[Show abstract][Hide abstract] ABSTRACT: We previously used a single nucleotide polymorphism (SNP) in the CHRNA5-A3-B4 gene cluster associated with heaviness of smoking within smokers to confirm the causal effect of smoking in reducing body mass index (BMI) in a Mendelian randomisation analysis. While seeking to extend these findings in a larger sample we found that this SNP is associated with 0.74% lower body mass index (BMI) per minor allele in current smokers (95% CI -0.97 to -0.51, P = 2.00×10-10), but also unexpectedly found that it was associated with 0.35% higher BMI in never smokers (95% CI +0.18 to +0.52, P = 6.38×10-5). An interaction test confirmed that these estimates differed from each other (P = 4.95×10-13). This difference in effects suggests the variant influences BMI both via pathways unrelated to smoking, and via the weight-reducing effects of smoking. It would therefore be essentially undetectable in an unstratified genome-wide association study of BMI, given the opposite association with BMI in never and current smokers. This demonstrates that novel associations may be obscured by hidden population sub-structure. Stratification on well-characterized environmental factors known to impact on health outcomes may therefore reveal novel genetic associations.
[Show abstract][Hide abstract] ABSTRACT: We examined mean effects and variance moderating effects of measures of physical activity and fitness on six measures of adiposity and their reciprocal effects in a subsample of the population-representative Danish Twin Registry. Consistent with prior studies, higher levels of physical activity suppressed variance in adiposity, but this study provided further insight. Variance suppression appeared to have both genetic and environmental pathways. Some mean effects appeared due to reciprocal influences of environmental circumstances differing among families but not between co-twins, suggesting these reciprocal effects are uniform. Some variance moderating effects also appeared due to biases in individual measures of adiposity, as well as to differences and inaccuracies in measures of physical activity. This suggests a need to avoid reliance on single measures of both physical activity and adiposity in attempting to understand the pathways involved in their linkages, and constraint in interpreting results if only single measures are available. Future research indications include identifying which physical activity-related environmental circumstances have relatively uniform effects on adiposity in everyone, and which should be individually tailored to maximize motivation to continue involvement.
[Show abstract][Hide abstract] ABSTRACT: Objectives
Maternal body mass index (BMI), birth weight, and preschool BMI may help identify children at high risk of overweight as they are (1) similarly linked to adolescent overweight at different stages of the obesity epidemic, (2) linked to adult obesity and metabolic alterations, and (3) easily obtainable in health examinations in young children. The aim was to develop early childhood prediction models of adolescent overweight, adult overweight, and adult obesity.Methods
Prediction models at various ages in the Northern Finland Birth Cohort born in 1966 (NFBC1966) were developed. Internal validation was tested using a bootstrap design, and external validation was tested for the model predicting adolescent overweight using the Northern Finland Birth Cohort born in 1986 (NFBC1986).ResultsA prediction model developed in the NFBC1966 to predict adolescent overweight, applied to the NFBC1986, and aimed at labelling 10% as “at risk” on the basis of anthropometric information collected until 5 years of age showed that half of those at risk in fact did become overweight. This group constituted one-third of all who became overweight.Conclusions
Our prediction model identified a subgroup of children at very high risk of becoming overweight, which may be valuable in public health settings dealing with obesity prevention.
[Show abstract][Hide abstract] ABSTRACT: Greater attained height and greater body mass index (BMI; weight (kg)/height (m)(2)) in young adulthood have been associated with glioma risk, but few studies have investigated the association with body size at birth or during childhood, when the brain undergoes rapid cell growth and differentiation. The Copenhagen School Health Records Register includes data on 320,425 Danish schoolchildren born between 1930 and 1989, with height and weight measurements from ages 7-13 years and parentally recorded birth weights. We prospectively evaluated associations between childhood height and BMI, birth weight, and adult glioma risk. During follow-up (1968-2010), 355 men and 253 women aged ≥18 years were diagnosed with glioma. In boys, height at each age between 7 and 13 years was positively associated with glioma risk; hazard ratios per standard-deviation score at ages 7 (approximately 5.1 cm) and 13 (approximately 7.6 cm) years were 1.17 (95% confidence interval (CI): 1.05, 1.30) and 1.21 (95% CI: 1.09, 1.35), respectively. No associations were observed for childhood height in girls or for BMI. Birth weight was positively associated with risk (per 0.5 kg: hazard ratio = 1.13, 95% CI: 1.04, 1.24). These results suggest that exposures associated with higher birth weight and, in boys, greater height during childhood may contribute to the etiology of adult glioma.
American Journal of Epidemiology 09/2014; · 4.78 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The present study examined whether exposure to vitamin D from fortified margarine and milk during prenatal life influenced mean birth weight and the risk of high or low birth weight. The study was based on the Danish vitamin D fortification programme, which was a societal intervention with mandatory fortification of margarine during 1961-1985 and voluntary fortification of low-fat milk between 1972 and 1976. The influence of prenatal vitamin D exposure on birth weight was investigated among 51 883 Danish children, by comparing birth weight among individuals born during 2 years before or after the initiation and termination of vitamin D fortification programmes. In total, four sets of analyses were performed. Information on birth weight was available in the Copenhagen School Health Record Register for all school children in Copenhagen. The mean birth weight was lower among the exposed than non-exposed children during all study periods (milk initiation - 20·3 (95 % CI - 39·2, - 1·4) g; milk termination - 25·9 (95 % CI - 46·0, - 5·7) g; margarine termination - 45·7 (95 % CI - 66·6, - 24·8) g), except during the period around the initiation of margarine fortification, where exposed children were heavier than non-exposed children (margarine initiation 27·4 (95 % CI 10·8, 44·0) g). No differences in the odds of high (>4000 g) or low ( < 2500 g) birth weight were observed between the children exposed and non-exposed to vitamin D fortification prenatally. Prenatal exposure to vitamin D from fortified margarine and milk altered birth weight, but the effect was small and inconsistent, reaching the conclusion that vitamin D fortification seems to be clinically irrelevant in relation to fetal growth.
British Journal Of Nutrition 09/2014; 112(5):785-793. · 3.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Several studies have shown that adherence to the Mediterranean Diet measured by using the Mediterranean diet score (MDS) is associated with lower obesity risk. The newly proposed Nordic Diet could hold similar beneficial effects. Because of the increasing focus on the interaction between diet and genetic predisposition to adiposity, studies should consider both diet and genetics.
American Journal of Clinical Nutrition 08/2014; · 6.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Low plasma 25-hydroxyvitamin D (25[OH]D) concentration is associated with high arterial blood pressure and hypertension risk, but whether this association is causal is unknown. We used a mendelian randomisation approach to test whether 25(OH)D concentration is causally associated with blood pressure and hypertension risk.
In this mendelian randomisation study, we generated an allele score (25[OH]D synthesis score) based on variants of genes that affect 25(OH)D synthesis or substrate availability (CYP2R1 and DHCR7), which we used as a proxy for 25(OH)D concentration. We meta-analysed data for up to 108 173 individuals from 35 studies in the D-CarDia collaboration to investigate associations between the allele score and blood pressure measurements. We complemented these analyses with previously published summary statistics from the International Consortium on Blood Pressure (ICBP), the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and the Global Blood Pressure Genetics (Global BPGen) consortium.
In phenotypic analyses (up to n=49 363), increased 25(OH)D concentration was associated with decreased systolic blood pressure (β per 10% increase, −0·12 mm Hg, 95% CI −0·20 to −0·04; p=0·003) and reduced odds of hypertension (odds ratio [OR] 0·98, 95% CI 0·97—0·99; p=0·0003), but not with decreased diastolic blood pressure (β per 10% increase, −0·02 mm Hg, −0·08 to 0·03; p=0·37). In meta-analyses in which we combined data from D-CarDia and the ICBP (n=146 581, after exclusion of overlapping studies), each 25(OH)D-increasing allele of the synthesis score was associated with a change of −0·10 mm Hg in systolic blood pressure (−0·21 to −0·0001; p=0·0498) and a change of −0·08 mm Hg in diastolic blood pressure (−0·15 to −0·02; p=0·01). When D-CarDia and consortia data for hypertension were meta-analysed together (n=142 255), the synthesis score was associated with a reduced odds of hypertension (OR per allele, 0·98, 0·96—0·99; p=0·001). In instrumental variable analysis, each 10% increase in genetically instrumented 25(OH)D concentration was associated with a change of −0·29 mm Hg in diastolic blood pressure (−0·52 to −0·07; p=0·01), a change of −0·37 mm Hg in systolic blood pressure (−0·73 to 0·003; p=0·052), and an 8·1% decreased odds of hypertension (OR 0·92, 0·87—0·97; p=0·002).
Increased plasma concentrations of 25(OH)D might reduce the risk of hypertension. This finding warrants further investigation in an independent, similarly powered study.
[Show abstract][Hide abstract] ABSTRACT: To investigate if dietary protein and degree of adiposity interacts in relation to change in body weight and waist circumference (WC) in the general population.
[Show abstract][Hide abstract] ABSTRACT: The genetic contribution to the variation in human lifespan is approximately 25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality.We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥ 85 years) and 16121 younger controls (< 65 years) followed by replication in an additional set of 13060 long-lived individuals and 61156 controls. In addition, we performed a subset analysis in cases≥90 years.We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR=1.10, P =1.74 x 10(-8)). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR=0.72, P=3.40 x 10(-36)), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n=34103) the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR=0.95, P=0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure.We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.
Human Molecular Genetics 03/2014; · 7.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We analysed single nucleotide polymorphisms (SNPs) tagging the genetic variability of six candidate genes (ATF6, FABP1, LPIN2, LPIN3, MLXIPL and MTTP) involved in the regulation of hepatic lipid metabolism, an important regulatory site of energy balance for associations with body mass index (BMI) and changes in weight and waist circumference. We also investigated effect modification by sex and dietary intake. Data of 6,287 individuals participating in the European prospective investigation into cancer and nutrition were included in the analyses. Data on weight and waist circumference were followed up for 6.9 ± 2.5 years. Association of 69 tagSNPs with baseline BMI and annual changes in weight as well as waist circumference were investigated using linear regression analysis. Interactions with sex, GI and intake of carbohydrates, fat as well as saturated, monounsaturated and polyunsaturated fatty acids were examined by including multiplicative SNP-covariate terms into the regression model. Neither baseline BMI nor annual weight or waist circumference changes were significantly associated with variation in the selected genes in the entire study population after correction for multiple testing. One SNP (rs1164) in LPIN2 appeared to be significantly interacting with sex (p = 0.0003) and was associated with greater annual weight gain in men (56.8 ± 23.7 g/year per allele, p = 0.02) than in women (-25.5 ± 19.8 g/year per allele, p = 0.2). With respect to gene-nutrient interaction, we could not detect any significant interactions when accounting for multiple testing. Therefore, out of our six candidate genes, LPIN2 may be considered as a candidate for further studies.
[Show abstract][Hide abstract] ABSTRACT: Social inequalities in overweight and obesity (OWOB) have persisted in the affluent and reputedly egalitarian Nordic countries. In this review we examine associations between socioeconomic position (SEP) and OWOB, and secular trends in such associations. Determinants and possible causes of the relations are discussed together with opportunities to cope with OWOB as a public health problem. The findings show a persisting inverse social gradient. An interaction between SEP and gender is noted for adults in Denmark, Finland and Iceland and for children in Sweden. There are overall tendencies for increased inequality, however no consistent trend for an increased social gradient in OWOB. Reasons that increased inequality does not unequivocally mirror in a steepened social gradient in obesity may include methodological questions as well as societal efforts to counteract obesity. Multi-level efforts are needed to prevent OWOB.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND:
Studies indicate an effect of dietary calcium on change in body weight (BW) and waist circumference (WC), but the results are inconsistent. Furthermore, a relation could depend on genetic predisposition to obesity.
The objective was to examine whether genetic predisposition to higher body mass index (BMI), WC, or waist-hip ratio (WHR) interacts with dietary calcium in relation to subsequent annual change in BW (ΔBW) and WC (ΔWC).
The study is based on 7569 individuals from the MONItoring trends and determinants of CArdiovascular disease Study, a sample from the Danish Diet, Cancer and Health Study and the INTER99 study, with information on diet; 54 single-nucleotide polymorphisms (SNPs) associated with BMI, WC, or WHR adjusted for BMI; and potential confounders. The SNPs were combined in 4 scores as indicators of genetic predisposition; all SNPs in a general score and a score for each of 3 phenotype: BMI, WC, and WHR. Linear regression was used to examine the association between calcium intake and ΔBW or ΔWC adjusted for concurrent ΔBW. SNP score × calcium interactions were examined by adding product terms to the models.
We found a significant ΔBW of -0.076 kg (P = 0.021; 95% CI: -0.140, -0.012) per 1000 mg Ca. No significant association was observed between dietary calcium and ΔWC. In the analyses with ΔBW as outcome, we found no significant interactions between the developed predisposition scores and calcium. However, we found a significant interaction between a score of 6 WC-associated SNPs and calcium in relation to ΔWC. Each risk allele was associated with a ΔWC of -0.043 cm (P = 0.038; 95% CI: -0.083, -0.002) per 1000 mg Ca.
Our study suggests that dietary calcium relates weakly to BW loss. We found no evidence of a general association between calcium and ΔWC, but calcium may reduce WC among people genetically predisposed to a high WC. However, further replication of this finding is needed.
American Journal of Clinical Nutrition 02/2014; · 6.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: An association between maternal pre-pregnancy BMI and childhood intelligence quotient (IQ) has repeatedly been found but it is unknown if this association is causal or due to confounding caused by genetic or social factors.
We used a cohort of 1,783 mothers and their 5-year-old children sampled from the Danish National Birth Cohort. The children participated between 2003 and 2008 in a neuropsychological assessment of cognitive ability including IQ tests taken by both the mother and the child. Linear regression analyses were used to estimate the associations between parental BMI and child IQ adjusted for a comprehensive set of potential confounders. Child IQ was assessed with the Wechsler Primary and Preschool Scales of Intelligence - Revised (WPPSI-R).
The crude association between maternal BMI and child IQ showed that BMI was adversely associated with child IQ with a reduction in IQ of -0.40 point for each one unit increase in BMI. This association was attenuated after adjustment for social factors and maternal IQ to a value of -0.27 (-0.50 to -0.03). After mutual adjustment for the father's BMI and all other factors except maternal IQ, the association between paternal BMI and child IQ yielded a regression coefficient of -0.26 (-0.59 to 0.07), which was comparable to that seen for maternal BMI (-0.20 (-0.44 to 0.04)).
Although maternal pre-pregnancy BMI was inversely associated with the IQ of her child, the similar association with paternal BMI suggests that it is not a specific pregnancy related adiposity effect.
PLoS ONE 01/2014; 9(4):e94498. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Some obese individuals have no cardiometabolic abnormalities; they are 'metabolically healthy, but obese' (MHO). Similarly, some non-obese individuals have cardiometabolic abnormalities, that is, 'metabolically at risk, normal weight' (MANW). Previous studies have suggested that early-onset obesity may be associated with MHO. We aimed to assess whether body mass index (BMI) in childhood and early-onset obesity are associated with MHO.
General population longitudinal cohort study, Denmark.
From 362 200 young men (mean age 20) examined for Danish national service between 1943 and 1977, all obese men (BMI ≥31 kg/m(2), N=1930) were identified along with a random 1% sample of the others (N=3601). Our analysis includes 2392 of these men attending a research clinic in mid-life (mean age 42). For 613 of these men, data on childhood BMI are available. We summarised childhood BMI growth (7-13 years) using a multilevel model. Early-onset obesity was defined as obesity at examination for national service.
We defined metabolic health at the mid-life clinic as non-fasting serum cholesterol <6.6 mmol/L, non-fasting glucose <8.39 mmol/L and pulse pressure <48 mm Hg. Participants were categorised into four groups according to their obesity (BMI ≥30 kg/m(2)) and metabolic health in mid-life.
297 of 1097 (27.1%) of obese men were metabolically healthy; 826 of 1295 (63.8%) non-obese men had at least one metabolic abnormality. There was no evidence that rapid BMI growth in childhood or early-onset obesity was associated with either MHO or the MANW phenotype, for example, among obese men in mid-life, the OR for MHO comparing early-onset obesity with non-early-onset obesity was 0.97 (95% CI 0.85 to 1.10).
We found no robust evidence that early-onset obesity or rapid BMI growth in childhood is protective for cardiometabolic health.
BMJ Open 01/2014; 4(4):e004827. · 2.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: If preschool measures of body size routinely collected at preventive health examinations are associated with adult central obesity and metabolic syndrome, a focused use of these data for the identification of high risk children is possible. The aim of this study was to test the associations between preschool weight and body mass index (BMI) and adult BMI, central obesity and metabolic alterations.
The Northern Finland Birth Cohort 1966 (NFBC1966) (N = 4111) is a population-based cohort. Preschool weight (age 5 months and 1 year) and BMI (age 2-5 years) were studied in relation to metabolic syndrome as well as BMI, waist circumference, lipoproteins, blood pressure, and fasting glucose at the age of 31 years. Linear regression models and generalized linear regression models with log link were used.
Throughout preschool ages, weight and BMI were significantly linearly associated with adult BMI and waist circumference. Preschool BMI was inversely associated with high-density lipoprotein levels from the age of 3 years. Compared with children in the lower half of the BMI range, the group of children with the 5% highest BMI at the age of 5 years had a relative risk of adult obesity of 6.2(95% CI:4.2-9.3), of adult central obesity of 2.4(95% CI:2.0-2.9), and of early onset adult metabolic syndrome of 2.5(95% CI:1.7-3.8).
High preschool BMI is consistently associated with adult obesity, central obesity and early onset metabolic syndrome. Routinely collected measures of body size in preschool ages can help to identify children in need of focused prevention due to their increased risk of adverse metabolic alterations in adulthood.
PLoS ONE 01/2014; 9(3):e89986. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Physiological evidence indicates that high-protein diets reduce caloric intake and increase thermogenic response, which may prevent weight gain and regain after weight loss. Clinical trials have shown such effects, whereas observational cohort studies suggest an association between greater protein intake and weight gain. In both types of studies the results are based on average weight changes, and show considerable diversity in both directions. This study investigates whether the discrepancy in the evidence could be due to recruitment of overweight and obese individuals into clinical trials.
PLoS ONE 01/2014; 9(7):e101134. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the association between exposure to mothers smoking during prenatal and early postnatal life and risk of overweight at age 7 years, while taking birth weight into account.
PLoS ONE 01/2014; 9(10):e109184. · 3.53 Impact Factor