Preeclampsia, a new-onset hypertensive disorder of pregnancy, is associated with lifetime cardiovascular disease risk, but less is known about risk after other pregnancy-related hypertension.
The ...Northern Finland Birth Cohort 1966 included all expected births from 1 year (N=12 055 women). Blood pressure measurements and other prospective data were determined from prenatal care records and questionnaires for 10 314 women. Subsequent diagnoses were ascertained from Finnish registries (average follow-up, 39.4 years). Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) estimate risks in hypertensive women compared with normotensive women. Hypertension during pregnancy was associated with increased risk of subsequent cardiovascular disease and arterial hypertension. Women with chronic hypertension and superimposed preeclampsia/eclampsia had high risk for future diseases. Gestational hypertension was associated with increased risk of ischemic heart disease (HR, 1.44 95% CI, 1.24-1.68), myocardial infarcts (HR, 1.75 95% CI, 1.40-2.19), myocardial infarct death (HR, 3.00 95% CI, 1.98-4.55), heart failure (HR, 1.78 95% CI, 1.43-2.21), ischemic stroke (HR, 1.59 95% CI, 1.24-2.04), kidney disease (HR, 1.91 95% CI, 1.18-3.09), and diabetes mellitus (HR, 1.52 95% CI, 1.21-1.89). Isolated systolic hypertension was associated with increased risk of myocardial infarct death (HR, 2.15 95% CI, 1.35-3.41), heart failure (HR, 1.43 95% CI, 1.13-1.82), and diabetes mellitus (HR, 1.42 95% CI, 1.13-1.78), whereas isolated diastolic hypertension was associated with increased risk of ischemic heart disease (HR, 1.26 95% CI, 1.05-1.50). Results were similar in nonsmoking women aged <35 years with normal weight and no diabetes mellitus during pregnancy.
Elevated blood pressure during pregnancy, regardless of type and even without known risk factors, signals high risk of later cardiovascular disease, chronic kidney disease, and diabetes mellitus. Clinical monitoring, risk factor evaluation, and early intervention could benefit women with hypertension in pregnancy.
Free fatty acids provide an important energy source as nutrients, and act as signalling molecules in various cellular processes. Several G-protein-coupled receptors have been identified as ...free-fatty-acid receptors important in physiology as well as in several diseases. GPR120 (also known as O3FAR1) functions as a receptor for unsaturated long-chain free fatty acids and has a critical role in various physiological homeostasis mechanisms such as adipogenesis, regulation of appetite and food preference. Here we show that GPR120-deficient mice fed a high-fat diet develop obesity, glucose intolerance and fatty liver with decreased adipocyte differentiation and lipogenesis and enhanced hepatic lipogenesis. Insulin resistance in such mice is associated with reduced insulin signalling and enhanced inflammation in adipose tissue. In human, we show that GPR120 expression in adipose tissue is significantly higher in obese individuals than in lean controls. GPR120 exon sequencing in obese subjects reveals a deleterious non-synonymous mutation (p.R270H) that inhibits GPR120 signalling activity. Furthermore, the p.R270H variant increases the risk of obesity in European populations. Overall, this study demonstrates that the lipid sensor GPR120 has a key role in sensing dietary fat and, therefore, in the control of energy balance in both humans and rodents.
Increased adiposity is linked with higher risk for cardiometabolic diseases. We aimed to determine to what extent elevated body mass index (BMI) within the normal weight range has causal effects on ...the detailed systemic metabolite profile in early adulthood.
We used Mendelian randomization to estimate causal effects of BMI on 82 metabolic measures in 12,664 adolescents and young adults from four population-based cohorts in Finland (mean age 26 y, range 16-39 y; 51% women; mean ± standard deviation BMI 24 ± 4 kg/m(2)). Circulating metabolites were quantified by high-throughput nuclear magnetic resonance metabolomics and biochemical assays. In cross-sectional analyses, elevated BMI was adversely associated with cardiometabolic risk markers throughout the systemic metabolite profile, including lipoprotein subclasses, fatty acid composition, amino acids, inflammatory markers, and various hormones (p<0.0005 for 68 measures). Metabolite associations with BMI were generally stronger for men than for women (median 136%, interquartile range 125%-183%). A gene score for predisposition to elevated BMI, composed of 32 established genetic correlates, was used as the instrument to assess causality. Causal effects of elevated BMI closely matched observational estimates (correspondence 87% ± 3%; R(2)= 0.89), suggesting causative influences of adiposity on the levels of numerous metabolites (p<0.0005 for 24 measures), including lipoprotein lipid subclasses and particle size, branched-chain and aromatic amino acids, and inflammation-related glycoprotein acetyls. Causal analyses of certain metabolites and potential sex differences warrant stronger statistical power. Metabolite changes associated with change in BMI during 6 y of follow-up were examined for 1,488 individuals. Change in BMI was accompanied by widespread metabolite changes, which had an association pattern similar to that of the cross-sectional observations, yet with greater metabolic effects (correspondence 160% ± 2%; R(2) = 0.92).
Mendelian randomization indicates causal adverse effects of increased adiposity with multiple cardiometabolic risk markers across the metabolite profile in adolescents and young adults within the non-obese weight range. Consistent with the causal influences of adiposity, weight changes were paralleled by extensive metabolic changes, suggesting a broadly modifiable systemic metabolite profile in early adulthood. Please see later in the article for the Editors' Summary.
To assess the frequency and perinatal outcomes of gestational diabetes mellitus (GDM) defined by the criteria according to the International Association of Diabetes in Pregnancy Study Group (IADPSG) ...and the National Institute for Health and Care Excellence (NICE) diagnostic criteria for GDM.
A retrospective cohort study.
Six secondary and tertiary delivery hospitals in Finland in 2009.
Pregnant women (N = 4,033) and their offspring.
We used data on comprehensive screening of pregnant women with a 2-h 75-g oral glucose tolerance test (OGTT), performed between gestational weeks 24 and 40. OGTT glucose concentrations were used to identify women who fulfilled IADPSG and NICE criteria. While cut-offs according to Finnish national criteria partly overlapped with both criteria, a subgroup of IADPSG- or NICE-positive GDM women remained undiagnosed by Finnish criteria and hence non-treated. They were analysed as subgroups and compared to controls who were negative with all cut-offs.
GDM prevalence, birth weight SD score (BWSDS), large for gestational age (LGA) and caesarean section (CS) rates.
Among the 4,033 women screened for GDM, 1,249 (31.0%) and 529 (13.1%) had GDM according to the IADPSG and NICE criteria, respectively. The LGA rate was similar in both groups. Regardless of the diagnostic criteria, women with GDM had a higher risk of induced delivery and CSs than controls. In IADPSG-positive non-treated women, offspring's BWSDS and CS rate were higher than in controls.
GDM prevalence was 2.4-fold higher according to the IADPSG compared with the NICE criteria but the LGA rate did not differ. BWSDS and CS rate were increased already with mild untreated hyperglycaemia.
Genome-wide association studies (GWAS) of longitudinal birth cohorts enable joint investigation of environmental and genetic influences on complex traits. We report GWAS results for nine quantitative ...metabolic traits (triglycerides, high-density lipoprotein, low-density lipoprotein, glucose, insulin, C-reactive protein, body mass index, and systolic and diastolic blood pressure) in the Northern Finland Birth Cohort 1966 (NFBC1966), drawn from the most genetically isolated Finnish regions. We replicate most previously reported associations for these traits and identify nine new associations, several of which highlight genes with metabolic functions: high-density lipoprotein with NR1H3 (LXRA), low-density lipoprotein with AR and FADS1-FADS2, glucose with MTNR1B, and insulin with PANK1. Two of these new associations emerged after adjustment of results for body mass index. Gene-environment interaction analyses suggested additional associations, which will require validation in larger samples. The currently identified loci, together with quantified environmental exposures, explain little of the trait variation in NFBC1966. The association observed between low-density lipoprotein and an infrequent variant in AR suggests the potential of such a cohort for identifying associations with both common, low-impact and rarer, high-impact quantitative trait loci.
Adolescents and adults born as small preterm infants show more pronounced risk factors of cardiovascular disease. Whether similar risks apply across all degrees of preterm birth is poorly known.
We ...studied the association between preterm birth and cardiovascular risk factors in 6642 16-year-old adolescents of the population-based Northern Finland Birth Cohort 1986. Of these, 79 (1.2%) were born at <34 gestational weeks (early preterm), 238 (3.6%) at 34 to 36 weeks (late preterm), and 6325 at term (controls).
Girls born early preterm had 6.7 mm Hg (95% confidence interval: 3.1-10.2) higher systolic blood pressure (BP) and 3.5 mm Hg (1.1-5.8) higher diastolic BP, but no difference in serum lipid levels compared with control girls. Boys showed no differences in BP, but boys born early preterm had 6.7% (0.2%-13.7%) higher total cholesterol, 11.7% (2.1%-22.3%) higher low-density lipoprotein cholesterol, and 12.3% (3.1%-22.4%) higher apolipoprotein B concentrations. The differences were similar (BP) or stronger (lipids) when adjusted for maternal smoking, birth weight SD score, parental education, pubertal stage, BMI, and lifestyle. There were similar associations with length of gestation as a continuous variable. Accordingly, mean differences between late preterm and controls were in the same direction but weaker, although most were not statistically significant.
Preterm birth was associated with elevated BP in adolescent girls and an atherogenic lipid profile in boys. Because these associations were strongest among those born early preterm, our findings are consistent with a dose-response relationship between shorter length of gestation and cardiovascular risk factors.
Long-term physical inactivity seems to cause many health problems. We studied whether persistent physical activity compared with inactivity has a global effect on serum metabolome toward reduced ...cardiometabolic disease risk.
Sixteen same-sex twin pairs (mean age, 60 years) were selected from a cohort of twin pairs on the basis of their >30-year discordance for physical activity. Persistently (≥5 years) active and inactive groups in 3 population-based cohorts (mean ages, 31-52 years) were also studied (1037 age- and sex-matched pairs). Serum metabolome was quantified by nuclear magnetic resonance spectroscopy. We used permutation analysis to estimate the significance of the multivariate effect combined across all metabolic measures; univariate effects were estimated by paired testing in twins and in matched pairs in the cohorts, and by meta-analysis over all substudies. Persistent physical activity was associated with the multivariate metabolic profile in the twins (P=0.003), and a similar pattern was observed in all 3 population cohorts with differing mean ages. Isoleucine, α1-acid glycoprotein, and glucose were lower in the physically active than in the inactive individuals (P<0.001 in meta-analysis); serum fatty acid composition was shifted toward a less saturated profile; and lipoprotein subclasses were shifted toward lower very-low-density lipoprotein (P<0.001) and higher large and very large high-density lipoprotein (P<0.001) particle concentrations. The findings persisted after adjustment for body mass index.
The numerous differences found between persistently physically active and inactive individuals in the circulating metabolome together indicate better metabolic health in the physically active than in inactive individuals.
Pre-eclampsia is a common and complex pregnancy disorder that often involves impaired placental development. In order to identify altered gene expression in pre-eclamptic placenta, we sequenced ...placental transcriptomes of nine pre-eclamptic and nine healthy pregnant women in pools of three. The differential gene expression was tested both by including all the pools in the analysis and by excluding some of the pools based on phenotypic characteristics. From these analyses, we identified altogether 53 differently expressed genes, a subset of which was validated by qPCR in 20 cases and 19 controls. Furthermore, we conducted pathway and functional analyses which revealed disturbed vascular function and immunological balance in pre-eclamptic placenta. Some of the genes identified in our study have been reported by numerous microarray studies (BHLHE40, FSTL3, HK2, HTRA4, LEP, PVRL4, SASH1, SIGLEC6), but many have been implicated in only few studies or have not previously been linked to pre-eclampsia (ARMS2, BTNL9, CCSAP, DIO2, FER1L4, HPSE, LOC100129345, LYN, MYO7B, NCMAP, NDRG1, NRIP1, PLIN2, SBSPON, SERPINB9, SH3BP5, TET3, TPBG, ZNF175). Several of the molecules produced by these genes may have a role in the pathogenesis of pre-eclampsia, and some could qualify as biomarkers for prediction or detection of this pregnancy complication.
Context: Knowledge is scarce concerning the significance of thyroid dysfunction/antibodies during pregnancy in regard to pregnancy complications/later maternal morbidity.
Objective: The aim of this ...study was to evaluate the association between maternal thyroid dysfunction/antibodies during pregnancy and pregnancy complications or later maternal hypertension, diabetes, and thyroid disease.
Design and Setting: We studied a prospective population-based cohort, Northern Finland Birth Cohort 1986 (NFBC 1986), with follow-up of 20 yr. Medication and hospital discharge records were used to assess maternal morbidity to hypertension, diabetes, and thyroid diseases.
Participants: The study consisted of mothers of NFBC 1986 with early pregnancy serum samples for thyroid function and antibody analyses (n = 5805). Mothers were grouped and compared according to these test results.
Main Outcome Measures: We focused on preeclampsia and gestational diabetes during index pregnancy, later maternal hypertension, diabetes, and thyroid disease morbidity and total mortality.
Results: Thyroid dysfunction and antibodies were not associated with pregnancy complications. Overt hypothyroidism was associated with subsequent maternal thyroid disease hazard ratio (HR) (95% confidence interval), 17.7 (7.8–40.6) and diabetes 6.0 (2.2–16.4). Subclinical hypothyroidism 3.3 (1.6–6.9), TPO-Ab-positivity 4.2 (2.3–7.4), and TG-Ab-positivity 3.3 (1.9–6.0) were also associated with later thyroid disease. No association was found between thyroid dysfunction/antibodies and hypertension or overall mortality.
Conclusions: Thyroid dysfunction and antibodies during pregnancy seem to predict later thyroid disease. Overt hypothyroidism poses risk of diabetes.
Thyroid dysfunction and antibodies during pregnancy seem to predict later maternal morbidity to thyroid diseases.
OBJECTIVE: Early pubertal onset in females is associated with increased risk for adult obesity and cardiovascular disease, but whether this relationship is independent of preceding childhood growth ...events is unclear. Furthermore, the association between male puberty and adult disease remains unknown. To clarify the link between puberty and adult health, we evaluated the relationship between pubertal timing and risk factors for type 2 diabetes and cardiovascular disease in both males and females from a large, prospective, and randomly ascertained birth cohort from Northern Finland. RESEARCH DESIGN AND METHODS: Pubertal timing was estimated based on pubertal height growth in 5,058 subjects (2,417 males and 2,641 females), and the relationship between puberty and body weight, glucose and lipid homeostasis, and blood pressure at age 31 years was evaluated with linear regression modeling. RESULTS: Earlier pubertal timing associated with higher adult BMI, fasting insulin, diastolic blood pressure, and decreased HDL cholesterol in both sexes (P < 0.002) and with higher total serum cholesterol, LDL cholesterol, and triglycerides in males. The association with BMI and diastolic blood pressure remained statistically significant in both sexes, as did the association with insulin levels and HDL cholesterol concentrations in males after adjusting for covariates reflecting both fetal and childhood growth including childhood BMI. CONCLUSIONS: We demonstrate independent association between earlier pubertal timing and adult metabolic syndrome-related derangements both in males and females. The connection emphasizes that the mechanisms advancing puberty may also contribute to adult metabolic disorders.
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