While there is clear evidence of familial influences on suicide, the origin of these is less certain. We have investigated genetic and familial environmental factors by studying the occurrence of suicide in biological and adoptive siblings of adoptees who died by suicide compared to siblings of surviving adoptees.
We used the Danish Adoption Register and Danish population registers to compare 221 siblings of adoptees who died by suicide with the siblings of 1,903 adoptees who did not die by suicide. All adoptions in the Danish Adoption Register are non-familial, i.e. the adoptive parents are biologically unrelated to the adoptee. Analyses were conducted on incidence rates of suicide in biological and adoptive siblings given occurrence of suicide in the adoptees while also taking into account psychiatric disorders.
The risk of suicide in full siblings of adoptees who died by suicide before age 60 years was significantly higher than in full siblings of adoptees who had not died by suicide (incidence rate ratios (IRR) = 5.01; 95% confidence interval [CI] = 1.28 - 19.6). This increase persisted after adjustment for history of psychiatric admission of siblings (IRR = 4.19; 95% CI = 1.00 - 17.5).
Genetic factors influence risk of suicide, probably independently of psychiatric disorder. This is relevant in provision of advice to families, including possible prevention of suicide.
In the same period as the increasing obesity epidemic, there has been an increased consumption of highly processed foods with a high salt content, and a few studies have suggested that a diet with a high salt content may be associated with obesity.
To investigate the association between 24 h urinary sodium excretion and subsequent change in body weight (BW), waist circumference (WC), body fat (BF) and fat free mass (FFM) among adults.
A longitudinal population study based on the Danish part of the MONICA project, with examinations in 1987–1988 and 1993–1994. Complete information on 24 h urinary sodium excretion along with repeated measures of obesity, as well as on potential confounders, was obtained from 215 subjects. Linear regression was used to examine the association between sodium excretion, as a measure of salt consumption, and subsequent changes in BW, WC, BF and FFM, and further evaluated by restricted cubic splines. Stepwise adjustments were made for selected covariates.
Neither the crude nor the adjusted models showed any statistically significant associations between sodium excretion and change in BW or WC. Likewise, we found no significant association between sodium excretion and change in BF and FFM in the unadjusted models. However, after adjusting for potential baseline confounders and the concurrent BW change, we found a significant increase in BF of 0.24 kg (P = 0.015, CI: 0.05 to 0.43) per 100 mmol increase in 24 h urinary sodium excretion (equivalent to 6 g of salt), during the 6-year study period. Moreover, during the same period, we found a significant association with FFM of −0.21 kg (P = 0.041, CI: −0.40 to −0.01).
These results suggest that a diet with a high salt content may have a negative influence on development in body composition by expanding BF and reducing FFM.
After the worldwide steep increase in child and adolescent overweight and obesity during the last decades, there is now evidence of a levelling off in the prevalence in many countries in the Western world.
To examine whether there still is a plateau in the prevalence of overweight and obesity in Danish children and adolescents, or whether the prevalence is decreasing or rising again.
The trends in the prevalence rates were based on three data sets providing comparable repeated estimates: 1) the Danish Health Visitors Child Health Database (DHVCHD) with measurements on infant and childhood height and weight from 2002 to 2011 (n up to 39,984), 2) the Danish National Birth Cohort (DNBC) with maternal reports of measured infant and childhood height and weight from 1998 to 2010 (n up to 56,826) and 3) the Danish part of the Health Behaviour in School-aged Children survey (HBSC) with self-reported information on adolescent height and weight from the years 2002 to 2010 (n = 16,557). Overweight and obesity were categorized according to WHO growth standards. Trends were assessed by repeated point estimates and linear regression analyses providing regression coefficients for changes in per cent per year with 95% confidence intervals (CI).
The prevalence rates of overweight and obesity for infants, children and adolescents showed a mixed pattern of decline, stability and increase (ranging from -1.10 through 0.29 per cent per year with CI’s from -3.10 through 2.37). Overall, there were no consistent statistically significant trends upwards or downwards, although some significant downward trends in childhood and adolescence were observed.
This study, based on data from 1998 through 2011, showed that the prevalence rates of overweight and obesity among Danish infants, children and adolescents were largely still on a plateau with tendencies for a decline among children and adolescents.
Identifying individuals at high risk of excess weight gain may help targeting prevention efforts at those at risk of various metabolic diseases associated with weight gain. Our aim was to develop a risk score to identify these individuals and validate it in an external population.
We used lifestyle and nutritional data from 53°758 individuals followed for a median of 5.4 years from six centers of the European Prospective Investigation into Cancer and Nutrition (EPIC) to develop a risk score to predict substantial weight gain (SWG) for the next 5 years (derivation sample). Assuming linear weight gain, SWG was defined as gaining ≥10% of baseline weight during follow-up. Proportional hazards models were used to identify significant predictors of SWG separately by EPIC center. Regression coefficients of predictors were pooled using random-effects meta-analysis. Pooled coefficients were used to assign weights to each predictor. The risk score was calculated as a linear combination of the predictors. External validity of the score was evaluated in nine other centers of the EPIC study (validation sample).
Our final model included age, sex, baseline weight, level of education, baseline smoking, sports activity, alcohol use, and intake of six food groups. The model's discriminatory ability measured by the area under a receiver operating characteristic curve was 0.64 (95% CI = 0.63–0.65) in the derivation sample and 0.57 (95% CI = 0.56–0.58) in the validation sample, with variation between centers. Positive and negative predictive values for the optimal cut-off value of ≥200 points were 9% and 96%, respectively.
The present risk score confidently excluded a large proportion of individuals from being at any appreciable risk to develop SWG within the next 5 years. Future studies, however, may attempt to further refine the positive prediction of the score.
We examined whether analysis of lipids by ultra-performance liquid chromatography (UPLC) coupled to MS allows the development of a laboratory test for non-alcoholic fatty-liver disease (NAFLD), and how a lipid-profile biomarker compares with the prediction of NAFLD and liver-fat content based on routinely available clinical and laboratory data.
We analysed the concentrations of molecular lipids by UPLC-MS in blood samples of 679 well-characterised individuals in whom liver-fat content was measured using proton magnetic resonance spectroscopy (1H-MRS) or liver biopsy. The participants were divided into biomarker-discovery (n = 287) and validation (n = 392) groups to build and validate the diagnostic models, respectively.
Individuals with NAFLD had increased triacylglycerols with low carbon number and double-bond content while lysophosphatidylcholines and ether phospholipids were diminished in those with NAFLD. A serum-lipid signature comprising three molecular lipids (‘lipid triplet’) was developed to estimate the percentage of liver fat. It had a sensitivity of 69.1% and specificity of 73.8% when applied for diagnosis of NAFLD in the validation series. The usefulness of the lipid triplet was demonstrated in a weight-loss intervention study.
The liver-fat-biomarker signature based on molecular lipids may provide a non-invasive tool to diagnose NAFLD, in addition to highlighting lipid molecular pathways involved in the disease.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-013-2981-2) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Lipidomics; Mass spectrometry; Non-alcoholic fatty-liver disease
To examine the association between apolipoprotein E (APOE) gene variants and waist circumference, fasting plasma glucose, serum insulin, serum high-density lipoprotein cholesterol, and serum triglycerides, all metabolic traits known as cardiovascular disease (CVD) endophenotypes, in a population of stressed individuals and controls. Abdominal obesity, insulin resistance, elevated serum lipid concentration, and APOE polymorphisms have been associated with CVD risk. Current evidence supports the hypothesis that gene-environment interactions modulate serum lipid concentrations.
The association between rs769450, rs405509, rs439401, and metabolic traits were analyzed in a U.S. sample of 126 white caregivers of a relative with Alzheimer's disease or other major dementia and 122 white controls. The associations were analyzed, using multivariate analysis of variance adjusted for age, sex, and medications.
Significant multivariate interactions were found, using both additive (p = .009) and dominant (p = .047) models between rs439401 (C/T) and caregiver stress in relation to a profile of metabolic variables. Univariate analyses found the TT genotype to be associated with more adverse levels of waist circumference (interaction, p = .026), triglycerides (interaction, p = .001) and high-density lipoprotein cholesterol (interaction, p = .001) among caregivers but with a more favorable profile of these endophenotypes among controls. There were no significant associations or interactions involving the other two single nucleotide polymorphisms.
The APOE rs439401 TT genotype is associated with an adverse metabolic profile among chronically stressed individuals compared with individuals not similarly stressed in whom a more favorable profile is expressed. Confirmation of these results in further research would indicate that the TT genotype can be used to identify persons at high risk for CVD when subjected to chronic stress.
apolipoprotein E; obesity; metabolic traits; stress; epidemiology; gene-environment interaction
Studies have suggested that number of siblings and birth order is associated with obesity. However, studies combining these exposures are needed. This study aimed at investigating obesity in children and young adults in regard to different combinations of family size and birth order.
Two cohorts selected from the general population were investigated: The Copenhagen School Health Records Register (CSHRR) and a Draft Board (DB) sample with measured heights and weights in childhood (age 13 years) and young adulthood (age 19 years), respectively. Information on birth order, number of siblings, and relevant covariates were available on 29 327 children, as well as on 323 obese young men and 575 randomly selected controls of young men representing approximately 58 000. The relation between number of siblings and birth order, respectively, and having a Body Mass Index (BMI) z-score above or equal to the 95th percentile in childhood or having a BMI of at least 31.00 kg/m2 in young adulthood was analysed using logistic regression analyses adjusted for relevant confounders.
Only children had significantly higher odds of obesity both in childhood and in young adulthood compared with children with siblings, odds ratio (OR) = 1.44 (95% Confidence Interval (CI): 1.26–1.66) and OR = 1.76 (95% CI: 1.18–2.61), respectively. No association between first-born status and obesity was found. The OR of last-born children being obese was also significantly increased in childhood, e.g. OR = 1.93 (95% CI: 1.09−3.43) of obesity if last-born in a family of four children. This was not found in young adulthood. Additionally, higher spacing to previous sibling (average 1872 vs. 1303 days; p = 0.026 in four children families) was observed in obese last-born compared to non-obese last-born children.
Being an only or last-born child is associated with obesity. These associations may provide leads to targeted prevention of obesity in children.
Prevalence of obesity is the result of preceding incidence of newly developed obesity and persistence of obesity. We investigated whether increasing incidence and/or persistence during childhood drove the prevalence of childhood obesity during the emerging epidemic.
Height and weight were measured at ages 7 and 13 years in 192,992 Danish school children born 1930–1969. Trends in the incidence (proportion obese at 13 years among those not obese at 7 years) and persistence (proportion obese at 13 years among those obese at 7 years) across birth cohort periods (1930–41 with low stable prevalence of obesity, 1942–51 with increasing prevalence, 1952–69 with the higher, but stable prevalence) were investigated. Logistic regression was used to examine the associations between BMI at 7 years as a continuous trait, allowing interactions with the birth cohorts, and occurrence of obesity at 13 years.
The prevalence of obesity was similar at 7 and 13 years and increased across birth cohorts in boys from around 0.1% to 0.5% and in girls from around 0.3% to 0.7%. The incidence of obesity between ages 7 and 13 years increased from 0.15% to 0.35% in boys and from 0.20% to 0.44% in girls. The persistence increased from 28.6% to 41.4% in boys and from 16.4% to 31.0% in girls. Despite a decrease over time, the remission of obesity occurred in >60% of obese children in the last birth cohort. However, the odds ratios of obesity at age 13 years in relation to the full range of BMI at 7 years remained unchanged across the birth cohort periods.
The development of the obesity epidemic in children was due to an increase in both incidence and persistence of obesity. Contrary to prevailing expectations, a large, although declining, proportion of children obese at an early age underwent remission during childhood.
Background: The genetic predisposition to obesity may have contributed to the obesity epidemic through assortative mating. We investigated whether spouses were positively assorted by body mass index (BMI; = kg/m2) in late childhood, and whether changes in assorted marriage by upper BMI-percentiles occurred during the obesity epidemic. Methods: In the Copenhagen School Health Records Register (CSHRR) boys and girls with measures of BMI at age 13 years later became 37,792 spousal-pairs who married between 1945 and 2010. Trends in the spousal BMI correlations using sex-, age-, and birth cohort-specific BMI z-scores across time were investigated. Odds ratios (ORs) of marriage among spouses both with BMI z-scores >90th or >95th percentile compared with marriage among spouses ≤90th percentile were analyzed for marriages entered during the years prior to (1945–1970), and during the obesity epidemic (1971–2010). Findings: Spousal BMI correlations were around 0.05 and stayed similar across time. ORs of marriage among spouses with BMIs >90th percentile at age 13 were 1.21, 1.05–1.39, in 1945–1970, and increased to 1.63, 1.40–1.91, in 1971–2010 (p = 0.006). ORs of marriage among spouses both >95th BMI percentile were higher and increased more; from 1.39, 1.10–1.81, to 2.39, 1.85–3.09 (p = 0.004). Interpretation: Spousal correlations by pre-marital BMIs were small and stable during the past 65 years. Yet, there were assorted marriages between spouses with high BMI at age 13 years and the tendency increased alongside with the obesity epidemic which may increase the offsprings' predisposition to obesity.
assortative mating; body mass index; childhood; obesity; overweight; phenotype; human genetics
Background. Maternal distress during pregnancy increases the intrauterine level of glucocorticoids, which may have long-term health consequences for the child.
Objective. To examine if distress as a combined measure of anxiety, depression, and stress of the mother during pregnancy was associated with offspring childhood overweight at age 7.
Methods. We performed a cohort study using prospective data from 37,764 women and child dyads from the Danish National Birth Cohort (1996–2002). At a telephone interview at approximately 30 weeks gestation, the women reported whether they felt anxious, depressed, or stressed. The 95 percentile for body mass index in an international reference defined childhood overweight at any given age. Logistic regression was used for the analyses. Results. The prevalence of overweight children at 7 years of age was 9.9%. Prenatal exposure to maternal distress during pregnancy was not associated with childhood overweight at 7 years of age (adjusted OR 1.06 (95% CI 0.96; 1.18)). In analyses stratified on sex, a small tendency of overweight was seen in boys (OR 1.15 (0.99; 1.33)), but not in girls (OR 0.98 (0.85; 1.13)). Conclusions. Maternal distress during pregnancy appeared to have limited, if any, influence on the risk of overweight in offspring at 7 years of age.
Exposures during fetal life may have long-term health consequences including risk of childhood overweight. We investigated the associations between maternal recreational exercise during early and late pregnancy and the children's body mass index (BMI) and risk of overweight at 7 years. Data on 40,280 mother-child pairs from the Danish National Birth Cohort was used. Self-reported information about exercise was obtained from telephone interviews around gestational weeks 16 and 30. Children's weight and height were reported in a 7-year follow-up and used to calculate BMI and overweight status. Data was analyzed using multiple linear and logistic regression models. Recreational exercise across pregnancy was inversely related to children's BMI and risk of overweight, but all associations were mainly explained by smoking habits, socioeconomic status, and maternal pre-pregnancy BMI. Additionally, we did not find exercise intensity or changes in exercise habits in pregnancy related to the children's BMI or risk of overweight.
Adult height is inversely associated with the risk of coronary heart disease (CHD), but it is still unknown which phase of the human growth period is critical for the formation of this association. We investigated the association between growth in height from 7 to 13 years of age and the risk of CHD in adulthood.
Methods and Findings
The heights of almost all children born 1930 through 1976 who attended school in the Copenhagen municipality (232,063 children) were measured annually from 7 to 13 years of age. Birth weight data were available since 1936. Fatal and non-fatal CHD events were ascertained by register linkage until 2008 (25,214 cases). Hazard ratios (HR) with 95% confidence intervals (CI) were estimated by Cox proportional hazards regression for height z-scores (standard deviation units) and change in height z-scores. Height z-scores were inversely related to the risk of CHD. The association was strongest at 7 years of age (HR = 0.91, CI 0.90–0.92 in boys and 0.88, CI 0.86–0.90 in girls) and steadily weakened thereafter, yet it still remained at 13 years of age (HR = 0.95, CI 0.94–0.97 and 0.91, CI 0.89–0.93, boys and girls respectively). The associations were not modified by birth weight. Independent of the age-specific risk, rapid growth was associated with an increased CHD risk, most pronounced between 9 and 11 years in girls (HR = 1.22, CI 1.14–1.31) and between 11 and 13 years in boys (HR = 1.28, CI 1.22–1.33) per unit increase in z-score. Adjustment for body mass index somewhat strengthened the associations of CHD risk with height and weakened the association with growth.
Risk of CHD in adulthood is inversely related to height at ages 7 through 13 years, but strongest in the youngest, and, independently hereof, the risk increased by growth velocity.
We attempt to elucidate whether there might be a causal connection between the socioeconomic status (SES) of the rearing environment and obesity in the offspring using data from two large-scale adoption studies: (1) The Copenhagen Adoption Study of Obesity (CASO), and (2) The Survey of Holt Adoptees and Their Families (HOLT). In CASO, the SES of both biological and adoptive parents was known, but all children were adopted. In HOLT, only the SES of the rearing parents was known, but the children could be either biological or adopted. After controlling for relevant covariates (e.g., adoptee age at measurement, adoptee age at transfer, adoptee sex) the raw (unstandardized) regression coefficients for adoptive and biological paternal SES on adoptee body mass index (BMI: kg/m2) in CASO were -.22 and -.23, respectively, both statistically significant (p = 0.01). Controlling for parental BMI (both adoptive and biological) reduced the coefficient for biological paternal SES by 44% (p = .034) and the coefficient for adoptive paternal SES by 1%. For HOLT, the regression coefficients for rearing parent SES were -.42 and -.25 for biological and adoptive children, respectively. Controlling for the average BMI of the rearing father and mother (i.e., mid-parental BMI) reduced the SES coefficient by 47% in their biological offspring (p≤.0001), and by 12% in their adoptive offspring (p = .09). Thus, despite the differing structures of the two adoption studies, both suggest that shared genetic diathesis and direct environmental transmission contribute about equally to the association between rearing SES and offspring BMI.
Background and Objectives
There is no doubt that the dramatic worldwide increase in obesity prevalence is due to changes in environmental factors. However, twin and family studies suggest that genetic differences are responsible for the major part of the variation in adiposity within populations. Recent studies show that the genetic effects on body mass index (BMI) may be stronger when combined with presumed risk factors for obesity. We tested the hypothesis that the genetic variance of BMI has increased during the obesity epidemic.
The data comprised height and weight measurements of 1,474,065 Swedish conscripts at age 18–19 y born between 1951 and 1983. The data were linked to the Swedish Multi-Generation Register and the Swedish Twin Register from which 264,796 full-brother pairs, 1,736 monozygotic (MZ) and 1,961 dizygotic (DZ) twin pairs were identified. The twin pairs were analysed to identify the most parsimonious model for the genetic and environmental contribution to BMI variance. The full-brother pairs were subsequently divided into subgroups by year of birth to investigate trends in the genetic variance of BMI.
The twin analysis showed that BMI variation could be explained by additive genetic and environmental factors not shared by co-twins. On the basis of the analyses of the full-siblings, the additive genetic variance of BMI increased from 4.3 [95% CI 4.04–4.53] to 7.9 [95% CI 7.28–8.54] within the study period, as did the unique environmental variance, which increased from 1.4 [95% CI 1.32–1.48] to 2.0 [95% CI 1.89–2.22]. The BMI heritability increased from 75% to 78.8%.
The results confirm the hypothesis that the additive genetic variance of BMI has increased strongly during the obesity epidemic. This suggests that the obesogenic environment has enhanced the influence of adiposity related genes.
Lipoprotein lipase (LPL) has a prominent role in the metabolism of triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C) and is a potential interesting target for the development of antiatherogenic treatment. To provide deeper insight into the role of natural variation in this gene, we investigated the association between the LPL S447X variant with lipids and risk of coronary heart disease (CHD) in three independent, prospective studies.
The S447X variant was genotyped in case-control studies of incident CHD nested within the Nurses’ Health Study (NHS), the Health Professionals Follow-up Study (HPFS), and the Danish Diet, Cancer and Health (DCH) study, totaling 245, 258, and 962 cases, respectively.
S447X-carriers tended to have lower TG and higher HDL-C concentrations than non-carriers. The S447X variant was associated with a lower risk of CHD in the NHS, the association was weaker in the HPFS and not statistically significant in the DCH women and men. The pooled relative risk per minor allele was 0.74 (0.56–1.00). There was a suggestion that the associations of the S447X variant with plasma lipids and CHD-risk were more pronounced in obese individuals in the NHS study, but this finding was not consistent across the studies.
The LPL S447X variant tended to be associated with lower TG and higher HDL-C levels, and lower risk of CHD in all three cohorts. LPL is an attractive target for clinical intervention, but studies are needed to clarify whether greater benefit from this variant may be conferred in some subgroups.
Genetic epidemiology; CHD; prospective study; lipoprotein lipase; plasma lipids
Waist circumference (WC) measured at one point in time is positively associated with the risk of acute myocardial infarction (MI), but the association with changes in WC (DWC) is not clear. We investigated the association between DWC and the risk of MI in middle-aged men and women, and evaluated the influence from concurrent changes in BMI (DBMI).
Data on 38,593 participants from the Danish Diet, Cancer and Health study was analysed. Anthropometry was assessed in 1993–97 and 1999–02. Information on fatal and non-fatal MI was obtained from National Registers. Cases were validated by review of the medical records. Hazard ratios (HR) were calculated from Cox proportional hazard models with individuals considered at risk from 1999–02 until December 30 2009. During 8.4 years of follow-up, 1,041 incident cases of MI occurred. WC was positively associated with the risk of MI, but weakly after adjustment for BMI. DWC was not associated with the risk of MI (HR per 5 cm change = 1.01 (0.95, 1.09) with adjustment for covariates, baseline WC, BMI and DBMI). Associations with DWC were not notably different in sub-groups stratified according to baseline WC or DBMI, or when individuals with MI occurring within the first years of follow-up were excluded.
WC was positively associated with the risk of MI in middle-aged men and women, but changes in WC were not. These findings suggest that a reduction in WC may be an insufficient target for prevention of MI in middle-aged men and women.
Waist circumference (WC) is positively associated with diabetes, but the association with changes in WC (DWC) is less clear. We investigated the association between DWC and the subsequent risk of diabetes in middle-aged men and women, and evaluated the influence from concurrent changes in body mass index (DBMI).
Data on 15,577 men and 20,066 women from the Danish Diet, Cancer and Health study were analyzed. Anthropometry was assessed in 1993–97 and 1999–02. Information on diabetes was obtained from The Danish National Diabetes Register. Hazard ratios (HR) were calculated from Cox' proportional hazard models with individuals considered at risk from 1999–02 until December 31 2006. During 5.4 years of follow-up, 1,027 and 876 new cases of diabetes occurred among men and women, respectively. WC was positively associated with diabetes in both sexes also with adjustment for covariates and BMI. DWC was positively associated with diabetes in women, but not in men (HR per 5 cm change = 1.09 (1.04∶1.15) in women, and 1.00 (0.94, 1.07) in men with adjustment for covariates, baseline WC, BMI and DBMI). Associations with DWC were not notably different in sub-groups stratified according to baseline WC or DBMI, or when individuals with diseases or diabetes occurring within the first years of follow-up were excluded.
While this study confirmed that WC is positively associated with the risk of diabetes in middle-aged men and women, it surprisingly showed that changes in WC were not associated with the subsequent risk of diabetes in men, and only weakly positively associated with the risk of diabetes in women. Accordingly, these findings suggest that a reduction in WC may be a weak or insufficient or target for prevention of diabetes in middle-aged men and women.
Background and objectives
There is no doubt that the dramatic worldwide increase in obesity prevalence is due to changes in environmental factors. However, twin studies suggest that genetic differences are responsible for the major part of the variation in body mass index (BMI) and other measures of body fatness within populations. Several recent studies suggest that the genetic effects on adiposity may be stronger when combined with presumed risk factors for obesity. We tested the hypothesis that a higher prevalence of obesity and overweight and a higher BMI mean is associated with a larger genetic variation in BMI.
The data consisted of self-reported height and weight from two Danish twin surveys in 1994 and 2002. A total of 15,017 monozygotic and dizygotic twin pairs were divided into subgroups by year of birth (from 1931 through 1982) and sex. The genetic and environmental variance components of BMI were calculated for each subgroup using the classical twin design. Likewise, the prevalence of obesity, prevalence of overweight and the mean of the BMI distribution was calculated for each subgroup and tested as explanatory variables in a random effects meta-regression model with the square root of the additive genetic variance (equal to the standard deviation) as the dependent variable.
The size of additive genetic variation was positively and significantly associated with obesity prevalence (p = 0.001) and the mean of the BMI distribution (p = 0.015). The association with prevalence of overweight was positive but not statistically significant (p = 0.177).
The results suggest that the genetic variation in BMI increases as the prevalence of obesity, prevalence of overweight and the BMI mean increases. The findings suggest that the genes related to body fatness are expressed more aggressively under the influence of an obesity-promoting environment.
Common variants in the melatonin receptor type 1B (MTNR1B) locus have been shown to increase fasting plasma glucose (FPG) and the risk of type 2 diabetes. The aims of this study were to evaluate whether nonsynonymous variants in MTNR1B associate with monogenic forms of hyperglycemia, type 2 diabetes, or related metabolic traits.
RESEARCH DESIGN AND METHODS
MTNR1B was sequenced in 47 probands with clinical maturity-onset diabetes of the young (MODY), in 51 probands with early-onset familial type 2 diabetes, and in 94 control individuals. Six nonsynonymous variants (G24E, L60R, V124I, R138C, R231H, and K243R) were genotyped in up to 22,142 Europeans. Constitutive and melatonin-induced signaling was characterized for the wild-type melatonin receptor type 1B (MT2) and the 24E, 60R, and 124I MT2 mutants in transfected COS-7 cells.
No mutations in MTNR1B were MODY specific, and none of the investigated MTNR1B variants associated with type 2 diabetes. The common 24E variant associated with increased prevalence of obesity (odds ratio 1.20 [1.08–1.34]; P = 8.3 × 10−4) and increased BMI (β = 0.5 kg/m2; P = 1.2 × 10−5) and waist circumference (β = 1.2 cm; P = 9 × 10−6) in combined Danish and French study samples. 24E also associated with decreased FPG (β = −0.08 mmol/l; P = 9.2 × 10−4) in the Danish Inter99 population. Slightly decreased constitutive activity was observed for the MT2 24E mutant, while the 124I and 60R mutants displayed considerably decreased or completely disrupted signaling, respectively.
Nonsynonymous mutations in MTNR1B are not a common cause of MODY or type 2 diabetes among Danes. MTNR1B 24E associates with increased body mass and decreased FPG. Decreased MT2 signaling does apparently not directly associate with FPG or type 2 diabetes.
Genetic differences have been proposed to play a strong role in risk of death from infectious diseases. The study base of 44,005 included all same-sex twin pairs born in 1870–2001, with both twins alive on January 1, 1943, or those born thereafter. Cause of death was obtained from the Danish Cause of Death Register and was available for 18,359 deaths. The authors classified death due to infections by 3 definitions (narrow, broader, and broadest) and calculated concordance rates for same-sex monozygotic and dizygotic twin pairs. Heritability was estimated by using structural equation models. When the 3 definitions were applied, 211 (1.1%), 1,089 (5.9%), and 2,907 (15.8%) deaths, respectively, were due to infections. The probandwise concordance rates for monozygotic twin pairs were consistently higher than for dizygotic twin pairs regardless of the definition (9% vs. 0% (P = 0.04), 10% vs. 3% (P < 0.01), and 19% vs. 15% (P = 0.07), respectively). For the broader and broadest definitions, heritability was 40% (95% confidence interval: 12, 50) and 19% (95% confidence interval: 3, 35), respectively. The concordance rates were generally low, and, although a genetic influence on the risk of death from infectious diseases could be demonstrated, the absolute effect of the genetic component on mortality was small.
cause of death; genetics; infection; twins
The worldwide epidemic of childhood obesity is progressing at an alarming rate. Risk factors for coronary heart disease (CHD) are already identifiable in overweight children. The severity of the long-term effects of excess childhood weight on CHD, however, remains unknown.
We investigated the association between body-mass index (BMI) in childhood (7 through 13 years of age) and CHD in adulthood (25 years of age or older), with and without adjustment for birth weight. The subjects were a cohort of 276,835 Danish schoolchildren for whom measurements of height and weight were available. CHD events were ascertained by linkage to national registers. Cox regression analyses were performed.
In 5,063,622 person-years of follow-up, 10,235 men and 4318 women for whom childhood BMI data were available received a diagnosis of CHD or died of CHD as adults. The risk of any CHD event, a nonfatal event, and a fatal event among adults was positively associated with BMI at 7 to 13 years of age for boys and 10 to 13 years of age for girls. The associations were linear for each age, and the risk increased across the entire BMI distribution. Furthermore, the risk increased as the age of the child increased. Adjustment for birth weight strengthened the results.
Higher BMI during childhood is associated with an increased risk of CHD in adulthood. The associations are stronger in boys than in girls and increase with the age of the child in both sexes. Our findings suggest that as children are becoming heavier worldwide, greater numbers of them are at risk of having CHD in adulthood.
Obesity is more common among the less educated, suggesting education-related environmental triggers. Such triggers may act differently dependent on genetic and environmental predisposition to obesity. In a Danish Twin Registry survey, 21,522 twins of same-sex pairs provided zygosity, height, weight, and education data. Body mass index (BMI = kg weight/ m height2) was used to measure degree of obesity. We used quantitative genetic modeling to examine how genetic and shared and nonshared environmental variance in BMI differed by level of education and to estimate how genetic and shared and nonshared environmental correlations between education and BMI differed by level of education, analyzing women and men separately. Correlations between education and BMI were −.13 in women, −.15 in men. High BMI's were less frequent among well-educated participants, generating less variance. In women, this was due to restriction of all forms of variance, overall by a factor of about 2. In men, genetic variance did not vary with education, but results for shared and nonshared environmental variance were similar to those for women. The contributions of the shared environment to the correlations between education and BMI were substantial among the well-educated, suggesting importance of familial environmental influences common to high education and lower BMI. Family influence was particularly important in linking high education and lower levels of obesity.
A recent study reported that the fatness associated A-allele of FTO rs9939609 increased plasma high sensitivity C-reactive protein (hs-CRP) levels independent of fatness. We aimed to investigate if this gene variant had fatness-independent effects on plasma hs-CRP and 10 additional circulating obesity-related adipokines throughout a broad range of body mass index (BMI) among Danish men.
In a population of 362,200 young men, examined for military service between 1943 and 1977, two groups were identified: 1) a random 1% sample and 2) all obese men (BMI = 31.0 kg/m2, all of whom were above the 99th percentile of this population). At an average age of 49 years (range: 39 through 65 years), 551 men, hereof 231 of the obese, were re-examined, including genotyping and measurement of the fasting circulating inflammatory markers hs-CRP, IL-1β, IL-6, IL-10, IL-18, mip1α, mip1β, sTNFα-R1, TGF-β, TNF-α and leptin. Men with known disease were excluded from the examination. All the inflammatory markers were log-transformed to approximate a normal distribution. Genotype-phenotype relationships were studied using linear regression analyses with the inflammatory markers as the response variable. Significant positive associations between hs-CRP, leptin and a broad range of BMI were observed, but the associations did not significantly differ across FTO rs9939609 genotype. There were no significant associations between the other inflammatory markers, FTO rs9939609 genotype or BMI, respectively.
No fatness-independent effects of the FTO rs9939609 A-allele on a series of inflammatory markers were observed in this cohort of healthy middle-aged men representing a broad range of fatness.
Background and objective
Adoption studies have been used to disentangle the influence of genes from shared familial environment on various traits and disease risks. However, both the factors leading to adoption and living as an adoptee may bias the studies with regard to the relative influence of genes and environment compared to the general population. The aim was to investigate whether the cohort of domestic adoptees used for these studies in Denmark is similar to the general population with respect to all-cause mortality and cause-specific mortality rates.
13,111 adoptees born in Denmark in 1917, or later, and adopted in 1924 to 1947 were compared to all Danes from the same birth cohorts using standardized mortality ratios (SMR). The 12,729 adoptees alive in 1970 were similarly compared to all Danes using SMR as well as cause-specific SMR.
The excess in all-cause mortality before age 65 years in adoptees was estimated to be 1.30 (95% CI 1.26–1.35). Significant excess mortality before age 65 years was also observed for infections, vascular deaths, cancer, alcohol-related deaths and suicide. Analyses including deaths after age 65 generally showed slightly less excess in mortality, but the excess was significant for all-cause mortality, cancer, alcohol-related deaths and suicides.
Adoptees have an increased all-cause mortality compared to the general population. All major specific causes of death contributed, and the highest excess is seen for alcohol-related deaths.