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124: Genomic variants associated with resistance to high fat diet induced obesity in a primate model
Poster Session I
ajog.org OBJECTIVE: Maternal obesity from HFD intake contributes to an
increased risk of morbidity and mortality for both the mother and her offspring, and is associated with dysbiosis of the microbiome. We spent the last decade establishing our primate model of maternal obesity, and have previously observed that while a majority of dams become obese on the HFD, approximately 30% are resistant and remain lean. We have recently identified polymorphisms (SNPs) in apolipoprotein B and phospholipase A2 that drive this resistance. Here, we aimed to determine if these SNPs are in turn associated with differences in the microbiome structure/function in our primate model. STUDY DESIGN: Using our primate model, functional SNPs of interest were identified using a novel exon-capture hybrid array targeting 783 lipid metabolism and obesity related genes. Metagenomic samples were collected from multiple body sites (gut/mouth/vagina) from pregnant/non-pregnant dams and offspring (n¼25). Microbial 16S rDNA was isolated, sequenced (Roche 454 platform), and analyzed using QIIME. RESULTS: We found significant differences in microbial community structure related to our previously identified SNPs (p<0.014; Fig.1). Differences were observed within body sites and pregnancy status, including variance in taxonomic abundance (Fig.2). Furthermore, analysis of maternal-offspring pairs revealed differences in the offspring microbiome based on maternal genotype. CONCLUSION: Taken together, our data suggest that variation in the host genotype in two genes important for lipid metabolism are associated with differences in both the maternal and offspring microbiome and resistance to obesity. These findings offer potential novel mechanisms for host-microbiome interactions around lipid metabolism, and risk of maternal obesity.
124 Genomic variants associated with resistance to high fat diet induced obesity in a primate model
125 Whole exome sequencing (WES) in prenatal diagnosis for carefully selected cases
Ryan M. Pace1, R. Alan Harris1, Callison E. Alcott1, Elinor L. Sullivan2, Diana Takahashi2, Carrie E. McCurdy3, Sarah Comstock4, Karalee Baquero2, Peter Blundell2, Antonio E. Frias5, Maike Kahr1, Melissa Suter1, Stephanie Wesolowski6, Jacob E. Friedman6, Kevin L. Grove2, Kjersti M. Aagaard1 1
OBJECTIVE: Obesity results from a complex set of interactions between genetics and the environment, and contributes to an increased risk of lifelong morbidity and mortality. In order to better understand the molecular mechanisms underlying these risks, we established and extensively characterized a primate model in Macaca fuscata (Japanese macaque) and have demonstrated that a high fat, caloric dense maternal diet structures the offspring’s epigenome, metabolome, and gut microbiome. We have consistently observed that a 36% fat diet leads to obesity in the majority, but not all, of exposed dams. In this study, we aimed to identify and ascribe genomic loci to traits of adult maternal obesity resistance, relative weight stability, and insulin sensitivity following prolonged high fat diet exposure among female macaque dams in a well-developed primate model. STUDY DESIGN: Using our primate model, functional SNPs of interest were identified through extensive phenotyping of 37 traits together with a novel exon-capture hybrid array targeting 783 Genes related to obesity, hyperlipidemia, insulin resistance, and lipid metabolism. To assure high quality SNP identification, we used three tools to call SNPs (Atlas-SNP2, SNPTools, and ssahaSNP). RESULTS: We identified three novel single nucleotide polymorphisms (SNPs), two in apolipoprotein B (APOB) and one in phospholipase A2 (PLA2G4A) that are significantly associated with persistent weight stability and insulin sensitivity in lean macaques. By application of explicit orthogonal modeling (NOIA), we estimated the polygenic and interactive nature of these loci against multiple metabolic traits and their measures (i.e., serum LDL levels) which collectively render a maternal obesity resistant phenotype in our adult female dams. CONCLUSION: Taken together, these studies provide evidence supporting a genomic and evolutionarily conserved predisposition to maternal obesity resistance in a robust and relevant primate model of maternal obesity with chronic high fat diet consumption.
Stacy M. Yadava, Elena Ashkinadze Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ
OBJECTIVE: Whole exome sequencing (WES) performed based on
Baylor College of Medicine, Houston, TX, 2Oregon National Primate Research Center, Oregon Health & Science University (OHSU), Beaverton, OR, 3University of Oregon, Eugene, OR, 4Corban University, Salem, OR, 5 Oregon Health & Science University, Portland, OR, 6University of Colorado Anschutz Medical Campus, Aurora, CO
ultrasound abnormalities alone has a reported diagnostic yield of 2143%. We sought to determine whether careful selection of cases would yield a higher diagnostic rate. STUDY DESIGN: This is a report of the first five prenatal cases of WES at Rutgers Robert Wood Johnson Medical School. Candidates for testing were either in consanguineous relationships, had large
Supplement to JANUARY 2017 American Journal of Obstetrics & Gynecology
S87
ajog.org OBJECTIVE: Maternal obesity from HFD intake contributes to an
increased risk of morbidity and mortality for both the mother and her offspring, and is associated with dysbiosis of the microbiome. We spent the last decade establishing our primate model of maternal obesity, and have previously observed that while a majority of dams become obese on the HFD, approximately 30% are resistant and remain lean. We have recently identified polymorphisms (SNPs) in apolipoprotein B and phospholipase A2 that drive this resistance. Here, we aimed to determine if these SNPs are in turn associated with differences in the microbiome structure/function in our primate model. STUDY DESIGN: Using our primate model, functional SNPs of interest were identified using a novel exon-capture hybrid array targeting 783 lipid metabolism and obesity related genes. Metagenomic samples were collected from multiple body sites (gut/mouth/vagina) from pregnant/non-pregnant dams and offspring (n¼25). Microbial 16S rDNA was isolated, sequenced (Roche 454 platform), and analyzed using QIIME. RESULTS: We found significant differences in microbial community structure related to our previously identified SNPs (p<0.014; Fig.1). Differences were observed within body sites and pregnancy status, including variance in taxonomic abundance (Fig.2). Furthermore, analysis of maternal-offspring pairs revealed differences in the offspring microbiome based on maternal genotype. CONCLUSION: Taken together, our data suggest that variation in the host genotype in two genes important for lipid metabolism are associated with differences in both the maternal and offspring microbiome and resistance to obesity. These findings offer potential novel mechanisms for host-microbiome interactions around lipid metabolism, and risk of maternal obesity.
124 Genomic variants associated with resistance to high fat diet induced obesity in a primate model
125 Whole exome sequencing (WES) in prenatal diagnosis for carefully selected cases
Ryan M. Pace1, R. Alan Harris1, Callison E. Alcott1, Elinor L. Sullivan2, Diana Takahashi2, Carrie E. McCurdy3, Sarah Comstock4, Karalee Baquero2, Peter Blundell2, Antonio E. Frias5, Maike Kahr1, Melissa Suter1, Stephanie Wesolowski6, Jacob E. Friedman6, Kevin L. Grove2, Kjersti M. Aagaard1 1
OBJECTIVE: Obesity results from a complex set of interactions between genetics and the environment, and contributes to an increased risk of lifelong morbidity and mortality. In order to better understand the molecular mechanisms underlying these risks, we established and extensively characterized a primate model in Macaca fuscata (Japanese macaque) and have demonstrated that a high fat, caloric dense maternal diet structures the offspring’s epigenome, metabolome, and gut microbiome. We have consistently observed that a 36% fat diet leads to obesity in the majority, but not all, of exposed dams. In this study, we aimed to identify and ascribe genomic loci to traits of adult maternal obesity resistance, relative weight stability, and insulin sensitivity following prolonged high fat diet exposure among female macaque dams in a well-developed primate model. STUDY DESIGN: Using our primate model, functional SNPs of interest were identified through extensive phenotyping of 37 traits together with a novel exon-capture hybrid array targeting 783 Genes related to obesity, hyperlipidemia, insulin resistance, and lipid metabolism. To assure high quality SNP identification, we used three tools to call SNPs (Atlas-SNP2, SNPTools, and ssahaSNP). RESULTS: We identified three novel single nucleotide polymorphisms (SNPs), two in apolipoprotein B (APOB) and one in phospholipase A2 (PLA2G4A) that are significantly associated with persistent weight stability and insulin sensitivity in lean macaques. By application of explicit orthogonal modeling (NOIA), we estimated the polygenic and interactive nature of these loci against multiple metabolic traits and their measures (i.e., serum LDL levels) which collectively render a maternal obesity resistant phenotype in our adult female dams. CONCLUSION: Taken together, these studies provide evidence supporting a genomic and evolutionarily conserved predisposition to maternal obesity resistance in a robust and relevant primate model of maternal obesity with chronic high fat diet consumption.
Stacy M. Yadava, Elena Ashkinadze Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ
OBJECTIVE: Whole exome sequencing (WES) performed based on
Baylor College of Medicine, Houston, TX, 2Oregon National Primate Research Center, Oregon Health & Science University (OHSU), Beaverton, OR, 3University of Oregon, Eugene, OR, 4Corban University, Salem, OR, 5 Oregon Health & Science University, Portland, OR, 6University of Colorado Anschutz Medical Campus, Aurora, CO
ultrasound abnormalities alone has a reported diagnostic yield of 2143%. We sought to determine whether careful selection of cases would yield a higher diagnostic rate. STUDY DESIGN: This is a report of the first five prenatal cases of WES at Rutgers Robert Wood Johnson Medical School. Candidates for testing were either in consanguineous relationships, had large
Supplement to JANUARY 2017 American Journal of Obstetrics & Gynecology
S87