Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

https://dash.harvard.edu/bitstream/handle/1/21459269/4338562.pdf?sequence=1

New genetic loci link adipose and insulin biology to body fat distribution

Genome-wide association (GWA) studies have typically focused on the analysis of single markers, which often lacks the power to uncover the relatively small effect sizes conferred by most genetic variants. Recently, pathway-based approaches have been developed, which use prior biological knowledge on gene function to facilitate more powerful analysis of GWA study data sets. These approaches typically examine whether a group of related genes in the same functional pathway are jointly associated with a trait of interest. Here we review the development of pathway-based approaches for GWA studies, discuss their practical use and caveats, and suggest that pathway-based approaches may also be useful for future GWA studies with sequencing data.

Analysing biological pathways in genome-wide association studies

Introduction: Regenerative medicine involves research in a number of fields and disciplines such as stem cell research, tissue engineering and biological therapy in general. As research in these ar...

/pdf/emerging-trends-in-regenerative-medicine-a-scientometric-4zt7g2hp1c.pdf

Emerging trends in regenerative medicine: a scientometric analysis in CiteSpace

An interactive resource to identify cancer genetic and lineage dependencies targeted by small molecules

Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10(-8) to P = 10(-190)). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1, EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function.

/pdf/genome-wide-association-study-identifies-loci-influencing-rl0j1qd90j.pdf

Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma.

Once a list of differentially expressed genes has been identified from a microarray experiment, a subsequent post-analysis task is required in order to find the main biological processes associated to the experimental system. This paper describes two pathways analysis tools, ArrayUnlock and Ingenuity Pathways Analysis (IPA) to deal with the post-analyses of microarray data, in the context of the EADGENE and SABRE post-analysis workshop. Dataset employed in this study proceeded from an experimental chicken infection performed to study the host reactions after a homologous or heterologous secondary challenge with two species of Eimeria. Analysis of the same microarray data source employing both commercial pathway analysis tools in parallel let to identify several biological and/or molecular functions altered in the chicken Eimeria maxima infection model, including several immune system related pathways. Biological functions differentially altered in the homologous and heterologous second infection were identified. Similarly, the effect of the timing in a homologous second infection was characterized by several biological functions. Functional analysis with ArrayUnlock and IPA provided information related to functional differences with the three comparisons of the chicken infection leading to similar conclusions. ArrayUnlock let an improvement of the annotations of the chicken genome adding InterPro annotations to the data set file. IPA provides two powerful tools to understand the pathway analysis results: the networks and canonical pathways that showed several pathways related to an adaptative immune response.

/pdf/biological-pathway-analysis-by-arrayunlock-and-ingenuity-217d7wx9rd.pdf

Biological pathway analysis by ArrayUnlock and Ingenuity Pathway Analysis

Target vs spectral fingerprint data analysis of Iberian ham samples for avoiding labelling fraud using headspace - gas chromatography-ion mobility spectrometry

Salmonella enterica serovar Typhimurium causes enteric disease and compromises food safety. In pigs, the molecular response of the intestine to S. typhimurium has been traditionally characterized by in vitro models that do not reflect the actual immunological competence of the intestinal mucosa. In this work, we performed an oral S. typhimurium infection study to obtain insight into the in vitro response in three different sections (jejunum, ileum and colon) of the porcine intestine. For this, samples from one- month-old infected piglets were collected during a time course comprising 1, 2, and 6 days post inoculation to evaluate the intestinal response by quantifying the mRNA expression of gene coding for 28 innate immune system molecules using quantitative real-time PCR assays. In addition, samples from non-infected control animals were also employed to establish differences in the steady state gene expression between intestinal sections. The panel of quantified molecules included an assortment of cytokines, chemokines, pattern-recognition receptors, intracellular signaling molecules, transcription factors and antimicrobial molecules. Changes in gene expression occurred in the three different parts of the intestine and during the course of the S. typhimurium infection. Moreover, the high variation observed in expression patterns of genes coding for inflammatory mediators could indicate that each intestinal section responds differently to the infection. Thus, on the contrary to findings in the jejunum and colon, a down-regulation and lack of induction of some proinflammatory cytokine transcripts was observed in the ileum. Nevertheless, all chemoattractant cytokines assayed were up-regulated in the ileum and jejunum whereas only interleukin-8 and MIP-1a mRNA were over expressed in the colon. In conclusion, our results reveal regional differences in gene expression profiles along the porcine intestinal gut as well as regional differences in the inflammatory response to S. typhimurium infection. Taken together, these data should provide a basis for a complete understanding of the porcine intestinal response to bacterial infection.

/pdf/quantitative-analysis-of-the-immune-response-upon-salmonella-24jd8hlmki.pdf

Quantitative analysis of the immune response upon Salmonella typhimurium infection along the porcine intestinal gut.

The innate immune system has the basic function of identifying and eradicating microbial invaders and alerting the adaptative immune system to their presence. In this study, the porcine intestinal innate immune response was evaluated by analysing the expression of TLRs, cytokines and chemokines in two porcine epithelial cell lines from different regions: IPEC-J2 (jejunum) and IPI-2I (ileum). Both cells lines were stimulated with 1microg of LPS from Salmonella typhimurium. RNA was collected at 30min, 1, 2, 3 and 4h after treatment. Expression of TLR-1, -2, -3, -4, -6, -8, -9, -10, TNF-alpha, IL-1beta, -8 and MCP-1 was quantified relative to the quantity of Cyclophilin-A mRNA using real-time quantitative PCR (RTQ-PCR). The results obtained show up differences in the gene expression between both cell lines IPEC-J2 and IPI-2I as response to LPS from S. typhimurium during the activation time, which may suggest an in vivo variability in the innate immune response against pathogens in different regions of the host's gut.

Cristina Arce

Papers

Biological pathway analysis by ArrayUnlock and Ingenuity Pathway Analysis

Target vs spectral fingerprint data analysis of Iberian ham samples for avoiding labelling fraud using headspace - gas chromatography-ion mobility spectrometry

Quantitative analysis of the immune response upon Salmonella typhimurium infection along the porcine intestinal gut.

Innate immune activation of swine intestinal epithelial cell lines (IPEC-J2 and IPI-2I) in response to LPS from Salmonella typhimurium.

Target identification of volatile metabolites to allow the differentiation of lactic acid bacteria by gas chromatography-ion mobility spectrometry.