DOCSLIB.ORG

Brief Genetics Report

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Brief Genetics Report Brief Genetics Report Quantitative Trait Loci for Obesity- and Diabetes-Related Traits and Their Dietary Responses to High-Fat Feeding in LGXSM Recombinant Inbred Mouse Strains James M. Cheverud,1 Thomas H. Ehrich,1 Tomas Hrbek,1 Jane P. Kenney,1 L. Susan Pletscher,1 and Clay F. Semenkovich2 Genetic variation in response to high-fat diets is impor- tant in understanding the recent secular trends that have led to increases in obesity and type 2 diabetes. The he prevalence of obesity and its correlates, such examination of quantitative trait loci (QTLs) for both as type 2 diabetes, has increased greatly over the obesity- and diabetes-related traits and their responses last 20 years (1). There has also been a concom- to a high-fat diet can be effectively addressed in mouse Titant change in the age of onset for type 2 model systems, including LGXSM recombinant inbred diabetes, with increasing diagnoses of this disease in (RI) mouse strains. A wide range of obesity- and diabe- children, adolescents, and young adults (2). These secular tes-related traits were measured in animals from 16 RI changes in obesity and diabetes are not due to genetic strains with 8 animals of each sex fed a high- or low-fat changes in populations (3), rather they are due to environ- diet from each strain. Marker associations were mea- mental changes in nutrition and activity over time. Even sured at 506 microsatellite markers spread throughout so, there is genetic variation in humans in the response to the mouse genome using a nested ANOVA. Locations with significant effects on the traits themselves and/or dietary and activity factors. Some individuals respond trait dietary responses were identified after correction strongly to an obesogenic environment by becoming for multiple comparisons by limiting the false detection obese, while other individuals remain lean when chal- rate. Nonsyntenic associations of marker genotypes lenged by the same environment (4). These variations in were common at QTL locations so that the significant response to environmental stimuli are, in part, due to results were limited to loci still significant in multiple genetic variations between people. QTL models. We discovered 91 QTLs at 39 locations. Study of differential response to dietary factors in also showed genetic human populations can be challenging because of the (31 ؍ Many of these locations (n effects on dietary response, typically because the loci difficulty in controlling or accurately recording diet over produced significantly larger effects on the high-fat diet. an extended period of time. Animal studies of the genetic Fat depot weights, leptin levels, and body weight at basis for differential response to dietary factors can play necropsy tended to map to the same locations and were an important role in attempts to understand the genetics responsible for a majority of the dietary response QTLs. involved in recent increases in obesity and type 2 diabetes. Basal glucose levels and the response to glucose chal- We have used the cross of inbred mouse strains LG/J and lenge mapped together in locations distinct from those affecting obesity. These QTL locations form a panel for SM/J over the past years to study the genetic architecture further research and fine mapping of loci affecting underlying complex traits (5), including growth (6,7), obesity- and diabetes-related traits and their responses obesity (8), and skeletal morphology (5). In continuing to high-fat feeding. Diabetes 53:3328–3336, 2004 studies we have shown that these parental strains vary in obesity- and diabetes-related traits and in responses to dietary fat (9,10). Recently, we documented significant genetic variation in dietary response for fat depot weights, From the 1Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri; and the 2Department of Medicine, liver weight, leptin levels, fasting glucose levels, and area Washington University School of Medicine, St. Louis, Missouri. under the glucose response curve in the LGXSM recombi- Address correspondence and reprint requests to James M. Cheverud, nant inbred (RI) strain set (11). Additionally, genetic Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110. E-mail: cheverud@ variation in dietary response for obesity- and diabetes- pcg.wustl.edu. related traits was detected in the F16 generation of an Received for publication 23 July 2004 and accepted in revised form 25 August 2004. advanced intercross (AI) line of LG/J and SM/J formed Additional information for this article can be found in an online appendix at from the same F2 intercross source population as the RI http:// diabetes.diabetesjournals.org. strains used here (WUSTL:LG,SM-G14), where litters were FDR, false discovery rate; FPR, false-positive rate; QTL, quantitative trait locus. divided into high- and low-fat diet treatments (12). An AI © 2004 by the American Diabetes Association. line is a randomly bred population formed from the F2 3328 DIABETES, VOL. 53, DECEMBER 2004 J.M. CHEVERUD AND ASSOCIATES TABLE 1 solution for every gram of body weight. Additional glucose readings were Composition of high- and low-fat diets obtained 15, 30, 60, and 120 min after the initial injection. The graph of the glucose levels over the period of the test are summarized by the area under the Component High fat Low fat curve, which is used as a general measure of an animal’s response to a glucose challenge. Lower values indicate a more robust response to glucose. Strain- Energy from fat 42% 15% and sex-specific glucose tolerance curves were presented by Cheverud et al. Casein (g/kg) 195 197 (11). Sugars (g/kg) 341 307 At a later time, animals were again fasted for 4 h and anesthetized with Corn starch (g/kg) 150 313 sodium pentobarbital, and a terminal blood sample was obtained via cardiac Cellulose (g/kg) 50 30 puncture. Blood plasma was separated through centrifugation and analyzed Corn oil (g/kg) 58 for free fatty acids, cholesterol, triglycerides, leptin, and insulin. Internal organs (liver, spleen, heart, and kidneys) and fat depots (reproductive, renal, Hydrogenated coconut oil (g/kg) 7 mesenteric, and inguinal) were removed and weighed. Anhydrous milk fat (g/kg) 210 Genotypes are available for the RI strains at 506 microsatellite loci spread Cholesterol (g/kg) 1.5 across the mouse chromosomes with a marker every 2 or 3 cM (T.H., L.S.P., Kilojoules per gram 18.95 16.99 R. Alves de Brito, J.M.C., unpublished observations). Genotypes were scored as corresponding to the LG/J or SM/J parental alleles. Loci showing residual heterozygosity were scored as missing data. A list of the loci scored and their intercross of a pair of inbred strains and maintained at a genomic positions is provided in online appendix A (available from http:// reasonably large census size (N Ͼ 100). It is designed to diabetes.diabetesjournals.org). Genotypes for specific strains can be obtained allow fine scale quantitative trait loci (QTLs) mapping from our laboratory web site (http://thalamus.wustl.edu/cheverudlab/ using the additional recombinations accumulated over the projects.html). Statistical analysis. The data were first analyzed for QTL effects at each generations. These earlier results promise success in map- marker scored along the mouse chromosomes using the following nested ping QTLs in crosses of the LG/J and SM/J inbred mouse ANOVA model (17), lines. Here, we present QTL mapping of obesity- and ϭ␮ϩ ϩ ϩ ϩ ϫ ϩ ϫ ϩ diabetes-related traits and their responses to increased Yijklm sexi dietj genotypek sexi dietj sexi genotypek dietj ϫ ϩ ϫ ϫ ϩ dietary fat in the LGXSM RI strain set. While a few of these genotypek sexi dietj genotypek strainl(sexi ϫ ϫ ϩ traits have been subject to previous genome-wide QTL dietj genotypek) eijklm scans, many novel traits and dietary responses have not th where Yijklm is the phenotype of interest for the m animal of sex (i), diet (j), been mapped previously in our cross, including regional and genotype (k) in strain l, and ␮ is the constant. Strain is nested within the fat depots, leptin, cholesterol, free fatty acid, triglycerides, sex-by-diet-by-genotype interaction. The effects of sex, diet, strain, and their insulin, fasting glucose levels, and response to an intra- interactions were reported by Cheverud et al. (11) and do not vary substan- tially across the genome scan. The effects of interest here are those due to peritoneal glucose tolerance test. Regions identified here genotype and its interactions. A significant test for the genotype effect as carrying QTLs will be subject to further research and indicates that a QTL affecting the trait of interest resides near the marker. A fine mapping in the WUSTL:LG,SM-G14 AI line. significant diet-by-genotype interaction indicates that the effect of the QTL varies depending on the diet. Thus, this factor identifies QTLs affecting dietary response. A significant sex-by-genotype interaction identifies a QTL with RESEARCH DESIGN AND METHODS different effects in males and females. A significant sex-by-diet-by-genotype The LGXSM recombinant inbred line set was produced from the F2 intercross interaction indicates that a QTL with different effects on male and female of LG/J females with SM/J males obtained from Jackson Laboratories. Details dietary responses is present in the region. of the line formation and history are presented by T.H., L.S.P., R. Alves de Given interactions between genotype and other factors, we also performed Brito, and J.M.C. (unpublished observations). The parental strains were genome-wide mapping analyses on each sex and diet cohort separately using derived from separate selection experiments for high (LG/J) (14) and low the following nested ANOVA model, (SM/J) (15) adult body weight, respectively.
Load more

Recommended publications
  • Goat Anti-PCK1 / PEPCKC (Internal) Antibody Peptide-Affinity Purified Goat Antibody Catalog # Af1796b
    10320 Camino Santa Fe, Suite G San Diego, CA 92121 Tel: 858.875.1900 Fax: 858.622.0609 Goat Anti-PCK1 / PEPCKC (internal) Antibody Peptide-affinity purified goat antibody Catalog # AF1796b Specification Goat Anti-PCK1 / PEPCKC (internal) Antibody - Product Information Application IHC Primary Accession P35558 Other Accession NP_002582, 5105 Reactivity Human Predicted Mouse, Rat, Pig, Dog, Cow Host Goat Clonality Polyclonal Concentration 100ug/200ul Isotype IgG Calculated MW 69195 AF1796b (2 µg/ml) staining of paraffin embedded Human Cerebral Cortex. Steamed antigen retrieval with citrate buffer pH 6, Goat Anti-PCK1 / PEPCKC (internal) Antibody - AP-staining. Additional Information Goat Anti-PCK1 / PEPCKC (internal) Gene ID 5105 Antibody - Background Other Names Phosphoenolpyruvate carboxykinase, This gene is a main control point for the cytosolic [GTP], PEPCK-C, 4.1.1.32, PCK1, regulation of gluconeogenesis. The cytosolic PEPCK1 enzyme encoded by this gene, along with GTP, catalyzes the formation of Format phosphoenolpyruvate from oxaloacetate, with 0.5 mg IgG/ml in Tris saline (20mM Tris the release of carbon dioxide and GDP. The pH7.3, 150mM NaCl), 0.02% sodium azide, expression of this gene can be regulated by with 0.5% bovine serum albumin insulin, glucocorticoids, glucagon, cAMP, and diet. Defects in this gene are a cause of Storage cytosolic phosphoenolpyruvate carboxykinase Maintain refrigerated at 2-8°C for up to 6 deficiency. A mitochondrial isozyme of the months. For long term storage store at encoded protein also has been characterized. -20°C in small aliquots to prevent freeze-thaw cycles. Goat Anti-PCK1 / PEPCKC (internal) Antibody - References Precautions Goat Anti-PCK1 / PEPCKC (internal) Antibody COMMON VARIANTS IN 40 GENES ASSESSED is for research use only and not for use in FOR DIABETES INCIDENCE AND RESPONSE TO diagnostic or therapeutic procedures.
    [Show full text]
  • Genome-Wide Linkage and Admixture Mapping of Type 2 Diabetes In
    ORIGINAL ARTICLE Genome-Wide Linkage and Admixture Mapping of Type 2 Diabetes in African American Families From the American Diabetes Association GENNID (Genetics of NIDDM) Study Cohort Steven C. Elbein,1,2 Swapan K. Das,1,2 D. Michael Hallman,3 Craig L. Hanis,3 and Sandra J. Hasstedt4 OBJECTIVE—We used a single nucleotide polymorphism (SNP) map in a large cohort of 580 African American families to identify regions linked to type 2 diabetes, age of type 2 diabetes ype 2 diabetes is marked by a clear genetic diagnosis, and BMI. propensity, a high concordance in identical twins, tendencies for both diabetes and age of RESEARCH DESIGN AND METHODS—After removing outli- onset to be familial (1), and marked differences ers and problematic samples, we conducted linkage analysis T in prevalence among ethnic groups (2). Despite consider- using 5,914 SNPs in 1,344 individuals from 530 families. Linkage analysis was conducted using variance components for type 2 able evidence for a genetic predisposition, unraveling the diabetes, age of type 2 diabetes diagnosis, and BMI and nonpara- genetic etiology has been daunting, with few confirmed metric linkage analyses. Ordered subset analyses were con- genes identified from genome-wide linkage scans. Recent ducted ranking on age of type 2 diabetes diagnosis, BMI, waist successes with genome-wide association scans (3) have circumference, waist-to-hip ratio, and amount of European ad- greatly increased the number of confirmed genetic loci, mixture. Admixture mapping was conducted using 4,486 markers but these successes have been limited primarily to Cauca- not in linkage disequilibrium.
    [Show full text]
  • Expression of Candidate Genes Associated with Obesity in Peripheral White Blood Cells of Mexican Children
    Basic research Expression of candidate genes associated with obesity in peripheral white blood cells of Mexican children Marcela Ulloa-Martínez1, Ana I. Burguete-García2, Selvasankar Murugesan1,3, Carlos Hoyo-Vadillo3, Miguel Cruz-Lopez4, Jaime García-Mena1 1Departamento de Genética y Biología Molecular, Centro de Investigación y de Corresponding author: Estudios Avanzados del IPN, México, México Jaime García-Mena PhD 2Dirección de Infecciones Crónicas y Cáncer, CISEI, Instituto Nacional de Salud Pública, Departamento de Genética México, México y Biología Molecular 3Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Centro de Investigación IPN, México, México y de Estudios Avanzados 4Unidad Unidad de Investigación Médica en Bioquímica, Centro Médico Nacional del IPN Siglo XXI, Instituto Mexicano del Seguro Social, México, México Av IPN #2508 Col Zacatenco Submitted: 3 December 2014 07360 México, México Accepted: 4 February 2015 Phone: +52 55 5747-3800 ext. 5328 Arch Med Sci 2016; 12, 5: 968–976 E-mail: [email protected] DOI: 10.5114/aoms.2016.58126 Copyright © 2016 Termedia & Banach Abstract Introduction: Obesity is a chronic, complex, and multifactorial disease, char- acterized by excess body fat. Diverse studies of the human genome have led to the identification of susceptibility genes that contribute to obesity. However, relatively few studies have addressed specifically the association between the level of expression of these genes and obesity. Material and methods: We studied 160 healthy and obese unrelated Mexi- can children aged 6 to 14 years. We measured the transcriptional expression of 20 genes associated with obesity, in addition to the biochemical parame- ters, in peripheral white blood cells.
    [Show full text]
  • Human Induced Pluripotent Stem Cell–Derived Podocytes Mature Into Vascularized Glomeruli Upon Experimental Transplantation
    BASIC RESEARCH www.jasn.org Human Induced Pluripotent Stem Cell–Derived Podocytes Mature into Vascularized Glomeruli upon Experimental Transplantation † Sazia Sharmin,* Atsuhiro Taguchi,* Yusuke Kaku,* Yasuhiro Yoshimura,* Tomoko Ohmori,* ‡ † ‡ Tetsushi Sakuma, Masashi Mukoyama, Takashi Yamamoto, Hidetake Kurihara,§ and | Ryuichi Nishinakamura* *Department of Kidney Development, Institute of Molecular Embryology and Genetics, and †Department of Nephrology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; ‡Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima, Japan; §Division of Anatomy, Juntendo University School of Medicine, Tokyo, Japan; and |Japan Science and Technology Agency, CREST, Kumamoto, Japan ABSTRACT Glomerular podocytes express proteins, such as nephrin, that constitute the slit diaphragm, thereby contributing to the filtration process in the kidney. Glomerular development has been analyzed mainly in mice, whereas analysis of human kidney development has been minimal because of limited access to embryonic kidneys. We previously reported the induction of three-dimensional primordial glomeruli from human induced pluripotent stem (iPS) cells. Here, using transcription activator–like effector nuclease-mediated homologous recombination, we generated human iPS cell lines that express green fluorescent protein (GFP) in the NPHS1 locus, which encodes nephrin, and we show that GFP expression facilitated accurate visualization of nephrin-positive podocyte formation in
    [Show full text]
  • Insig2 Polyclonal Antibody Purified Rabbit Polyclonal Antibody (Pab) Catalog # AP58480
    10320 Camino Santa Fe, Suite G San Diego, CA 92121 Tel: 858.875.1900 Fax: 858.622.0609 Insig2 Polyclonal Antibody Purified Rabbit Polyclonal Antibody (Pab) Catalog # AP58480 Specification Insig2 Polyclonal Antibody - Product Information Application WB Primary Accession Q9Y5U4 Reactivity Rat, Pig, Dog, Cow Host Rabbit Clonality Polyclonal Calculated MW 24778 Insig2 Polyclonal Antibody - Additional Information Gene ID 51141 Other Names Insulin-induced gene 2 protein, INSIG-2, INSIG2 {ECO:0000303|PubMed:12242332, Sample: Liver (Mouse) Lysate at 40 ug ECO:0000312|HGNC:HGNC:20452} Primary: Anti-Insig2 (bs-6625R) at 1/300 dilution Format Secondary: HRP conjugated Goat-Anti-rabbit 0.01M TBS(pH7.4) with 1% BSA, 0.09% IgG (bs-0295G-HRP) at 1/5000 dilution (W/V) sodium azide and 50% Glyce Predicted band size: 25 kD Observed band size: 23 kD Storage Store at -20 ℃ for one year. Avoid repeated freeze/thaw cycles. When reconstituted in sterile pH 7.4 0.01M PBS or diluent of antibody the antibody is stable for at least two weeks at 2-4 ℃. Insig2 Polyclonal Antibody - Protein Information Name INSIG2 {ECO:0000303|PubMed:12242332, ECO:0000312|HGNC:HGNC:20452} Function Oxysterol-binding protein that mediates feedback control of cholesterol synthesis by controlling both endoplasmic reticulum to Golgi transport of SCAP and degradation of HMGCR (PubMed:<a href="http://www.unip rot.org/citations/12242332" target="_blank">12242332</a>, Page 1/3 10320 Camino Santa Fe, Suite G San Diego, CA 92121 Tel: 858.875.1900 Fax: 858.622.0609 PubMed:<a href="http://www.uniprot.org/ci tations/16606821" target="_blank">16606821</a>, PubMed:<a href="http://www.uniprot.org/ci tations/32322062" target="_blank">32322062</a>).
    [Show full text]
  • WMC-79, a Potent Agent Against Colon Cancers, Induces Apoptosis Through a P53-Dependent Pathway
    1617 WMC-79, a potent agent against colon cancers, induces apoptosis through a p53-dependent pathway Teresa Kosakowska-Cholody,1 Introduction 1 2 W. Marek Cholody, Anne Monks, The bisimidazoacridones are bifunctional antitumor Barbara A. Woynarowska,3 agents with strong selectivity against colon cancers (1, 2). and Christopher J. Michejda1 Recent studies of the effect of bisimidazoacridones on sensitive colon tumors cells revealed that these com- 1 Molecular Aspects of Drug Design, Structural Biophysics pounds act as cytostatic agents that completely arrest cell Laboratory, Center for Cancer Research; 2Screening Technologies Branch, Laboratory of Functional Genomics, Science Applications growth at G1 and G2-M check points but do not trigger International Corporation, National Cancer Institute at Frederick, cell death even at high concentrations (10 Amol/L; ref. 3). Frederick, Maryland; and 3Department of Radiation Oncology, The chemical structure of bisimidazoacridones is symmet- University of Texas Health Science Center, San Antonio, Texas rical in that it consists of two imidazoacridone moieties held together by linkers of various lengths and rigidities. Abstract We recently reported on the synthesis of unsymmetrical variants of the original bisimidazoacridones (4). WMC-79 WMC-79 is a synthetic agent with potent activity (Fig. 1), a compound consisting of an imidazoacridone against colon and hematopoietic tumors. In vitro, the moiety linked to a 3-nitronaphthalimide moiety via agent is most potent against colon cancer cells that 1,4-bispropenopiperazine linker, was found to be a potent carry the wild-type p53 tumor suppressor gene (HCT- but selective cytotoxic agent in a variety of tumor cell f 116 and RKO cells: GI50 <1 nmol/L, LC50 40 nmol/L).
    [Show full text]
  • Original Article Genetic Polymorphisms of INSIG2 Were Associated with Coronary Artery Disease in Uygur Chinese Population in Xinjiang, China
    Int J Clin Exp Pathol 2016;9(8):8575-8585 www.ijcep.com /ISSN:1936-2625/IJCEP0026579 Original Article Genetic polymorphisms of INSIG2 were associated with coronary artery disease in Uygur Chinese population in Xinjiang, China Dilare Adi1,2*, Yun Wu3*, Xiang Xie1,2, Gulinaer Baituola1,2, Fen Liu2, Ying-Ying Zheng1,2, Yi-Ning Yang1,2, Xiao-Mei Li1,2, Ding Huang1,2, Xiang Ma1,2, Bang-Dang Chen2, Min-Tao Gai2, Xiao-Cui Chen2, Zhen-Yan Fu1,2, Yi-Tong Ma1,2 1Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, People’s Republic of China; 2Xinjiang Key Laboratory of Cardiovascular Disease Research, Urumqi, People’s Republic of China; 3Department of General Medicine, First Affiliated Hospital of Xinjiang Medical University, Urumqi, People’s Republic of China. *Equal contributors. Received February 24, 2016; Accepted May 21, 2016; Epub August 1, 2016; Published August 15, 2016 Abstract: Background: Dyslipidemia is a major and independent risk factor for the development of Coronary artery disease (CAD). The protein which is encoded by insulin induced gene2 (INSIG2) plays an important role in the media- tion of the feedback control of cholesterol synthesis, lipogenesis and glucose homeostasis. The aim of the present study was to assess the association between the human INSIG2 gene and CAD in Han Chinese and Uygur Chinese population of Xinjiang, China. Methods: A total of 832 CAD patients (334 Han, 498 Uygur) and 919 controls (346 Han, 573Uygur) were selected for the present Case-control study. Three tagging SNPs (rs1261829, rs21613329 and rs17047757) of INSIG2 gene were genotyped using TaqMan® assays from Applied Biosystems following the manufacturer’s instructions and analyzed in an ABI 7900HT Fast Real-Time PCR System.
    [Show full text]
  • Activation of Sterol Regulatory Element‑Binding Proteins in Mice Exposed to Perfluorooctanoic Acid for 28 Days
    Arch Toxicol DOI 10.1007/s00204-014-1322-7 MOLECULAR TOXICOLOGY Activation of sterol regulatory element‑binding proteins in mice exposed to perfluorooctanoic acid for 28 days Shengmin Yan · Jianshe Wang · Jiayin Dai Received: 10 April 2014 / Accepted: 21 July 2014 © Springer-Verlag Berlin Heidelberg 2014 Abstract Perfluoroalkyl acids are widely used in numer- lipid content and PPARα in Hepa 1-6 cells after exposure ous industrial and commercial applications due to their to PFOA for 72 h but SREBPs were not activated in vitro. unique physical and chemical characteristics. Although per- These results demonstrated that SREBPs were maturated fluorooctanoic acid (PFOA) is associated with hepatomeg- by activating the miR-183-96-182 cluster-SREBP regula- aly through peroxisome proliferator-activated receptor α tory loop in PFOA-exposed mouse liver. (PPARα) activation, liver fat accumulation and changes in gene expression related to fatty acid metabolism could still Keywords SREBP · Lipid metabolism · PPAR · be found in PPARα-null mice exposed to PFOA. To explore Perfluorononanoic acid the potential effects of PFOA on sterol regulatory element- binding proteins (SREBPs) activity, male mice were dosed with either Milli-Q water or PFOA at doses of 0.08, 0.31, Introduction 1.25, 5, and 20 mg/kg/day by gavage for 28 days. Liver total cholesterol concentrations and PFOA contents showed Perfluoroalkyl acids (PFAAs) are a family of anthropo- a dose-dependent decrease and increase, respectively. Tran- genic compounds widely used in industrial and commer- scriptional activity of PPARα and SREBPs was signifi- cial applications due to their unique physical and chemical cantly enhanced in livers.
    [Show full text]
  • Gene Interactions of the INSIG1 and INSIG2 in Metabolic Syndrome in Schizophrenic Patients Treated with Atypical Antipsychotics
    The Pharmacogenomics Journal (2012) 12, 54–61 & 2012 Macmillan Publishers Limited. All rights reserved 1470-269X/12 www.nature.com/tpj ORIGINAL ARTICLE Gene–gene interactions of the INSIG1 and INSIG2 in metabolic syndrome in schizophrenic patients treated with atypical antipsychotics Y-J Liou1,2,3,8, YM Bai1,2,8, The use of atypical antipsychotics (AAPs) is associated with increasing the risk 4,5 6 6 of the metabolic syndrome (MetS), which is an important risk factor for E Lin , J-Y Chen , T-T Chen , cardiovascular disease and diabetes. Two insulin-induced gene (INSIG) 1,2,7 1,2 C-J Hong and S-J Tsai isoforms, designated INSIG-1 and INSIG-2 encode two proteins that mediate feedback control of lipid metabolism. In this genetic case–control study, we 1Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; 2Division of investigated whether the common variants in INSIG1 and INSIG2 genes were Psychiatry, School of Medicine, National Yang- associated with MetS in schizophrenic patients treated with atypical Ming University, Taipei, Taiwan; 3Institute of antipsychctics. The study included 456 schizophrenia patients treated with Clinical Medicine, School of Medicine, National 4 clozapine (n ¼ 171), olanzapine (n ¼ 91) and risperidone (n ¼ 194), for an Yang-Ming University, Taipei, Taiwan; Vita ± Genomics, Taipei, Taiwan; 5Graduate Institute of average of 45.5 27.6 months. The prevalence of MetS among all subjects Clinical Medical Science, China Medical was 22.8% (104/456). Two single-nucleotide polymorphisms (SNPs) of the University, Taichung, Taiwan; 6Department of INSIG1 gene and seven SNPs of the INSIG2 gene were chosen as haplotype- Psychiatry, Yuli Veterans Hospital, Yuli, Hualien, tagging SNPs.
    [Show full text]
  • INSIG2 Variants, Dietary Patterns and Metabolic Risk in Samoa
    European Journal of Clinical Nutrition (2013) 67, 101–107 & 2013 Macmillan Publishers Limited All rights reserved 0954-3007/13 www.nature.com/ejcn ORIGINAL ARTICLE INSIG2 variants, dietary patterns and metabolic risk in Samoa A Baylin1,2, R Deka3, J Tuitele4, S Viali5, DE Weeks6,7 and ST McGarvey2,8 BACKGROUND/OBJECTIVES: Association of insulin-induced gene 2 (INSIG2) variants with obesity has been confirmed in several but not all follow-up studies. Differences in environmental factors across populations may mask some genetic associations and therefore gene–environment interactions should be explored. We hypothesized that the association between dietary patterns and components of the metabolic syndrome could be modified by INSIG2 variants. SUBJECTS/METHODS: We conducted a longitudinal study of adiposity and cardiovascular disease risk among 427 and 290 adults from Samoa and American Samoa (1990–1995). Principal component analysis on food items from a validated food frequency questionnaire was used to identify neotraditional and modern dietary patterns. We explored gene–dietary pattern interactions with the INSIG2 variants rs9308762 and rs7566605. RESULTS: Results for American Samoans were mostly nonsignificant. In Samoa, the neotraditional dietary pattern was associated with lower triglycerides, body mass index (BMI), waist circumference, systolic and diastolic blood pressure and fasting glucose (all P-for-trendo0.05). The modern pattern was significantly associated with higher triglycerides, BMI, waist circumference and lower high-density lipoprotein-cholesterol (all P-for-trendo0.05). A significant interaction for triglycerides was found between the modern pattern and the rs9308762 polymorphism (P ¼ 0.04). Those from Samoa consuming the modern pattern have higher triglycerides if they are homozygous for the rs9308762 C allele.
    [Show full text]
  • Open Mithun Shah.Pdf
    The Pennsylvania State University The Graduate School Department of Molecular Medicine ROLE OF SPHINGOLIPID SIGNALING IN PATHOGENESIS OF LARGE GRANULAR LYMPHOCYTE LEUKEMIA A Dissertation in Molecular Medicine by Mithun Vinod Shah © 2009 Mithun Vinod Shah Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy May 2009 ii The dissertation of Mithun Vinod Shah was reviewed and approved* by the following: Thomas P. Loughran, Jr. Professor of Medicine Dissertation Advisor Co-Chair of Committee Rosalyn B. Irby Assistant Professor of Medicine Co-chair of Committee Gary Clawson Professor of Pathology, and Biochemistry and Molecular Biology Edward J. Gunther Assistant Professor of Medicine Charles H. Lang Director, Molecular Medicine Graduate Program *Signatures are on file in the Graduate School iii ABSTRACT Large granular lymphocyte (LGL) leukemia is a disorder of mature cytotoxic cells. LGL leukemia is characterized by accumulation of cytotoxic cells in blood and infiltration in bone marrow and other tissues. Leukemic LGL could arise from expansion of either CD3+ CD8+ T-cells (T-cell LGL leukemia or T-LGL leukemia) or those arising from CD3- natural killer (NK)-cells (NK-cell LGL leukemia or NK-LGL leukemia). LGL leukemia is a rare disorder consisting of less than 5% of non-B cell leukemia. Clinically, LGL leukemia can manifest along a spectrum of disorders ranging from slowly progressing indolent disorder to an aggressive leukemia that could be fatal within months. About fifty percent of LGL leukemia patients also present with variety of autoimmune conditions, rheumatoid arthritis being the most common one. Normally, following antigen clearance, cytotoxic T-lymphocytes (CTL) become sensitive to Fas-mediated apoptosis resulting in activation-induced cell death (AICD).
    [Show full text]
  • Interaction Networks of Lithium and Valproate Molecular Targets Reveal a Striking Enrichment of Apoptosis Functional Clusters and Neurotrophin Signaling
    The Pharmacogenomics Journal (2012) 12, 328–341 & 2012 Macmillan Publishers Limited. All rights reserved 1470-269X/12 www.nature.com/tpj ORIGINAL ARTICLE Interaction networks of lithium and valproate molecular targets reveal a striking enrichment of apoptosis functional clusters and neurotrophin signaling A Gupta1, TG Schulze2, The overall neurobiological mechanisms by which lithium and valproate 3 1 stabilize mood in bipolar disorder patients have yet to be fully defined. The V Nagarajan , N Akula , therapeutic efficacy and dissimilar chemical structures of these medications 1 1 W Corona , X-y Jiang , suggest that they perturb both shared and disparate cellular processes. To N Hunter1, FJ McMahon1 and investigate key pathways and functional clusters involved in the global action SD Detera-Wadleigh1 of lithium and valproate, we generated interaction networks formed by well- supported drug targets. Striking functional similarities emerged. Intersecting 1Human Genetics Branch, National Institute of nodes in lithium and valproate networks highlighted a strong enrichment Mental Health, National Institutes of Health, of apoptosis clusters and neurotrophin signaling. Other enriched pathways 2 Bethesda, MD, USA; Department of Psychiatry included MAPK, ErbB, insulin, VEGF, Wnt and long-term potentiation and Psychotherapy, University Medical Center, Georg-August-Universita¨t, Go¨ttingen, Germany indicating a widespread effect of both drugs on diverse signaling systems. and 3Bioinformatics and Computational MAPK1/3 and AKT1/2 were the most preponderant nodes across pathways Biosciences Branch, Office of Cyber Infrastructure suggesting a central role in mediating pathway interactions. The conver- and Computational Biology, National Institute of gence of biological responses unveils a functional signature for lithium and Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA valproate that could be key modulators of their therapeutic efficacy.
    [Show full text]