Adult Cardiometabolic Disease Research Articles

Causal associations of body mass index and waist-to-hip ratio with cardiometabolic traits among Chinese children: A Mendelian randomization study

Background and aimsBody mass index (BMI) and waist-to-hip ratio (WHR) have been reported to be causally associated with cardiometabolic diseases in adults in European populations. However, this causality was less explored in East Asian populations and in children. Our study aimed to explore and compare the causal associations of general obesity (measured by BMI) and central obesity (measured by WHR) with cardiometabolic traits. Methods and resultsWe performed a Mendelian randomization (MR) analysis in 2030 unrelated children from two independent case–control studies in Beijing, China. BMI-associated single nucleotide polymorphisms (SNPs) and WHR-SNPs identified by previous genome-wide association studies were used as genetic instruments to examine the casual associations of BMI and WHR with cardiometabolic traits, including glycemic traits, blood lipids, and blood pressure. Each 1-SD increase in BMI and WHR were significantly associated with 0.111 mmol/L and 0.110 mmol/L increase in log-transformed fasting insulin (FINS), 0.049 and 0.060 increase in log-transformed HOMA-β, 0.112 and 0.108 increase in log-transformed HOMA-IR, 0.009 mmol/L and 0.015 mmol/L increase in log-transformed triglyceride, and 15.527 mmHg and 7.277 mmHg increase in systolic blood pressure, respectively (all P < 0.05). The receiver operating characteristic curves showed that WHR had a stronger effect on FINS, HOMA-β, HOMA-IR, and triglyceride than BMI (all P < 0.05). ConclusionsUsing the MR method, we found that the genetic predisposition to higher BMI or WHR was associated with altered cardiometabolic traits in Chinese children. When compared with general obesity, central obesity might have stronger effects on glycemic traits and blood lipids among children.

Trans-ethnic meta-analysis of genome-wide association studies identifies maternal ITPR1 as a novel locus influencing fetal growth during sensitive periods in pregnancy.

Abnormal fetal growth is a risk factor for infant morbidity and mortality and is associated with cardiometabolic diseases in adults. Genetic influences on fetal growth can vary at different gestation times, but genome-wide association studies have been limited to birthweight. We performed trans-ethnic genome-wide meta-analyses and fine mapping to identify maternal genetic loci associated with fetal weight estimates obtained from ultrasound measures taken during pregnancy. Data included 1,849 pregnant women from four race/ethnic groups recruited through the NICHD Fetal Growth Studies. We identified a novel genome-wide significant association of rs746039 [G] (ITPR1) with reduced fetal weight from 24 to 33 weeks gestation (P<5x10-8; log10BF>6). Additional tests revealed that the SNP was associated with head circumference (P = 4.85x10-8), but not with abdominal circumference or humerus/femur lengths. Conditional analysis in an independent sample of mother-offspring pairs replicated the findings and showed that the effect was more likely maternal but not fetal. Trans-ethnic approaches successfully narrowed down the haplotype block that contained the 99% credible set of SNPs associated with head circumference. We further demonstrated that decreased placental expression of ITPR1 was correlated with increased placental epigenetic age acceleration, a risk factor for reduced fetal growth, among male fetuses (r = -0.4, P = 0.01). Finally, genetic risk score composed of known maternal SNPs implicated in birthweight among Europeans was associated with fetal weight from mid-gestation onwards among Whites only. The present study sheds new light on the role of common maternal genetic variants in the inositol receptor signaling pathway on fetal growth from late second trimester to early third trimester.Clinical Trial Registration: ClinicalTrials.gov, NCT00912132.

Liver Fat and Cardiometabolic Risk Factors Among School-Age Children.

Background and AimsNonalcoholic fatty liver disease is a major risk factor for cardiometabolic disease in adults. The burden of liver fat and associated cardiometabolic risk factors in healthy children is unknown. In a population‐based prospective cohort study among 3,170 10‐year‐old children, we assessed whether both liver fat accumulation across the full range and nonalcoholic fatty liver disease are associated with cardiometabolic risk factors already in childhood.Approach and ResultsLiver fat fraction was measured by magnetic resonance imaging, and nonalcoholic fatty liver disease was defined as liver fat fraction ≥5.0%. We measured body mass index, blood pressure, and insulin, glucose, lipids, and C‐reactive protein concentrations. Cardiometabolic clustering was defined as having three or more risk factors out of high visceral fat mass, high blood pressure, low high‐density‐lipoprotein cholesterol or high triglycerides, and high insulin concentrations. Nonalcoholic fatty liver disease prevalences were 1.0%, 9.1%, and 25.0% among children who were normal weight, overweight, and obese, respectively. Both higher liver fat within the normal range (<5.0% liver fat) and nonalcoholic fatty liver disease were associated with higher blood pressure, insulin resistance, total cholesterol, triglycerides, and C‐reactive protein concentrations (P values < 0.05). As compared with children with <2.0% liver fat, children with ≥5.0% liver fat had the highest odds of cardiometabolic clustering (odds ratio 24.43 [95% confidence interval 12.25, 48.60]). The associations remained similar after adjustment for body mass index and tended to be stronger in children who were overweight and obese.ConclusionsHigher liver fat is, across the full range and independently of body mass index, associated with an adverse cardiometabolic risk profile already in childhood. Future preventive strategies focused on improving cardiometabolic outcomes in later life may need to target liver fat development in childhood.

Obesity in Toddlers and Young Children: Causes and Consequences.

The rapid rise in obesity in toddlers and young children (aged 0-5 years) is a major concern for public health globally. Understanding risk factors for obesity in the early years is therefore fundamental to help guide parents, educators, and health care professionals caring for young children and to develop preventative strategies. Most research has focused on biological risk factors, which can be broadly categorized as genetic predisposition, poor diet (and the behaviors that influence excessive food intake), insufficient physical activity, and the role of developmental factors in early life that influence long-term health. The latter includes establishment of dietary habits and dietary patterns in young (preschool) children and the effect of a high protein intake on the increasing risk of later obesity. Other risk factors particularly relevant to young children include inadequate sleep, high consumption of sugar-sweetened drinks, and large food portions. Understanding the causes of obesity in preschool children is particularly important in view of long-term detrimental consequences of obesity in this age group on the risk of obesity and cardiometabolic disease in adults. The present chapter reviews causes of obesity in preschool children and its consequences for long-term health, focusing particularly on modifiable nutritional risk factors.

Associação entre qualidade do sono e doenças cardiometabólicas de pacientes da Atenção Primária à Saúde

A privação do sono está relacionada ao desenvolvimento de doenças cardiometabólicas. O objetivo deste estudo foi analisar a associação entre qualidade do sono e ocorrência de doenças cardiometabólicas em adultos atendidos na Atenção Primária à Saúde. Estudo longitudinal composto por 169 adultos (68,6% do sexo feminino), média de idade 61,80 (desvio padrão = 8,80), acompanhados por 30 meses. A presença das doenças hipertensão arterial, dislipidemia, diabetes mellitus e ocorrência de infarto e a qualidade do sono foram mensuradas por meio de questionários. Os participantes foram divididos em grupos de acordo com a qualidade do sono (adequada/inadequada). Para verificar a diferença de idade, classe econômica, atividade física habitual e circunferência de cintura, entre os grupos a e b, utilizou-se o teste t de Student para amostras independentes. Para comparar a proporção das doenças (hipertensão arterial, infarto, diabetes e dislipidemias) entre os grupos, utilizou-se o teste Qui-quadrado com correção de Yates. A regressão logística binária foi utilizada para testar a magnitude de tais associações, ajustadas por sexo, idade, atividade física, obesidade abdominal, etilismo e tabagismo. As análises estatísticas foram realizadas no software BioEstat (versão 5.0) e o nível de significância adotado foi de p &lt; 0,05. Verificou-se que 83,4% dos adultos reportaram ao menos uma alteração na qualidade do sono e os que apresentaram inadequada qualidade do sono tiveram 3,4 vezes mais chances de reportar diabetes (OR = 3,47; IC95%: 1,06 - 11,30), comparados aos com o sono adequado. Inadequada qualidade do sono parece contribuir para o aumento da ocorrência de diabetes mellitus, independente do tempo de prática de atividade física e a obesidade abdominal.

Exposure to improved nutrition from conception to age 2 years and adult cardiometabolic disease risk: a modelling study

• In this 40-year, longitudinal cohort in Guatemala, protein-energy nutritional supplementation during the first 2 years of life reduced the odds of diabetes but increased the risk of obesity and several obesity-related conditions in adulthood.

Associations between neonatal serum bilirubin and childhood hypertension.

Mild hyperbilirubinemia is inversely associated with cardiometabolic diseases in adults. The aim of this study was to evaluate the association between neonatal serum bilirubin levels and childhood hypertension. Data were obtained from the U.S. Collaborative Perinatal Project conducted at 12 U.S. medical centers from 1959 to 1965. This multicenter study recruited participants before phototherapy was routinely used, thereby excluding the influence of phototherapy. In 37,544 newborns (31,819 term and 5,725 preterm births), a generalized linear model and a logistic regression model were used to calculate the linear coefficients and adjusted odds ratios (ORs) of blood pressure and hypertension at 7 years of age based on neonatal serum bilirubin levels. No significant correlation was observed between serum bilirubin at 48 hours after birth and blood pressure at the age of 7 years in the whole study population and in the subgroup of term infants. In preterm infants, a lower total serum bilirubin and unconjugated bilirubin of 3 mg/dl were associated with a higher systolic blood pressure of 62 mmHg (0.38–0.86, p <0.001) and 0.70 mmHg (0.10–1.30, p <0.05) respectively. Relative to a total serum bilirubin level <3 mg/dl among preterm infants, total serum bilirubin levels of 3–6 mg/dl (adjusted OR 1.36; 95% CI: 0.98–1.89), 6–9 mg/dl (adjusted OR 1.35; 95% CI: 0.98–1.85), 9–12 mg/dl (adjusted OR 1.55; 95% CI: 1.10–2.19), and ≥12 mg/dl (adjusted OR 1.42; 95% CI: 1.01–2.00) were associated with higher risks of hypertension. After stratifying for the subtypes of bilirubin, the associations only existed for unconjugated bilirubin. In addition, consistent findings existed when using maximum neonatal serum bilirubin as an exposure factor. Neonatal serum bilirubin levels are positively associated with childhood blood pressure/hypertension in preterm infants. Our findings may shed some light on the role of bilirubin in the prevention of hypertension.

Race–ethnic differences in the associations of maternal lipid trait genetic risk scores with longitudinal fetal growth

Fetal growth, an important predictor of cardiometabolic diseases in adults, is influenced by maternal and fetal genetic and environmental factors. We investigated the association between maternal lipid genetic risk score (GRS) and fetal growth among 4 US racial-ethnic populations (Whites, Blacks, Hispanics, and Asians). We extracted genotype data for 2008 pregnant women recruited in the National Institute of Child Health and Human Development Fetal Growth Studies-Singleton cohort with up to 6 standardized ultrasound examinations. GRS was calculated using 240 single-nucleotide polymorphisms previously associated with higher total cholesterol (GRSTChol), low-density lipoprotein cholesterol (GRSLDLc), and triglycerides (GRSTG) and lower high-density lipoprotein cholesterol (GRSHDLc). At 40 weeks' gestation, a unit increase in GRSTG was associated with 11.4g higher fetal weight (95% confidence interval [CI] 2.8-20.0g) among normal-weight Whites, 26.3g (95% CI 6.0-46.6g) among obese Blacks, and 30.8g (95% CI 6.3-55.3g) among obese Hispanics. Higher GRSHDLc was associated with increased fetal weight across 36 to 40weeks among normal-weight Whites and across 13 to 20weeks among normal-weight Asians, but with decreased fetal weight across 26 to 40weeks among normal-weight Hispanics. Higher GRSTChol was suggestively associated with increased fetal weight in males and decreased in females. Associations remained consistent after adjustment for serum lipids. Associations between fetal weight and maternal lipid GRS appear to vary by maternal race-ethnic group, obesity status, and offspring sex. Genetic susceptibility to unfavorable lipid profiles contributes to fetal growth differences even among normal-weight women suggesting a potential future application in predicting aberrant fetal growth.

1332-P: Complement C3 and C4 Levels Predict Cardiometabolic Risk in Healthy Adolescents

Complement, in addition to its immunologic functions, also helps regulate inflammation and fat metabolism. Thus, complement may play a role in the development of the metabolic syndrome. In adults complement component C3 is a risk factor for the development of type 2 diabetes, and a determinant of cardiometabolic risk. Adult cardiometabolic disease has its origins in childhood and adolescence. Therefore, if we are to fully understand the role of complement in cardiometabolic disease we need to study this age group. 56 healthy, non-Hispanic white adolescents (28 F, age 15.4±1.7 years; BMI 22.0±4.9 kg/m2 (mean±SD) were studied. Cardiometabolic risk factors were studied in the fasting state and included measures of vascular function [reactive hyperemia (RH), augmentation index (AI)], lipids, inflammation [white blood cell (WBC) and neutrophil (ANC) count, c-reactive protein (CRP), interleukin 6 (IL6)], carbohydrate metabolism [OGTT: insulin sensitivity (ISEN), insulin secretion (ISEC), disposition index, DI], endothelin 1 and plasminogen activator inhibitor 1 (PAI-1). RH worsened, HDL decreased and ANC, LDL, triglycerides and ISEC increased with increasing C3. RH and HDL were also negatively related to C4 while WBC, ANC, IL6 and DI were positively related to C4. Adjustment for body habitus eliminated the relationships of HDL, LDL and ISEC but not ANC or triglycerides to C3 and/or C4. Adjusted PAI-1 was significantly related to C3. Except for the positive relationship between C4 and DI these relationships demonstrate that increasing levels of C3 and C4 are associated with increasing cardiometabolic risk in healthy, non-Hispanic white adolescents. Increasing C3 levels may influence increasing triglyceride levels while increasing C4 is more closely related to increasing inflammation. Disclosure R.P. Hoffman: Other Relationship; Self; Novo Nordisk A/S. C. Yu: None. Funding American Heart Association; National Institutes of Health

Association of perfluoroalkyl substances exposure with cardiometabolic traits in an island population of the eastern Adriatic coast of Croatia

BackgroundExposure to perfluoroalkyl substances (PFAS), ubiquitous environmental contaminants, may be related to cardiometabolic diseases in adults. Studies in European populations to examine the association of PFAS exposure and comprehensive cardiometabolic traits and metabolic syndrome (MetS) are limited. MethodsIn this pilot cross-sectional study of a well-characterized adult population of the island of Hvar, situated off the eastern Adriatic coast of Croatia, we measured PFAS concentrations in plasma samples collected during 2007–2008 and examined their cross-sectional associations with cardiometabolic traits and MetS after adjustment of covariates (n = 122). PFAS investigated in this study included perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), and perfluorononanoic acid (PFNA). ResultsThe geometric mean (range) was 8.91 (2.36, 33.67) ng/mL for PFOS, 2.87 (1.03, 8.02) ng/mL for PFOA, 0.77 (0.25, 2.40) ng/mL for PFHxS, and 1.29 (0.48, 3.46) ng/mL for PFNA, with frequency of detection at 100%, 100%, 95.9%, and 100%, respectively. PFOS, PFOA, and PFNA concentrations were positively associated with the risk of MetS as defined by the Adult Treatment Panel III (ATP III) criteria, with estimated odds ratios and 95% confidence intervals at 1.89 (0.93, 3.86), 2.19 (0.88, 5.44), and 2.95 (1.12, 7.80), respectively, with only PFNA reaching statistical significance. PFNA concentrations were associated with increased risk of overweight or obesity. ConclusionsBackground exposure to PFOS, PFOA, and PFNA was marginally associated with increased risk of MetS in this small study, and these results should be confirmed with a larger sample size and longitudinal follow-up.

Shared genetic underpinnings of childhood obesity and adult cardiometabolic diseases

BackgroundObesity during childhood can lead to increased risk of adverse cardiometabolic diseases such as type 2 diabetes and coronary artery disease during adult life. Evidence for strong genetic correlations between child and adult body mass index (BMI) suggest the possibility of shared genetic effects. We performed a test for pleiotropy (shared genetics) and functional enrichment of single nucleotide polymorphisms (SNPs) associated with childhood BMI and 15 adult cardiometabolic traits using a unified statistical approach that integrates pleiotropy and functional annotation data.ResultsPleiotropic genetic effects were significantly abundant in 13 out of 15 childhood BMI-adult cardiometabolic trait tests (P < 3.3 × 10−3). SNPs associated with both childhood BMI and adult traits were more likely to be functionally deleterious than SNPs associated with neither trait. Genetic variants associated with increased childhood obesity tend to increase risk of cardiometabolic diseases in adulthood. We replicated 39 genetic loci that are known to be associated with childhood BMI and adult traits (coronary artery disease, HDL cholesterol, myocardial infarction, triglycerides, total cholesterol, type 2 diabetes, BMI, waist circumference, and waist-to-hip ratio) in previous genome-wide association studies. We also found a novel association of rs12446632 near GPRC5B, which is highly expressed in adipose tissue and the central nervous system, with adult HDL cholesterol.ConclusionsThis study found significant pleiotropic genetic effects and enrichment of functional annotations in genetic variants that were jointly associated with childhood obesity and adult cardiometabolic diseases. The findings provide new avenues to disentangle the genetic basis of life course associations between childhood obesity and adult cardiometabolic diseases.

Childhood maltreatment and biomarkers for cardiometabolic disease in mid-adulthood in a prospective British birth cohort: associations and potential explanations

ObjectivesResearch on associations between childhood maltreatment and adult cardiometabolic disease risk is sparse. We aimed to investigate associations between different forms of child maltreatment and mid-adult cardiometabolic markers and whether...

Genetic overlap between birthweight and adult cardiometabolic diseases has implications for genomic medicine

Before implementing therapeutic genomic interventions for optimizing health in early life, comprehensive understanding of their effect on several traits across the life course is warranted. Abnorml birthweight is associated with cardiometabolic disease risk in adulthood; however, the extent of genetic pleiotropy in the association has not been comprehensively investigated. We tested for pleiotropy and enrichment of functional loci between birthweight and 15 cardiometabolic disease traits (CMD). We found significantly abundant genetic pleiotropy (P < 3.3 × 10−3) and enrichment of functional annotations (P < 3.3 × 10−3) in loci influencing both birthweight and CMD. We did not observe consistent effect directions of pleiotropic loci on the traits. A total of 67 genetic loci, of which 65 loci have been reported in previous genome-wide association studies, were associated with both birthweight and CMD at a false discovery rate of 5%. Two novel loci were associated with birthweight and adult coronary artery disease (rs2870463 in CTRB1) and with birthweight and adult waist circumference (rs12704673 in CALCR). Both loci are known to have regulatory effects on expression of nearby genes. In all, our findings revealed pervasive genetic pleiotropy in early growth and adulthood cardiometabolic diseases, implying the need for caution when considering genetic loci as therapeutic targets.

The Placental Transcriptome in Late Gestational Hypoxia Resulting in Murine Intrauterine Growth Restriction Parallels Increased Risk of Adult Cardiometabolic Disease

Intrauterine growth restriction (IUGR) enhances risk for adult onset cardiovascular disease (CVD). The mechanisms underlying IUGR are poorly understood, though inadequate blood flow and oxygen/nutrient provision are considered common endpoints. Based on evidence in humans linking IUGR to adult CVD, we hypothesized that in murine pregnancy, maternal late gestational hypoxia (LG-H) exposure resulting in IUGR would result in (1) placental transcriptome changes linked to risk for later CVD, and 2) adult phenotypes of CVD in the IUGR offspring. After subjecting pregnant mice to hypoxia (10.5% oxygen) from gestational day (GD) 14.5 to 18.5, we undertook RNA sequencing from GD19 placentas. Functional analysis suggested multiple changes in structural and functional genes important for placental health and function, with maximal dysregulation involving vascular and nutrient transport pathways. Concordantly, a ~10% decrease in birthweights and ~30% decrease in litter size was observed, supportive of placental insufficiency. We also found that the LG-H IUGR offspring exhibit increased risk for CVD at 4 months of age, manifesting as hypertension, increased abdominal fat, elevated leptin and total cholesterol concentrations. In summary, this animal model of IUGR links the placental transcriptional response to the stressor of gestational hypoxia to increased risk of developing cardiometabolic disease.

Complement Components, C3 and C4, and the Metabolic Syndrome.

Increased systemic inflammation plays a significant role in the development of adult cardiometabolic diseases such as insulin resistance, dyslipidemia, atherosclerosis, and hypertension. The complement system is a part of the innate immune system and plays a key role in the regulation of inflammation. Of particular importance is the activation of complement components C3 and C4. C3 is produced primarily by the liver but is also produced in adipocytes, macrophages and endothelial cells, all of which are present in adipose tissues. Dietary fat and chylomicrons stimulate C3 production. Adipocytes in addition to producing C3 also have receptors for activated C3 and other complement components and thus also respond to as well as produce a target for complement. C3adesArg, also known as acylation stimulation factor, increases adipocyte triglyceride synthesis and release. These physiological effects play a significant role in the development of metabolic syndrome. Epidemiologically, obese adults and non-obese adults with cardiometabolic disease who are not obese have been shown to have increased complement levels. C4 levels also correlate with body mass index. Genetically, specific C3 polymorphisms have been shown to predict future cardiovascular events and. D decreased C4 long gene copy number is associated with increased longevity. Future research is clearly needed to clarify the role of complement in the development of cardiovascular disease and mechanisms for its action. The complement system may provide a new area for intervention in the prevention of cardiometabolic diseases.

Childhood BMI and Adult Type 2 Diabetes, Coronary Artery Diseases, Chronic Kidney Disease, and Cardiometabolic Traits: A Mendelian Randomization Analysis

OBJECTIVE To test the causal effect of childhood BMI on adult cardiometabolic diseases using a Mendelian randomization analysis. RESEARCH DESIGN AND METHODS We used 15 single nucleotide polymorphisms as instrumental variables for childhood BMI to test the causal effect of childhood BMI on cardiometabolic diseases using summary-level data from consortia. RESULTS We found that a 1-SD increase in childhood BMI (kg/m 2 ) was associated with an 83% increase in risk of type 2 diabetes (odds ratio [OR] 1.83 [95% CI 1.46, 2.30]; P = 2.5 × 10 −7 ) and a 28% increase in risk of coronary artery disease (CAD) (OR 1.28 [95% CI 1.17, 1.39]; P = 2.1 × 10 −8 ) at the Bonferroni-adjusted level of significance ( P 2 ), a 0.062-SD increase in hip circumference (cm), a 0.602-SD increase in waist circumference (cm), a 0.111 pmol/L increase in log fasting insulin, a 0.068 increase in log-transformed HOMA of s-cell function (%), a 0.126 increase in log-transformed HOMA of insulin resistance (%), and a 0.109-SD increase in triglyceride (mg/dL) but a 0.138-SD decrease in HDL (mg/dL) in adults at the Bonferroni-adjusted level of significance ( P CONCLUSIONS A genetic predisposition to higher childhood BMI was associated with increased risk of type 2 diabetes and CAD in adult life. These results provide evidence supportive of a causal association between childhood BMI and these outcomes.

Cumulative childhood adversity and adult cardiometabolic disease: A meta-analysis.

Adverse childhood experiences may be associated with cardiometabolic morbidity and mortality in adulthood. There is heterogeneity in this literature regarding the type of items in cumulative adversity indices, sample sizes, demographics, and covariates. The present review used quantitative meta-analysis to examine this association and potential moderators. Included studies had a measure of cumulative adversity (an index of at least 2 adverse childhood experiences from age 0 to 18) and a measure of cardiometabolic disease: cardiovascular disease (CVD) clinical outcomes (hypertension, coronary heart disease, ischemic heart disease, myocardial infarction, stroke, cerebrovascular disease) and metabolic outcomes (diabetes, metabolic syndrome) at age 18 or older. Given different interpretations of odds ratios (OR) versus hazard ratios (HR), effects were pooled separately. Overall, 9 HR studies (15 effects) based on 179,612 participants and 29 OR studies (62 effects) based on 247,393 participants were included. On the basis of retrospectively assessed adversity, combined studies showed a significant estimated effect of cumulative childhood adversity on adult cardiometabolic disease (HR = 1.42, 95% CI [1.20, 1.67]; OR = 1.36 [1.27, 1.46]). Results varied somewhat by type of cardiometabolic disease, analytic strategy, and number and type of covariates. The literature suggests that cumulative childhood adversity is modestly related to adult cardiometabolic disease, with effects somewhat stronger for CVD clinical outcomes. The absence of a consistent operational and conceptual definition of adversity and paucity of prospective designs temper the conclusions. It is time for further evaluation of the types and timing of childhood events that have maximal impact on adult cardiometabolic disease. (PsycINFO Database Record

Exposure to improved nutrition from conception to age 2 years and adult cardiometabolic disease risk: a modelling study.

Low-income and middle-income countries with populations that are chronically undernourished in early life are undergoing a nutrition transition and are experiencing an epidemic of cardiometabolic disease. These dual burdens are thought to be causally related; therefore, the extent to which improvements in early-life nutrition can offset adult-onset disease is important. The aim of this study was to examine whether improvement of protein-energy nutrition from conception to age 2 years can attenuate the risk of cardiometabolic disease. We followed up a cohort of 2392 individuals born between Jan 1, 1962, and Feb 28, 1977, in four villages in Guatemala who had participated in a cluster-randomised protein-energy nutritional supplementation (Atole) trial. Of 1661 participants available for follow-up from Feb 26, 2015, to April 29, 2017, we studied 684 women and 455 men. We assessed cardiometabolic disease risk at ages 37-54 years using anthropometry, fasting and post-challenge glucose, fasting lipid concentrations, and blood pressure. We used generalised linear and logistic regression modelling to estimate the effect of Atole from conception to age 2 years (the first 1000 days) on cardiometabolic disease risk. Exposure to Atole from conception to age 2 years was associated with increased fatness (body-mass index [1·29 kg/m2, 95% CI 0·08 to 2·50], body fat [1·73%, 0·20 to 3·26], and obesity [odds ratio 1·94, 1·11 to 3·40]), diastolic blood pressure (1·59 mm Hg, -0·74 to 3·92), and blood lipids (total cholesterol [10·10 mg/dL, 0·80 to 19·40] and non-HDL cholesterol [10·41 mg/dL, 1·51 to 19·31]), reduced post-challenge glucose (-5·84 mg/dL, -12·51 to 0·83), and reduced odds of diabetes (odds ratio 0·46, 0·21 to 0·97). We found stratum heterogeneity by sex in pooled models for non-HDL cholesterol (4·34 mg/dL, 95% CI -6·86 to 15·55 for women vs 19·84 mg/dL, 5·86 to 33·82 for men) and post-challenge glucose (-0·19 mg/dL, -8·63 to 8·24 for women vs -13·10 mg/dL, -23·64 to -2·56 for men). p values for interaction of sex and exposure to Atole from conception to age 2 years were 0·09 and 0·04, respectively. Improved protein-energy nutrition from conception to the 2nd birthday reduced the odds of diabetes at ages 37-54 years; however, this protein-energy supplementation also increased the risk of obesity and several obesity-related conditions. Our findings suggest a mixed ability of protein-energy nutritional supplementation in early life to prevent adult cardiometabolic disease incidence in the context of high childhood stunting and high adult overweight and obesity. National Institutes of Health.

Prenatal Growth Patterns and Birthweight Are Associated With Differential DNA Methylation and Gene Expression of Cardiometabolic Risk Genes in Human Placentas: A Discovery-Based Approach.

Inherent genetic programming and environmental factors affect fetal growth in utero. Epidemiologic data in growth-altered fetuses, either intrauterine growth restricted (IUGR) or large for gestational age (LGA), demonstrate that these newborns are at increased risk of cardiometabolic disease in adulthood. There is growing evidence that the in utero environment leads to epigenetic modification, contributing to eventual risk of developing heart disease or diabetes. In this study, we used reduced representation bisulfite sequencing to examine genome-wide DNA methylation variation in placental samples from offspring born IUGR, LGA, and appropriate for gestational age (AGA) and to identify differential methylation of genes important for conferring risk of cardiometabolic disease. We found that there were distinct methylation signatures for IUGR, LGA, and AGA groups and identified over 500 differentially methylated genes (DMGs) among these group comparisons. Functional and gene network analyses revealed expected relationships of DMGs to placental physiology and transport, but also identified novel pathways with biologic plausibility and potential clinical importance to cardiometabolic disease. Specific loci for DMGs of interest had methylation patterns that were strongly associated with anthropometric presentations. We further validated altered gene expression of these specific DMGs contributing to vascular and metabolic diseases (SLC36A1, PTPRN2, CASZ1, IL10), thereby establishing transcriptional effects toward assigning functional significance. Our results suggest that the gene expression and methylation state of the human placenta are related and sensitive to the intrauterine environment, as it affects fetal growth patterns. We speculate that these observed changes may affect risk for offspring in developing adult cardiometabolic disease.

Childhood BMI and Adult Type 2 Diabetes, Coronary Artery Diseases, Chronic Kidney Disease, and Cardiometabolic Traits: A Mendelian Randomization Analysis.

To test the causal effect of childhood BMI on adult cardiometabolic diseases using a Mendelian randomization analysis. We used 15 single nucleotide polymorphisms as instrumental variables for childhood BMI to test the causal effect of childhood BMI on cardiometabolic diseases using summary-level data from consortia. We found that a 1-SD increase in childhood BMI (kg/m2) was associated with an 83% increase in risk of type 2 diabetes (odds ratio [OR] 1.83 [95% CI 1.46, 2.30]; P = 2.5 × 10-7) and a 28% increase in risk of coronary artery disease (CAD) (OR 1.28 [95% CI 1.17, 1.39]; P = 2.1 × 10-8) at the Bonferroni-adjusted level of significance (P < 0.017) in adults. In addition, a 1-SD increase in childhood BMI was associated with a 0.587-SD increase in adulthood BMI (kg/m2), a 0.062-SD increase in hip circumference (cm), a 0.602-SD increase in waist circumference (cm), a 0.111 pmol/L increase in log fasting insulin, a 0.068 increase in log-transformed HOMA of ß-cell function (%), a 0.126 increase in log-transformed HOMA of insulin resistance (%), and a 0.109-SD increase in triglyceride (mg/dL) but a 0.138-SD decrease in HDL (mg/dL) in adults at the Bonferroni-adjusted level of significance (P < 0.0026). A genetic predisposition to higher childhood BMI was associated with increased risk of type 2 diabetes and CAD in adult life. These results provide evidence supportive of a causal association between childhood BMI and these outcomes.