Aims/hypothesis
Not all obese individuals display the metabolic disturbances commonly associated with excess fat accumulation. Mechanisms maintaining this ‘metabolically healthy obesity’ (MHO) are as ...yet unknown. We aimed to study different fat depots and transcriptional pathways in subcutaneous adipose tissue (SAT) as related to the MHO phenomenon.
Methods
Sixteen rare young adult obesity-discordant monozygotic (MZ) twin pairs (intra-pair difference (∆) in BMI ≥3 kg/m
2
), aged 22.8–35.8 years, were examined for detailed characteristics of metabolic health (subcutaneous, intra-abdominal and liver fat magnetic resonance imaging/spectroscopy), OGTT, lipids, adipokines and C-reactive protein (CRP). Affymetrix U133 Plus 2.0 chips were used to analyse transcriptomics pathways related to mitochondrial function and inflammation in SAT.
Results
Based on liver fat accumulation, two metabolically different subgroups emerged. In half (8/16) of the pairs (∆weight 17.1 ± 2.0 kg), the obese co-twin had significantly higher liver fat (∆718%), 78% increase in AUC insulin during OGTT and CRP, significantly more disturbance in the lipid profile and greater tendency for hypertension compared with the lean co-twin. In these obese co-twins, SAT expression of mitochondrial oxidative phosphorylation, branched-chain amino acid catabolism, fatty acid oxidation and adipocyte differentiation pathways were downregulated and chronic inflammation upregulated. In the other eight pairs (∆weight 17.4 ± 2.8 kg), the obese co-twin did not differ from the non-obese co-twin in liver fat (∆8%), insulin sensitivity, CRP, lipids, blood pressure or SAT transcriptomics.
Conclusions/interpretation
Our results suggest that maintenance of high mitochondrial transcription and lack of inflammation in SAT are associated with low liver fat and MHO.
Proton magnetic resonance spectroscopy ((1)H MRS) neurometabolite abnormalities have been detected widely in subjects with and at risk for schizophrenia. We hypothesized that such abnormalities would ...be present both in patients with schizophrenia and in their unaffected twin siblings. We acquired magnetic resonance spectra (TR/TE=3000/30 ms) at voxels in the mesial prefrontal gray matter, left prefrontal white matter and left hippocampus in 14 twin pairs discordant for schizophrenia (2 monozygotic, 12 dizygotic), 13 healthy twin pairs (4 monozygotic, 9 dizygotic) and 1 additional unaffected co-twin of a schizophrenia proband. In the mesial prefrontal gray matter voxel, N-acetylaspartate (NAA), creatine+phosphocreatine (Cr), glycerophosphocholine+phosphocholine (Cho) and myo-inositol (mI) did not differ significantly between patients with schizophrenia, their unaffected co-twins or healthy controls. However, glutamate (Glu) was significantly lower in patients with schizophrenia (31%, percent difference) and unaffected co-twins (21%) than in healthy controls (collapsed across twin pairs). In the left hippocampus voxel, levels of NAA (23%), Cr (22%) and Cho (36%) were higher in schizophrenia patients compared with controls. Hippocampal NAA (25%), Cr (22%) and Cho (37%) were also significantly higher in patients than in their unaffected co-twins. Region-to-region differences in metabolite levels were also notable within all three diagnosis groups. These findings suggest that (1)H MRS neurometabolite abnormalities are present not only in patients with schizophrenia, but also in their unaffected co-twins. Thus, reduced mesial prefrontal cortical Glu and elevated hippocampal NAA, Cr and Cho may represent trait markers of schizophrenia risk and, when exacerbated, state markers of schizophrenia itself.
Personality traits have been studied extensively as risk and prognostic factors for cancer; however, the association remains unclear. This prospective, population-based cohort study comprised 59,548 ...Swedish (1974–1999) and Finnish (1976–2004) participants who completed a questionnaire eliciting information for the Eysenck Personality Inventory and on health behavior at baseline. To analyze the association of personality traits extraversion and neuroticism with risk of cancer, the authors identified 4,631 cancer cases for a maximum 30 years of follow-up. To assess the association with cancer survival among the Finnish participants, they identified 2,733 cancer cases and, later, 1,548 deaths for a maximum 29 years of follow-up. Hazard ratios were estimated by treating the personality scales as continuous variables and are presented per one increase in score on each scale. In multivariate analyses, extraversion and neuroticism were not significantly associated with risk of cancers at all sites (extraversion: hazard ratio = 0.99, 95% confidence interval: 0.98, 1.01; neuroticism: hazard ratio = 1.00, 95% confidence interval: 0.99, 1.02). Results showed no significant association between these traits and the hazard ratio for death after cancers at all sites, and they do not support the hypothesis that extraversion and neuroticism are direct risk factors for cancer or survival after cancer.
Background The purpose of the present study was to examine, first, whether hearing acuity predicts falls and whether the potential association is explained by postural balance and, second, to examine ...whether shared genetic or environmental effects underlie these associations. Methods Hearing was measured using a clinical audiometer as a part of the Finnish Twin Study on Aging in 103 monozygotic and 114 dizygotic female twin pairs aged 63–76 years. Postural balance was indicated as a center of pressure (COP) movement in semitandem stance, and participants filled in a fall-calendar daily for an average of 345 days after the baseline. Results Mean hearing acuity (better ear hearing threshold level at 0.5–4 kHz) was 21 dB (standard deviation SD 12). Means of the COP velocity moment for the best to the poorest hearing quartiles increased linearly from 40.7 mm2/s (SD 24.4) to 52.8 mm2/s (SD 32.0) (p value for the trend = .003). Altogether 199 participants reported 437 falls. Age-adjusted incidence rate ratios (IRRs) for falls, with the best hearing quartile as a reference, were 1.2 (95% confidence interval CI = 0.4–3.8) in the second, 4.1 (95% CI = 1.1–15.6) in the third, and 3.4 (95% CI = 1.0–11.4) in the poorest hearing quartiles. Adjustment for COP velocity moment decreased IRRs markedly. Twin analyses showed that the association between hearing acuity and postural balance was not explained by genetic factors in common for these traits. Conclusion People with poor hearing acuity have a higher risk for falls, which is partially explained by their poorer postural control. Auditory information about environment may be important for safe mobility.
Adipocyte size and number have been suggested to predict the development of metabolic complications in obesity. However, the genetic and environmental determinants behind this phenomenon remain ...unclear.
We studied this question in rare-weight discordant (intra-pair difference (Δ) body mass index (BMI) 3-10 kg m(-2), n=15) and concordant (ΔBMI 0-2 kg m(-)(2), n=5) young adult (22-35 years) monozygotic twin pairs identified from 10 birth cohorts of Finnish twins (n=5 500 pairs). Subcutaneous abdominal adipocyte size from surgical biopsies was measured under a light microscope. Adipocyte number was calculated from cell size and total body fat (D × A).
The concordant pairs were remarkably similar for adipocyte size and number (intra-class correlations 0.91-0.92, P<0.01), suggesting a strong genetic control of these measures. In the discordant pairs, the obese co-twins (BMI 30.6 ± 0.9 kg m(-2)) had significantly larger adipocytes (volume 547 ± 59 pl), than the lean co-twins (24.9 ± 0.9 kg m(-)(2); 356 ± 34 pl, P<0.001). In 8/15 pairs, the obese co-twins had less adipocytes than their co-twins. These hypoplastic obese twins had significantly higher liver fat (spectroscopy), homeostatic model assessment-index, C-reactive protein and low-density lipoprotein cholesterol than their lean co-twins. Hyperplastic obesity was observed in the rest (7/15) of the pairs, obese and lean co-twins having similar metabolic measures. In all pairs, Δadipocyte volume correlated positively and Δcell number correlated negatively with Δhomeostatic model assessment-index and Δlow-density lipoprotein, independent of Δbody fat. Transcripts most significantly correlating with Δadipocyte volume were related to a reduced mitochondrial function, membrane modifications, to DNA damage and cell death.
Together, hypertrophy and hypoplasia in acquired obesity are related to metabolic dysfunction, possibly through disturbances in mitochondrial function and increased cell death within the adipose tissue.
Background
Aggression in children has genetic and environmental causes. Studies of aggression can pool existing datasets to include more complex models of social effects. Such analyses require large ...datasets with harmonized outcome measures. Here, we made use of a reference panel for phenotype data to harmonize multiple aggression measures in school‐aged children to jointly analyze data from five large twin cohorts.
Methods
Individual level aggression data on 86,559 children (42,468 twin pairs) were available in five European twin cohorts measured by different instruments. A phenotypic reference panel was collected which enabled a model‐based phenotype harmonization approach. A bi‐factor integration model in the integrative data analysis framework was developed to model aggression across studies while adjusting for rater, age, and sex. Finally, harmonized aggression scores were analyzed to estimate contributions of genes, environment, and social interaction to aggression. The large sample size allowed adequate power to test for sibling interaction effects, with unique dynamics permitted for opposite‐sex twins.
Results
The best‐fitting model found a high level of overall heritability of aggression (~60%). Different heritability rates of aggression across sex were marginally significant, with heritability estimates in boys of ~64% and ~58% in girls. Sibling interaction effects were only significant in the opposite‐sex twin pairs: the interaction effect of males on their female co‐twin differed from the effect of females on their male co‐twin. An aggressive female had a positive effect on male co‐twin aggression, whereas more aggression in males had a negative influence on a female co‐twin.
Conclusions
Opposite‐sex twins displayed unique social dynamics of aggressive behaviors in a joint analysis of a large, multinational dataset. The integrative data analysis framework, applied in combination with a reference panel, has the potential to elucidate broad, generalizable results in the investigation of common psychological traits in children.
Mobility decline, the coexistence of several sensory difficulties and fear of falling (FOF) are all common concerns in older people; however, knowledge about the combined effect of FOF and coexisting ...sensory difficulties on mobility is lacking.
Data on self-reported FOF, difficulties in hearing, vision, balance, and walking 2 km were gathered with a structured questionnaire among 434 women aged 63-76 years at baseline and after a 3-year follow-up. Logistic regression models were used for analyses.
Every third participant reported difficulties in walking 2 km at baseline. In cross-sectional analysis, the odds ratio for difficulties in walking 2 km was higher among persons who reported FOF compared with persons without FOF and the odds increased with the increasing number of sensory difficulties. Persons who reported FOF and who had three sensory difficulties had almost fivefold odds (odds ratio = 4.7, 95% confidence interval = 1.9-11.7) for walking difficulties compared with those who reported no FOF and no sensory difficulties. Among the 290 women without walking difficulties at baseline, 54 participants developed difficulty in walking 2 km during the 3-year follow-up. Odds ratio for incident walking difficulty was 3.5 (95% confidence interval = 1.6-7.8) in participants with FOF and with 2-3 sensory difficulties compared with persons without FOF and with at most one sensory difficulty at baseline.
Older women who have several coexisting sensory difficulties combined with FOF are particularly vulnerable to mobility decline. Avoidance of walking as a result of FOF is likely to be reinforced when multiple sensory difficulties hinder reception of accurate information about the environment, resulting in accelerated decline in walking ability.
Few studies have examined both gene expression and DNA methylation profiles in subcutaneous adipose tissue (SAT) during long-term weight loss. Thus, molecular mechanisms in weight loss and regain ...remain elusive.
We performed a 1-year weight loss intervention on 19 healthy obese participants (mean body mass index (BMI) 34.6 kg m
) and studied longitudinal gene expression (Affymetrix Human Genome U133 Plus 2.0) and DNA methylation (Infinium HumanMethylation450 BeadChip) in SAT at 0, 5 and 12 months. To examine whether weight loss and acquired obesity produce reciprocal profiles, we verified our findings in 26 BMI-discordant monozygotic twin pairs.
We found altered expression of 69 genes from 0 to 5' months (short-term) weight loss. Sixty of these genes showed reversed expression in acquired obesity (twins). Altogether 21/69 genes showed significant expression-DNA methylation correlations. Pathway analyses revealed increased high-density lipoprotein-mediated lipid transport characteristic to short-term weight loss. After the fifth month, two groups of participants evolved: weight losers (WLs) and weight regainers (WRs). In WLs five genes were differentially expressed in 5 vs 12 months, three of which significantly correlated with methylation. Signaling by insulin receptor pathway showed increased expression. We further identified 35 genes with differential expression in WLs from 0 to 12 months (long-term) weight loss, with 20 showing opposite expression patterns in acquired obesity, and 16/35 genes with significant expression-DNA methylation correlations. Pathway analyses demonstrated changes in signal transduction, metabolism, immune system and cell cycle. Notably, seven genes (UCHL1, BAG3, TNMD, LEP, BHMT2, EPDR1 and OSTM1) were found to be downregulated during both short- and long-term weight loss.
Our study indicates short- and long-term weight loss influences in transcription and DNA methylation in SAT of healthy participants. Moreover, we demonstrate that same genes react in an opposite manner in weight loss and acquired obesity.
The Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study (1985–1993) recruited 29,133 Finnish male cigarette smokers, finding that vitamin E supplementation had no overall effect on ...mortality. The authors of this paper found that the effect of vitamin E on respiratory infections in ATBC Study participants was modified by age, smoking, and dietary vitamin C intake; therefore, they examined whether the effect of vitamin E supplementation on mortality is modified by the same variables. During a median follow-up time of 6.1 years, 3,571 deaths occurred. Age and dietary vitamin C intake had a second-order interaction with vitamin E supplementation of 50 mg/day. Among participants with a dietary vitamin C intake above the median of 90 mg/day, vitamin E increased mortality among those aged 50–62 years by 19% (95% confidence interval: 5, 35), whereas vitamin E decreased mortality among those aged 66–69 years by 41% (95% CI: −56, −21). Vitamin E had no effect on participants who had a dietary vitamin C intake below the median. Smoking quantity did not modify the effect of vitamin E. This study provides strong evidence that the effect of vitamin E supplementation on mortality varies between different population groups. Further study is needed to confirm this heterogeneity.
Background and Objective: Exercise is thought to reduce high-risk body fat, but intervention studies are frequently limited by short follow-ups and observational studies by genetic selection. ...Therefore, we studied the effects of a physically inactive vs active lifestyle on high-risk (visceral, liver and intramuscular) fat in twin pairs discordant for leisure-time physical activity habits for over 30 years. Design: A longitudinal population-based twin study. Subjects: Sixteen middle-aged (50–74 years) same-sex twin pairs (seven monozygotic (MZ), nine dizygotic (DZ)) with long-term discordance for physical activity habits were comprehensively identified from the Finnish Twin Cohort (TWINACTIVE study). Discordance was initially defined in 1975 and the same co-twin remained significantly more active during the 32-year-long follow-up. Main Outcome Measures: Magnetic resonance imaging-assessed visceral, liver and intramuscular fat. Results: In within-pair analyses carried out after the adult life-long discordance in physical activity habits, the physically inactive co-twins had 50% greater visceral fat area compared with the active co-twins (mean difference 55.5 cm2, 95% confidence interval (CI) 7.0–104.1, P=0.010). The liver fat score was 170% higher (13.2, 95% CI 3.5–22.8, P=0.030) and the intramuscular fat area 54% higher (4.9 cm2, 95% CI 1.9–7.9, P=0.002) among the inactive co-twins. All the trends were similar for MZ and DZ pairs. Peak oxygen uptake was inversely associated with visceral (r=-0.46, P=0.012) and intramuscular fat area (r=-0.48, P=0.028), with similar trends in intrapair difference correlations (r=-0.57, P=0.021 and r=-0.50, P=0.056, respectively). The intrapair difference correlation between visceral and intramuscular fat was also high (r=0.65, P=0.009). Conclusion: Regular physical activity seems to be an important factor in preventing the accumulation of high-risk fat over time, even after controlling for genetic liability and childhood environment. Therefore, the prevention and treatment of obesity should emphasize the role of regular leisure-time physical activity.
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