No interactions between previously associated 2-hour glucose gene variants and physical activity or BMI on 2-hour glucose levels.

Gene-lifestyle interactions have been suggested to contribute to the development of type 2 diabetes. Glucose levels 2 h after a standard 75-g glucose challenge are used to diagnose diabetes and are associated with both genetic and lifestyle factors. However, whether these factors interact to determine 2-h glucose levels is unknown. We meta-analyzed single nucleotide polymorphism (SNP) × BMI and SNP × physical activity (PA) interaction regression models for five SNPs previously associated with 2-h glucose levels from up to 22 studies comprising 54,884 individuals without diabetes. PA levels were dichotomized, with individuals below the first quintile classified as inactive (20%) and the remainder as active (80%). BMI was considered a continuous trait. Inactive individuals had higher 2-h glucose levels than active individuals (β = 0.22 mmol/L [95% CI 0.13-0.31], P = 1.63 × 10(-6)). All SNPs were associated with 2-h glucose (β = 0.06-0.12 mmol/allele, P ≤ 1.53 × 10(-7)), but no significant interactions were found with PA (P > 0.18) or BMI (P ≥ 0.04). In this large study of gene-lifestyle interaction, we observed no interactions between genetic and lifestyle factors, both of which were associated with 2-h glucose. It is perhaps unlikely that top loci from genome-wide association studies will exhibit strong subgroup-specific effects, and may not, therefore, make the best candidates for the study of interactions

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10-5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10-5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10-10, odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression

Lactulose breath test results in patients with persistent abdominal symptoms following giardia lamblia infection

Objective. Bacterial overgrowth has been implicated in the pathogenesis of irritable bowel syndrome (IBS). The objective of this study was to investigate whether post-infectious IBS following Giardia lamblia infection is related to intestinal bacterial overgrowth, as diagnosed by the lactulose breath test (LBT). Material and methods. Seventy-seven patients with persistent gastrointestinal complaints related to a recent outbreak of G. lamblia infection were included in the study. Despite one or several courses of treatment with metronidazole during the previous months, 23 of the patients were still stool positive for G. lamblia, whereas the remaining 54 patients had cleared the infection. All patients and 42 healthy volunteers underwent a LBT with 10 g lactulose, and their customary and post-LBT abdominal symptoms were scored. Results. Ninety-five percent of the patients had IBS. Lactulose-induced hydrogen breath excretion was not significantly different in patients and controls. Customary and post-LBT symptoms were abnormally high in the patients, irrespective of both G. lamblia infection status and LBT results. Furthermore, lactulose challenge replicated the patients' customary complaints in 70% of the patients. Conclusions. Gastrointestinal complaints in patients with persistent or cleared giardiasis were unrelated to hydrogen breath excretion after lactulose challenge. Post-giardiasis IBS cannot be ascribed to intestinal bacterial overgrowth, as diagnosed by LBTMette H. Morken, Gunnar Nysaeter, Elisabeth A. Strand, Trygve Hausken and Arnold Bersta

Monitoring children and adolescents with severe obesity: body mass index (BMI), BMI z-score or percentage above the International Obesity Task Force overweight cut-off?

AIM: Body mass index (BMI) metrics are widely used as a proxy for adiposity in children with severe obesity. The BMI expressed as the percentage of a cut-off percentile for overweight or obesity has been proposed as a better alternative than BMI z-scores when monitoring children and adolescents with severe obesity. METHODS: Annual changes in BMI, BMI z-score and the percentage above the International Obesity Task Force overweight cut-off (%IOTF-25) were compared with dual-energy X-ray absorptiometry (DXA) derived body fat (%BF-DXA) in 59 children and adolescents with severe obesity. RESULTS: The change in %BF-DXA was correlated with the change in %IOTF-25 (r = 0.68) and BMI (r = 0.70), and somewhat less with the BMI z-score (r = 0.57). Cohen's Kappa statistic to detect an increase or decrease in %BF-DXA was fair for %IOTF-25 (κ = 0.25; p = 0.04) and BMI (κ = 0.33; p = 0.01), but not for the BMI z-score (κ = 0.08; p = 0.5). The change in BMI was positively biased due to a natural increase with age. CONCLUSION: Changes in the BMI metrics included in the study are associated differently with changes in %BF-DXA. The BMI z-score is widely used to monitor changes in adiposity in children and adolescents with severe obesity, but the %IOTF-25 might be a better alternative.status: publishe

Abdominal Aortic Aneurysm Is Associated with a Variant in Low-Density Lipoprotein Receptor-Related Protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10−5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10−5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10−10, odds ratio 1.15 [1.10–1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04–1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression