Subcutaneous adipose tissue (SAT) undergoes major changes in obesity, but little is known about the whole-genome scale patterns of these changes or about their variation between different obesity ...sub-groups. We sought to compare how transcriptomics profiles in SAT differ between monozygotic (MZ) co-twins who are discordant for body mass index (BMI), whether the profiles vary between twin pairs and whether the variation can be linked to clinical characteristics.
We analysed the transcriptomics (Affymetrix U133 Plus 2.0) patterns of SAT in young MZ twin pairs (n=26, intra-pair difference in BMI >3 kg m
, aged 23-36), from 10 birth cohorts of adult Finnish twins. The clinical data included measurements of body composition, insulin resistance, lipids and adipokines.
We found 2108 genes differentially expressed (false discovery rate (FDR)<0.05) in SAT of the BMI-discordant pairs. Pathway analyses of these genes revealed a significant downregulation of mitochondrial oxidative pathways (P<0.05) and upregulation of inflammation pathways (P<0.05). Hierarchical clustering of heavy/lean twin ratios, representing effects of acquired obesity in the transcriptomics data, revealed three sub-groups with different molecular profiles (FDR<0.05). Analyses comparing these sub-groups showed that, in the heavy co-twins, downregulation of the mitochondrial pathways, especially that of branched chain amino acid degradation was more evident in two clusters while and upregulation of the inflammatory response was most evident in the last, presumably the unhealthiest cluster. High-fasting insulin levels and large adipocyte diameter were the predominant clinical characteristic of the heavy co-twins in this cluster (Bonferroni-adjusted P<0.05).
This is the first study in BMI-discordant MZ twin pairs reporting sub-types of obesity based on both SAT gene expression profiles and clinical traits. We conclude that a decrease in mitochondrial BCAA degradation and an increase in inflammation in SAT co-occur and associate with hyperinsulinemia and large adipocyte size in unhealthy obesity.
Obesity is a genetically complex disorder that produces a myriad of health problems. Most of the recognized complications of obesity are not only strongly influenced by lifestyle factors, but also ...present with independent genetic predispositions that are notoriously difficult to disentangle in humans. Most studies on the causes and consequences of acquired obesity are encumbered by the incomplete ability to control for genetic influences. However, utilizing a unique experiment of nature, namely monozygotic twins (MZ) discordant for obesity as 'clonal controls' of obese and non-obese individuals has enabled the fine characterization of the effects and possible antecedents of acquired obesity while controlling for the genetic background, as well as pointed to novel obesity predisposing candidate genes. This review is a distillation of the findings from more than 10 years of research done in an exceptionally well-characterized collection of MZ and dizygotic (DZ) twins, based on the Finnish Twin Cohorts. Topics covered include the nature of development of obesity from the childhood onwards, the role of exercise in modifying the genetic susceptibility, the resulting inflammatory, prediabetic and preatherosclerotic changes in whole body and adipose tissue physiology, as well as the newest insights provided by the omics revolution.
Many genes and molecular pathways are associated with obesity, but the mechanisms from genes to obesity are less well known. Eating behaviors represent a plausible pathway, but because the ...relationships of eating behaviors and obesity may be bi-directional, it remains challenging to resolve the underlying pathways. A longitudinal approach is needed to assess the contribution of genetic risk during the development of obesity in childhood. In this study we aim to examine the relationships between the polygenic risk score for body mass index (PRS-BMI), parental concern of overeating and obesity indices during childhood. The IDEFICS/I.Family study is a school-based multicenter pan-European cohort of children observed for 6 years (mean + or - SD follow-up 5.8 + or - 0.4). Children examined in 2007/2008 (wave 1) (mean + or - SD age: 4.4 + or - 1.1, range: 2-9 years), in 2009/2010 (wave 2) and in 2013/2014 (wave 3) were included. A total of 5112 children (49% girls) participated at waves 1, 2 and 3. For 2656 children with genome-wide data we constructed a PRS based on 2.1 million single nucleotide polymorphisms. Z-score BMI and z-score waist circumference (WC) were assessed and eating behaviors and relevant confounders were reported by parents via questionnaires. Parental concern of overeating was derived from principal component analyses from an eating behavior questionnaire. In cross-lagged models, the prospective associations between z-score obesity indices and parental concern of overeating were bi-directional. In mediation models, the association between the PRS-BMI and parental concern of overeating at wave 3 was mediated by baseline z-BMI (beta = 0.16, 95% CI: 0.10, 0.21) and baseline z-WC (beta = 0.17, 95% CI: 0.11, 0.23). To a lesser extent, baseline parental concern of overeating also mediated the association between the PRS-BMI and z-BMI at wave 3 (beta = 0.10, 95% CI: 0.07, 0.13) and z-WC at wave 3 (beta = 0.09, 95% CI: 0.07, 0.12). The findings suggest that the prospective associations between obesity indices and parental concern of overeating are likely bi-directional, but obesity indices have a stronger association with future parental concern of overeating than vice versa. The findings suggest parental concern of overeating as a possible mediator in the genetic susceptibility to obesity and further highlight that other pathways are also involved. A better understanding of the genetic pathways that lead to childhood obesity can help to prevent weight gain.
Drug addiction remains a substantial health issue with limited treatment options currently available. Despite considerable advances in the understanding of human genetic architecture, the genetic ...underpinning of complex disorders remains elusive. On the basis of our current understanding of neurobiology, numerous candidate genes have been implicated in the etiology and response to treatment for different addictions. Genome‐wide association (GWA) studies have also identified novel targets. However, replication of these studies is often lacking, and this complicates interpretation. The situation is expected to improve as issues such as phenotypic characterization, the apparent “missing heritability,” the identification of functional variants, and possible gene–environment (G × E) interactions are addressed. In addition, there is growing evidence that genetic information can be useful in refining the choice of addiction treatment. As genetic testing becomes more common in the practice of medicine, a variety of ethical and practical challenges, some of which are unique to drug addiction, will also need to be considered.
Clinical Pharmacology & Therapeutics (2010) 88 6, 779–791. doi: 10.1038/clpt.2010.175
To date, studies on the contributions of genetic factors to oral health have been inconclusive. We hypothesized that major dental diseases show a significant genetic component. The study was based on ...self-reported oral health among young adult twins. The data were derived from the fourth wave of the longitudinal FinnTwin16 study, in which participants completed a questionnaire in 2000-2002 enquiring about the number of filled teeth and the prevalence of gingival bleeding. We used quantitative genetic modeling, based on the genetic similarity of identical and non-identical twins, to calculate the most probable model for both filled teeth and gingival bleeding. The models revealed a strong genetic component behind the number of filled teeth, differing between males (49%) and females (68%), and a weaker genetic component affecting gingival bleeding, being similar for males and females (32%). Genetic factors contribute to inter-individual differences in oral health among young adults.
BACKGROUND: Remarkable overlap exists in symptoms between asthma and chronic obstructive pulmonary disease (COPD), and the symptoms of the patients with mild asthma are often falsely thought to be ...caused by smoking. The objective of the study was to determine the prevalence of doctor-diagnosed asthma, asthmatic symptoms and doctor-diagnosed COPD in an adult population. The prevalence and relation to asthma of aspirin intolerance, nasal polyposis, allergic rhinitis and smoking habits were also examined. METHODS: Postal questionnaire survey of a population-based random sample (4300) of adult women and men aged 18-65 years served by the Päijät-Häme Central Hospital in southern Finland (a region with 208 000 inhabitants) was performed. RESULTS: The non-response-adjusted prevalence (Drane's linear method) of doctor-diagnosed asthma was 4.4% (95% CI: 3.3-5.5%) and of COPD 3.7% (95% CI: 2.7-4.8%). The prevalence of allergic rhinitis was 37.3% (95% CI: 33.3-41.2%), and of overall aspirin intolerance 5.7% (95% CI: 4.4-7.1%). The observed prevalence of aspirin intolerance causing shortness of breath or attacks of asthma was 1.2% and it was higher in patients with doctor-diagnosed asthma than without (8.8% versus 0.8%, relative risk RR = 11.4, P < 0.0001), and higher in those with allergic-like rhinitis than without (2.6% versus 0.3%, RR = 7.7, P < 0.0001). The prevalence of nasal polyposis was 4.3% (95% CI : 2.8-5.8%). CONCLUSIONS: The current prevalence of doctor-diagnosed asthma among adults is 4.4%, and allergic rhinitis, nasal polyposis and aspirin intolerance are associated with an increased risk of asthma. There is also association between aspirin-induced asthma and allergic-like rhinitis.
Objective: To study whether eating or physical-activity (PA) habits differ between obese and non-obese monozygotic (MZ) co-twins independent of genetic effects. Methods: Rare MZ pairs discordant for ...obesity (n=14, body mass index difference 5.2±1.8 kg m–2) and weight-concordant control pairs (n=10, 1.0±0.7 kg m–2), identified through a population-based registry of 24–28-year-old twins (n=658 MZ pairs), completed 3-day food and PA diaries and eating behavior questionnaires. Each twin was asked to compare his/her own eating and PA patterns with the co-twin's behavior by structured questionnaires. Accuracy of energy intake was validated by doubly labeled water. Results: Non-obese co-twins consistently reported that their obese twin siblings ate more food overall, consumed less healthy foods and exercised less than the non-obese co-twins do. However, no differences in energy intake (9.6±1.0 MJ per day vs 9.8±1.1 MJ per day, respectively) in the food diaries or in the mean PA level (1.74±0.02 vs 1.79±0.04, respectively) in the PA diaries were found between obese and non-obese co-twins. A considerable underreporting of energy intake (3.2±1.1 MJ per day, P=0.036) and overreporting of PA (1.8±0.8 MJ per day, P=0.049) was observed in the obese, but not in the non-obese co-twins. Conclusions: On the basis of rare MZ twin pairs discordant for obesity, the co-twin assessments confirmed substantial differences in eating and PA behavior between obese and non-obese persons. These may be overlooked in population studies using food and PA diaries because of considerable misreporting by the obese.
Smoking is a major risk factor for several somatic diseases and is also emerging as a causal factor for neuropsychiatric disorders. Genome-wide association (GWA) and candidate gene studies for ...smoking behavior and nicotine dependence (ND) have disclosed too few predisposing variants to account for the high estimated heritability. Previous large-scale GWA studies have had very limited phenotypic definitions of relevance to smoking-related behavior, which has likely impeded the discovery of genetic effects. We performed GWA analyses on 1114 adult twins ascertained for ever smoking from the population-based Finnish Twin Cohort study. The availability of 17 smoking-related phenotypes allowed us to comprehensively portray the dimensions of smoking behavior, clustered into the domains of smoking initiation, amount smoked and ND. Our results highlight a locus on 16p12.3, with several single-nucleotide polymorphisms (SNPs) in the vicinity of CLEC19A showing association (P<1 × 10(-6)) with smoking quantity. Interestingly, CLEC19A is located close to a previously reported attention-deficit hyperactivity disorder (ADHD) linkage locus and an evident link between ADHD and smoking has been established. Intriguing preliminary association (P<1 × 10(-5)) was detected between DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) ND diagnosis and several SNPs in ERBB4, coding for a Neuregulin receptor, on 2q33. The association between ERBB4 and DSM-IV ND diagnosis was replicated in an independent Australian sample. Recently, a significant increase in ErbB4 and Neuregulin 3 (Nrg3) expression was revealed following chronic nicotine exposure and withdrawal in mice and an association between NRG3 SNPs and smoking cessation success was detected in a clinical trial. ERBB4 has previously been associated with schizophrenia; further, it is located within an established schizophrenia linkage locus and within a linkage locus for a smoker phenotype identified in this sample. In conclusion, we disclose novel tentative evidence for the involvement of ERBB4 in ND, suggesting the involvement of the Neuregulin/ErbB signalling pathway in addictions and providing a plausible link between the high co-morbidity of schizophrenia and ND.
For the elderly, the association between waist circumference (WC) and mortality considering body mass index (BMI) remains unclear, and thereby also the evidence base for using these anthropometric ...measures in clinical practice. This meta-analysis examined the association between WC categories and (cause-specific) mortality within BMI categories. Furthermore, the association of continuous WC with lowest and increased mortality risks was examined.
Age- and smoking-adjusted relative risks (RRs) of mortality associated with WC-BMI categories and continuous WC (including WC and WC(2)) were calculated by the investigators and pooled by means of random-effects models.
During a 5-year-follow-up of 32 678 men and 25 931 women, we ascertained 3318 and 1480 deaths, respectively. A large WC (men: ≥102 cm, women: ≥88 cm) was associated with increased all-cause mortality RRs for those in the 'healthy' weight {1.7 95% confidence interval (CI): 1.2-2.2, 1.7 (95% CI: 1.3-2.3)}, overweight 1.1(95% CI: 1.0-1.3), 1.4 (95%: 1.1-1.7) and obese 1.1 (95% CI: 1.0-1.3), 1.6 (95% CI: 1.3-1.9) BMI category compared with the 'healthy' weight (20-24.9 kg/m(2)) and a small WC (<94 cm, men; <80 cm, women) category. Underweight was associated with highest all-cause mortality RRs in men 2.2 (95% CI: 1.8-2.8) and women 2.3 (95% CI: 1.8-3.1. We found a J-shaped association for continuous WC with all-cause, cardiovascular (CVD) and cancer, and a U-shaped association with respiratory disease mortality (P < 0.05). An all-cause (CVD) mortality RR of 2.0 was associated with a WC of 132 cm (123 cm) in men and 116 cm (105 cm) in women.
Our results showed increased mortality risks for elderly people with an increased WC-even across BMI categories- and for those who were classified as 'underweight' using BMI. The results provide a solid basis for re-evaluation of WC cut-points in ageing populations.
Objective: To study genetic and environmental factors affecting body mass index (BMI) and BMI phenotypic correlations across adolescence. Design: Prospective, population-based, twin cohort study. ...Participants and methods: We used twin modeling in 2413 monozygotic and same-sex and opposite-sex dizygotic Finnish twin pairs born in 1983-1987 and assessed using self-report questionnaires at 11-12, 14 and 17 years of age. Results: Heritability of BMI was estimated to be 0.58-0.69 among 11-12- and 14-year-old boys and girls, 0.83 among 17-year-old boys and 0.74 among 17-year-old girls. Common environmental effects shared by siblings were 0.15-0.24 among 11-12- and 14-year-old boys and girls but no longer discernible at 17 years of age. Unique environmental effects were 0.15-0.23. Additive genetic factors explained 90-96% of the BMI phenotypic correlations across adolescence, whereas unique environmental factors explained the rest. Common environment had no effect on BMI phenotypic correlations. Conclusions: The genetic contribution to BMI is strong during adolescence, and it mainly explains BMI phenotypic correlations across adolescence. Common environmental factors have an effect on BMI during early adolescence, but that effect disappears by late adolescence.
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