67 research outputs found
Impact of Common Variation in Bone-Related Genes on Type 2 Diabetes and Related Traits.
No full textExploring genetic pleiotropy can provide clues to a mechanism underlying the observed epidemiological association between type 2 diabetes and heightened fracture risk. We examined genetic variants associated with bone mineral density (BMD) for association with type 2 diabetes and glycemic traits in large well-phenotyped and -genotyped consortia. We undertook follow-up analysis in ∼19,000 individuals and assessed gene expression. We queried single nucleotide polymorphisms (SNPs) associated with BMD at levels of genome-wide significance, variants in linkage disequilibrium (r2 > 0.5), and BMD candidate genes. SNP rs6867040, at the ITGA1 locus, was associated with a 0.0166 mmol/L (0.004) increase in fasting glucose per C allele in the combined analysis. Genetic variants in the ITGA1 locus were associated with its expression in the liver but not in adipose tissue. ITGA1 variants appeared among the top loci associated with type 2 diabetes, fasting insulin, β-cell function by homeostasis model assessment, and 2-h post–oral glucose tolerance test glucose and insulin levels. ITGA1 has demonstrated genetic pleiotropy in prior studies, and its suggested role in liver fibrosis, insulin secretion, and bone healing lends credence to its contribution to both osteoporosis and type 2 diabetes. These findings further underscore the link between skeletal and glucose metabolism and highlight a locus to direct future investigations.Liana K. Billings, Yi-Hsiang Hsu, Rachel J. Ackerman, Josée Dupuis, Benjamin F. Voight, Laura J. Rasmussen-Torvik, Serge Hercberg, Mark Lathrop, Daniel Barnes, Claudia Langenberg, Jennie Hui, Mao Fu, Nabila Bouatia-Naji, Cecile Lecoeur, Ping An, Patrik K. Magnusson, Ida Surakka, Samuli Ripatti, Lene Christiansen, Christine Dalgård, Lasse Folkersen, Elin Grundberg, the MAGIC Investigators, the DIAGRAM, Consortium, the MuTHER Consortium, the ASCOT Investigators, the GEFOS Consortium, Per Eriksson, Jaakko Kaprio, Kirsten Ohm Kyvik, Nancy L. Pedersen, Ingrid B. Borecki, Michael A. Province, Beverley Balkau, Philippe Froguel, Alan R. Shuldiner, Lyle J. Palmer, Nick Wareham, Pierre Meneton, Toby Johnson, James S. Pankow, David Karasik, James B. Meigs, Douglas P. Kiel, and Jose C. Flore
Interfacial behaviour in stratified and stratifying annular flows
No full textThis thesis describes work which was focused on stratifying annular flow in horizontal tubes. Stratifying-annular flows in horizontal tubes are characterized by the tube being wetted with liquid over its whole periphery but with a tendency for more of the liquid to be present in the layer at the bottom of the tube. For such a condition to exist, there have to be some mechanisms by which the liquid is transported at the top of the pipe in opposition to the influence of gravity. Such flows are typically experienced in hydrocarbon recovery and in many other applications as for instance in gas-condensate lines. Unless the liquid phase (to which a corrosion inhibitor is often added) can adequately wet the top of the pipe, corrosion and ultimate pipe failure may occur in this region; this is a crucial problem for the petroleum industry. Three physical mechanisms have been identified for the transport of the liquid phase to the top of the tube, namely: droplet transport, wave spreading and mixing, and secondary flow. The secondary flow mechanism seems unlikely to contribute significantly and the wave spreading mechanism is only significant in smaller diameter tubes (typically 25 mm). For larger pipes, it is the droplet transport mechanism which is likely to occur; in this mechanism, droplets are entrained from the liquid layer at the bottom of the pipe and transported in the gas core at the top where they deposit to form a liquid film. Two mechanisms of droplet transport seem to be significant, namely ballistic transport in which larger droplets move in a direction governed by their initial release velocity and diffusional transport in which droplets move randomly under the influence of the gas flow turbulence. For pipes of medium diameter (for example in the 78 mm diameter pipe used in the experiments described here), ballistic droplet transport is likely to be the dominant mechanism but diffusional transport is expected to be dominant for large diameter pipes.
The work described in the thesis comprised both experimental and computational studies. In the experimental work, a special visualization method (namely axial view photography) was employed to study the droplet entrainment and transport mechanisms. The distribution of liquid film flow rate around the pipe was determined using a film extractor device. The axial viewing system was used to investigate droplet entrainment in stratifying-annular air-water flows in a 0.078 m diameter horizontal pipe. The process of droplet entrainment was captured using a high speed cine camera. Both ligament and bag breakup mechanisms leading to droplet entrainment were identified. The creation of a ballistic droplet from a ligament was clearly observed. The film flow rate measurements were used in conjunction with previous measurements of droplet mass flux in the core in comparisons with a computational model which aimed to predict the transport of droplets using Reynolds Averaged Navier Stokes (RANS) modelling embodied in a commercial CFD code (CFX). In this model, the turbulent gas core was modelled and the motion of droplets emitted from the liquid layer at the bottom of the pipe was tracked in this turbulent field. Ultimately, the droplets are deposited on the tube wall and the film flow rate may be calculated using the predicted deposition rates as input data. The thesis closes with a description of a numerical experiment aimed at investigating the influence of the turbulence model on droplet transport. Specifically, comparisons were made between RANS and Large Eddy Simulation (LES) models. [For supplementary files please contact author]
Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution
No full textWaist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions
Novel Approach Identifies SNPs in SLC2A10 and KCNK9 with Evidence for Parent-of-Origin Effect on Body Mass Index
No full textThe phenotypic effect of some single nucleotide polymorphisms (SNPs) depends on their parental origin. We present a novel approach to detect parent-of-origin effects (POEs) in genome-wide genotype data of unrelated individuals. The method exploits increased phenotypic variance in the heterozygous genotype group relative to the homozygous groups. We applied the method to >56,000 unrelated individuals to search for POEs influencing body mass index (BMI). Six lead SNPs were carried forward for replication in five family-based studies (of ~4,000 trios). Two SNPs replicated: the paternal rs2471083-C allele (located near the imprinted KCNK9 gene) and the paternal rs3091869-T allele (located near the SLC2A10 gene) increased BMI equally (beta = 0.11 (SD), P<0.0027) compared to the respective maternal alleles. Real-time PCR experiments of lymphoblastoid cell lines from the CEPH families showed that expression of both genes was dependent on parental origin of the SNPs alleles (P<0.01). Our scheme opens new opportunities to exploit GWAS data of unrelated individuals to identify POEs and demonstrates that they play an important role in adult obesity. © 2014 Hoggart et al
Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
No full textApproaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups
Cytotoxicity and effectiveness of archetypal Metal-Organic Frameworks (HKUST-1, UiO-66, MIL-53, MIL-125) against coronaviruses (HCoV-229E and SARS-CoV-2)
No full textInternational audienceIn order to use MOFs in virus decontamination processes, four archetypal MOFs with different metal clusters have been chosen: UiO-66 (Zr), HKUST-1 (Cu), MIL-53 (Fe) and MIL-125 (Ti). Five different concentrations (from 0.01 to 1 mg/mL) for each MOF and three different cell lines (Huh7 TMPRSS2, VeroE6 and Vero81.6) were investigated in aqueous medium (DMEM). Moreover, different cytotoxicity assays were evaluated (MTS, Neutral Red and LDH) and critically compared for the first time, with Neutral Red seemingly to be the most appropriate. HKUST-1 was found to be toxic above 0.1 mg/mL for all of the three cell lines, while the other three MOFs appear to be nontoxic, even above 1 mg/mL. Then, their effect against viruses was monitored, mainly for HCoV-229E and SARS-CoV-2, two different coronaviruses that still cause a lot of infection cases and deaths up to now. Following 1 hour contact with the viruses, HKUST-1 (Cu) and MIL-125 (Ti) were able to greatly diminish the viral titer by 86% and 79.2%, respectively, for HCoV-229E, whereas for SARS-CoV-2 HKUST-1 (Cu), MIL-53 (Fe) and UiO-66 (Zr), demonstrated an efficacy of 68.4%, 63.1% and 56.1%, respectively
Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
No full textObesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and similar to 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 x 10(-8)), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation
A variation in the ghrelin gene increases weight and decreases insulin secretion in tall, obese children.
No full textGhrelin is a recently recognized gut-brain peptide originally derived from the gastric mucosa. It stimulates growth hormone release, increases appetite and facilitates fat storage, and may interact with glucose metabolism. We studied the ghrelin gene in a group of 70 tall and obese children (mean age 9.4 year, Z body mass index [BMI] and Z height >3 and/or BMI percentile >99%). We found 10 single nucleotide polymorphisms. One common polymorphism of the ghrelin gene, which corresponds to an amino acid change in the tail of the prepro-ghrelin molecule, was significantly associated with children with a higher BMI (P = 0.001), and with lower insulin secretion during the first part of an oral glucose tolerance test (P = 0.05) although no difference in glucose levels was noted. This might suggest increased insulin sensitivity, although this is not supported by the lack of difference in fasting and 2 hour insulin levels; alternatively, this may be indicative of impaired first phase insulin secretion. These data suggest that variations in the ghrelin gene contribute to obesity in children and may modulate glucose-induced insulin secretion
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