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1.
J Pediatr ; 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31399247

RESUMO

OBJECTIVE: To evaluate postexercise heart rate recovery (HRR) in adults born preterm. STUDY DESIGN: We studied the association between preterm birth and postexercise HRR in 545 adults (267 women) at 23.3 years of age (range 19.9-26.3 years). One hundred three participants were born early preterm (<34 completed weeks), 178 late preterm (34-36), and 264 were full term (control group). HRR was calculated as change in heart rate (HR) 30 seconds and 60 seconds after cessation of submaximal step test and maximum HR slope during the first minute after. RESULTS: Mean peak HR was 159.5 bpm in the early preterm (P = .16 with controls), 157.8 bpm in the late preterm (P = .56), and 157.0 bpm in the control group. Mean HRR 30 seconds after exercise was 3.2 bpm (95% CI 1.1-5.2) lower in the early preterm group and 2.1 bpm (0.3-3.8) lower in the late preterm group than the full term controls. Mean 60s HRR was 2.5 (-0.1 to 5.1) lower in the early preterm group and 2.8 bpm (0.6-4.9) lower in the late preterm group. Mean maximum slope after exercise was 0.10 beats/s (0.02-0.17) lower in the early preterm group and 0.06 beats/s (0.00-0.12) lower in the late preterm group. CONCLUSIONS: Our results suggest reduced HRR after exercise in adults born preterm, including those born late preterm. This suggests altered reactivation of the parasympathetic nervous system, which may contribute to cardiovascular risk among adults born preterm.

2.
Nature ; 572(7769): 323-328, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31367044

RESUMO

Exome-sequencing studies have generally been underpowered to identify deleterious alleles with a large effect on complex traits as such alleles are mostly rare. Because the population of northern and eastern Finland has expanded considerably and in isolation following a series of bottlenecks, individuals of these populations have numerous deleterious alleles at a relatively high frequency. Here, using exome sequencing of nearly 20,000 individuals from these regions, we investigate the role of rare coding variants in clinically relevant quantitative cardiometabolic traits. Exome-wide association studies for 64 quantitative traits identified 26 newly associated deleterious alleles. Of these 26 alleles, 19 are either unique to or more than 20 times more frequent in Finnish individuals than in other Europeans and show geographical clustering comparable to Mendelian disease mutations that are characteristic of the Finnish population. We estimate that sequencing studies of populations without this unique history would require hundreds of thousands to millions of participants to achieve comparable association power.

3.
Clin Epigenetics ; 11(1): 97, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31262328

RESUMO

BACKGROUND: Maternal smoking during pregnancy is associated with adverse offspring health outcomes across their life course. We hypothesize that DNA methylation is a potential mediator of this relationship. METHODS: We examined the association of prenatal maternal smoking with offspring blood DNA methylation in 2821 individuals (age 16 to 48 years) from five prospective birth cohort studies and perform Mendelian randomization and mediation analyses to assess whether methylation markers have causal effects on disease outcomes in the offspring. RESULTS: We identify 69 differentially methylated CpGs in 36 genomic regions (P value < 1 × 10-7) associated with exposure to maternal smoking in adolescents and adults. Mendelian randomization analyses provided evidence for a causal role of four maternal smoking-related CpG sites on an increased risk of inflammatory bowel disease or schizophrenia. Further mediation analyses showed some evidence of cg25189904 in GNG12 gene mediating the effect of exposure to maternal smoking on schizophrenia-related outcomes. CONCLUSIONS: DNA methylation may represent a biological mechanism through which maternal smoking is associated with increased risk of psychiatric morbidity in the exposed offspring.

4.
Nord J Psychiatry ; 73(6): 340-348, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31259640

RESUMO

Purpose: This study examined a developmental model that links affect-regulation difficulties in childhood with three dimensions of alexithymia in adolescence (difficulty identifying feelings, difficulty describing feelings, and externally oriented thinking) and substance use and depression in adulthood, while accounting for cumulative contextual risk in childhood, and testing potential gender moderation. Methods: Multiple group path analyses were conducted using data from the Northern Finland Birth Cohort 1986 (N = 6963). Analyses used data collected during prenatal/birth, childhood, adolescence, and young adulthood periods. Results: Our examination of early precursors for alexithymia indicated that the associations of affect-regulation problems in childhood with alexithymia were stronger for girls, potentially putting girls with affect-regulation difficulties in childhood at higher risk for developing alexithymia in adolescence. The associations of cumulative contextual risk in childhood with alexithymia, substance use disorder, and depression diagnosis in adulthood were significant for both girls and boys. Our findings in regard to substance use and depression disorders revealed that alexithymia in adolescence predicted depression diagnosis in adulthood, particularly due to a contribution from the alexithymia domain of 'difficulties identifying feelings.' However, none of the alexithymia domains was directly associated with substance use disorder in adulthood. Conclusions: Our study contributes to research that links alexithymia with difficulties in affect regulation and cumulative contextual risk in childhood, yielding findings that may be relevant for preventive interventions.

6.
Nutrients ; 11(6)2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31151163

RESUMO

INTRODUCTION: Vitamin D deficiency has been linked to the increased risk of several chronic diseases, especially in people living in the Northern Latitudes. The aim of this study was to assess the vitamin D status in older subjects born in 1945 in Northern Finland (latitude 65°North), and to examine its associations to components of metabolic syndrome (MetS). METHODS: In this cross-sectional study, we invited 904 subjects born in 1945 from the Oulu region (Oulu45 cohort), out of an original cohort of 1332 subjects. In the cohort, plasma 25 hydroxyvitamin D (25OHD) levels were determined by an enzyme immunoassay of 263 men and 373 women, with a mean age baseline of 69±0.5 years old. We assessed the participants' usage of vitamin D supplements, as well as their lifestyle factors, using a questionnaire. RESULTS: Nearly 80% of the subjects had low vitamin D levels [either vitamin D deficient (<50 nmol/L) or insufficient (50 - 75 nmol/L)], and only 20% of the participants had sufficient vitamin D levels (>75 nmol/L) (based on the American Endocrine Society guidelines). The low vitamin D status was associated with a high prevalence of MetS; a significantly higher number of subjects with MetS (41%) had low vitamin D levels in comparison to the non-MetS subjects (38%) (p ≤ 0.05). The subjects under vitamin D supplementation had a significantly lower incidence of MetS (42.6% vs 57.4%) and its components in comparison to the non-supplemented subjects (p ≤ 0.05). CONCLUSIONS: Low vitamin D levels are a risk factor for MetS amongst other lifestyle factors, such as dietary habits and physical inactivity, among older subjects in the Northern Latitudes (65°North). Optimal supplementation of vitamin D, along with rich dietary sources of vitamin D, are highly recommended for older subjects as a means to positively affect, e.g., hypertension, insulin resistance, and obesity, as components of the MetS.

7.
J Med Genet ; 56(9): 607-616, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31217265

RESUMO

BACKGROUND: Inflammatory processes contribute to the pathophysiology of multiple chronic conditions. Genetic factors play a crucial role in modulating the inflammatory load, but the exact mechanisms are incompletely understood. OBJECTIVE: To assess genetic determinants of 16 circulating cytokines and cell adhesion molecules (inflammatory phenotypes) in Finns. METHODS: Genome-wide associations of the inflammatory phenotypes were studied in Northern Finland Birth Cohort 1966 (N=5284). A subsequent meta-analysis was completed for 10 phenotypes available in a previous genome-wide association study, adding up to 13 577 individuals in the study. Complementary association tests were performed to study the effect of the ABO blood types on soluble adhesion molecule levels. RESULTS: We identified seven novel and six previously reported genetic associations (p<3.1×10-9). Three loci were associated with soluble vascular cell adhesion molecule-1 (sVCAM-1) level, one of which was the ABO locus that has been previously associated with soluble E-selectin (sE-selectin) and intercellular adhesion molecule-1 (sICAM-1) levels. Our findings suggest that the blood type B associates primarily with sVCAM-1 level, while the A1 subtype shows a robust effect on sE-selectin and sICAM-1 levels. The genotypes in the ABO locus associating with higher soluble adhesion molecule levels tend to associate with lower circulating cholesterol levels and lower cardiovascular disease risk. CONCLUSION: The present results extend the knowledge about genetic factors contributing to the inflammatory load. Our findings suggest that two distinct mechanisms contribute to the soluble adhesion molecule levels in the ABO locus and that elevated soluble adhesion molecule levels per se may not increase risk for cardiovascular disease.

8.
Eur J Obstet Gynecol Reprod Biol ; 238: 44-48, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31082743

RESUMO

OBJECTIVE: To test whether maternal hemoglobin during pregnancy associates with offspring perinatal outcomes in a developed country. Changes in maternal hemoglobin concentration during pregnancy are partly physiological phenomena reflecting alterations of maternal blood volume. Especially hemoglobin measures outside the physiological range may influence maternal health and fetal growth with long-lasting consequences. STUDY DESIGN: We studied an unselected sample drawn from two regional birth cohorts born 20 years apart: The Northern Finland Birth Cohorts 1966 and 1986. These are two mother-and-child population-based birth cohorts together comprising 21,710 mothers and their children. After exclusions, the sample size of the current study was 20,554. Concentrations of maternal hemoglobin at first and last antenatal visits were categorized as low (lowest 10%), medium (reference) or high (highest 10%). Multinomial logistic regression analyses for categories of maternal hemoglobin and perinatal outcomes such as preterm delivery and full-term small and large for gestational age were conducted with adjustments for maternal cofactors. RESULTS: Low maternal hemoglobin at early pregnancy associated with decreased risk of full-term small for gestational age (adjusted OR 0.73, 95% CI [0.58, 0.93], p = 0.010). At late pregnancy, low maternal hemoglobin associated with increased risk of preterm delivery (adjusted OR 1.60, 95% CI [1.26, 2.02], p < 0.0005) whereas high maternal hemoglobin associated with increased risk of full-term small for gestational age (adjusted OR 1.29, 95% CI [1.07, 1.56], p = 0.009). Maternal hemoglobin did not show constant association with risk of large for gestational age. CONCLUSION: The results from this study support evidence that both low and high maternal hemoglobin associate with adverse perinatal outcomes. Low maternal hemoglobin associated with preterm delivery and high with full-term small for gestational age. Association was mainly present when maternal hemoglobin was measured during the third trimester. These results indicate that it is important to monitor both extremes of maternal hemoglobin throughout the pregnancy.

9.
Int J Epidemiol ; 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31074781

RESUMO

BACKGROUND: Maternal pre-pregnancy body mass index (BMI) is positively associated with offspring birth weight (BW) and BMI in childhood and adulthood. Each of these associations could be due to causal intrauterine effects, or confounding (genetic or environmental), or some combination of these. Here we estimate the extent to which the association between maternal BMI and offspring body size is explained by offspring genotype, as a first step towards establishing the importance of genetic confounding. METHODS: We examined the associations of maternal pre-pregnancy BMI with offspring BW and BMI at 1, 5, 10 and 15 years, in three European birth cohorts (n ≤11 498). Bivariate Genomic-relatedness-based Restricted Maximum Likelihood implemented in the GCTA software (GCTA-GREML) was used to estimate the extent to which phenotypic covariance was explained by offspring genotype as captured by common imputed single nucleotide polymorphisms (SNPs). We merged individual participant data from all cohorts, enabling calculation of pooled estimates. RESULTS: Phenotypic covariance (equivalent here to Pearson's correlation coefficient) between maternal BMI and offspring phenotype was 0.15 [95% confidence interval (CI): 0.13, 0.17] for offspring BW, increasing to 0.29 (95% CI: 0.26, 0.31) for offspring 15 year BMI. Covariance explained by offspring genotype was negligible for BW [-0.04 (95% CI: -0.09, 0.01)], but increased to 0.12 (95% CI: 0.04, 0.21) at 15 years, which is equivalent to 43% (95% CI: 15%, 72%) of the phenotypic covariance. Sensitivity analyses using weight, BMI and ponderal index as the offspring phenotype at all ages showed similar results. CONCLUSIONS: Offspring genotype explains a substantial fraction of the covariance between maternal BMI and offspring adolescent BMI. This is consistent with a potentially important role for genetic confounding as a driver of the maternal BMI-offspring BMI association.

10.
Eur Respir J ; 54(1)2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31073081

RESUMO

Previous reports link differential DNA methylation (DNAme) to environmental exposures that are associated with lung function. Direct evidence on lung function DNAme is, however, limited. We undertook an agnostic epigenome-wide association study (EWAS) on pre-bronchodilation lung function and its change in adults.In a discovery-replication EWAS design, DNAme in blood and spirometry were measured twice, 6-15 years apart, in the same participants of three adult population-based discovery cohorts (n=2043). Associated DNAme markers (p<5×10-7) were tested in seven replication cohorts (adult: n=3327; childhood: n=420). Technical bias-adjusted residuals of a regression of the normalised absolute ß-values on control probe-derived principle components were regressed on level and change of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and their ratio (FEV1/FVC) in the covariate-adjusted discovery EWAS. Inverse-variance-weighted meta-analyses were performed on results from discovery and replication samples in all participants and never-smokers.EWAS signals were enriched for smoking-related DNAme. We replicated 57 lung function DNAme markers in adult, but not childhood samples, all previously associated with smoking. Markers not previously associated with smoking failed replication. cg05575921 (AHRR (aryl hydrocarbon receptor repressor)) showed the statistically most significant association with cross-sectional lung function (FEV1/FVC: pdiscovery=3.96×10-21 and pcombined=7.22×10-50). A score combining 10 DNAme markers previously reported to mediate the effect of smoking on lung function was associated with lung function (FEV1/FVC: p=2.65×10-20).Our results reveal that lung function-associated methylation signals in adults are predominantly smoking related, and possibly of clinical utility in identifying poor lung function and accelerated decline. Larger studies with more repeat time-points are needed to identify lung function DNAme in never-smokers and in children.

11.
Subst Use Misuse ; 54(10): 1679-1690, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31035853

RESUMO

Background: Exposure to cumulative contextual risk within the family early in life increases children's risk for substance involvement and related difficulties, including school failure, in adolescence and young adulthood. However, potential protective factors that buffer these risk associations are relatively untested, yet such tests are needed to improve existing preventive interventions for enhancing resilience among vulnerable children. Objectives: This study tested child reading engagement with parents at home as a moderator of cumulative family risk associations with adolescent substance use and academic performance as well as young adult substance abuse. Methods: Population register data as well as parent-report and adolescent-report data from 6,963 participants of the 1986 Northern Finland Birth Cohort study were analyzed via structural equation modeling with latent variable interactions. Results: Results showed that child reading engagement moderated the associations of cumulative family risk with both adolescent academic performance and young adult substance abuse, but not with adolescent substance use. The highest levels of academic performance were observed under conditions of low risk and high reading engagement. Interestingly, cumulative family risk had a small positive association with substance abuse when reading engagement was low and a negative association with the young adult outcome when reading engagement was high. Conclusions/Importance: Moderation tests revealed complex interaction forms that may have implications for both theory and family-based preventive interventions.

12.
J Am Heart Assoc ; 8(10): e011922, 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31070104

RESUMO

Background Recent studies have revealed sexually dimorphic associations between the carbamoyl-phosphate synthase 1 locus, intermediates of the metabolic pathway leading from choline to urea, and risk of coronary artery disease ( CAD ) in women. Based on evidence from the literature, the atheroprotective association with carbamoyl-phosphate synthase 1 could be mediated by the strong genetic effect of this locus on increased circulating glycine levels. Methods and Results We sought to identify additional genetic determinants of circulating glycine levels by carrying out a meta-analysis of genome-wide association study data in up to 30 118 subjects of European ancestry. Mendelian randomization and other analytical approaches were used to determine whether glycine-associated variants were associated with CAD and traditional risk factors. Twelve loci were significantly associated with circulating glycine levels, 7 of which were not previously known to be involved in glycine metabolism ( ACADM , PHGDH , COX 18- ADAMTS 3, PSPH , TRIB 1, PTPRD , and ABO ). Glycine-raising alleles at several loci individually exhibited directionally consistent associations with decreased risk of CAD . However, these effects could not be attributed directly to glycine because of associations with other CAD -related traits. By comparison, genetic models that only included the 2 variants directly involved in glycine degradation and for which there were no other pleiotropic associations were not associated with risk of CAD or blood pressure, lipid levels, and obesity-related traits. Conclusions These results provide additional insight into the genetic architecture of glycine metabolism, but do not yield conclusive evidence for a causal relationship between circulating levels of this amino acid and risk of CAD in humans.

13.
J Clin Endocrinol Metab ; 104(7): 2785-2795, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30835282

RESUMO

CONTEXT: Maternal gestational diabetes mellitus (GDM) and prepregnancy overweight/obesity [body mass index (BMI) ≥25 kg/m2] might adversely affect offspring cardiometabolic health. OBJECTIVE: To assess the associations between maternal GDM and prepregnancy overweight/obesity with adult offspring cardiometabolic risk factors. DESIGN: Longitudinal cohort study (ESTER Maternal Pregnancy Disorders Study and the Arvo Ylppö Longitudinal Study). SETTING: Province of Uusimaa and Northern Finland. PARTICIPANTS: At a mean age of 24.1 ± 1.3 years, we classified offspring as offspring of mothers with GDM regardless of the prepregnancy BMI (OGDM; n = 193); normoglycemic mothers with prepregnancy overweight/obesity (ONO; n = 157); and normoglycemic mothers with prepregnancy BMI <25 kg/m2 (controls; n = 556). MAIN OUTCOME MEASURES: We assessed the cardiometabolic biomarkers from blood and measured the blood pressure at rest and heart rate. RESULTS: Compared with the controls, the OGDM and ONO groups had greater fasting glucose (1.6%; 95% CI, 0.1% to 3.1%; and 2.3%; 95% CI, 0.5% to 4.3%, respectively) and insulin (12.7%; 95% CI, 4.4% to 21.9%; and 8.7%; 95% CI, 0.2% to 17.8%). These differences attenuated to nonsignificance when adjusted for confounders and/or current offspring characteristics, including BMI or body fat percentage. The OGDM group had lower SHBG (men, -12.4%; 95% CI, -20.2% to -3.9%; women, -33.2%; 95% CI, -46.3% to -16.8%), high-density lipoprotein (-6.6%; 95% CI, -10.9% to -2.2%), and apolipoprotein A1 (-4.5%; 95% CI, -7.5% to -1.4%). These differences survived the adjustments. The heart rate and other biomarkers were similar among the groups. CONCLUSIONS: Adult offspring of mothers with GDM have increased markers of insulin resistance and a more atherogenic lipid profile. These were only partly explained by confounders or current offspring adiposity. Maternal prepregnancy overweight/obesity was associated with impaired offspring glucose regulation, which was explained by confounders and/or current adiposity.

14.
Int J Obes (Lond) ; 2019 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-30718821

RESUMO

OBJECTIVES: To test the hypothesis that age and body mass index (BMI) at BMI peak during infancy and at BMI rebound in childhood are related to cardiovascular autonomic modulation in adulthood. METHODS: At the age of 46 years, a sample (n = 5861) of the participants of the Northern Finland Birth Cohort 1966 took part in follow-up examinations. Heart rate variability (HRV), baroreflex sensitivity (BRS) and low-frequency oscillations of systolic blood pressure (LFSBP) were measured during sympathetic stimulus by standing. BMI at various ages was calculated from frequent anthropometric measurements collected from child welfare clinical records. BRS and LFSBP were available for 1243 participants with BMI peak data and 1524 participants with BMI rebound data, and HRV for 2137 participants with BMI peak data and 2688 participants with BMI rebound data. RESULTS: Age at BMI rebound had a significant inverse association with LFSBP (beta = -0.071, p = 0.006) after all adjustments (p < 0.001) and was also directly associated with BRS (beta = 0.082, p = 0.001) independently of birth and maternal factors (p = 0.023). BMI at BMI peak and at BMI rebound was inversely associated with high-frequency component of HRV (HF) (beta = -0.045, p = 0.036 for BMI at peak; beta = -0.043, p = 0.024 for BMI at rebound) and directly associated with the ratio of low- and high-frequency components of HRV (LF/HF ratio) (beta = 0.084, p = < 0.001 for BMI at peak; beta = 0.069, p < 0.001 for BMI at rebound). These associations remained significant after all adjustments (p < 0.05 for all). CONCLUSIONS: This novel study shows that younger age at BMI rebound and higher BMI at BMI peak and at BMI rebound are associated with higher levels in markers suggestive of augmented sympathetic and reduced vagal cardiovascular modulation in midlife.

15.
J Pediatr ; 208: 96-103.e4, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30732997

RESUMO

OBJECTIVE: To evaluate cardiac autonomic function in adults born preterm. STUDY DESIGN: We studied the association between prematurity and cardiac autonomic function using heart rate variability measurements in 600 adults (mean age of 23.3 years) from a geographically based cohort in Northern Finland. There were 117 young adults born early preterm (<34 weeks), 207 born late preterm (34-36 weeks), and 276 born at term (≥37 weeks, controls). Autonomic function was analyzed by calculating time and frequency domain heart rate variability measurements using linear regression. RESULTS: Compared with controls, the mean difference in root mean square of successive differences (indicating cardiac vagal activity) was -12.0% (95% CI -22.2%, -0.5%, adjusted for sex, age, source cohort, and season P = .04) for the early preterm group and -7.8% (-16.8%, 2.0%, P = .12) for the late preterm group. Mean differences with controls in low frequency power (indicating cardiac vagal activity, including some sympathetic- and baroreflex-mediated effects) were -13.6% (-26.7%, 1.8%, P = .08) for the early preterm group and -16.4% (-27.0%, -4.3%, P = .01) for the late preterm group. Mean differences in high frequency power (quantifying cardiac vagal modulation in respiratory frequency) were -19.2% (-36.6%, 2.9%, P = .09) for the early preterm group and -13.8% (-29.4%, 5.3%, P = .15) for the late preterm group. Differences were attenuated when controlled for body mass index and physical activity. CONCLUSIONS: Our results suggest altered autonomic regulatory control in adults born preterm, including those born late preterm. Altered autonomic regulatory control may contribute to increased cardiovascular risk in adults born preterm.

16.
PLoS Med ; 16(2): e1002746, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30807570

RESUMO

BACKGROUND: Antenatal corticosteroid therapy (ACT) is used clinically to prepare the fetal lung for impending preterm birth, but animal and human studies link corticosteroids to smaller birth size. Whether ACT is associated with birth size is debated; therefore, we assessed differences in birth size in treated versus untreated pregnancies. METHODS AND FINDINGS: This observational register-based study used data from the Finnish Medical Birth Register (FMBR) covering all births in Finland (January 1, 2006-December 31, 2010). We used unadjusted and adjusted regression analyses as well as propensity score matching (PSM) to analyze whether birth size differed by ACT exposure. PSM provides a stringent comparison, as subsamples were created matched on baseline and medical characteristics between treated and untreated women. All analyses were stratified by timing of birth. The primary study outcome was birth size: birth weight (BWT), birth length (BL), ponderal index (PI), and head circumference (HC) measured immediately after birth and recorded in the FMBR. Additional analyses explored indicators of neonatal health in relation to ACT exposure and birth size. A total of 278,508 live-born singleton births with ≥24 gestational completed weeks were registered in the FMBR during the 5-year study period. Over 4% of infants were born preterm, and 4,887 women were treated with ACT (1.75%). More than 44% of the exposed infants (n = 2,173) were born at term. First, results of unadjusted regression analyses using the entire sample showed the greatest reductions in BWT as compared to the other analytic methods: very preterm -61.26 g (±SE 24.12, P < 0.01), preterm -232.90 g (±SE 17.24, P < .001), near term -171.50 g (±SE 17.52, P < .001), and at term -101.95 g (±SE 10.89, P < .001). Second, using the entire sample, regression analyses adjusted for baseline and medical conditions showed significant differences in BWT between exposed and unexposed infants: very preterm -61.54 g (±SE 28.62, P < .03), preterm -222.78 g (±SE 19.64, P < .001), near term -159.25 g (±SE 19.14, P < .001), and at term -91.62 g (±SE 11.86, P < .03). Third, using the stringent PSM analyses based on matched subsamples, infants exposed to ACT weighed less at birth: -220.18 g (±SE 21.43, P < .001), -140.68 g (±SE 23.09, P < .001), and -89.38 g (±SE 14.16, P < .001), born preterm, near term, and at term, respectively. Similarly, significant reductions in BL and HC were also observed using the three analytic methods. There were no differences among postterm infants regardless of analytic method. Likewise, we observed no differences with respect to PI. Additional analyses showed that exposed and unexposed infants had generally similar Apgar scores at birth, yet the ACT-treated infants received greater medical care during the first 7 days of life and beyond. Our study is mainly limited by lack of data in FMBR specifying the interval between treatment and birth as well as other potential confounders that could not be tested. CONCLUSIONS: In this study, ACT was consistently associated with reduction in birth size for infants born preterm, near term, or at term. Further investigation is warranted alongside reevaluation of guidelines. Efforts need to be made to correctly identify and target patients who will deliver preterm. Reduced growth should be considered when deliberating early care decisions.

17.
Int J Epidemiol ; 48(3): 978-993, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30689875

RESUMO

BACKGROUND: Quantitative molecular data from urine are rare in epidemiology and genetics. NMR spectroscopy could provide these data in high throughput, and it has already been applied in epidemiological settings to analyse urine samples. However, quantitative protocols for large-scale applications are not available. METHODS: We describe in detail how to prepare urine samples and perform NMR experiments to obtain quantitative metabolic information. Semi-automated quantitative line shape fitting analyses were set up for 43 metabolites and applied to data from various analytical test samples and from 1004 individuals from a population-based epidemiological cohort. Novel analyses on how urine metabolites associate with quantitative serum NMR metabolomics data (61 metabolic measures; n = 995) were performed. In addition, confirmatory genome-wide analyses of urine metabolites were conducted (n = 578). The fully automated quantitative regression-based spectral analysis is demonstrated for creatinine and glucose (n = 4548). RESULTS: Intra-assay metabolite variations were mostly <5%, indicating high robustness and accuracy of urine NMR spectroscopy methodology per se. Intra-individual metabolite variations were large, ranging from 6% to 194%. However, population-based inter-individual metabolite variations were even larger (from 14% to 1655%), providing a sound base for epidemiological applications. Metabolic associations between urine and serum were found to be clearly weaker than those within serum and within urine, indicating that urinary metabolomics data provide independent metabolic information. Two previous genome-wide hits for formate and 2-hydroxyisobutyrate were replicated at genome-wide significance. CONCLUSION: Quantitative urine metabolomics data suggest broad novelty for systems epidemiology. A roadmap for an open access methodology is provided.

18.
J Trace Elem Med Biol ; 51: 12-18, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30466920

RESUMO

BACKGROUND: Copper is an abundant trace element in humans where alterations in the circulating concentration could inform on chronic disease aetiology. To date, data are lacking to study how copper may associate with cardiovascular disease (CVD) risk factors in young and healthy population. Molecular evidence suggests an important role of copper in liver metabolism, an essential organ in maintaining cardiovascular health and inflammation, therefore supporting copper as an associated biomarker of the risk. OBJECTIVE: We performed a cross-sectional analysis to examine the possible associations between blood copper levels and risk factors for CVD and pre-inflammatory process. DESIGN: The data has been collected from a sub-sample set of the Northern Finland Birth Cohort 1966 (NFBC1966) at 31 years. PARTICIPANTS: The study included 206 individuals, 116 men and 90 women. To reduce environmental individual variations affecting both copper and the metabolic profile in the study sample, the participants were selected as: i) being born in Finnish Lapland and ii) living in their birth place for the last five years preceding blood sampling. MAIN OUTCOME MEASURES: Fasting blood copper concentration was measured by inductively coupled plasma mass spectrometer. The CVD risk factors included 6 metabolic clusters (30 cardiovascular and pro-inflammatory factors) assessed by nuclear magnetic resonance. Multivariate linear regression analysis was performed to test the linear association between blood copper and 6 metabolic clusters for CVD risk. Associations were assessed under correction for multiple testing. RESULTS: Copper (Cu) levels were comparable in men and women, with no difference between sexes (p-value <0.60). In multiple regression models, sex adjusted, copper was associated with 9 metabolites from 4 metabolic clusters. After adjustment with BMI, copper was associated with 4 metabolites from 3 metabolic clusters: glutamine, beta-hydroxybutyrate, alpha-1-acid glycoprotein (AGP) and high-sensitive C-reactive protein (hs-CRP). After correction for multiple testing, Cu was found positively associated with only 2 biomarkers of inflammation including AGP [p = 0.04] and hs-CRP [p = 0.0001]. CONCLUSIONS: Considering the strength and limitation of the study design, the present study does not support evidence for an independent role of copper on biomarkers for CVD risk. Nevertheless, we are reporting a robust association of copper with the inflammatory load that is important to consider in light with the inflammatory component of chronic health. In addition, the association of copper with metabolites may be attributable to BMI or environmental factors associated to it, and warrants further research in large population samples.


Assuntos
Doenças Cardiovasculares/sangue , Cobre/sangue , Adulto , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Estudos de Coortes , Feminino , Finlândia , Humanos , Inflamação/sangue , Inflamação/diagnóstico , Inflamação/epidemiologia , Masculino , Fatores de Risco
19.
Int J Obes (Lond) ; 2018 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-30518826

RESUMO

BACKGROUND AND AIMS: Prepregnancy maternal obesity is a global health problem and has been associated with offspring metabolic and mental ill-health. However, there is a knowledge gap in understanding potential neurobiological factors related to these associations. This study explored the relation between maternal prepregnancy body mass index (BMI) and offspring brain white matter microstructure at the age of 6, 10, and 26 years in three independent cohorts. SUBJECTS AND METHODS: The study used data from three European birth cohorts (n = 116 children aged 6 years, n = 2466 children aged 10 years, and n = 437 young adults aged 26 years). Information on maternal prepregnancy BMI was obtained before or during pregnancy and offspring brain white matter microstructure was measured at age 6, 10, or 26 years. We used magnetic resonance imaging-derived fractional anisotropy (FA) and mean diffusivity (MD) as measures of white matter microstructure in the brainstem, callosal, limbic, association, and projection tracts. Linear regressions were fitted to examine the association of maternal BMI and offspring white matter microstructure, adjusting for several socioeconomic and lifestyle-related confounders, including education, smoking, and alcohol use. RESULTS: Maternal BMI was associated with higher FA and lower MD in multiple brain tracts, for example, association and projection fibers, in offspring aged 10 and 26 years, but not at 6 years. In each cohort maternal BMI was related to different white matter tract and thus no common associations across the cohorts were found. CONCLUSIONS: Maternal BMI was associated with higher FA and lower MD in multiple brain tracts in offspring aged 10 and 26 years, but not at 6 years of age. Future studies should examine whether our observations can be replicated and explore the potential causal nature of the findings.

20.
Circulation ; 138(22): 2499-2512, 2018 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-30524137

RESUMO

Background: Both statins and PCSK9 inhibitors lower blood low-density lipoprotein cholesterol (LDL-C) levels to reduce risk of cardiovascular events. To assess potential differences between metabolic effects of these two lipid-lowering therapies, we performed detailed lipid and metabolite profiling of a large randomized statin trial and compared the results with the effects of genetic inhibition of PCSK9, acting as a naturally occurring trial. Methods: 228 circulating metabolic measures were quantified by nuclear magnetic resonance spectroscopy, including lipoprotein subclass concentrations and their lipid composition, fatty acids, and amino acids, for 5,359 individuals (2,659 on treatment) in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial at 6-months post-randomization. The corresponding metabolic measures were analyzed in eight population cohorts (N=72,185) using PCSK9 rs11591147 as an unconfounded proxy to mimic the therapeutic effects of PCSK9 inhibitors. Results: Scaled to an equivalent lowering of LDL-C, the effects of genetic inhibition of PCSK9 on 228 metabolic markers were generally consistent with those of statin therapy (R 2=0.88). Alterations in lipoprotein lipid composition and fatty acid distribution were similar. However, discrepancies were observed for very-low-density lipoprotein (VLDL) lipid measures. For instance, genetic inhibition of PCSK9 had weaker effects on lowering of VLDL-cholesterol compared with statin therapy (54% vs. 77% reduction, relative to the lowering effect on LDL-C; P=2x10-7 for heterogeneity). Genetic inhibition of PCSK9 showed no significant effects on amino acids, ketones, or a marker of inflammation (GlycA) whereas statin treatment weakly lowered GlycA levels. Conclusions: Genetic inhibition of PCSK9 had similar metabolic effects to statin therapy on detailed lipid and metabolite profiles. However, PCSK9 inhibitors are predicted to have weaker effects on VLDL lipids compared with statins for an equivalent lowering of LDL-C, which potentially translate into smaller reductions in cardiovascular disease risk.

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