Effects of genetic loci associated with central obesity on adipocyte lipolysis

Objectives: Numerous genetic loci have been associated with measures of central fat accumulation, such as waist-to-hip ratio adjusted for body mass index (WHRadjBMI). However the mechanisms by which genetic variations influence obesity remain largely elusive. Lipolysis is a key process for regulation of lipid storage in adipocytes, thus is implicated in obesity and its metabolic complications. Here, genetic variants at 36 WHRadjBMI-associated loci were examined for their influence on abdominal subcutaneous adipocyte lipolysis. Subjects and Methods: Fasting subcutaneous adipose tissue biopsies were collected from 789 volunteers (587 women and 202 men, body mass index (BMI) range 17.7–62.3 kg/m2). We quantified subcutaneous adipocyte lipolysis, both spontaneous and stimulated by the catecholamine isoprenaline or a cyclic AMP analogue. DNA was extracted from peripheral blood mononuclear cells and genotyping of SNPs associated with WHRadjBMI conducted. The effects on adipocyte lipolysis measures were assessed for SNPs individually and combined in a SNP score. Results: The WHRadjBMI-associated loci CMIP, PLXND1, VEGFA and ZNRF3-KREMEN1 demonstrated nominal associations with spontaneous and/or stimulated lipolysis. Candidate genes in these loci have been reported to influence NFκB-signaling, fat cell size and Wnt signalling, all of which may influence lipolysis. Significance: This report provides evidence for specific WHRadjBMI-associated loci as candidates to modulate adipocyte lipolysis. Additionally, our data suggests that genetically increased central fat accumulation is unlikely to be a major cause of altered lipolysis in abdominal adipocytes

Gene-Gene Interaction between APOA5 and USF1: Two Candidate Genes for the Metabolic Syndrome

Objective: The metabolic syndrome, a major cluster of risk factors for cardiovascular diseases, shows increasing prevalence worldwide. Several studies have established associations of both apolipoprotein A5 (APOA5) gene variants and upstream stimulatory factor 1 (USF1) gene variants with blood lipid levels and metabolic syndrome. USF1 is a transcription factor for APOA5. Methods: We investigated a possible interaction between these two genes on the risk for the metabolic syndrome, using data from the German population-based KORA survey 4 (1,622 men and women aged 55-74 years). Seven APOA5 single nucleotide polymorphisms (SNPs) were analyzed in combination with six USF1 SNPs, applying logistic regression in an additive model adjusting for age and sex and the definition for metabolic syndrome from the National Cholesterol Education Program's Adult Treatment Panel III (NCEP (AIII)) including medication. Results: The overall prevalence for metabolic syndrome was 41%. Two SNP combinations showed a nominal gene-gene interaction (p values 0.024 and 0.047). The effect of one SNP was modified by the other SNP, with a lower risk for the metabolic syndrome with odds ratios (ORs) between 0.33 (95% CI = 0.13-0.83) and 0.40 (95% CI = 0.15-1.12) when the other SNP was homozygous for the minor allele. Nevertheless, none of the associations remained significant after correction for multiple testing. Conclusion: Thus, there is an indication of an interaction between APOA5 and USF1 on the risk for metabolic syndrome

Cereulide synthetase gene cluster from emetic Bacillus cereus: Structure and location on a mega virulence plasmid related to Bacillus anthracis toxin plasmid pXO1

BACKGROUND: Cereulide, a depsipeptide structurally related to valinomycin, is responsible for the emetic type of gastrointestinal disease caused by Bacillus cereus. Recently, it has been shown that this toxin is produced by a nonribosomal peptide synthetase (NRPS), but its exact genetic organization and biochemical synthesis is unknown. RESULTS: The complete sequence of the cereulide synthetase (ces) gene cluster, which encodes the enzymatic machinery required for the biosynthesis of cereulide, was dissected. The 24 kb ces gene cluster comprises 7 CDSs and includes, besides the typical NRPS genes like a phosphopantetheinyl transferase and two CDSs encoding enzyme modules for the activation and incorporation of monomers in the growing peptide chain, a CDS encoding a putative hydrolase in the upstream region and an ABC transporter in the downstream part. The enzyme modules responsible for incorporation of the hydroxyl acids showed an unusual structure while the modules responsible for the activation of the amino acids Ala and Val showed the typical domain organization of NRPS. The ces gene locus is flanked by genetic regions with high homology to virulence plasmids of B. cereus, Bacillus thuringiensis and Bacillus anthracis. PFGE and Southern hybridization showed that the ces genes are restricted to emetic B. cereus and indeed located on a 208 kb megaplasmid, which has high similarities to pXO1-like plasmids. CONCLUSION: The ces gene cluster that is located on a pXO1-like virulence plasmid represents, beside the insecticidal and the anthrax toxins, a third type of B. cereus group toxins encoded on megaplasmids. The ces genes are restricted to emetic toxin producers, but pXO1-like plasmids are also present in emetic-like strains. These data might indicate the presence of an ancient plasmid in B. cereus which has acquired different virulence genes over time. Due to the unusual structure of the hydroxyl acid incorporating enzyme modules of Ces, substantial biochemical efforts will be required to dissect the complete biochemical pathway of cereulide synthesis

BMI at Age 8 Years Is Influenced by the Type 2 Diabetes Susceptibility Genes HHEX-IDE and CDKAL1

OBJECTIVE: To determine whether HHEX-IDE and CDKAL1 genes, which are associated with birth weight and susceptibility to type 2 diabetes, continue to influence growth during childhood. RESEARCH DESIGN AND METHODS: BMI, weight, and height at age 8 years expressed as age- and sex-corrected standard deviation scores (SDS) against national reference data and single-nucleotide polymorphism genotyping of HHEX-IDE and CDKAL1 loci were analyzed in 646 prospectively followed children in the German BABYDIAB cohort. All children were singleton full-term births; 386 had mothers with type 1 diabetes, and 260 had fathers with type 1 diabetes and a nondiabetic mother. RESULTS: Type 2 diabetes risk alleles at the HHEX-IDE locus were associated with reduced BMI-SDS at age 8 years (0.17 SDS per allele; P = 0.004). After stratification for birth weight, both HHEX-IDE and CDKAL1 risk alleles were associated with reduced BMI-SDS (0.45 SDS, P = 0.0002; 0.52 SDS, P = 0.0001) and weight-SDS (0.22 SDS, P = 0.04; 0.56 SDS, P = 0.0002) in children born large for gestational age (>90th percentile) but not children born small or appropriate for gestational age. Within children born large for gestational age, BMI and weight decreased with each additional type 2 diabetes risk allele ( approximately -2 kg per allele; >8 kg overall). Findings were consistent in children of mothers with type 1 diabetes (P < 0.0001) and children of nondiabetic mothers (P = 0.008). CONCLUSIONS: The type 2 diabetes susceptibility alleles at HHEX-IDE and CDKAL1 loci are associated with low BMI at age 8 years in children who were born large for gestational age

Associations between BMI and the FTO Gene Are Age Dependent: Results from the GINI and LISA Birth Cohort Studies up to Age 6 Years

Objective: The association between polymorphisms in intron 1 of the fat mass and obesity associated gene (FTO) and obesity-related traits is one of the most robust associations reported for complex traits and is established both in adults and children. However, little is known about the longitudinal dynamics of these polymorphisms on body mass index (BMI), overweight, and obesity. Methods: This study is based on the 2,732 full-term neonates of the German GINI-plus and LISA-plus birth cohorts, for whom genotyping data on the FTO variants rs1558902 (T>A) or rs9935401 (G>A) were available. Children were followed from birth up to age 6 years. Up to 9 anthropometric measurements of BMI were obtained. Fractional-Polynomial-Generalized-Estimation-Equation modeling was used to assess developmental trends and their potential dependence on genotype status. Results: We observed no evidence for BMI differences between genotypes of both variants for the first 3 years of life. However, from age 3 years onwards, we noted a higher BMI for the homozygous minor alleles carriers in comparison to the other two genotype groups. However, evidence for statistical significance was reached from the age of 4 years onwards. Conclusions: This is one of the first studies investigating in detail the development of BMI depending on FTO genotype between birth and the age of 6 years in a birth cohort not selected for the phenotype studied. We observed that the association between BMI and FTO genotype evolves gradually and becomes descriptively detectable from the age of 3 years onwards

A randomization-based causal inference framework for uncovering environmental exposure effects on human gut microbiota

Statistical analysis of microbial genomic data within epidemiological cohort studies holds the promise to assess the influence of environmental exposures on both the host and the host-associated microbiome. However, the observational character of prospective cohort data and the intricate characteristics of microbiome data make it challenging to discover causal associations between environment and microbiome. Here, we introduce a causal inference framework based on the Rubin Causal Model that can help scientists to investigate such environment-host microbiome relationships, to capitalize on existing, possibly powerful, test statistics, and test plausible sharp null hypotheses. Using data from the German KORA cohort study, we illustrate our framework by designing two hypothetical randomized experiments with interventions of (i) air pollution reduction and (ii) smoking prevention. We study the effects of these interventions on the human gut microbiome by testing shifts in microbial diversity, changes in individual microbial abundances, and microbial network wiring between groups of matched subjects via randomization-based inference. In the smoking prevention scenario, we identify a small interconnected group of taxa worth further scrutiny, including Christensenellaceae and Ruminococcaceae genera, that have been previously associated with blood metabolite changes. These findings demonstrate that our framework may uncover potentially causal links between environmental exposure and the gut microbiome from observational data. We anticipate the present statistical framework to be a good starting point for further discoveries on the role of the gut microbiome in environmental health

Fecal bile acids and neutral sterols are associated with latent microbial subgroups in the human gut

Bile acids, neutral sterols, and the gut microbiome are intricately intertwined and each affects human health and metabolism. However, much is still unknown about this relationship. This analysis included 1280 participants of the KORA FF4 study. Fecal metabolites (primary and secondary bile acids, plant and animal sterols) were analyzed using a metabolomics approach. Dirichlet regression models were used to evaluate associations between the metabolites and twenty microbial subgroups that were previously identified using latent Dirichlet allocation. Significant associations were identified between 12 of 17 primary and secondary bile acids and several of the microbial subgroups. Three subgroups showed largely positive significant associations with bile acids, and six subgroups showed mostly inverse associations with fecal bile acids. We identified a trend where microbial subgroups that were previously associated with “healthy” factors were here inversely associated with fecal bile acid levels. Conversely, subgroups that were previously associated with “unhealthy” factors were positively associated with fecal bile acid levels. These results indicate that further research is necessary regarding bile acids and microbiota composition, particularly in relation to metabolic health

Non-replication of an association of CTNNBL1 polymorphisms and obesity in a population of Central European ancestry

<p>Abstract</p> <p>Background</p> <p>A recent genome-wide association (GWA) study of U.S. Caucasians suggested that eight single nucleotide polymorphisms (SNPs) in <it>CTNNBL1 </it>are associated with obesity and increased fat mass. We analysed the respective SNPs in data from our previously published GWA for early onset obesity (case-control design), in GWA data from a population-based cohort of adults, and in an independent family-based obesity study. We investigated whether variants in <it>CTNNBL1 </it>(including rs6013029) and in three other genes (<it>SH3PXD2B</it>, <it>SLIT3 </it>and <it>FLJ42133</it>,) were associated with obesity.</p> <p>Methods</p> <p>The GWA studies were carried out using Affymetrix^®SNP Chips with approximately 500,000 markers each. In the families, SNP rs6013029 was genotyped using the TaqMan^®allelic discrimination assay. The German case-control GWA included 487 extremely obese children and adolescents and 442 healthy lean individuals. The adult GWA included 1,644 individuals from a German population-based study (KORA). The 775 independent German families consisted of extremely obese children and adolescents and their parents.</p> <p>Results</p> <p>We found no evidence for an association of the reported variants in <it>CTNNBL1 </it>with early onset obesity or increased BMI. Further, in our family-based study we found no evidence for over-transmission of the rs6013029 risk-allele T to obese children. Additionally, we found no evidence for an association of <it>SH3PXD2B</it>, <it>SLIT3 and FLJ42133 </it>variants in our two GWA samples.</p> <p>Conclusion</p> <p>We detected no confirmation of the recent association of variants in <it>CTNNBL1 </it>with obesity in a population of Central European ancestry.</p