Publications

OBJECTIVE We examined lifestyle factors with midlife weight change according to history of gestational diabetes mellitus (GDM) in a large longitudinal female cohort. RESEARCH DESIGN AND METHODS In the Nurses’ Health Study II, we categorized changes in lifestyle within 4-year periods and estimated their associations with concurrent changes in body weight (kilograms) among parous women after age 40 years by GDM history status (N = 54,062; 5.3% with a history of GDM) for the following: diet quality (Alternate Healthy Eating Index [AHEI]), leisure-time physical activity (PA), alcohol consumption, and smoking status. RESULTS Over a median follow-up of 13 years, average 4-year weight gain was 1.10 and 1.33 kg for women with and without prior GDM, respectively. Women with improved diet quality had favorable 4-year weight change, particularly those with a history of GDM (AHEI change [95% CI] from low to high −2.97 kg [−4.34, −1.60] vs. −1.19 kg [−1.41, −0.96] for GDM vs. non-GDM, respectively; P heterogeneity = 0.04). Increasing PA was associated with weight maintenance for GDM women only (PA increase [95% CI] from low to high 0.26 kg [−0.25, 0.77] vs. 0.90 kg [0.80, 1.01] for GDM vs. non-GDM, respectively; P heterogeneity = 0.02). For both GDM and non-GDM women, weight change did not differ significantly with change in alcohol consumption, while women who quit smoking had significant weight gain (4.38 kg for GDM and 3.85 kg for non-GDM). CONCLUSIONS Improvements in diet quality and PA were related to less weight gain in midlife among parous women, and the benefit of such improvements on weight management was particularly pronounced among women with a history of GDM.

<p>Objective: Dietary glycemic index (GI) and glycemic load (GL) are associated with cardio–metabolic health in children and adolescents, with potential distinct effects in people with increased body mass index (BMI). DNA methylation (DNAm) may mediate these effects. Thus, we conducted meta–analyses of epigenome–wide association studies (EWASs) between dietary GI and GL and blood DNAm of children and adolescents.</p><p>Research Design and Methods: We calculated dietary GI and GL and performed EWASs in children and adolescents (age range: 4.5–17 years) from six cohorts (ntotal = 1,187). We performed stratified analyses of participants with normal–weight (ntotal = 801) or overweight/obesity (ntotal = 386). We performed look–ups for the identified cytosine–phosphate–guanine (CpG) sites (false discovery rate (FDR) < 0.05) with tissue–specific gene expression of 832 blood and 223 subcutaneous adipose tissue samples of children and adolescents.</p><p>Results: Dietary GL was positively associated with DNAm of cg20274553 (FDR < 0.05), annotated to WDR27. Several CpGs were identified in the normal–weight (GI: 85, GL: 17) and overweight/obese strata (GI: 136, GL: 298; FDR < 0.05), of which none overlapped between the strata. In participants with overweight/obesity, identified CpGs showed relations to RNA expression of genes associated with impaired metabolism, e.g., FRAT1 and CSF3.</p><p>Conclusions: We identified 537 associations between dietary GI and GL and blood DNAm, mainly in children and adolescents with overweight/obesity. High GI and/or GL diets may influence epigenetic gene regulation and thereby, promote metabolic derangements in young persons with increased BMI.</p>

High-throughput technology for molecular biomarkers is increasingly producing multivariate phenotype data exhibiting strong correlation structures. Existing approaches for combining such data with genetic variants for multivariate Quantitative Trait Loci analysis generally either ignore correlation structure or make other restrictive assumptions about the associations between phenotypes and genetic loci. We present a Bayesian Variable Selection (BVS) model with sparse variable and covariance selection for high-dimensional seemingly unrelated regressions. The model includes a matrix of binary variable selection indicators for multivariate regression, thus allowing different phenotype responses to be associated with different genetic predictors (a seemingly unrelated regressions framework). A general covariance structure is allowed for the residuals relating to the conditional dependencies between phenotype variables. The covariance structure may be dense (unrestricted) or sparse, with a graphical modelling prior. The graphical structure amongst the multivariate responses can be estimated as part of the model. To achieve feasible computation of the large and complex model space, we exploit a factorisation of the covariance matrix parameter to enable faster computation using Markov Chain Monte Carlo (MCMC) methods. We are able to infer associations with thousands of candidate predictors multivariately on hundreds of responses. We illustrate the model using a dataset of 158 NMR spectroscopy measured metabolites and over 9000 Single Nucleotide Polymorphisms on chromosome 16, measured in a cohort of more than 5000 people.

This paper describes a microfluidic device, fabricated in poly(dimethylsiloxane), that is used for potentiometric titrations. This system generates step gradients of redox potentials in a series of microchannels. These potentials are probed by microelectrodes that are integrated into the chip; the measured potentials were used to produce a titration curve from which the end point of a reaction was measured.

Objective. To determine whether Chlamydia pneumoniae antibodies and highly sensitive C-reactive protein (hsCRP) levels in maternal sera are associated with preeclampsia or gestational hypertension. Methods. C. pneumoniae antibodies and hsCRP levels were measured in maternal serum during first trimester (mean, 10.4 weeks of gestation) using the microimmunofluorescence (MIF) test and a highly sensitive immunoenzymometric assay, respectively. Results. No differences in the IgG antibody levels against C. pneumoniae or hsCRP levels were seen between the women with preeclampsia or gestational hypertension and those in the reference group. However, the women with preeclampsia and preterm delivery had serum IgG antibodies to C. pneumoniae (IgG titre ≥32) significantly more often in their first trimester sera compared with women having preeclampsia and full-term deliveries (p = 0.03). In addition, the proportion of subjects with C. pneumoniae IgG antibodies (IgG titre ≥32) and/or elevated CRP levels (≥3.8 mg/L, upper quartile) was double among the women with preeclampsia and elective preterm delivery compared with the women with preeclampsia who delivered at term (p = 0.01). Conclusion. Our results suggest that chronic C. pneumoniae infection and systemic low-grade inflammation may be associated with preeclampsia requiring elective delivery before 37 weeks gestation.

Author(s): Lotfipour, Shahrdad; Lotfipour, Shahrdad; Ferguson, Eamonn; Leonard, Gabriel; Miettunen, Jouko; Perron, Michel; Pike, G Bruce; Richer, Louis; Seguin, Jean R; Veillette, Suzanne; Jarvelin, Marjo-Riitta; Moilanen, Irma; Maki, Pirjo; Nordstrom, Tanja; Pausova, Zdenka; Veijola, Juha; Paus, Tomas | Abstract: Background and aimsPrenatal exposure to maternal cigarette smoking (PEMCS) is associated with a higher probability of substance use in adolescence. We explore if externalizing behavior mediates this relationship, while controlling for a number of potential covariates of this mediation process.MethodsWe used data obtained in two geographically distinct community samples of adolescents. The first (cross-sectional) sample consisted of 996 adolescents (12-18 years of age) recruited from the Saguenay Youth Study (SYS) in Canada (47% with PEMCS). The second (longitudinal) sample consisted of 1141 adolescents (49% with PEMCS) from the Northern Finland Birth Cohort (NFBC1986). In both samples, externalizing behavior and substance use were assessed during adolescence. In the NFBC1986 cohort, externalizing behavior was also assessed in childhood.ResultsIn both populations, PEMCS is associated with a higher likelihood of adolescent drug experimentation. In the NFBC1986 cohort, exposed (versus non-exposed) adolescents experiment with an extra 1.27 [B = 0.24, 95% confidence intervals (CI) = 0.15, 0.33 P l 0.001] drugs. In the SYS cohort, a clear protective effect of not being exposed is shown: non-exposed (versus exposed) adolescents are 1.5 times [B = -0.42, 95% CI = -0.75, -0.09, P = 0.013] less likely to take drugs. These associations between PEMCS and drug experimentation remain in the multivariate and mediational analyses.ConclusionsPrenatal exposure to maternal cigarette smoking appears to be associated with a higher probability of experimenting with drugs during adolescence, both directly and indirectly via externalizing behavior and the number of peers reported as using drugs.

The timing of parturition is crucial for neonatal survival and infant health. Yet, its genetic basis remains largely unresolved. We present a maternal genome-wide meta-analysis of gestational duration (n = 195,555), identifying 22 associated loci (24 independent variants) and an enrichment in genes differentially expressed during labor. A meta-analysis of preterm delivery (18,797 cases, 260,246 controls) revealed six associated loci and large genetic similarities with gestational duration. Analysis of the parental transmitted and nontransmitted alleles (n = 136,833) shows that 15 of the gestational duration genetic variants act through the maternal genome, whereas 7 act both through the maternal and fetal genomes and 2 act only via the fetal genome. Finally, the maternal effects on gestational duration show signs of antagonistic pleiotropy with the fetal effects on birth weight: maternal alleles that increase gestational duration have negative fetal effects on birth weight. The present study provides insights into the genetic effects on the timing of parturition and the complex maternal-fetal relationship between gestational duration and birth weight.

Background: Metabolomics technologies can efficiently profile a large number of structurally diverse lipids, e.g., glycerophospholipids, sphingolipids, and glycerolipids, that may play differential roles in pathogenesis of cardiovascular disease (CVD). However, existing studies were focused more on discovering individual lipid metabolites for CVD risk prediction than inferring perturbed pathways responsible for the pathological processes. Hypothesis: We hypothesized that different lipid metabolic pathways, captured by network analysis, were divergently associated with CVD risk; the associations could be modified by the Mediterranean diet (MedDiet) intervention. Methods: We conducted this study in the PREDIMED trial with participants randomized to three intervention diets: MedDiet with extra-virgin olive oil, MedDiet with nuts, or a low-fat control diet. This study comprises a subcohort of 788 participants randomly selected from the PREDIMED cohort and 230 cases. The outcome was a composite endpoint of non-fatal acute myocardial infarction, non-fatal stroke and cardiovascular death. We performed network analysis using Gaussian graphic model among 200 targeted lipid metabolites and subsequent dimensionality reduction using Greedy Modularity Optimization to detect subnetworks. We calculated the subnetwork scores by summing up the products of the topological connectivity weight (representing network structure) and metabolite level and included the scores into Cox proportional hazards model with simultaneous adjustment for other subnetwork scores and covariates. The Benjamini-Hochberg procedure was applied to detect smaller subnetworks of specific interest for further investigation. Results: We detected 4 major subnetworks of lipid metabolic pathway. Most lipid metabolites with larger numbers of carbon atom and double bond clustered within a same subnetwork (subnetwork 2), while those with smaller numbers of carbon atom and double bond clustered within other 3 subnetworks (subnetworks 1, 3 and 4). The hazard ratio (HR) of CVD across quartiles of the subnetwork score 2 was 0.56 (95% CI, 0.35, 0.91, P trend =0.008) after multivariable adjustment. The HRs of CVD comparing extreme quartiles of subnetwork scores 3 and 4 were 1.85 (95% CI, 1.15, 2.97, P trend =0.02) and 1.93 (95% CI, 1.19, 3.14, P trend =0.01), respectively. The MedDiet appeared to enhance the inverse association between subnetwork score 2 and CVD ( P interaction =0.03). We detected several smaller subnetworks with functional interpretation related to CVD pathogenesis such as the ceramide pathway and the pathway including phospholipids with high unsaturation. Conclusions: Based on topological structure of lipid metabolic pathways, we detected biologically meaningful pathways. We found divergent associations between subnetworks and CVD and smaller subnetworks with functional interpretation.