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The prevalence of type 2 diabetes (T2D) is rapidly increasing worldwide. Although genome-wide association studies have identified polymorphisms contributing to the risk of T2D, a person's lifestyle is a key [...], To identify epigenetic patterns, which may predispose to type 2 diabetes (T2D) due to a family history (FH) of the disease, we analyzed DNA methylation genome-wide in skeletal muscle from individuals with ([FH.sup.+]) or without ([FH.sup.-]) an FH of T2D. We found differential DNA methylation of genes in biological pathways including mitogen-activated protein kinase (MAPK), insulin, and calcium signaling (P ≤ 0.007) and of individual genes with known function in muscle, including MAPK1, MYO18B, HOXC6, and the AMP-activated protein kinase subunit PRKAB1 in skeletal muscle of [FH.sup.+] compared with [FH.sup.-] men. We further validated our findings from [FH.sup.+] men in monozygotic twin pairs discordant for T2D, and 40% of 65 analyzed genes exhibited differential DNA methylation in muscle of both [FH.sup.+] men and diabetic twins. We further examined if a 6-month exercise intervention modifies the genome-wide DNA methylation pattern in skeletal muscle of the [FH.sup.+] and [FH.sup.-] individuals. DNA methylation of genes in retinol metabolism and calcium signaling pathways (P < 3 x [10.sup.-6]) and with known functions in muscle and T2D including MEF2A, RUNX1, NDUFC2, and THADA decreased after exercise. Methylation of these human promoter regions suppressed reporter gene expression in vitro. In addition, both expression and methylation of several genes, i.e., ADIPOR1, BDKRB2, and TRIB1, changed after exercise. These findings provide new insights into how genetic background and environment can alter the human epigenome.

Obesity and type 2 diabetes are heterogenous disorders caused by both nongenetic and genetic components. Recent studies identified common variants in FTO (the fat mass--and obesity-associated gene) to be associated [...], OBJECTIVE--Common variants in FTO (the fat mass- and obesity-associated gene) associate with obesity and type 2 diabetes. The regulation and biological function of FTO mRNA expression in target tissue is unknown. We investigated the genetic and nongenetic regulation of FTO mRNA in skeletal muscle and adipose tissue and their influence on in vivo glucose and fat metabolism. RESEARCH DESIGN AND METHODS--The FTO rs9939609 polymorphism was genotyped in two twin cohorts: 1) 298 elderly twins aged 62-83 years with glucose tolerance ranging from normal to type 2 diabetes and 2) 196 young (25-32 years) and elderly (58-66 years) nondiabetic twins examined by a hyperinsulinemic-euglycemic clamp including indirect calorimetry. FTO mRNA expression was determined in subcutaneous adipose tissue (n = 226) and skeletal muscle biopsies (n = 158). RESULTS--Heritability of FTO expression in both tissues was low, and FTO expression was not influenced by FTO rs9939609 genotype. FTO mRNA expression in skeletal muscle was regulated by age and sex, whereas age and BMI were predictors of adipose tissue FTO mRNA expression. FTO mRNA expression in adipose tissue was associated with an atherogenic lipid profile. In skeletal muscle, FTO mRNA expression was negatively associated to fat and positively to glucose oxidation rates as well as positively correlated with expression of genes involved in oxidative phosphorylation including PGC1α. CONCLUSIONS--The heritability of FTO expression in adipose tissue and skeletal muscle is low and not influenced by obesity-associated FTO genotype. The age-dependent decline in FTO expression is associated with peripheral defects of glucose and fat metabolism.

Ticks are important vectors of infectious emerging diseases and tick-borne phleboviruses represent a growing threat to humans globally. We employed here a high-resolution, label-free mass spectrometry and RNA interference screen approach to reveal the host cell protein GBF1 as a proviral factor, not only for tick-borne phleboviruses, but also for many other important zoonotic RNA viruses. This study lays the basis for the development of innovative antiviral strategies against a broad range of human pathogenic viruses.

Insulin resistance in skeletal muscle is a major risk factor for the development of type 2 diabetes in women with polycystic ovary syndrome (PCOS). Despite this, the mechanisms underlying insulin resistance in PCOS are largely unknown.

An increasing number of older people in the population will bring new challenges for the society and care coordination. One of the most important questions in care coordination is the employees’ work performance. The overall aim of this study was to examine care employees’ experience of factors that rule how they allocate their time and tasks in the care work. The study was qualitative and consists of focus group interviews with 36 employees in elderly care in five Swedish municipalities. Much of the work that care employees perform is controlled by others in the municipality organised health care. The employees had a limited possibility to decide what should be given priority in their work. However, the employees who participated in the focus group interviews did not want to prioritise tasks and duties they felt were faulty or in direct conflict with their own convictions. When employees experienced that the assistance assessments were correct and helpful to the individual elderly patient this contributed to the employees’ priority and performance of the task. The formal and informal control systems caused the employees’ priority to be mainly quantitative and visible work tasks, rather than more qualitative tasks and care giving to the elderly. In the intention to organise good care coordination that fit each elderly patients’ need it is important that those who work closest to the patient to a greater extent are given the opportunity to make their voice heard in decisions of care planning and assistance assessments.

ABSTRACTBoth genetic and lifestyle factors contribute to the risk of non-alcoholic steatohepatitis (NASH). Additionally, epigenetic modifications may also play a key role in the pathogenesis of NASH. We therefore investigated liver DNA methylation, as a marker for epigenetic alterations, in individuals with simple steatosis and NASH, and further tested if these alterations were associated with clinical phenotypes. Liver biopsies obtained from 95 obese individuals (age: 49.5 ± 7.7 years, BMI: 43 ± 5.7 kg/m2, type 2 diabetes [T2D]: 35) as a wedge biopsy during a Roux-en-Y gastric bypass operation were investigated. Thirty-four individuals had a normal liver phenotype, 35 had simple steatosis, and 26 had NASH. Genome-wide DNA methylation pattern was analyzed using the Infinium HumanMethylation450 BeadChip. mRNA expression was analyzed from 42 individuals using the HumanHT-12 Expression BeadChip. We identified 1,292 CpG sites representing 677 unique genes differentially methylated in liver of individuals with NASH (q < 0.001), independently of T2D, age, sex, and BMI. Focusing on the top-ranking 30 and another 37 CpG sites mapped to genes enriched in pathways of metabolism (q = 0.0036) and cancer (q = 0.0001) all together, 59 NASH-associated CpG sites correlated with fasting insulin levels independently of age, fasting glucose, or T2D. From these, we identified 30 correlations between DNA methylation and mRNA expression, for example LDHB(r = −0.45, P= 0.003). We demonstrated that NASH, more than simple steatosis, associates with differential DNA methylation in the human liver. These epigenetic alterations in NASH are linked with insulin metabolism.

ABSTRACTIdentification of subjects with a high risk of developing type 2 diabetes (T2D) is fundamental for prevention of the disease. Consequently, it is essential to search for new biomarkers that can improve the prediction of T2D. The aim of this study was to examine whether 5 DNA methylation loci in blood DNA (ABCG1, PHOSPHO1, SOCS3, SREBF1, and TXNIP), recently reported to be associated with T2D, might predict future T2D in subjects from the Botnia prospective study. We also tested if these CpG sites exhibit altered DNA methylation in human pancreatic islets, liver, adipose tissue, and skeletal muscle from diabetic vs. non-diabetic subjects. DNA methylation at the ABCG1locus cg06500161 in blood DNA was associated with an increased risk for future T2D (OR = 1.09, 95% CI = 1.02–1.16, P-value = 0.007, Q-value = 0.018), while DNA methylation at the PHOSPHO1locus cg02650017 in blood DNA was associated with a decreased risk for future T2D (OR = 0.85, 95% CI = 0.75–0.95, P-value = 0.006, Q-value = 0.018) after adjustment for age, gender, fasting glucose, and family relation. Furthermore, the level of DNA methylation at the ABCG1locus cg06500161 in blood DNA correlated positively with BMI, HbA1c, fasting insulin, and triglyceride levels, and was increased in adipose tissue and blood from the diabetic twin among monozygotic twin pairs discordant for T2D. DNA methylation at the PHOSPHO1locus cg02650017 in blood correlated positively with HDL levels, and was decreased in skeletal muscle from diabetic vs. non-diabetic monozygotic twins. DNA methylation of cg18181703 (SOCS3), cg11024682 (SREBF1), and cg19693031 (TXNIP) was not associated with future T2D risk in subjects from the Botnia prospective study.

Objective:Epigenetic variation may contribute to the development of complex metabolic diseases such as type 2 diabetes (T2D). Hepatic insulin resistance is a hallmark of T2D. However, it remains unknown whether epigenetic alterations take place in the liver from diabetic subjects. Therefore, we investigated the genome-wide DNA methylation pattern in the liver from subjects with T2D and nondiabetic controls and related epigenetic alterations to gene expression and circulating folate levels.Research Design and Methods:Liver biopsies were obtained from 35 diabetic and 60 nondiabetic subjects, which are part of the Kuopio Obesity Surgery Study. The genome-wide DNA methylation pattern was analyzed in the liver using the HumanMethylation450 BeadChip. RNA expression was analyzed from a subset of subjects using the HumanHT-12 Expression BeadChip.Results:After correction for multiple testing, we identified 251 individual CpG sites that exhibit differential DNA methylation in liver obtained from T2D compared with nondiabetic subjects (Q< .05). These include CpG sites annotated to genes that are biologically relevant to the development of T2D such as GRB10, ABCC3, MOGAT1,and PRDM16. The vast majority of the significant CpG sites (94%) displayed decreased DNA methylation in liver from subjects with T2D. The hypomethylation found in liver from diabetic subjects may be explained by reduced folate levels. Indeed, subjects with T2D had significantly reduced erythrocyte folate levels compared with nondiabetic subjects. We further identified 29 genes that displayed both differential DNA methylation and gene expression in human T2D liver including the imprinted gene H19.Conclusions:Our study highlights the importance of epigenetic and transcriptional changes in the liver from subjects with T2D. Reduced circulating folate levels may provide an explanation for hypomethylation in the human diabetic liver.

BACKGROUND:The risk for congenital malformations is increased in infants born after in vitro fertilization IVF. Some specific malformations appear to be more affected than others.METHODS:The presence of congenital malformations in 15,570 infants born after IVF with an embryo transfer between April 1, 2001, and the end of 2006 were compared with all infants born in Sweden during 2001 to 2007 n 689,157. Risk estimates were made after adjusting for year of birth, maternal age, parity, smoking, and body mass index. The risks of specific malformations were compared with data from a previous study 1982 to March 31, 2001 of 16,280 infants born after IVF. Different IVF methods were compared to respect to malformation risk.RESULTS:Increased risks of a similar magnitude were found for most cardiovascular malformations and limb reduction defects for both study periods. For neural tube defects, cardiac septal defects, and esophageal atresia, there was still an increased risk, but it was lower during the second than during the first period. For small bowel atresia, anal atresia, and hypospadias, the risk increase observed during the first study period had disappeared during the second period. An increased risk was seen for some syndromes that have been associated with imprinting errors. No difference in malformation risk according to IVF method was apparent.CONCLUSIONS:A slightly increased risk for congenital malformations after IVF persists. A decreasing risk is seen for some specific malformations, either true or the result of multiple testing. Birth Defects Research Part A, 2010. © 2010 WileyLiss, Inc.

The upstream transcription factor 1 (USF1) gene is associated with familial combined hyperlipidemia, the most common genetic dyslipidemia in humans, as well as with various dyslipidemic changes in numerous other studies. Typical of complex disease-associated genes, neither the explicit mutations have been described nor the functional consequences for risk allele carriers been reported at the cellular or tissue level.

AbstractObstetric complications increase the risk of schizophrenia. However, it is not known whether there is a causal relation or whether the association is mediated by genetic and/or shared environmental effects. The aim of this study was to investigate the associations between birthweight, other birth characteristics, and schizophrenia. Twin pairs discordant for schizophrenia will also control for unmeasured genetic and shared environmental effects. Prospectively filed obstetric records were used for a cohort analysis of 11,360 same-sexed twins, and within?twin pair analyses were conducted on 90 twin pairs discordant for schizophrenia. The results from the cohort study showed that low birthweight (less than or equal to 1999 grams; odds ratio [OR] 1.67, 95% confidence interval [CI] 0.88?3.14 and 2000?2299 grams; OR 1.79, 95% CI 1.07?3.01) and small head circumference (less than or equal to 31.5 cm; OR 1.61, 95% CI 1.03?2.51) were associated with later development of schizophrenia. The associations remained in the within-pair analyses. The association between low birthweight and schizophrenia is partly a function of reduced fetal growth. Fetal growth restriction seems to be associated with risk of schizophrenia independently of familial factors.

Aims Normal values of left ventricular mass (LVM) and cardiac chamber sizes are prerequisites for the diagnosis of individuals with heart disease. LVM and cardiac chamber sizes may be recorded during cardiac computed tomography angiography (CCTA), and thus modality specific normal values are needed. Methods and results We studied 569 healthy subjects undergoing 320-detector CCTA as a part of the Copenhagen General Population Study. LVM as well as ventricular and atrial volumes was assessed with semi-automated software stratified by gender and age decades and indexed by body surface area (BSA). Mean age was 55 (range: 40–84) years, and 188 (33%) were men. BSA-indexed 97.5th percentile cut-off values: LVM = 80 and 65 gr/m2, left ventricular volume = 97 and 83 mL/m2, right ventricular volume = 120 and 102 mL/m2, left atrial volume = 60 and 57 mL/m2, and right atrial volume = 85 and 73 mL/m2 for men and women, respectively. Men had greater absolute and indexed LVM and chamber volumes than women. For both genders, indexed ventricular volumes declined, whereas indexed atrial volumes increased in advancing age groups. For men, indexed LVM declined in advancing age groups. In multivariate analyses, gender, BSA, systolic blood pressure, and hard physical activity accounted for 63% of variance in LVM. Conclusion In this cross-sectional general population study, men have greater indexed LVM and chamber volumes than women, and cardiac indexed volumes vary between age groups in both genders. These findings demonstrate the need for age- and gender-specific normal values for clinical diagnostic purposes.

Dystocia, a prolonged and difficult labor, complicates from 3% to 8% of all deliveries worldwide. There is evidence of familial aggregation of the disorder, prompting this population-based retrospective study using registry information on dystocia in sisters and mothers. The goal was to detect any genetic influences on susceptibility to dystocia. The study group included 2,539,534 births taking place in Sweden from 1973 through 1997. Relationships between sibling and mother–daughter pairs were examined, and model fitting served to estimate the relative contributions of genetic and environmental factors to dystocia.