants with placenta samples, collected at birth, and childhood health outcomes from CANDLE (Memphis, TN) (n = 776) and GAPPS (Seattle, WA) (n = 205) cohorts of the ECHO-PATHWAYS Consortium were included in this study. PM2.5 exposures during trimesters 1, 2, 3, and the first and last months of pregnancy, were estimated using a spatiotemporal model. Cohort-specific linear adjusted models were fit for each exposure window and expression of >11,000 protein coding genes from paired end RNA sequencing data. Models with interaction terms were used to examine PM2.5-offspring sex interactions. False discovery rate (FDR

BackgroundPolycyclic aromatic hydrocarbons (PAHs) are ubiquitous chemicals with mechanisms of toxicity that include endocrine disruption. We examined associations of prenatal urinary PAH with spontaneous preterm birth (PTB) and gestational age (GA) at birth. We also assessed whether infant sex modifies the association of PAH exposure with spontaneous PTB and GA at birth.MethodsParticipants included 1,677 non-smoking women from three cohorts (CANDLE, TIDES, and GAPPS) in the ECHO PATHWAYS Consortium. Twelve monohydroxylated-PAHs were measured in second trimester maternal urine. Seven metabolites with >60% overall detection were included in analyses: 1-hydroxynaphthalene [1-OH-NAP], 2-hydroxynaphthalene [2-OH-NAP], 2-hydroxyphenanthrene [2-OH-PHEN], 3-hydroxyphenanthrene [3-OH-PHEN], 1/9-hydroxyphenanthrene [1/9-OH-PHEN], 2/3/9-hydroxyfluorene [2/3/9-OH-FLUO], and 1-hydroxypyrene [1-OH-PYR]. Logistic and linear regression models were fit for spontaneous PTB and GA among births ≥34 weeks, respectively, with log10-transformed OH-PAH concentrations as the exposure, adjusted for specific gravity and suspected confounders. Effect modification by infant sex was assessed using interaction terms and marginal estimates.ResultsPercent detection was highest for 2-OH-NAP (99.8%) and lowest for 1-OH-PYR (65.2%). Prevalence of spontaneous PTB was 5.5% (N = 92). Ten-fold higher 2-OH-NAP exposure was associated with 1.60-day (95% CI: -2.92, -0.28) earlier GA at birth. Remaining associations in the pooled population were null. Among females, we observed significant inverse associations between 1-OH-PYR and PTB (OR: 2.65 [95% CI: 1.39, 5.05]); and 2-OH-NAP with GA: -2.46 days [95% CI: -4.15, -0.77]). Among males, we observed an inverse association between 2/3/9-OH-FLUO and PTB (OR = 0.40 [95% CI: 0.17,0.98]). ORs for PTB were higher among females than males for 2-OH-PHEN (p = 0.02) and 1-OH-PYR (p = 0.02).DiscussionWe observed inverse associations of 2-OH-NAP exposure with GA and null associations of remaining OH-PAHs with GA and PTB. Females may be more susceptible to spontaneous PTB or shorter GA following prenatal exposure to some OH-PAHs. This study is the first to assess sex-specific OH-PAH toxicity in relation to spontaneous PTB and GA.

Air pollution might affect atherosclerosis through DNA methylation changes in cells crucial to atherosclerosis, such as monocytes. We conducted an epigenome-wide study of DNA methylation in CD14+ monocytes and long-term ambient air pollution exposure in adults participating in the Multi-Ethnic Study of Atherosclerosis (MESA). We also assessed the association between differentially methylated signals and cis-gene expression. Using spatiotemporal models, one-year average concentrations of outdoor fine particulate matter (PM2.5) and oxides of nitrogen (NOX) were estimated at participants' homes. We assessed DNA methylation and gene expression using Illumina 450k and HumanHT-12 v4 Expression BeadChips, respectively (n = 1,207). We used bump hunting and site-specific approaches to identify differentially methylated signals (false discovery rate of 0.05) and used linear models to assess associations between differentially methylated signals and cis-gene expression. Four differentially methylated regions (DMRs) located on chromosomes 5, 6, 7, and 16 (within or near SDHAP3, ZFP57, HOXA5, and PRM1, respectively) were associated with PM2.5. The DMRs on chromosomes 5 and 6 also associated with NOX. The DMR on chromosome 5 had the smallest p-value for both PM2.5 (p = 1.4×10-6) and NOX (p = 7.7×10-6). Three differentially methylated CpGs were identified for PM2.5, and cg05926640 (near TOMM20) had the smallest p-value (p = 5.6×10-8). NOX significantly associated with cg11756214 within ZNF347 (p = 5.6×10-8). Several differentially methylated signals were also associated with cis-gene expression. The DMR located on chromosome 7 was associated with the expression of HOXA5, HOXA9, and HOXA10. The DMRs located on chromosomes 5 and 16 were associated with expression of MRPL36 and DEXI, respectively. The CpG cg05926640 was associated with expression of ARID4B, IRF2BP2, and TOMM20. We identified differential DNA methylation in monocytes associated with long-term air pollution exposure. Methylation signals associated with gene expression might help explain how air pollution contributes to cardiovascular disease.

BackgroundPhthalates are commonly used endocrine-disrupting chemicals that are ubiquitous in the general population. Prenatal phthalate exposure may alter placental physiology and fetal development, leading to adverse perinatal and childhood health outcomes.ObjectiveWe examined associations between prenatal phthalate exposure in the second and third trimesters and the placental transcriptome at birth, including genes and long noncoding RNAs (lncRNAs), to gain insight into potential mechanisms of action during fetal development.MethodsThe ECHO PATHWAYs consortium quantified 21 urinary phthalate metabolites from 760 women enrolled in the CANDLE study (Shelby County, TN) using high-performance liquid chromatography-tandem mass spectrometry. Placental transcriptomic data were obtained using paired-end RNA sequencing. Linear models were fitted to estimate separate associations between maternal urinary phthalate metabolite concentration during the second and third trimester and placental gene expression at birth, adjusted for confounding variables. Genes were considered differentially expressed at a Benjamini-Hochberg false discovery rate (FDR) p

BackgroundMany pregnant people find no bridge to ongoing specialty or primary care after giving birth, even when clinical and social complications of pregnancy signal need. Black, indigenous, and all other women of color are especially harmed by fragmented care and access disparities, coupled with impacts of racism over the life course and in health care.MethodsWe launched the initiative "Bridging the Chasm between Pregnancy and Health across the Life Course" in 2018, bringing together patients, advocates, providers, researchers, policymakers, and systems innovators to create a National Agenda for Research and Action. We held a 2-day conference that blended storytelling, evidence analysis, and consensus building to identify key themes related to gaps in care and root causes of inequities. In 2019, more than 70 stakeholders joined six working groups to reach consensus on strategic priorities based on equity, innovation, effectiveness, and feasibility.FindingsWorking groups identified six key strategic areas for bridging the chasm. These include: 1) progress toward eliminating institutional and interpersonal racism and bias as a requirement for accreditation of health care institutions, 2) infrastructure support for community-based organizations, 3) extension of holistic team-based care to the postpartum year and beyond, with integration of doulas and community health workers on the team, 4) extension of Medicaid coverage and new quality and pay-for-performance metrics to link maternity care and primary care, 5) systems to preserve maternal narratives and data across providers, and 6) alignment of research with women's lived experiences.ConclusionsThe resulting agenda presents a path forward to remedy the structural chasms in women's health care, with key roles for advocates, policymakers, researchers, health care leaders, educators, and the media.

BackgroundLimited data suggest air pollution exposures may contribute to pediatric high blood pressure (HBP), a known predictor of adult cardiovascular diseases.MethodsWe investigated this association in the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) study, a sociodemographically diverse pregnancy cohort in the southern United States with participants enrolled from 2006 to 2011. We included 822 mother-child dyads with available address histories and a valid child blood pressure measurement at 4-6 y. Systolic (SBP) and diastolic blood pressures (DBP) were converted to age-, sex-, and height-specific percentiles for normal-weight U.S. children. HBP was classified based on SBP or DBP ≥90th percentile. Nitrogen dioxide (NO2) and particulate matter ≤2.5μm in aerodynamic diameter (PM2.5) estimates in both pre- and postnatal windows were obtained from annual national models and spatiotemporal models, respectively. We fit multivariate Linear and Poisson regressions and explored multiplicative joint effects with maternal nutrition, child sex, and maternal race using interaction terms.ResultsMean PM2.5 and NO2 in the prenatal period were 10.8 [standard deviation (SD): 0.9] μg/m3 and 10.0 (SD: 2.4) ppb, respectively, and 9.9 (SD: 0.6) μg/m3 and 8.8 (SD: 1.9) ppb from birth to the 4-y-old birthday. On average, SBP percentile increased by 14.6 (95% CI: 4.6, 24.6), and DBP percentile increased by 8.7 (95% CI: 1.4, 15.9) with each 2-μg/m3 increase in second-trimester PM2.5. PM2.5 averaged over the prenatal period was only significantly associated with higher DBP percentiles [β= 11.6 (95% CI: 2.9, 20.2)]. Positive associations of second-trimester PM2.5 with SBP and DBP percentiles were stronger in children with maternal folate concentrations in the lowest quartile (pinteraction= 0.05 and 0.07, respectively) and associations with DBP percentiles were stronger in female children (pinteraction= 0.05). We did not detect significant association of NO2, road proximity, and postnatal PM2.5 with any outcomes.ConclusionsThe findings suggest that higher prenatal PM2.5 exposure, particularly in the second trimester, is associated with elevated early childhood blood pressure. This adverse association could be modified by pregnancy folate concentrations. https://doi.org/10.1289/EHP7486.

BackgroundThe intrauterine environment may influence offspring blood pressure, with effects possibly extending into adulthood. The associations between prenatal nutrition and offspring blood pressure, alone or in combination with other sociodemographic or behavioral factors, are unclear.ObjectivesTo investigate the associations of maternal dietary patterns and plasma folate concentrations with blood pressure in children aged 4-6 years, and assess the potential effect modifications by child sex, maternal race, pre-pregnancy overweight or obesity, maternal smoking, and breastfeeding.MethodsParticipants were 846 mother-child dyads from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) study. Maternal nutrition was characterized by the Healthy Eating Index 2010 (HEI) scores and plasma folate concentrations in pregnancy. We calculated the systolic blood pressure (SBP) and diastolic blood pressure percentiles, incorporating sex, age, and height, and categorized children as either having high blood pressure (HBP; ≥90th percentile) or normal blood pressure. Linear regressions were performed to quantify the associations between maternal nutrition and continuous blood pressure percentiles, and Poisson regressions were used to estimate the incidence rate ratio (IRR) of binary HBP. We examined the effect modifications using interaction models.ResultsMean HEI scores and folate concentrations were 60.0 (SD, 11.3) and 23.1 ng/mL (SD, 11.1), respectively. Based on measurements at 1 visit, 29.6% of the children were defined as having HBP. Maternal HEI scores and plasma folate concentrations were not associated with child blood pressure percentiles or HBP in the full cohort. Among mothers self-identified as white, there was an inverse relationship between maternal HEI score and child SBP percentile (β, -0.40; 95%CI: -0.75 to -0.06). A maternal HEI score above 59 was associated with a reduced risk of HBP in girls (IRR, 0.53; 95% CI: 0.32-0.88). No modified associations by pre-pregnancy overweight or obesity, maternal smoking, or breastfeeding were indicated.ConclusionsWe found little evidence for effects of maternal nutrition during pregnancy on childhood blood pressure, but detected sex- and race-specific associations. The study contributes to the evolving scientific inquiry regarding developmental origins of disease.

BackgroundVitamin D is critical to embryonic neuronal differentiation and other developmental processes that may affect future neurocognitive function. However, observational studies have found inconsistent associations between gestational vitamin D and neurocognitive outcomes.ObjectivesWe examined the association of gestational 25-hydroxyvitamin D [25(OH)D] with children's IQ at 4-6 y, and explored whether associations differed by race.MethodsThis study used data from the CANDLE (Conditions Affecting Neurocognitive Development and Learning in Early Childhood) cohort. Between 2006 and 2011, CANDLE recruited 1503 women in their second trimester of healthy singleton pregnancies. Inclusion criteria for this analysis were gestation of ≥34 wk and availability of 25(OH)D and IQ data. Associations between second-trimester 25(OH)D plasma concentration and Stanford-Binet IQ scores in offspring at 4-6 y were examined using multivariable linear regression; interaction terms were used to explore possible effect modification by race.ResultsMean ± SD 25(OH)D concentration among 1019 eligible dyads was 21.6 ± 8.4 ng/mL, measured at a mean ± SD gestational age of 23.0 ± 3.0 wk. Vitamin D deficiency [25(OH)D

Purpose:Neonates born to mothers with obesity or gestational diabetes mellitus (GDM) have an increased chance of various metabolic disorders later in life. In India, it is unclear whether maternal obesity or GDM is related to offspring adiposity. We aimed to understand the independent effect of maternal obesity and GDM with neonatal adiposity and whether GDM has a mediating effect between maternal obesity and neonatal adiposity. Methods:We recruited a cohort of 1120 women (between April 2016 and February 2019) from the public hospitals in Bangalore, India, who voluntarily agreed to participate and provided written informed consent. The primary outcome was neonatal adiposity, defined as the sum of skinfold thickness >85th percentile. Exposure included maternal obesity, defined as >90th percentile of skinfold thickness. GDM, the potential mediator, was classified using the World Health Organization criteria by oral glucose tolerance test. Binary logistic regression was applied to test the effect of maternal obesity and GDM on neonatal adiposity, adjusting for potential confounders. We used Paramed command in STATA version 14 for analyzing mediating effects. Results:We found that maternal obesity (odds ratio (OR)=2.16, 95% CI 1.46, 3.18) and GDM (OR=2.21, 95% CI1.38, 3.52) have an independent effect on neonatal adiposity. GDM significantly mediates 25.2% of the total effect between maternal obesity and neonatal adiposity, (natural direct effect OR = 1.16 95% CI 1.04, 1.30) with significant direct effect of maternal obesity (natural direct effect OR = 1.90 95% CI 1.16, 3.10) and significant total effect (OR=2.20 95% CI 1.35, 3.58). Conclusion:We showed that maternal obesity and GDM are independently associated with offspring adiposity. Also, GDM mediates the association of maternal obesity on adiposity in children. Interventions focused on obesity prevention in women, and effective screening and management of GDM may contribute to reducing childhood obesity in India.

Background: Isoniazid preventive therapy (IPT) decreases risk of tuberculosis (TB) disease; impact on long-term infant growth is unknown. In a recent randomized trial (RCT), we assessed IPT effects on infant growth without known TB exposure. Methods: The infant TB Infection Prevention Study (iTIPS) trial was a non-blinded RCT among HIV-exposed uninfected (HEU) infants in Kenya. Inclusion criteria included age 6–10 weeks, birthweight ≥2.5 kg, and gestation ≥37 weeks. Infants in the IPT arm received 10 mg/kg isoniazid daily for 12 months, while the control trial received no intervention; post-trial observational follow-up continued through 24 months of age. We used intent-to-treat linear mixed-effects models to compare growth rates (weight-for-age z-score [WAZ] and height-for-age z-score [HAZ]) between trial arms. Results: Among 298 infants, 150 were randomized to IPT, 47.6% were females, median birthweight was 3.4 kg (interquartile range [IQR] 3.0–3.7), and 98.3% were breastfed. During the 12-month intervention period and 12-month post-RCT follow-up, WAZ and HAZ declined significantly in all children, with more HAZ decline in male infants. There were no growth differences between trial arms, including in sex-stratified analyses. In longitudinal linear analysis, mean WAZ (β = 0.04 [95% CI:-0.14, 0.22]), HAZ (β = 0.14 [95% CI:-0.06, 0.34]), and WHZ [β = -0.07 [95% CI:-0.26, 0.11]) z-scores were similar between arms as were WAZ and HAZ growth trajectories. Infants randomized to IPT had higher monthly WHZ increase (β to 24 months 0.02 [95% CI:0.01, 0.04]) than the no-IPT arm. Conclusion: IPT administered to HEU infants did not significantly impact growth outcomes in the first two years of life. [ABSTRACT FROM AUTHOR]

Background: Population-based research on the prevalence and determinants of dementia, Alzheimer's disease, and cognitive impairment is scarce in East Africa. Objective: To provide an overview of community- and population-based studies among older adults on the prevalence of dementia and cognitive impairment in East Africa, and identify research gaps. Methods: We carried out a literature search using three electronic databases (PubMed, Scopus, Google Scholar) using pertinent search terms. Results: After screening 445 publications, we identified four publications on the population-based prevalence of dementia, and three on cognitive impairment. Prevalence rates varied from 6– 23% for dementia, and 7– 44% for cognitive impairment, among participants aged≥50–70 years. Old age and a lower education level were risk factors for dementia and cognitive impairment. Physical inactivity, lack of a ventilated kitchen, and history of central nervous system infections and chronic headache were associated with increased odds of dementia. Female sex, depression, having no spouse, increased lifetime alcohol consumption, low income, rural residence, and low family support were associated with increased odds of cognitive impairment. Potential misclassification and non-standardized data collection methods are research gaps that should be addressed in future studies. Conclusions: Establishing collaborative networks and partnering with international research institutions may enhance the capacity for conducting population-based studies on dementia and cognitive impairment in East Africa. Longitudinal studies may provide valuable insights on incidence, as well as potential risk and protective factors of dementia and cognitive impairment, and may inform the development of targeted interventions including preventive strategies in the region. [ABSTRACT FROM AUTHOR]

Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the 'transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.

Loci identified in genome-wide association studies (GWAS) of cardio-metabolic traits account for a small proportion of the traits' heritability. To date, most association studies have not considered parent-of-origin effects (POEs). Here we report investigation of POEs on adiposity and glycemic traits in young adults. The Jerusalem Perinatal Family Follow-Up Study (JPS), comprising 1250 young adults and their mothers was used for discovery. Focusing on 18 genes identified by previous GWAS as associated with cardio-metabolic traits, we used linear regression to examine the associations of maternally- and paternally-derived offspring minor alleles with body mass index (BMI), waist circumference (WC), fasting glucose and insulin. We replicated and meta-analyzed JPS findings in individuals of European ancestry aged ≤50 belonging to pedigrees from the Framingham Heart Study, Family Heart Study and Erasmus Rucphen Family study (total N≅4800). We considered p0.6). Suggestive maternally-derived associations of rs1367117 were observed with fasting glucose (β = 0.9; 95%CI:0.3,1.5; p = 4.0x10-3) and insulin (ln-transformed, β = 0.06; 95%CI:0.03,0.1; p = 7.4x10-4). Bioinformatic annotation for rs1367117 revealed a variety of regulatory functions in this region in liver and adipose tissues and a 50% methylation pattern in liver only, consistent with allelic-specific methylation, which may indicate tissue-specific POE. Our findings demonstrate a maternal-specific association between a common APOB variant and adiposity, an association that was not previously detected in GWAS. These results provide evidence for the role of regulatory mechanisms, POEs specifically, in adiposity. In addition this study highlights the benefit of utilizing family studies for deciphering the genetic architecture of complex traits.

Thiazide diuretics and statins are used to improve cardiovascular outcomes, but may also cause type 2 diabetes (T2DM), although mechanisms are unknown. Gene expression studies may facilitate understanding of these associations. Participants from ongoing population-based studies were sampled for these longitudinal studies of peripheral blood microarray gene expression, and followed to incident diabetes. All sampled subjects were statin or thiazide users. Those who developed diabetes during follow-up comprised cases (44 thiazide users; 19 statin users), and were matched to drug-using controls who did not develop diabetes on several factors. Supervised normalization, surrogate variable analyses removed technical bias and confounding. Differentially-expressed genes were those with a false discovery rate Q-value

OBJECTIVE: To identify plasma miRNAs related to treatment failure in youth with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: We examined whether a panel of miRNAs could predict treatment failure in training/test data sets among participants in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study (N = 209). We also examined whether individual miRNAs were associated with treatment failure. RESULTS: Participants were age 14.5 years, and 62% were female. A panel of miRNAs did not predict treatment failure. However, for each doubling, miR-4306 was associated with a 12% decrease (P = 0.040) and miR-483-3p was marginally associated with a 12% increase (P = 0.080) in failure independently of sex, race/ethnicity, BMI, Tanner stage, HbA1c, maternal diabetes, oral disposition index, and treatment arm. The addition of both miRNAs improved model fit (log likelihood without vs. with miRNAs −360.3 vs. −363.5; P = 0.040). CONCLUSIONS: miR-483-3p and miR-4306 may be associated with treatment failure in youth with T2D. [ABSTRACT FROM AUTHOR]