Changes in BMI and physical activity from youth to adulthood distinguish normal-weight, metabolically obese adults from those who remain healthy.

Highlights: Adults with MONW have a lower BMI during youth until young adulthood, but higher BMI after this than adults with metabolically healthy normal weight. Adults with MONW have a greater decrease in physical activity from youth to adulthood than other adults. Healthy lifestyle is important in the prevention of metabolic disorders, particularly in individuals who are slim in childhood. Background: Individuals with metabolically obese normal-weight (MONW) have higher risk of cardiovascular events than those with obesity but a metabolically healthy status. Etiological factors leading to MONW are not well known. We hypothesized distinct trajectories of changes in BMI and physical activity may modify metabolic risk and distinguish individuals with MONW from those who remain healthy. Methods: We compared the mean levels of BMI and physical activity at eight time points (1980, 1983, 1986, 1989, 1992, 2001, 2007, 2011) between MONW and healthy normal-weight adults using linear mixed-model analysis. The analyses included 1180 participants of the Cardiovascular Risk in Young Finns study, a population-based study that represents six different age cohorts 3, 6, 9, 12, 15 and 18 years of age at baseline. Results: Individuals with adult MONW had significantly lower BMI in childhood and young adulthood, but their BMI increased more than in other adults after this age (p<0.001for interaction between time and MONW status). Physical activity decreased relatively more since youth in individuals with adult MONW (p<0.001). Conclusions: Relative leanness in youth and subsequent weight gain in young adulthood, and a gradual decrease in physical activity levels from youth to adulthood, predispose normal-weight individuals to metabolic impairments. The results highlight the importance of a healthy lifestyle in the prevention of metabolic disorders, particularly in individuals who are slim in childhood.

Evolution of genetic networks for human creativity.

The genetic basis for the emergence of creativity in modern humans remains a mystery despite sequencing the genomes of chimpanzees and Neanderthals, our closest hominid relatives. Data-driven methods allowed us to uncover networks of genes distinguishing the three major systems of modern human personality and adaptability: emotional reactivity, self-control, and self-awareness. Now we have identified which of these genes are present in chimpanzees and Neanderthals. We replicated our findings in separate analyses of three high-coverage genomes of Neanderthals. We found that Neanderthals had nearly the same genes for emotional reactivity as chimpanzees, and they were intermediate between modern humans and chimpanzees in their numbers of genes for both self-control and self-awareness. 95% of the 267 genes we found only in modern humans were not protein-coding, including many long-non-coding RNAs in the self-awareness network. These genes may have arisen by positive selection for the characteristics of human well-being and behavioral modernity, including creativity, prosocial behavior, and healthy longevity. The genes that cluster in association with those found only in modern humans are over-expressed in brain regions involved in human self-awareness and creativity, including late-myelinating and phylogenetically recent regions of neocortex for autobiographical memory in frontal, parietal, and temporal regions, as well as related components of cortico-thalamo-ponto-cerebellar-cortical and cortico-striato-cortical loops. We conclude that modern humans have more than 200 unique non-protein-coding genes regulating co-expression of many more protein-coding genes in coordinated networks that underlie their capacities for self-awareness, creativity, prosocial behavior, and healthy longevity, which are not found in chimpanzees or Neanderthals.

Circulating cell-free DNA level predicts all-cause mortality independent of other predictors in the Health 2000 survey.

Increased levels of circulating cell-free DNA (cf-DNA) are associated with and predict poor health outcomes. However, its predictive ability for mortality in population-based samples remains understudied. We analysed the capability of cf-DNA to predict all-cause mortality and assessed whether it adds predictive value on top of the other risk factors in the Health 2000 survey (n = 1,257, 46-76 years of age, 15-years-follow-up, 18% deceased). When analysed in a multivariate model with the other factors that independently predicted mortality in the sample (age, gender, self-rated health, smoking and plasma levels of glucose and adiponectin), increases in cf-DNA levels were associated with increased risk of mortality (hazard ratio [HR] for 0.1 µg increase in cf-DNA: 1.017, 95% confidence interval [CI] 1.008-1.026, p = 0.0003). Inclusion of cf-DNA in the model improved the model fit and discrimination. Stratifying the analysis by cardiovascular disease (CVD) status indicated that cf-DNA predicted mortality equally well in individuals with (HR 1.018, 95% CI 1.008-1.026, p = 0.002) and without (HR 1.018, 95% CI 1.001-1.035, p = 0.033) CVD. In conclusion, our study indicates that cf-DNA level predicts mortality in middle-aged and older individuals, also among those with established CVD, and adds significant value to mortality prediction. Our results thus underscore the role of cf-DNA as a viable marker of health.

Childhood Oral Infections Associate with Adulthood Metabolic Syndrome: A Longitudinal Cohort Study.

Chronic oral infection/inflammation is cross-sectionally associated with metabolic syndrome (MetS) in adults, but there are few longitudinal studies and studies on childhood oral infections and adult MetS risk. We investigated whether childhood clinical parameters indicative of oral infection/inflammation were associated with adulthood MetS and its components. A total of 755 children aged 6, 9, and 12 y underwent a clinical oral examination in 1980 as part of the Cardiovascular Risk in Young Finns Study. Oral health measures included bleeding on probing (BOP), periodontal probing pocket depth, caries, fillings, and visible plaque. Metabolic parameters were determined at baseline and during follow-up. MetS was diagnosed (n = 588, 77.9%) in the adulthood at 21 y (in 2001), 27 y (in 2007), and 31 y (in 2011) after the oral assessment, when the participants were 27 to 43 y old. Regression analyses were adjusted for childhood age, sex, body mass index, and family income, as well as adulthood smoking and education level. In adulthood, MetS was diagnosed in 11.9% (2001), 18.7% (2007), and 20.7% (2011) of participants at the 3 follow-ups. Childhood caries and fillings were associated with increased risk of adult MetS (risk ratio [95% CI], 1.25 [0.90 to 2.45] and 1.27 [1.02 to 1.99]) and with increased systolic blood pressure (1.78 [1.01 to 4.26] and 2.48 [1.11 to 4.12]) and waist circumference (2.25 [1.02 to 4.99] and 1.56 [1.01 to 3.25]), whereas BOP and visible plaque were associated with plasma glucose (1.97 [1.08 to 3.60] and 1.88 [1.00 to 3.53]). Severity of BOP (P = 0.015) and caries (P = 0.005) and teeth with plaque (P = 0.027) were associated with number of MetS components. No such trends were seen with probing pocket depth. Childhood oral infection/inflammation was associated with adverse metabolic parameters and MetS in adulthood.

Differences in Prognostic Factors and Recurrence Patterns After Curative-Intent Resection of Perihilar and Distal Cholangiocarcinomas.

BACKGROUND: Perihilar cholangiocarcinoma and distal cholangiocarcinoma arise from the same tissue but require different surgical treatment methods. It remains unclear whether these cholangiocarcinoma types have different outcomes, prognostic factors, and/or recurrence patterns. METHODS: This retrospective study evaluated patients who underwent curative-intent resection for perihilar cholangiocarcinoma or distal cholangiocarcinoma at a tertiary academic hospital during 2000-2015. Survival and prognostic factors were identified using Kaplan-Meier and Cox regression analyses. RESULTS: The 90-day mortality rates were 0% for perihilar cholangiocarcinoma (36 patients) and 4% for distal cholangiocarcinoma (47 patients). There were no significant differences between perihilar cholangiocarcinoma or distal cholangiocarcinoma in median overall survival (30.9 vs 40.4 months) or median disease-free survival (14.2 vs 21.4 months). Among perihilar cholangiocarcinoma patients, age > 65 years was an independent predictor of poorer overall survival (hazard ratio: 2.45, 95% confidence interval: 1.07-5.64), while requiring bile duct re-resection was an independent predictor of disease-free survival (hazard ratio: 2.76, 95% confidence interval: 1.01-7.51). Among distal cholangiocarcinoma patients, a pN1 category independently predicted poorer overall survival (hazard ratio: 3.40, 95% confidence interval: 1.14-10.11), while preoperative CA19-9 levels >30 U/mL (hazard ratio: 2.51, 95% confidence interval: 1.09-5.79) and pN1 category (hazard ratio: 2.51, 95% confidence interval: 1.09-5.79) predicted a shorter disease-free survival. Local recurrence was more common with perihilar cholangiocarcinoma (50% of recurrences), while multiple synchronous sites were more common for distal cholangiocarcinoma (41% of recurrences). CONCLUSION: Perihilar cholangiocarcinoma and distal cholangiocarcinoma patients have similar survival outcomes. However, local control appears to be more prognostic for perihilar cholangiocarcinoma patients, while positive lymph nodes are critical prognostic factor for distal cholangiocarcinoma patients.

Increase in adiposity from childhood to adulthood predicts a metabolically obese phenotype in normal-weight adults.

Normal weight is associated with a favorable cardiometabolic risk profile and low risk of type 2 diabetes and cardiovascular disease. However, some normal-weight individuals-the "metabolically obese normal weight" (MONW)-show a cardiometabolic risk profile similar to the obese. Previous studies have shown that older age, central body fat distribution, and unfavorable lifestyle increase the risk of MONW. However, the role of early-life factors in MONW remains unknown. We examined the associations of early-life factors with adult MONW in 1178 individuals from the Cardiovascular Risk in Young Finns study who were followed up from childhood to adulthood. The strongest early predictor for adult MONW was an increase in BMI from childhood to adulthood (p = 3.1 × 10-11); each 1 SD increase in BMI z-score from childhood to adulthood led to a 2.56-fold increase in the risk of adult MONW (CI 95% = 1.94-3.38). Other significant predictors of adult MONW were male sex (OR = 2.38, 95% = 1.63-3.47, p = 7.0 × 10-6), higher childhood LDL cholesterol (OR = 1.41 per 1 SD increase in LDL cholesterol, CI 95% = 1.14-1.73, p = 0.001), and lower HDL cholesterol (OR = 1.51 per 1 SD decrease in HDL cholesterol, CI 95% = 1.23-1.85, p = 5.4 × 10-5). Our results suggest that an increase in adiposity from childhood to adulthood is detrimental to cardiometabolic health, even among individuals remaining normal weight.

The rs2516839 variation of USF1 gene is associated with 4-year mortality of nonagenarian women: The Vitality 90+ study.

Upstream transcription factor 1 (USF1) regulates the transcription of many genes related to cell and organism survival processes such as stress and immune response, regulation of cellular senesce, and carcinogenesis. In this study, our aim was to investigate the effect of USF1 single nucleotide variations (SNVs) on longevity in the Vitality 90+ study, a population-based study of nonagenarians (90 ±1 years of age) living in the area of Tampere municipality, Finland. Altogether 509 voluntary nonagenarians (115 males, 394 females) were genotyped using the 5'-nuclease assay for rs2774279G > A, rs2516839T > C, and rs2073658C > T SNVs. During the 4 years of follow-up, the total mortality rate was 64.2%. In the study, we found that the frequency of C-allele of rs2516839 among nonsurviving nonagenarians (52.5%) was higher than those who survived (41.2%; P = 0.0006, odds ratio = 1.575, 95% confidence interval [CI]: 1.215-2.041). Furthermore, carriage of this variation and its haplotypes had a significant gender by genotype interaction (P < 0.05) on mortality. Kaplan-Meier log-rank test during 4-years of follow-up showed significantly higher mortality rate in the case of CC genotype carriage than other genotype carriages in nonagenarian women (P < 0.0001). In addition, after adjusting for age in Cox regression analysis, cardiovascular disease, diabetes, infectious disease, dementia, and living place (nursing home or home), CC genotype of rs2516839T > C was found to be associated with shorter life expectancy in nonagenarian women (hazard ratio = 2.27; 95% CI, 1.34-3.85 P = 0.002). In conclusion, rs2516839 variation and related haplotypes of the USF1 gene are strongly related to all-cause mortality in Finnish nonagenarians, especially among women.

Evaluation of serum miR-191-5p, miR-24-3p, miR-128-3p, and miR-376c-3 in multiple sclerosis patients.

BACKGROUND: Biomarkers that could be used in early diagnosis of multiple sclerosis (MS), segregation of disease subtypes, and discrimination of the aggressive disease course from the benign one are urgently needed. OBJECTIVE: The aim of this study was to investigate the specificity of circulating microRNAs: miR-191-5p, miR-128-3p, miR-24-3p, and miR-376c-3p in MS and evaluate their association with disease activity and disability progression. METHODS: The expressions of circulating miRNAs were studied in serum of 100 subjects (53 relapsing-remitting (RRMS), 20 primary progressive (PPMS), and 27 controls), using miScript serum miRNA RT-PCR assay techniques. RESULTS: In comparison with controls, miR-191-5p and miR-24-3p were overexpressed in RRMS and PPMS, with no differences between the subtypes. miR-24-3p correlated positively with the disability progression index in the combined group of all patients with MS. miR-128-3p showed tendency toward the predominant expression in PPMS and correlated positively with the annual relapse rate in RRMS. miR-376c-3p expression levels did not differ between the groups, and no associations were found to clinical parameters. CONCLUSION: This study highlighted the connection of circulating miRNAs to MS. miR-24-3p and miR-128-3p showed a tendency of association with disability accumulation and disease activity, respectively. Further studies should evaluate their suitability for clinical use.

Education as a moderator of genetic risk for higher body mass index: prospective cohort study from childhood to adulthood.

OBJECTIVES: The life-course development of body mass index (BMI) may be driven by interactions between genes and obesity-inducing social environments. We examined whether lower parental or own education accentuates the genetic risk for higher BMI over the life course, and whether diet and physical activity account for the educational differences in genetic associations with BMI. SUBJECTS/METHODS: The study comprised 2441 participants (1319 women, 3-18 years at baseline) from the prospective, population-based Cardiovascular Risk in Young Finns Study. BMI (kg/m2) trajectories were calculated from 18 to 49 years, using data from six time points spanning 31 years. A polygenic risk score for BMI was calculated as a weighted sum of risk alleles in 97 single-nucleotide polymorphisms. Education was assessed via self-reports, measured prospectively from participants in adulthood and from parents when participants were children. Diet and physical activity were self-reported in adulthood. RESULTS: Mean BMI increased from 22.6 to 26.6 kg/m2 during the follow-up. In growth curve analyses, the genetic risk score was associated with faster BMI increase over time (b=0.02, (95% CI, 0.01-0.02, P<0.001)). The association between the genetic risk score and BMI was more pronounced among those with lower educational level in adulthood (b=-0.12 (95% CI, -0.23-0.01); P=0.036)). No interaction effect was observed between the genetic risk score and parental education (b=0.05 (95% CI, -0.09-0.18; P=0.51)). Diet and physical activity explained little of the interaction effect between the genetic risk score and adulthood education. CONCLUSIONS: In this prospective study, the association of a risk score of 97 genetic variants with BMI was stronger among those with low compared with high education. This suggests lower education in adulthood accentuates the risk of higher BMI in people at genetic risk.

Synergistic Expression of Histone Deacetylase 9 and Matrix Metalloproteinase 12 in M4 Macrophages in Advanced Carotid Plaques.

OBJECTIVE/BACKGROUND: Expression patterns and association with cell specific gene expression signatures of the epigenetic regulator histone deacetylase 9 (HDAC9) and matrix metalloproteinase 12 (MMP12) in human plaque are not known. METHODS: This was a prospective cohort study. Genome wide expression analysis was performed in carotid, femoral, aortic plaques (n = 68) and left internal thoracic (LITA) controls (n = 28) and plaque histological severity assessed. Correlation and hierarchical cluster analysis was utilised. RESULTS: HDAC9 was associated with MMP12 expression in carotid plaques (r = .46, p = .012) and controls (r = -.44, p = .034). HDAC9 and MMP12 clustered with inflammatory macrophage markers but not with smooth muscle cell (SMC) rich markers. In plaques from all arterial sites, MMP12 but not HDAC9 showed positive correlation (p < .05) with M2 and M4 polarized macrophage markers, and negative correlation with SMC rich signatures. In the carotid plaques, all M4 macrophage markers associated with MMP12 and HDAC9. The negative association of MMP12 with SMC rich signatures was pronounced in the carotid plaques. Neither HDAC9 nor MMP12 associated consistently with plaque stabilisation or thrombosis related genes. Immunohistochemistry further supported the association between HDAC9 and MMP12 in atherosclerotic plaques. CONCLUSION: M4 macrophages are a possible source for HDAC9 and MMP12 expression in advanced human plaques.

Early work-related physical exposures and low back pain in midlife: the Cardiovascular Risk in Young Finns Study.

OBJECTIVE: To examine whether heavy physical workload in young adulthood increases the risk of local and radiating low back pain (LBP) in midlife. METHODS: Longitudinal nationally representative Young Finns Study data among women (n=414) and men (n=324), aged 18-24 years in 1986 (baseline), were used. Physical heaviness of work was reported at baseline and follow-up (2007), and local and radiating LBP at follow-up. Covariates were age, smoking and body mass index. Logistic regression was used to examine the associations between physical heaviness of work and LBP. Additionally, the mediating effect of back pain at baseline was examined (the Sobel test). RESULTS: After adjustment for the covariates, and as compared with sedentary/light physical workload, heavy physical workload was associated with radiating LBP among women (OR 4.09, 95% CI 1.62 to 10.31) and men (OR 2.01, 95% CI 1.06 to 3.82). Among men, early back pain mediated the association (p value from the Sobel test=0.006). Among women, early exposure to physically heavy work showed the most consistent associations, while early and late exposures were associated with radiating and local LBP among men. Persistently heavy physical work was associated with radiating LBP among women and men. CONCLUSIONS: Physically heavy work at a young age can have a long-lasting effect on the risk of LBP, radiating LBP in particular. These results highlight the need to consider early and persistent exposures to prevent the adverse consequences of physical workload for the low back.

Association study of arcuate nucleus neuropeptide Y neuron receptor gene variation and serum NPY levels in clozapine treated patients with schizophrenia.

BACKGROUND: Antipsychotic-induced weight gain (AIWG) leads to metabolic consequences and comorbidity, social stigmatization and nonadherence in patients with schizophrenia. Neuropeptide Y (NPY) has an important role in appetite and body weight regulation. Associations between AIWG and serum NPY levels, and genetic polymorphisms (SNPs) associated with its serum levels have been little studied in these patients. SUBJECTS AND METHODS: Associations between serum NPY concentration and other metabolic and inflammatory markers, and 215 SNPs in 21 genes (NPY gene, NPY receptor genes and genes encoding arcuate nucleus NPY neuron receptors) were studied in 180 patients with schizophrenia on clozapine treatment. RESULTS: The serum levels of NPY correlated with levels of resistin (r=0.31, P<0.001) and age (r=0.22, P=0.003). In the general linear univariate model the best-fitting model with explanatory factors age, serum resistin level, serum insulin level, BMI and gender explained 18.0% (P<0.001) of the variance of serum NPY. Genetic risk score (GRSNPY) analysis found twelve significant (P<0.05) serum NPY concentration related SNPs among α7 nicotinic acetylcholine receptor gene CHRNA7, insulin receptor gene INSR, leptin receptor gene LEPR, glucocorticoid receptor (GR) gene NR3C1, and NPY gene. However, after permutation test of gene score the predictive value of GRSNPY remained non-significant (P=0.078). CONCLUSIONS: Serum NPY level does not seem to be a feasible biomarker of AIWG. Serum NPY level alterations are not significantly associated with the candidate gene polymorphisms studied.

The trajectory of the blood DNA methylome ageing rate is largely set before adulthood: evidence from two longitudinal studies.

The epigenetic clock, defined as the DNA methylome age (DNAmAge), is a candidate biomarker of ageing. In this study, we aimed to characterize the behaviour of this marker during the human lifespan in more detail using two follow-up cohorts (the Young Finns study, calendar age i.e. cAge range at baseline 15-24 years, 25-year-follow-up, N = 183; The Vitality 90+ study, cAge range at baseline 19-90 years, 4-year-follow-up, N = 48). We also aimed to assess the relationship between DNAmAge estimate and the blood cell distributions, as both of these measures are known to change as a function of age. The subjects' DNAmAges were determined using Horvath's calculator of epigenetic cAge. The estimate of the DNA methylome age acceleration (Δ-cAge-DNAmAge) demonstrated remarkable stability in both cohorts: the individual rank orders of the DNAmAges remained largely unchanged during the follow-ups. The blood cell distributions also demonstrated significant intra-individual correlation between the baseline and follow-up time points. Interestingly, the immunosenescence-associated features (CD8+CD28- and CD4+CD28- cell proportions and the CD4/CD8 cell ratio) were tightly associated with the estimate of the DNA methylome age. In summary, our data demonstrate that the general level of Δ-cAge-DNAmAge is fixed before adulthood and appears to be quite stationary thereafter, even in the oldest-old ages. Moreover, the blood DNAmAge estimate seems to be tightly associated with ageing-associated shifts in blood cell composition, especially with those that are the hallmarks of immunosenescence. Overall, these observations contribute to the understanding of the longitudinal aspects of the DNAmAge estimate.

Aging-associated DNA methylation changes in middle-aged individuals: the Young Finns study.

BACKGROUND: Chronological aging-associated changes in the human DNA methylome have been studied by multiple epigenome-wide association studies (EWASs). Certain CpG sites have been identified as aging-associated in multiple studies, and the majority of the sites identified in various studies show common features regarding location and direction of the methylation change. However, as a whole, the sets of aging-associated CpGs identified in different studies, even with similar tissues and age ranges, show only limited overlap. In this study, we further explore and characterize CpG sites that show close relationship between their DNA methylation level and chronological age during adulthood and which bear the relationship regardless of blood cell type heterogeneity. RESULTS: In this study, with a multivariable regression model adjusted for cell type heterogeneity, we identified 1202 aging-associated CpG sites (a-CpGs, FDR < 5%), in whole blood in a population with an especially narrow age range (40 - 49 years). Repeatedly reported a-CpGs located in genes ELOVL2, FHL2, PENK and KLF14 were also identified. Regions with aging-associated hypermethylation were enriched regarding several gene ontology (GO) terms (especially in the cluster of developmental processes), whereas hypomethylated sites showed no enrichment. The genes with higher numbers of a-CpG hits were more often hypermethylated with advancing age. The comparison analysis revealed that of the 1202 a-CpGs identified in the present study, 987 were identified as differentially methylated also between nonagenarians and young adults in a previous study (The Vitality 90+ study), and importantly, the directions of changes were identical in the previous and in the present study. CONCLUSIONS: Here we report that aging-associated DNA methylation features can be identified in a middle-aged population with an age range of only 9 years. A great majority of these sites have been previously reported as aging-associated in a population aged 19 to 90 years. Aging is associated with different types of changes in DNA methylation, clock-like as well as random. We speculate that the a-CpGs identified here in a population with a narrow age-range represent clock-like changes, as they showed concordant methylation behavior in population spanning whole adulthood as well.

Longitudinal investigation of adenovirus 36 seropositivity and human obesity: the Cardiovascular Risk in Young Finns Study.

BACKGROUND/OBJECTIVES: Adenovirus-36 (Adv-36) infection is associated with exaggerated adipogenesis in cell culture and the development of obesity in animal models and humans, but a causal relationship remains unproven. Our objective was to determine whether serological evidence of Adv-36 infection in childhood and/or adulthood is associated with adult obesity. SUBJECTS/METHODS: Paired plasma concentrations of Adv-36 antibodies were measured by a novel enzyme-linked immunosorbent assay in a subgroup (n=449) of the Cardiovascular Risk in Young Finns Study in childhood (mean age 11.9 years) and adulthood (mean age 41.3 years). The study group included (1) individuals who had maintained normal-weight status (2) those who became obese adults from a normal-weight status in childhood and (3) those that were overweight/obese as a child and obese as an adult. RESULTS: Mean (s.d.) time between baseline and follow-up was 29.4 (3.2) years (range 21-31 years). A total of 24.4% of individuals who were normal weight throughout life were seropositive for Adv-36 during child and/or adulthood as compared with 32.3% of those who became obese adults (P=0.11). Those who became obese in adulthood were more likely to be Adv-36 seropositive as adults compared with those who maintained normal weight (21.3% vs. 11.6%, P=0.02). This difference was mediated by a decline in Adv-36 seropositivity between child and adulthood in those maintaining normal weight. No differences were observed in body mass index across the life course, nor in waist circumference in adult life, between those who were Adv-36 seronegative or seropositive at any age. CONCLUSIONS: Individuals who gained weight across the life course were more likely to be Adv-36 seropositive in adult life than those who did not gain weight. However, analysis of change in weight status in relation to Adv-36 positivity did not support a causal role for Adv-36 in the development of obesity.

Is the adiposity-associated FTO gene variant related to all-cause mortality independent of adiposity? Meta-analysis of data from 169,551 Caucasian adults.

Previously, a single nucleotide polymorphism (SNP), rs9939609, in the FTO gene showed a much stronger association with all-cause mortality than expected from its association with body mass index (BMI), body fat mass index (FMI) and waist circumference (WC). This finding implies that the SNP has strong pleiotropic effects on adiposity and adiposity-independent pathological pathways that leads to increased mortality. To investigate this further, we conducted a meta-analysis of similar data from 34 longitudinal studies including 169,551 adult Caucasians among whom 27,100 died during follow-up. Linear regression showed that the minor allele of the FTO SNP was associated with greater BMI (n = 169,551; 0.32 kg m(-2) ; 95% CI 0.28-0.32, P < 1 × 10(-32) ), WC (n = 152,631; 0.76 cm; 0.68-0.84, P < 1 × 10(-32) ) and FMI (n = 48,192; 0.17 kg m(-2) ; 0.13-0.22, P = 1.0 × 10(-13) ). Cox proportional hazard regression analyses for mortality showed that the hazards ratio (HR) for the minor allele of the FTO SNPs was 1.02 (1.00-1.04, P = 0.097), but the apparent excess risk was eliminated after adjustment for BMI and WC (HR: 1.00; 0.98-1.03, P = 0.662) and for FMI (HR: 1.00; 0.96-1.04, P = 0.932). In conclusion, this study does not support that the FTO SNP is associated with all-cause mortality independently of the adiposity phenotypes.

Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study.

Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based cohorts totaling 47 180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35- to 80-kb upstream from the thyroid-specific transcription factor PAX8 (lowest P=1.1 × 10(-9)). This finding was replicated in an African-American sample of 4771 individuals (lowest P=9.3 × 10(-4)). The strongest combined association was at rs1823125 (P=1.5 × 10(-10), minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.

Association study of the HTR2C, leptin and adiponectin genes and serum marker analyses in clozapine treated long-term patients with schizophrenia.

Clozapine treatment is associated with weight gain and cardio-metabolic consequences among patients with schizophrenia. Polymorphisms of leptin, serotonin receptor HTR2C and adiponectin genes have been associated with antipsychotic-induced weight gain and metabolic comorbidity. However, the results of the studies so far are inconclusive. The aim of the present study was first to test for a possible role of serum leptin and adiponectin levels as a marker of weight gain in association with inflammatory cytokines/adipokines (IL-6, IL-1Ra, hs-CRP and adipsin), and second to study associations between SNPs LEP rs7799039 (-2548 A/G), ADIPOQ rs1501299 and HTR2C rs1414334 and weight gain and levels of leptin and adiponectin, in 190 patients with schizophrenia on clozapine treatment, with retrospectively assessed weight change and cross-sectionally measured cytokine levels. A strong association was found between serum levels of leptin and weight gain and cytokines/adipokines related to metabolic comorbidity, especially among female patients (in women leptin vs. weight gain, IL-6 and IL-1Ra, P<0.001; in men leptin vs. weight gain, P=0.026, leptin vs. IL-1Ra, P<0.001). In male patients low adiponectin level was a more specific marker of clozapine-induced weight gain (P=0.037). The results of the present study do not support a major role of SNPs LEP rs7799039, ADIPOQ rs1501299 and HTR2C rs1414334 in the regulation of weight gain or association of serum levels of leptin and adiponectin and corresponding studied SNPs in patients with schizophrenia on clozapine treatment.

High serum n6 fatty acid proportion is associated with lowered LDL oxidation and inflammation: the Cardiovascular Risk in Young Finns Study.

The intake of polyunsaturated fatty acids (PUFAs) is generally linked with a reduced cardiovascular disease (CVD) risk, but an elevated n6PUFA intake, without simultaneous n3PUFA supply, may elevate the risk. PUFAs are suspected as being easily oxidized and have a potential role in lipoprotein oxidation and inflammation. Saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs) are resistant to oxidation. However, in a Western diet, their most important source is red meat, a food stuff rich in heme iron which can catalyze oxidative reactions. Therefore, different serum fatty acid (FA) proportions (free + esterified) were correlated with the status of low-density lipoprotein (LDL) oxidation in vivo (conjugated dienes = oxLDLlipids and antibody-based oxidized proteins = oxLDLprot) and inflammation (serum CRP) in 2196 Finnish subjects (age: 24-39 years) using CVD risk factor-adjusted linear regression models. High n6PUFA, PUFA/SFA and n6/n3 ratios, and low SFA and MUFA were all associated with reduced levels of oxLDLlipids, oxLDLprot, and CRP. These findings at the population level suggest that PUFAs are negatively and SFAs and MUFAs positively related with LDL oxidation and inflammation; these conclusions are in line with previous observations linking PUFAs, particularly n6PUFAs, with lower CVD risk, and SFAs with increased risk.

Childhood and adult socio-economic position and social mobility as determinants of low back pain outcomes.

BACKGROUND: Low back pain (LBP) is a prevalent problem and tends to be socio-economically patterned. Relatively little is known about life-course socio-economic circumstances as determinants of different types of LBP. Our aim was to examine whether childhood and adult socio-economic position and social mobility are associated with radiating and non-specific LBP and sciatica. METHOD: Data were derived from the Young Finns Study (n = 2231). Childhood socio-economic position was based on parental education, occupational class and family income at baseline in 1980. Data on own education and LBP outcomes were collected at the end of follow-up in 2007. Social mobility was based on parental and own education. Covariates were composed of age, parental body mass index and smoking. RESULTS: Both childhood and own socio-economic position remained associated with radiating LBP and sciatica after adjustments. However, the associations varied by socio-economic indicator and gender. Stable lower socio-economic position and downward mobility were associated with radiating LBP. CONCLUSION: Childhood socio-economic circumstances affect the risk of radiating LBP and sciatica in adulthood. To prevent low back disorders, early socio-economic circumstances need to be considered alongside own socio-economic position.