title: An Islet-Targeted Genome-Wide Association Scan Identifies Novel Genes Implicated in Cytokine-Mediated Islet Stress in Type 2 Diabetes.
abstract: Genome-wide association studies in human type 2 diabetes (T2D) have renewed interest in the pancreatic islet as a contributor to T2D risk. Chronic low-grade inflammation resulting from obesity is a risk factor for T2D and a possible trigger of β-cell failure. In this study, microarray data were collected from mouse islets after overnight treatment with cytokines at concentrations consistent with the chronic low-grade inflammation in T2D. Genes with a cytokine-induced change of >2-fold were then examined for associations between single nucleotide polymorphisms and the acute insulin response to glucose (AIRg) using data from the Genetics Underlying Diabetes in Hispanics (GUARDIAN) Consortium. Significant evidence of association was found between AIRg and single nucleotide polymorphisms in Arap3 (5q31.3), F13a1 (6p25.3), Klhl6 (3q27.1), Nid1 (1q42.3), Pamr1 (11p13), Ripk2 (8q21.3), and Steap4 (7q21.12). To assess the potential relevance to islet function, mouse islets were exposed to conditions modeling low-grade inflammation, mitochondrial stress, endoplasmic reticulum (ER) stress, glucotoxicity, and lipotoxicity. RT-PCR revealed that one or more forms of stress significantly altered expression levels of all genes except Arap3. Thapsigargin-induced ER stress up-regulated both Pamr1 and Klhl6. Three genes confirmed microarray predictions of significant cytokine sensitivity: F13a1 was down-regulated 3.3-fold by cytokines, Ripk2 was up-regulated 1.5- to 3-fold by all stressors, and Steap4 was profoundly cytokine sensitive (167-fold up-regulation). Three genes were thus closely associated with low-grade inflammation in murine islets and also with a marker for islet function (AIRg) in a diabetes-prone human population. This islet-targeted genome-wide association scan identified several previously unrecognized candidate genes related to islet dysfunction during the development of T2D.
authors.affiliation: Department of Medicine (P.R.S., E.A.D., J.W.R., C.S.N.), Center for Public Health Genomics (A.J.M., S.S.R.), and Department of Chemistry (E.A.D.), University of Virginia, Charlottesville, Virginia 22904; Department of Biochemistry (N.D.P.), Center for Genomics and Personalized Medicine Research (N.D.P.), Center for Diabetes Research (N.D.P.), Center for Public Health Genomics (C.D.L., N.D.P., L.E.W.), Department of Biostatistical Sciences (C.D.L.), and Division of Public Health Sciences (L.E.W.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157; Department of Physiology and Biophysics (R.M.W.), Department of Preventive Medicine, and USC Diabetes and Obesity Research Institute (R.M.W.), Keck School of Medicine of University of Southern California, Los Angeles, California 90033; and Institute for Translational Genomics and Population Sciences (K.D.T.) and Department of Pediatrics (K.D.T.), Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502.
authors.forename: Poonam R
authors.initials: PR
authors.lastname: Sharma
authors.affiliation: Department of Medicine (P.R.S., E.A.D., J.W.R., C.S.N.), Center for Public Health Genomics (A.J.M., S.S.R.), and Department of Chemistry (E.A.D.), University of Virginia, Charlottesville, Virginia 22904; Department of Biochemistry (N.D.P.), Center for Genomics and Personalized Medicine Research (N.D.P.), Center for Diabetes Research (N.D.P.), Center for Public Health Genomics (C.D.L., N.D.P., L.E.W.), Department of Biostatistical Sciences (C.D.L.), and Division of Public Health Sciences (L.E.W.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157; Department of Physiology and Biophysics (R.M.W.), Department of Preventive Medicine, and USC Diabetes and Obesity Research Institute (R.M.W.), Keck School of Medicine of University of Southern California, Los Angeles, California 90033; and Institute for Translational Genomics and Population Sciences (K.D.T.) and Department of Pediatrics (K.D.T.), Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Mackey
authors.affiliation: Department of Medicine (P.R.S., E.A.D., J.W.R., C.S.N.), Center for Public Health Genomics (A.J.M., S.S.R.), and Department of Chemistry (E.A.D.), University of Virginia, Charlottesville, Virginia 22904; Department of Biochemistry (N.D.P.), Center for Genomics and Personalized Medicine Research (N.D.P.), Center for Diabetes Research (N.D.P.), Center for Public Health Genomics (C.D.L., N.D.P., L.E.W.), Department of Biostatistical Sciences (C.D.L.), and Division of Public Health Sciences (L.E.W.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157; Department of Physiology and Biophysics (R.M.W.), Department of Preventive Medicine, and USC Diabetes and Obesity Research Institute (R.M.W.), Keck School of Medicine of University of Southern California, Los Angeles, California 90033; and Institute for Translational Genomics and Population Sciences (K.D.T.) and Department of Pediatrics (K.D.T.), Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502.
authors.forename: Eden A
authors.initials: EA
authors.lastname: Dejene
authors.affiliation: Department of Medicine (P.R.S., E.A.D., J.W.R., C.S.N.), Center for Public Health Genomics (A.J.M., S.S.R.), and Department of Chemistry (E.A.D.), University of Virginia, Charlottesville, Virginia 22904; Department of Biochemistry (N.D.P.), Center for Genomics and Personalized Medicine Research (N.D.P.), Center for Diabetes Research (N.D.P.), Center for Public Health Genomics (C.D.L., N.D.P., L.E.W.), Department of Biostatistical Sciences (C.D.L.), and Division of Public Health Sciences (L.E.W.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157; Department of Physiology and Biophysics (R.M.W.), Department of Preventive Medicine, and USC Diabetes and Obesity Research Institute (R.M.W.), Keck School of Medicine of University of Southern California, Los Angeles, California 90033; and Institute for Translational Genomics and Population Sciences (K.D.T.) and Department of Pediatrics (K.D.T.), Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502.
authors.forename: James W
authors.initials: JW
authors.lastname: Ramadan
authors.affiliation: Department of Medicine (P.R.S., E.A.D., J.W.R., C.S.N.), Center for Public Health Genomics (A.J.M., S.S.R.), and Department of Chemistry (E.A.D.), University of Virginia, Charlottesville, Virginia 22904; Department of Biochemistry (N.D.P.), Center for Genomics and Personalized Medicine Research (N.D.P.), Center for Diabetes Research (N.D.P.), Center for Public Health Genomics (C.D.L., N.D.P., L.E.W.), Department of Biostatistical Sciences (C.D.L.), and Division of Public Health Sciences (L.E.W.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157; Department of Physiology and Biophysics (R.M.W.), Department of Preventive Medicine, and USC Diabetes and Obesity Research Institute (R.M.W.), Keck School of Medicine of University of Southern California, Los Angeles, California 90033; and Institute for Translational Genomics and Population Sciences (K.D.T.) and Department of Pediatrics (K.D.T.), Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.affiliation: Department of Medicine (P.R.S., E.A.D., J.W.R., C.S.N.), Center for Public Health Genomics (A.J.M., S.S.R.), and Department of Chemistry (E.A.D.), University of Virginia, Charlottesville, Virginia 22904; Department of Biochemistry (N.D.P.), Center for Genomics and Personalized Medicine Research (N.D.P.), Center for Diabetes Research (N.D.P.), Center for Public Health Genomics (C.D.L., N.D.P., L.E.W.), Department of Biostatistical Sciences (C.D.L.), and Division of Public Health Sciences (L.E.W.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157; Department of Physiology and Biophysics (R.M.W.), Department of Preventive Medicine, and USC Diabetes and Obesity Research Institute (R.M.W.), Keck School of Medicine of University of Southern California, Los Angeles, California 90033; and Institute for Translational Genomics and Population Sciences (K.D.T.) and Department of Pediatrics (K.D.T.), Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502.
authors.forename: Nicholette D
authors.initials: ND
authors.lastname: Palmer
authors.affiliation: Department of Medicine (P.R.S., E.A.D., J.W.R., C.S.N.), Center for Public Health Genomics (A.J.M., S.S.R.), and Department of Chemistry (E.A.D.), University of Virginia, Charlottesville, Virginia 22904; Department of Biochemistry (N.D.P.), Center for Genomics and Personalized Medicine Research (N.D.P.), Center for Diabetes Research (N.D.P.), Center for Public Health Genomics (C.D.L., N.D.P., L.E.W.), Department of Biostatistical Sciences (C.D.L.), and Division of Public Health Sciences (L.E.W.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157; Department of Physiology and Biophysics (R.M.W.), Department of Preventive Medicine, and USC Diabetes and Obesity Research Institute (R.M.W.), Keck School of Medicine of University of Southern California, Los Angeles, California 90033; and Institute for Translational Genomics and Population Sciences (K.D.T.) and Department of Pediatrics (K.D.T.), Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502.
authors.forename: Kent D
authors.initials: KD
authors.lastname: Taylor
authors.affiliation: Department of Medicine (P.R.S., E.A.D., J.W.R., C.S.N.), Center for Public Health Genomics (A.J.M., S.S.R.), and Department of Chemistry (E.A.D.), University of Virginia, Charlottesville, Virginia 22904; Department of Biochemistry (N.D.P.), Center for Genomics and Personalized Medicine Research (N.D.P.), Center for Diabetes Research (N.D.P.), Center for Public Health Genomics (C.D.L., N.D.P., L.E.W.), Department of Biostatistical Sciences (C.D.L.), and Division of Public Health Sciences (L.E.W.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157; Department of Physiology and Biophysics (R.M.W.), Department of Preventive Medicine, and USC Diabetes and Obesity Research Institute (R.M.W.), Keck School of Medicine of University of Southern California, Los Angeles, California 90033; and Institute for Translational Genomics and Population Sciences (K.D.T.) and Department of Pediatrics (K.D.T.), Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502.
authors.forename: Lynne E
authors.initials: LE
authors.lastname: Wagenknecht
authors.affiliation: Department of Medicine (P.R.S., E.A.D., J.W.R., C.S.N.), Center for Public Health Genomics (A.J.M., S.S.R.), and Department of Chemistry (E.A.D.), University of Virginia, Charlottesville, Virginia 22904; Department of Biochemistry (N.D.P.), Center for Genomics and Personalized Medicine Research (N.D.P.), Center for Diabetes Research (N.D.P.), Center for Public Health Genomics (C.D.L., N.D.P., L.E.W.), Department of Biostatistical Sciences (C.D.L.), and Division of Public Health Sciences (L.E.W.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157; Department of Physiology and Biophysics (R.M.W.), Department of Preventive Medicine, and USC Diabetes and Obesity Research Institute (R.M.W.), Keck School of Medicine of University of Southern California, Los Angeles, California 90033; and Institute for Translational Genomics and Population Sciences (K.D.T.) and Department of Pediatrics (K.D.T.), Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Watanabe
authors.affiliation: Department of Medicine (P.R.S., E.A.D., J.W.R., C.S.N.), Center for Public Health Genomics (A.J.M., S.S.R.), and Department of Chemistry (E.A.D.), University of Virginia, Charlottesville, Virginia 22904; Department of Biochemistry (N.D.P.), Center for Genomics and Personalized Medicine Research (N.D.P.), Center for Diabetes Research (N.D.P.), Center for Public Health Genomics (C.D.L., N.D.P., L.E.W.), Department of Biostatistical Sciences (C.D.L.), and Division of Public Health Sciences (L.E.W.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157; Department of Physiology and Biophysics (R.M.W.), Department of Preventive Medicine, and USC Diabetes and Obesity Research Institute (R.M.W.), Keck School of Medicine of University of Southern California, Los Angeles, California 90033; and Institute for Translational Genomics and Population Sciences (K.D.T.) and Department of Pediatrics (K.D.T.), Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.affiliation: Department of Medicine (P.R.S., E.A.D., J.W.R., C.S.N.), Center for Public Health Genomics (A.J.M., S.S.R.), and Department of Chemistry (E.A.D.), University of Virginia, Charlottesville, Virginia 22904; Department of Biochemistry (N.D.P.), Center for Genomics and Personalized Medicine Research (N.D.P.), Center for Diabetes Research (N.D.P.), Center for Public Health Genomics (C.D.L., N.D.P., L.E.W.), Department of Biostatistical Sciences (C.D.L.), and Division of Public Health Sciences (L.E.W.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157; Department of Physiology and Biophysics (R.M.W.), Department of Preventive Medicine, and USC Diabetes and Obesity Research Institute (R.M.W.), Keck School of Medicine of University of Southern California, Los Angeles, California 90033; and Institute for Translational Genomics and Population Sciences (K.D.T.) and Department of Pediatrics (K.D.T.), Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502.
authors.forename: Craig S
authors.initials: CS
authors.lastname: Nunemaker
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005176:Factor XIII / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D053583:Interleukin-1beta; D015850:Interleukin-6; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D057057:Serine Proteases; D013312:Stress, Physiological
chemical_list: D002352:Carrier Proteins; D053583:Interleukin-1beta; D015850:Interleukin-6; C489839:Klhl6 protein, mouse; D008565:Membrane Proteins; C436323:Tiarp protein, mouse; D005176:Factor XIII; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506255:Ripk2 protein, mouse; D057057:Serine Proteases; C000602676:Pamr1 protein, mouse; D012697:Serine Endopeptidases