A haplotype at the UCP1 gene locus contributes to genetic risk for type 2 diabetes in Asian Indians (CURES-72)

BACKGROUND: The gene encoding for uncoupling protein-1 (UCP1) is considered to be a candidate gene for type 2 diabetes because of its role in thermogenesis and energy expenditure. The objective of the study was to examine whether genetic variations in the UCP1 gene are associated with type 2 diabetes and its related traits in Asian Indians. METHODS: The study subjects, 810 type 2 diabetic subjects and 990 normal glucose tolerant (NGT) subjects, were chosen from the Chennai Urban Rural Epidemiological Study (CURES), an ongoing population-based study in southern India. The polymorphisms were genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Linkage disequilibrium (LD) was estimated from the estimates of haplotypic frequencies. RESULTS: The three polymorphisms, namely -3826A-->G, an A-->C transition in the 5'-untranslated region (UTR) and Met229Leu, were not associated with type 2 diabetes. However, the frequency of the A-C-Met (-3826A-->G-5'UTR A-->C-Met229Leu) haplotype was significantly higher among the type 2 diabetic subjects (2.67%) compared with the NGT subjects (1.45%, P < 0.01). The odds ratio for type 2 diabetes for the individuals carrying the haplotype A-C-Met was 1.82 (95% confidence interval, 1.29-2.78, P = 0.009). CONCLUSIONS: The haplotype, A-C-Met, in the UCP1 gene is significantly associated with the increased genetic risk for developing type 2 diabetes in Asian Indians.

PPARGC1A sequence variation and cardiovascular risk-factor levels: a study of the main genetic effects and gene x environment interactions in children from the European Youth Heart Study.

AIMS/HYPOTHESIS: The PPARGC1A gene coactivates multiple nuclear transcription factors involved in cellular energy metabolism and vascular stasis. In the present study, we genotyped 35 tagging polymorphisms to capture all common PPARGC1A nucleotide sequence variations and tested for association with metabolic and cardiovascular traits in 2,101 Danish and Estonian boys and girls from the European Youth Heart Study, a multicentre school-based cross-sectional cohort study. METHODS: Fasting plasma glucose concentrations, anthropometric variables and blood pressure were measured. Habitual physical activity and aerobic fitness were objectively assessed using uniaxial accelerometry and a maximal aerobic exercise stress test on a bicycle ergometer, respectively. RESULTS: In adjusted models, nominally significant associations were observed for BMI (rs10018239, p = 0.039), waist circumference (rs7656250, p = 0.012; rs8192678 [Gly482Ser], p = 0.015; rs3755863, p = 0.02; rs10018239, beta = -0.01 cm per minor allele copy, p = 0.043), systolic blood pressure (rs2970869, p = 0.018) and fasting glucose concentrations (rs11724368, p = 0.045). Stronger associations were observed for aerobic fitness (rs7656250, p = 0.005; rs13117172, p = 0.008) and fasting glucose concentrations (rs7657071, p = 0.002). None remained significant after correcting for the number of statistical comparisons. We proceeded by testing for gene x physical activity interactions for the polymorphisms that showed nominal evidence of association in the main effect models. None of these tests was statistically significant. CONCLUSIONS/INTERPRETATION: Variants at PPARGC1A may influence several metabolic traits in this European paediatric cohort. However, variation at PPARGC1A is unlikely to have a major impact on cardiovascular or metabolic health in these children.

Association of lipoprotein lipase gene polymorphisms with obesity and type 2 diabetes in an Asian Indian population

AIMS: Lipoprotein lipase (LPL), a pivotal enzyme in lipoprotein metabolism, catalyzes the hydrolysis of triglycerides of very low-density lipoproteins and chylomicrons. Assuming that the variants in the promoter of the LPL gene may be associated with changes in lipid metabolism leading to obesity and type 2 diabetes, we examined the role of promoter variants (-T93G and -G53C) in the LPL gene in an urban South Indian population. METHODS: The study subjects (619 type 2 diabetic and 731 normal glucose-tolerant (NGT) subjects) were chosen from the Chennai Urban Rural Epidemiology Study, an ongoing population-based study in southern India. The polymorphisms were genotyped using polymerase chain reaction-restriction-fragment length polymorphism (PCR-RFLP). Linkage disequilibrium (LD) was estimated from the estimates of haplotypic frequencies. RESULTS: The two polymorphisms studied were not in LD. The -T93G was not associated with type 2 diabetes but was associated with obesity. 11.5% of the obese subjects (62/541) had the XG(TG+GG) genotype compared with 6.4% of the nonobese subjects (52/809; P=0.001). The odds ratio for obesity for the XG genotype was 1.766 (95% CI: 1.19-2.63, P=0.005). Subjects with XG genotype also had higher body mass index and waist circumference compared with those with TT genotype. With respect to G53C, subjects with the XC(GC+CC) genotype had 0.527 and 0.531 times lower risk for developing type 2 diabetes and obesity, respectively. CONCLUSIONS: Among Asian Indians, the -T93G SNP of the LPL gene is associated with obesity but not type 2 diabetes, whereas the -G53C SNP appears to be protective against both obesity and type 2 diabetes.

Role of genetic polymorphism peroxisome proliferator-activated receptor-gamma2 Pro12Ala on ethnic susceptibility to diabetes in South-Asian and Caucasian subjects: Evidence for heterogeneity

OBJECTIVE: To determine whether the peroxisome proliferator-activated receptor (PPAR)-gamma Pro12ala polymorphism modulates susceptibility to diabetes in South Asians. RESEARCH DESIGN AND METHODS: South Asians (n = 697) and Caucasians (n = 457) living in Dallas/Forth Worth, Texas, and South Asians living in Chennai, India (n = 1,619), were enrolled for this study. PPAR-gamma Pro12Ala was determined using restriction fragment-length polymorphism. Insulin responsiveness to an oral glucose tolerance test (OGTT) was measured in nondiabetic subjects. RESULTS: The Caucasian diabetic subjects had significantly lower prevalence of PPAR-gamma 12Ala when compared with the Caucasian nondiabetic subjects (20 vs. 9%, P = 0.006). However, there were no significant differences between diabetic and nondiabetic subjects with reference to the Pro12Ala polymorphism among the South Asians living in Dallas (20 vs. 23%) and in India (19 vs. 19.3%). Although Caucasians carrying PPAR-gamma Pro12Ala had lower plasma insulin levels at 2 h of OGTT than the wild-type (Pro/Pro) carriers (76 +/- 68 and 54 +/- 33 microU/ml, respectively, P = 0.01), no differences in either fasting or 2-h plasma insulin concentrations were found between South Asians carrying the PPAR-gamma Pro12Ala polymorphism and those with the wild-type genotype at either Chennai or Dallas. CONCLUSIONS: Although further replication studies are necessary to test the validity of the described genotype-phenotype relationship, our study supports the hypothesis that the PPAR-gamma Pro12Ala polymorphism is protective against diabetes in Caucasians but not in South Asians.

Peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PGC-1alpha) gene polymorphisms and their relationship to Type 2 diabetes in Asian Indians

AIMS: The objective of the present investigation was to examine the relationship of three polymorphisms, Thr394Thr, Gly482Ser and +A2962G, of the peroxisome proliferator activated receptor-gamma co-activator-1 alpha (PGC-1alpha) gene with Type 2 diabetes in Asian Indians. METHODS: The study group comprised 515 Type 2 diabetic and 882 normal glucose tolerant subjects chosen from the Chennai Urban Rural Epidemiology Study, an ongoing population-based study in southern India. The three polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Haplotype frequencies were estimated using an expectation-maximization (EM) algorithm. Linkage disequilibrium was estimated from the estimates of haplotypic frequencies. RESULTS: The three polymorphisms studied were not in linkage disequilibrium. With respect to the Thr394Thr polymorphism, 20% of the Type 2 diabetic patients (103/515) had the GA genotype compared with 12% of the normal glucose tolerance (NGT) subjects (108/882) (P = 0.0004). The frequency of the A allele was also higher in Type 2 diabetic subjects (0.11) compared with NGT subjects (0.07) (P = 0.002). Regression analysis revealed the odds ratio for Type 2 diabetes for the susceptible genotype (XA) to be 1.683 (95% confidence intervals: 1.264-2.241, P = 0.0004). Age adjusted glycated haemoglobin (P = 0.003), serum cholesterol (P = 0.001) and low-density lipoprotein (LDL) cholesterol (P = 0.001) levels and systolic blood pressure (P = 0.001) were higher in the NGT subjects with the XA genotype compared with GG genotype. There were no differences in genotype or allelic distribution between the Type 2 diabetic and NGT subjects with respect to the Gly482Ser and +A2962G polymorphisms. CONCLUSIONS: The A allele of Thr394Thr (G --> A) polymorphism of the PGC-1 gene is associated with Type 2 diabetes in Asian Indian subjects and the XA genotype confers 1.6 times higher risk for Type 2 diabetes compared with the GG genotype in this population.

Visceral and central abdominal fat and anthropometry in relation to diabetes in Asian Indians

OBJECTIVE: The objective of the study was to examine body fat distribution using computed tomography (CT), dual-energy X-ray absorptiometry (DEXA), and anthropometry in relation to type 2 diabetes in urban Asian Indians. RESEARCH DESIGN AND METHODS: This is a case-control study of 82 type 2 diabetic and 82 age- and sex-matched nondiabetic subjects from the Chennai Urban Rural Epidemiology Study, an ongoing epidemiological study in southern India. Visceral, subcutaneous, and total abdominal fat were measured using CT, while DEXA was used to measure central abdominal and total body fat. Anthropometric measures included BMI, waist circumference, sagittal abdominal diameter (SAD), and waist-to-hip ratio. RESULTS: Visceral and central abdominal fat showed a strong correlation with each other (P <0.0001), and kappa analysis revealed a fairly good agreement between tertiles of visceral and central abdominal fat (kappa=0.44, P <0.0001). Diabetic subjects had significantly higher visceral (P=0.005) and central abdominal (P=0.011) fat compared with nondiabetic subjects. Waist circumference and SAD showed a strong correlation with visceral (P <0.01) and central abdominal (P <0.0001) fat in both diabetic and nondiabetic subjects. Logistic regression analysis revealed visceral (odds ratio [OR] 1.011, P=0.004) and central abdominal (OR 1.001, P=0.013) fat to be associated with diabetes, even after adjusting for age and sex. CONCLUSIONS: Visceral and central abdominal fat showed a strong association with type 2 diabetes. Both measures correlated well with each other and with waist circumference and SAD in diabetic and nondiabetic urban Asian Indians.

Deficits in orthographic knowledge in children poor at rapid automatized naming (RAN) tasks?

The degree to which orthographic knowledge accounts for the link between Rapid Automatized Naming (RAN) and reading is contested, with mixed results reported. This longitudinal study compared two groups of 10-11 year old children, a low RAN group (N=69) and matched controls (N=74) on various measures of orthographic knowledge. The low RAN group showed a deficit in orthographic knowledge, both at the level of sub-word letter sequences and of whole words, as well as an unexpected strength in orthographic learning. Our findings underline the persistence of RAN-related reading problems, and raise questions about reading strategies in this group.

Assessment and management of anxiety disorders in children and adolescents

Anxiety disorders in childhood and adolescence are extremely common and are often associated with lifelong psychiatric disturbance. Consistent with DSM-5 and the extant literature, this review concerns the assessment and treatment of specific phobias, separation anxiety disorder, generalised anxiety disorder, social anxiety disorder, panic disorder and agoraphobia. Evidence-based psychological treatments (cognitive behaviour therapy; CBT) for these disorders have been developed and investigated, and in recent years promising low-intensity versions of CBT interventions have been proposed that offer a means to increase access to evidence-based treatments. There is some evidence of effectiveness of pharmacological treatments for anxiety disorders in children and young people, however, routine prescription is not recommended due to concerns about potential harm.

Emotional and behavioural problems in children with language impairments and children with autism spectrum disorders

Background: Although it is well-established that children with language impairment (LI) and children with autism spectrum disorders (ASD) both show elevated levels of emotional and behavioural problems, the level and types of difficulties across the two groups have not previously been directly compared. Aims: To compare levels of emotional and behavioural problems in children with LI and children with ASD recruited from the same mainstream schools. Methods & Procedures: We measured teacher-reported emotional and behavioural problems using the Strengths and Difficulties Questionnaire (SDQ) in a sample of 5-to-13-year old children with LI (N=62) and children with ASD (N=42) attending mainstream school but with identified special educational needs. Outcomes & Results: Both groups showed similarly elevated levels of emotional, conduct and hyperactivity problems. The only differences between the LI and ASD groups were on subscales assessing peer problems (which were higher in the ASD group) and prosocial behaviours (which were higher in the LI group). Overall, there were few associations between emotional and behavioural problems and child characteristics, reflecting the pervasive nature of these difficulties in children with LI and children with ASD, although levels of problems were higher in children with ASD with lower language ability. However, in the ASD group only, a measure of family social economic status was associated with language ability and attenuated the association between language ability and emotional and behavioural problems. Conclusions & Implications: Children with LI and children with ASD in mainstream school show similarly elevated levels of emotional and behavioural problems, which require monitoring and may benefit from intervention. Further work is required to identify the child, family and situational factors that place children with LI and children with ASD at risk of emotional and behavioural problems, and whether these differ between the two groups. This work can then guide the application of evidence-based interventions to these children.

Restrictive feeding practices and adiposity are differentially related to P3b cortical responses to food stimuli in children

Across two studies, we examined the association between adiposity, restrictive feeding practices and cortical processing bias to food stimuli in children. We assessed P3b event-related potential (ERP) during visual oddball tasks in which the frequently presented stimulus was non-food and the infrequently presented stimulus was either a food (Study 1) or non-food (Study 2) item. Children responded to the infrequently presented stimulus and accuracy and speed responses were collected. Restrictive feeding practices, children's height and weight were also measured. In Study 1, the difference in P3b amplitude for infrequently presented food stimuli, relative to frequently presented non-food stimuli, was negatively associated with adiposity and positively associated with restrictive feeding practices after controlling for adiposity. There was no association between P3b amplitude difference and adiposity or restriction in Study 2, suggesting that the effects seen in Study 1 were not due to general attentional processes. Taken together, our results suggest that attentional salience, as indexed by the P3b amplitude, may be important for understanding the neural correlates of adiposity and restrictive feeding practices in children.

The experience of friendship, victimization and bullying in children with an autism spectrum disorder: associations with child characteristics and school placement

Children with an autism spectrum disorder (ASD) may be vulnerable to social isolation and bullying. We measured the friendship, fighting/bullying and victimization experiences of 10–12-year-old children with an ASD (N = 100) using parent, teacher and child self-report. Parent and teacher reports were compared to an IQ-matched group of children with special educational needs (SEN) without ASD (N = 80) and UK population data. Parents and teachers reported a lower prevalence of friendships compared to population norms and to children with SEN without an ASD. Parents but not teachers reported higher levels of victimization than the SEN group. Half of the children with an ASD reported having friendships that involved mutuality. By teacher report children with an ASD who were less socially impaired in mainstream school experienced higher levels of victimization than more socially impaired children; whereas for more socially impaired children victimization did not vary by school placement. Strategies are required to support and improve the social interaction skills of children with an ASD, to enable them to develop and maintain meaningful peer friendships and avoid victimization.

Parent-reported gastro-intestinal symptoms in children with autism spectrum disorders

The objective of this study is to investigate whether parentally-reported gastro-intestinal (GI) symptoms are increased in a population-derived sample of children with autism spectrum disorders (ASD) compared to controls. Participants included 132 children with ASD and 81 with special educational needs (SEN) but no ASD, aged 10-14 years plus 82 typically developing (TD) children. Data were collected on GI symptoms, diet, cognitive abilities, and developmental histories. Nearly half (weighted rate 46.5 %) of children with ASD had at least one individual lifetime GI symptom compared with 21.8 % of TD children and 29.2 % of those with SEN. Children with ASD had more past and current GI symptoms than TD or SEN groups although fewer current symptoms were reported in all groups compared with the past. The ASD group had significantly increased past vomiting and diarrhoea compared with the TD group and more abdominal pain than the SEN group. The ASD group had more current constipation (when defined as bowel movement less than three times per week) and soiling than either the TD or SEN groups. No association was found between GI symptoms and intellectual ability, ASD severity, ASD regression or limited or faddy diet. Parents report more GI symptoms in children with ASD than children with either SEN or TD children but the frequency of reported symptoms is greater in the past than currently in all groups.

Computerised therapies for anxiety and depression in children and young people: a systematic review and meta-anaylsis

One quarter of children and young people (CYP) experience anxiety and/or depression before adulthood, but treatment is sometimes unavailable or inadequate. Self-help interventions may have a role in augmenting treatment and this work aimed to systematically review the evidence for computerised anxiety and depression interventions in CYP aged 5–25 years old. Databases were searched for randomised controlled trials and 27 studies were identified. For young people (12–25 years) with risk of diagnosed anxiety disorders or depression, computerised CBT (cCBT) had positive effects for symptoms of anxiety (SMD −0.77, 95% CI −1.45 to −0.09, k = 6, N = 220) and depression (SMD −0.62, 95% CI −1.13 to −0.11, k = 7, N = 279). In a general population study of young people, there were small positive effects for anxiety (SMD −0.15, 95% CI −0.26 to −0.03; N = 1273) and depression (SMD −0.15, 95% CI −0.26 to −0.03; N = 1280). There was uncertainty around the effectiveness of cCBT in children (5–11 years). Evidence for other computerised interventions was sparse and inconclusive. Computerised CBT has potential for treating and preventing anxiety and depression in clinical and general populations of young people. Further program development and research is required to extend its use and establish its benefit in children.

Serotonin transporter [corrected] methylation and response to cognitive behaviour therapy in children with anxiety disorders

Anxiety disorders that are the most commonly occurring psychiatric disorders in childhood, are associated with a range of social and educational impairments and often continue into adulthood. Cognitive behaviour therapy (CBT) is an effective treatment option for the majority of cases, although up to 35-45% of children do not achieve remission. Recent research suggests that some genetic variants may be associated with a more beneficial response to psychological therapy. Epigenetic mechanisms such as DNA methylation work at the interface between genetic and environmental influences. Furthermore, epigenetic alterations at the serotonin transporter (SERT) promoter region have been associated with environmental influences such as stressful life experiences. In this study, we measured DNA methylation upstream of SERT in 116 children with an anxiety disorder, before and after receiving CBT. Change during treatment in percentage DNA methylation was significantly different in treatment responders vs nonresponders. This effect was driven by one CpG site in particular, at which responders increased in methylation, whereas nonresponders showed a decrease in DNA methylation. This is the first study to demonstrate differences in SERT methylation change in association with response to a purely psychological therapy. These findings confirm that biological changes occur alongside changes in symptomatology following a psychological therapy such as CBT.

Maternal antenatal anxiety, postnatal stroking and emotional problems in children: outcomes predicted from pre and postnatal programming hypotheses

Background Mothers' self-reported stroking of their infants over the first weeks of life modifies the association between prenatal depression and physiological and emotional reactivity at 7 months, consistent with animal studies of the effects of tactile stimulation. We now investigate whether the effects of maternal stroking persist to 2.5 years. Given animal and human evidence for sex differences in the effects of prenatal stress we compare associations in boys and girls. Method From a general population sample of 1233 first-time mothers recruited at 20 weeks gestation we drew a random sample of 316 for assessment at 32 weeks, stratified by reported inter-partner psychological abuse, a risk indicator for child development. Of these mothers, 243 reported at 5 and 9 weeks how often they stroked their infants, and completed the Child Behavior Checklist (CBCL) at 2.5 years post-delivery. Results There was a significant interaction between prenatal anxiety and maternal stroking in the prediction of CBCL internalizing (p = 0.001) and anxious/depressed scores (p < 0.001). The effects were stronger in females than males, and the three-way interaction prenatal anxiety × maternal stroking × sex of infant was significant for internalizing symptoms (p = 0.003). The interactions arose from an association between prenatal anxiety and internalizing symptoms only in the presence of low maternal stroking. Conclusions The findings are consistent with stable epigenetic effects, many sex specific, reported in animal studies. While epigenetic mechanisms may be underlying the associations, it remains to be established whether stroking affects gene expression in humans.