An Islet-Targeted Genome-Wide Association Scan Identifies Novel Genes Implicated in Cytokine-Mediated Islet Stress in Type 2 Diabetes.
| Title: | An Islet-Targeted Genome-Wide Association Scan Identifies Novel Genes Implicated in Cytokine-Mediated Islet Stress in Type 2 Diabetes. |
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| Authors: | Sharma PR; 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.; Mackey AJ; 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.; Dejene EA; 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.; Ramadan JW; 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.; Langefeld CD; 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.; Palmer ND; 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.; Taylor KD; 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.; Wagenknecht LE; 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.; Watanabe RM; 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.; Rich SS; 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.; Nunemaker CS; 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. |
| Source: | Endocrinology [Endocrinology] 2015 Sep; Vol. 156 (9), pp. 3147-56. Date of Electronic Publication: 2015 May 27. |
| Publication Type: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Oxford University Press Country of Publication: United States NLM ID: 0375040 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1945-7170 (Electronic) Linking ISSN: 00137227 NLM ISO Abbreviation: Endocrinology Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2017- : New York : Oxford University Press; Original Publication: Los Angeles, Calif. : Association for the Study of Internal Secretions |
| MeSH Terms: | Stress, Physiological*; Diabetes Mellitus, Type 2/*metabolism ; Inflammation/*metabolism ; Islets of Langerhans/*metabolism; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Diabetes Mellitus, Experimental/metabolism ; Factor XIII/genetics ; Factor XIII/metabolism ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/genetics ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; Serine Endopeptidases/genetics ; Serine Endopeptidases/metabolism ; Animals ; Gene Expression Profiling ; Genome-Wide Association Study ; Humans ; Interleukin-1beta ; Interleukin-6 ; Male ; Mice ; Oligonucleotide Array Sequence Analysis ; Receptor-Interacting Protein Serine-Threonine Kinase 2 ; Serine Proteases |
| 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. |
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| Grant Information: | R01 DK089182 United States DK NIDDK NIH HHS; R01 DK085175 United States DK NIDDK NIH HHS; R01DK089182 United States DK NIDDK NIH HHS; R01 DK061628 United States DK NIDDK NIH HHS; HL47902 United States HL NHLBI NIH HHS; HL047890 United States HL NHLBI NIH HHS; HL047887 United States HL NHLBI NIH HHS; HL060919 United States HL NHLBI NIH HHS; UL1 TR000124 United States TR NCATS NIH HHS; R01 HL060944 United States HL NHLBI NIH HHS; K01DK081621 United States DK NIDDK NIH HHS; DK085175 United States DK NIDDK NIH HHS; U01 HL047902 United States HL NHLBI NIH HHS; P30 DK063491 United States DK NIDDK NIH HHS; K01 DK081621 United States DK NIDDK NIH HHS; R01 HL061019 United States HL NHLBI NIH HHS; HL060944 United States HL NHLBI NIH HHS; HL047889 United States HL NHLBI NIH HHS; DK061628 United States DK NIDDK NIH HHS; R01 HL060919 United States HL NHLBI NIH HHS; HL061019 United States HL NHLBI NIH HHS |
| Substance Nomenclature: | 0 (Carrier Proteins); 0 (Interleukin-1beta); 0 (Interleukin-6); 0 (Klhl6 protein, mouse); 0 (Membrane Proteins); 0 (Tiarp protein, mouse); 9013-56-3 (Factor XIII); EC 2.7.11.1 (Receptor-Interacting Protein Serine-Threonine Kinase 2); EC 2.7.11.1 (Receptor-Interacting Protein Serine-Threonine Kinases); EC 2.7.11.1 (Ripk2 protein, mouse); EC 3.4.- (Serine Proteases); EC 3.4.21.- (Pamr1 protein, mouse); EC 3.4.21.- (Serine Endopeptidases) |
| Entry Date(s): | Date Created: 20150529 Date Completed: 20151117 Latest Revision: 20201209 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC4541617 |
| DOI: | 10.1210/en.2015-1203 |
| PMID: | 26018251 |
| Database: | MEDLINE |
Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't