Identification of a Novel Gene for Diabetic Traits in Rats, Mice, and Humans

Genetics - Tập 198 Số 1 - Trang 17-29 - 2014
Shirng‐Wern Tsaih1, Katie Holl2,1, Shuang Jia2,1, Mary L. Kaldunski2,1, Michael Tschannen1, Hong He2,1, Jaime Wendt Andrae1, Shunhua Li2, Alexander J. Stoddard2,1, Andrew Wiederhold2, John Parrington3, Margarida Ruas3, Antony Galione3, James B. Meigs4, Raymond G. Hoffmann2,1, Pippa Simpson2,1, Howard J. Jacob2,1, Martin J. Hessner2,1, Leah C. Solberg Woods2,1
1Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
2Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
3Department of Pharmacology, University of Oxford, Oxford OX1 3QT, United Kingdom
4Department of Medicine , Harvard Medical School, General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts 02114

Tóm tắt

AbstractThe genetic basis of type 2 diabetes remains incompletely defined despite the use of multiple genetic strategies. Multiparental populations such as heterogeneous stocks (HS) facilitate gene discovery by allowing fine mapping to only a few megabases, significantly decreasing the number of potential candidate genes compared to traditional mapping strategies. In the present work, we employed expression and sequence analysis in HS rats (Rattus norvegicus) to identify Tpcn2 as a likely causal gene underlying a 3.1-Mb locus for glucose and insulin levels. Global gene expression analysis on liver identified Tpcn2 as the only gene in the region that is differentially expressed between HS rats with glucose intolerance and those with normal glucose regulation. Tpcn2 also maps as a cis-regulating expression QTL and is negatively correlated with fasting glucose levels. We used founder sequence to identify variants within this region and assessed association between 18 variants and diabetic traits by conducting a mixed-model analysis, accounting for the complex family structure of the HS. We found that two variants were significantly associated with fasting glucose levels, including a nonsynonymous coding variant within Tpcn2. Studies in Tpcn2 knockout mice demonstrated a significant decrease in fasting glucose levels and insulin response to a glucose challenge relative to those in wild-type mice. Finally, we identified variants within Tpcn2 that are associated with fasting insulin in humans. These studies indicate that Tpcn2 is a likely causal gene that may play a role in human diabetes and demonstrate the utility of multiparental populations for positionally cloning genes within complex loci.

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Tài liệu tham khảo

Aitman, 2006, Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans., Nature, 439, 851, 10.1038/nature04489

Alejandro, 2010, Acute insulin signaling in pancreatic beta-cells is mediated by multiple Raf-1 dependent pathways., Endocrinology, 151, 502, 10.1210/en.2009-0678

Arredouani, 2010, An emerging role for NAADP-mediated Ca2+ signaling in the pancreatic beta-cell., Islets, 2, 323, 10.4161/isl.2.5.12747

Baud, 2013, Combined sequence-based and genetic mapping analysis of complex traits in outbred rats., Nat. Genet., 45, 767, 10.1038/ng.2644

Behmoaras, 2008, Jund is a determinant of macrophage activation and is associated with glomerulonephritis susceptibility., Nat. Genet., 40, 553, 10.1038/ng.137

Benjamini, 1995, Controlling the false discovery rate: a practical and powerful approach to multiple testing., J. R. Stat. Soc. B, 57, 289, 10.1111/j.2517-6161.1995.tb02031.x

Brailoiu, 2009, Essential requirement for two-pore channel 1 in NAADP-mediated calcium signaling., J. Cell Biol., 186, 201, 10.1083/jcb.200904073

Cacho, 2008, Validation of simple indexes to assess insulin sensitivity during pregnancy in Wistar and Sprague-Dawley rats., Am. J. Physiol. Endocrinol. Metab., 295, E1269, 10.1152/ajpendo.90207.2008

Calcraft, 2009, NAADP mobilizes calcium from acidic organelles through two-pore channels., Nature, 459, 596, 10.1038/nature08030

Chen, 2008, Variations in DNA elucidate molecular networks that cause disease., Nature, 452, 429, 10.1038/nature06757

Chung, 1997, Genetic modifiers of Leprfa associated with variability in insulin production and susceptibility to NIDDM., Genomics, 41, 332, 10.1006/geno.1997.4672

Cohen, 2005, Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9., Nat. Genet., 37, 161, 10.1038/ng1509

Demarest, 2001, Further characterization and high-resolution mapping of quantitative trait loci for ethanol-induced locomotor activity., Behav. Genet., 31, 79, 10.1023/A:1010261909853

2014, Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility., Nat. Genet., 46, 234, 10.1038/ng.2897

Dupuis, 2010, New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk., Nat. Genet., 42, 105, 10.1038/ng.520

Farber, 2009, J. Bone Miner. Res.

Flint, 2012, Genome-wide association studies in mice., Nat. Rev. Genet., 13, 807, 10.1038/nrg3335

Flister, 2013, Identifying multiple causative genes at a single GWAS locus., Genome Res., 23, 1996, 10.1101/gr.160283.113

Galli, 1996, Genetic analysis of non-insulin dependent diabetes mellitus in the GK rat., Nat. Genet., 12, 31, 10.1038/ng0196-31

Garcia-Rua, 2012, Increased expression of fatty-acid and calcium metabolism genes in failing human heart., PLoS ONE, 7, e37505, 10.1371/journal.pone.0037505

Gauguier, 1996, Chromosomal mapping of genetic loci associated with non-insulin dependent diabetes in the GK rat., Nat. Genet., 12, 38, 10.1038/ng0196-38

Granhall, 2006, High-resolution quantitative trait locus analysis reveals multiple diabetes susceptibility loci mapped to intervals <800 kb in the species-conserved Niddm1i of the GK rat., Genetics, 174, 1565, 10.1534/genetics.106.062208

Hansen, 1984, Development of the National Institutes of Health genetically heterogeneous rat stock., Alcohol. Clin. Exp. Res., 8, 477, 10.1111/j.1530-0277.1984.tb05706.x

Hessner, 2004, Involvement of eotaxin, eosinophils, and pancreatic predisposition in development of type 1 diabetes mellitus in the BioBreeding rat., J. Immunol., 173, 6993, 10.4049/jimmunol.173.11.6993

Hu, 2012, What have we learned from six years of GWAS in autoimmune diseases, and what is next?, Curr. Opin. Immunol., 24, 571, 10.1016/j.coi.2012.09.001

Huang, 2009, High resolution mapping of expression QTLs in heterogeneous stock mice in multiple tissues., Genome Res., 19, 1133, 10.1101/gr.088120.108

Hubner, 2005, Integrated transcriptional profiling and linkage analysis for identification of genes underlying disease., Nat. Genet., 37, 243, 10.1038/ng1522

Johnsen, 2011, Genome-wide and species-wide dissection of the genetics of arthritis severity in heterogeneous stock mice., Arthritis Rheum., 63, 2630, 10.1002/art.30425

Kadar, 2011, Effects of isoflurane on Nfkappab p65, Gadd45a and Jnk1 expression in the vital organs of CBA/CA mice., In Vivo, 25, 241

Kanemoto, 1998, Genetic dissection of “OLETF”, a rat model for non-insulin-dependent diabetes mellitus., Mamm. Genome, 9, 419, 10.1007/s003359900789

Katter, 2013, Transposon-mediated transgenesis, transgenic rescue, and tissue-specific gene expression in rodents and rabbits., FASEB J., 27, 930, 10.1096/fj.12-205526

Katz, 2000, Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans., J. Clin. Endocrinol. Metab., 85, 2402, 10.1210/jcem.85.7.6661

Keane, 2011, Mouse genomic variation and its effect on phenotypes and gene regulation., Nature, 477, 289, 10.1038/nature10413

Kim, 2008, Generation of nicotinic acid adenine dinucleotide phosphate and cyclic ADP-ribose by glucagon-like peptide-1 evokes Ca2+ signal that is essential for insulin secretion in mouse pancreatic islets., Diabetes, 57, 868, 10.2337/db07-0443

Koressaar, 2007, Enhancements and modifications of primer design program Primer3., Bioinformatics, 23, 1289, 10.1093/bioinformatics/btm091

Leduc, 2011, Integration of QTL and bioinformatic tools to identify candidate genes for triglycerides in mice., J. Lipid Res., 52, 1672, 10.1194/jlr.M011130

Logan, 2013, High-precision genetic mapping of behavioral traits in the diversity outbred mouse population., Genes Brain Behav., 12, 424, 10.1111/gbb.12029

Matsuda, 2001, Mice lacking Ca(v)2.3 (alpha1E) calcium channel exhibit hyperglycemia., Biochem. Biophys. Res. Commun., 289, 791, 10.1006/bbrc.2001.6051

Matthews, 1985, Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man., Diabetologia, 28, 412, 10.1007/BF00280883

Morris, 2012, Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes., Nat. Genet., 44, 981, 10.1038/ng.2383

Morrissey, 2011, Integrated genomic approaches to identification of candidate genes underlying metabolic and cardiovascular phenotypes in the spontaneously hypertensive rat., Physiol. Genomics, 43, 1207, 10.1152/physiolgenomics.00210.2010

Mott, 2000, A method for fine mapping quantitative trait loci in outbred animal stocks., Proc. Natl. Acad. Sci. USA, 97, 12649, 10.1073/pnas.230304397

Naylor, 2009, Identification of a chemical probe for NAADP by virtual screening., Nat. Chem. Biol., 5, 220, 10.1038/nchembio.150

Nobrega, 2009, Distinct genetic regulation of progression of diabetes and renal disease in the Goto-Kakizaki rat., Physiol. Genomics, 39, 38, 10.1152/physiolgenomics.90389.2008

Ozcan, 2012, Calcium signaling through CaMKII regulates hepatic glucose production in fasting and obesity., Cell Metab., 15, 739, 10.1016/j.cmet.2012.03.002

Park, 2013, Autocrine/paracrine function of nicotinic acid adenine dinucleotide phosphate (NAADP) for glucose homeostasis in pancreatic beta-cells and adipocytes., J. Biol. Chem., 288, 35548, 10.1074/jbc.M113.489278

Petretto, 2008, Integrated genomic approaches implicate osteoglycin (Ogn) in the regulation of left ventricular mass., Nat. Genet., 40, 546, 10.1038/ng.134

Pfaffl, 2001, A new mathematical model for relative quantification in real-time RT-PCR., Nucleic Acids Res., 29, e45, 10.1093/nar/29.9.e45

Saar, 2008, SNP and haplotype mapping for genetic analysis in the rat., Nat. Genet., 40, 560, 10.1038/ng.124

Samuelson, 2007, Rat Mcs5a is a compound quantitative trait locus with orthologous human loci that associate with breast cancer risk., Proc. Natl. Acad. Sci. USA, 104, 6299, 10.1073/pnas.0701687104

Schieder, 2010, Characterization of two-pore channel 2 (TPCN2)-mediated Ca2+ currents in isolated lysosomes., J. Biol. Chem., 285, 21219, 10.1074/jbc.C110.143123

Scott, 2012, Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways., Nat. Genet., 44, 991, 10.1038/ng.2385

Shawl, 2009, Insulin receptor signaling for the proliferation of pancreatic beta-cells: involvement of Ca2+ second messengers, IP3, NAADP and cADPR., Islets, 1, 216, 10.4161/isl.1.3.9646

So, 2011, Evaluating the heritability explained by known susceptibility variants: a survey of ten complex diseases., Genet. Epidemiol., 35, 310, 10.1002/gepi.20579

Solberg Woods, 2014, QTL mapping in outbred populations: successes and challenges., Physiol. Genomics, 46, 81, 10.1152/physiolgenomics.00127.2013

Solberg Woods, 2009, Identification of genetic loci involved in diabetes using a rat model of depression., Mamm. Genome, 20, 486, 10.1007/s00335-009-9211-8

Solberg Woods, 2010, Fine-mapping a locus for glucose tolerance using heterogeneous stock rats., Physiol. Genomics, 41, 102, 10.1152/physiolgenomics.00178.2009

Solberg Woods, 2012, Fine-mapping diabetes-related traits, including insulin resistance, in heterogeneous stock rats., Physiol. Genomics, 44, 1013, 10.1152/physiolgenomics.00040.2012

Steinthorsdottir, 2014, Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes., Nat. Genet., 46, 294, 10.1038/ng.2882

Svenson, 2012, High-resolution genetic mapping using the Mouse Diversity outbred population., Genetics, 190, 437, 10.1534/genetics.111.132597

Swanberg, 2005, MHC2TA is associated with differential MHC molecule expression and susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction., Nat. Genet., 37, 486, 10.1038/ng1544

Talbot, 1999, High-resolution mapping of quantitative trait loci in outbred mice., Nat. Genet., 21, 305, 10.1038/6825

Talbot, 2003, Fine scale mapping of a genetic locus for conditioned fear., Mamm. Genome, 14, 223, 10.1007/s00335-002-3059-5

Taylor, 2011, Regulation of gene expression by carbon dioxide., J. Physiol., 589, 797, 10.1113/jphysiol.2010.201467

Untergasser, 2012, Primer3–new capabilities and interfaces., Nucleic Acids Res., 40, e115, 10.1093/nar/gks596

Valdar, 2006, Genome-wide genetic association of complex traits in heterogeneous stock mice., Nat. Genet., 38, 879, 10.1038/ng1840

Valdar, 2009, Mapping in structured populations by resample model averaging., Genetics, 182, 1263, 10.1534/genetics.109.100727

Voight, 2010, Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis., Nat. Genet., 42, 579, 10.1038/ng.609

Wallis, 2009, Type 1 diabetes in the BB rat: a polygenic disease., Diabetes, 58, 1007, 10.2337/db08-1215

Wei, 1999, Mapping and characterization of quantitative trait loci for non-insulin-dependent diabetes mellitus with an improved genetic map in the Otsuka Long-Evans Tokushima fatty rat., Mamm. Genome, 10, 249, 10.1007/s003359900982

Yalcin, 2004, Unexpected complexity in the haplotypes of commonly used inbred strains of laboratory mice., Proc. Natl. Acad. Sci. USA, 101, 9734, 10.1073/pnas.0401189101

Yalcin, 2004, Genetic dissection of a behavioral quantitative trait locus shows that Rgs2 modulates anxiety in mice., Nat. Genet., 36, 1197, 10.1038/ng1450

Yalcin, 2005, Using progenitor strain information to identify quantitative trait nucleotides in outbred mice., Genetics, 171, 673, 10.1534/genetics.104.028902

Yalcin, 2010, Commercially available outbred mice for genome-wide association studies., PLoS Genet., 6, 10.1371/journal.pgen.1001085

Zeggini, 2008, Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes., Nat. Genet., 40, 638, 10.1038/ng.120

Zuk, 2014, Searching for missing heritability: designing rare variant association studies., Proc. Natl. Acad. Sci. USA, 111, E455, 10.1073/pnas.1322563111

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Genetics

Tập 198 Số 1

17-29

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