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Gene expression profiling of liver from GSD1a patients: evidence of an inflammatory process The world of omics International meeting Glycogen Storage Diseases.

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Presentation on theme: "Gene expression profiling of liver from GSD1a patients: evidence of an inflammatory process The world of omics International meeting Glycogen Storage Diseases."— Presentation transcript:

1 Gene expression profiling of liver from GSD1a patients: evidence of an inflammatory process The world of omics International meeting Glycogen Storage Diseases associations Milan October 2 nd 2010 Luigi Varesio

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4 54000 probsets The chip

5 Gene expression profile of GSD1a liver Gene expression profile of the liver of three patients who underwent liver transplantation and of three normal tissues. Data analysis with Bibliosphere (Genomatics) to study metabolic pathways. Gene expression profile of the liver of three patients who underwent liver transplantation and of three normal tissues. Data analysis with Bibliosphere (Genomatics) to study metabolic pathways.

6 GSD1a Clinical manifestations hepatomegaly hypoglycemia hyperuricemia hyperlipidemia growth retardation Complications lack of growth delay of puberty gout juvenile pancreatitis arteriosclerosis hepatomas hypertension adenomas kidney diseases G6Pase sugars fat proteins ? What causes complications?

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9 GSD1a patients have higher levels of IL-6 Possible state of chronic inflammation

10 CX3CL1chemokine (C-X3-C motif) ligand 1 CCL2chemokine (C-C motif) ligand 2 CMKOR1chemokine orphan receptor 1 CXCR4chemokine (C-X-C motif) receptor 4 CXCR4chemokine (C-X-C motif) receptor 4 XCL1chemokine (C motif) ligand 1 CCL14chemokine (C-C motif) ligand 15 CCL3chemokine (C-C motif) ligand 3 CCL4chemokine (C-C motif) ligand 4 CXCL9chemokine (C-X-C motif) ligand 9 CRLF3cytokine receptor-like factor 3 SOCS3suppressor of cytokine signaling 3 CISHcytokine inducible SH2-containing protein IL17RCinterleukin 17 receptor C IL1RAPL1interleukin 1 receptor accessory protein-like 1 IL1RNinterleukin 1 receptor antagonist IL8 Homo sapiens interleukin 8 C-terminal variant (IL8) mRNA, complete cds. IL10interleukin 10 IL18RAPinterleukin 18 receptor accessory protein IL8RBinterleukin 8 receptor, beta IL1R2interleukin 1 receptor, type II IL6interleukin 6 (interferon, beta 2) IL10RAinterleukin 10 receptor, alpha IL1RL1LGinterleukin 1 receptor-like 1 ligand IL8interleukin 8 ILF2interleukin enhancer binding factor 2, 45kDa GSD1a can be associated with an inflammatory state

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12 IL-6 transgenic mice De Benedetti, J Clin Invest day-old littermates

13 GSD1a Clinical manifestations h epatomegaly hypoglycemia hyperuricemia hyperlipidemia growth retardation Complications lack of gowth delay of puberty gout juvenile pancreatitis arteriosclerosis hepatomas hypertension adenomas kidney diseases sugars fats proteins G6Pase Inflammation Cytokines IL-6, IL-8

14 Hypoxia in patho-physiological processes HYPOXIA (pO mm Hg) Growing tumors Cerebral ischemia Myocardial ischemia Pulmonary hypertension Rheumatoid arthritis Diabetic retinopathy Wound healing Preeclampsia Intrauterine growth retardation Energy metabolism Cell proliferation/ survival Angiogenesis Cell survival Cell migration Erytropoiesis Microbial infections Aherosclerosis

15 Hypoxia in the liver of GSD1a patients NAME 23 GENI OXP HYPOXIA_REG_UP LINES_MYC_LEA NB-HYPO_32 GENES L1L2_11PBST HYPOXIA_RCC_NOVHL_UP L1L2_M- V$HIF1_Q3 HYPOXIA_NORMAL_UP HIF1_TARGETS L1L2_M+ TRP_U133 HYPOXIA_REVIEW V$HIF1_Q5 HYPOXIA_RCC_UP LEA_C1_SET_TOP NAME HSA00190_OXIDATIVE_PHOSPHORYLATION HSA00330_ARGININE_AND_PROLINE_METABOLISM HSA01040_POLYUNSATURATED_FATTY_ACID_BIOSYNTHESIS HSA00272_CYSTEINE_METABOLISM HSA00360_PHENYLALANINE_METABOLISM HSA00010_GLYCOLYSIS_AND_GLUCONEOGENESIS HSA00020_CITRATE_CYCLE HSA00910_NITROGEN_METABOLISM HSA00252_ALANINE_AND_ASPARTATE_METABOLISM HSA00030_PENTOSE_PHOSPHATE_PATHWAY HSA04610_COMPLEMENT_AND_COAGULATION_CASCADES HSA00220_UREA_CYCLE_AND_METABOLISM_OF_AMINO_GROUPS

16 O2O2O2O2 CC-chemokine receptors Gro-chemokines Monocyte trapping Circulation Monocyte Hypoxic tissue Mn migration inhibiting factor (MIF) G-protein deactivator (RGS1) Motility-promoting factor (ENPP2) CXC-Chemokines Neutrophils recruitment

17 Necrotic foci, elevated chemokines and infiltrating neutrophils in the liver of glycogen storage disease type Ia. Kim DY et al, J Hepatol Necrotic foci, elevated chemokines and infiltrating neutrophils in the liver of glycogen storage disease type Ia. Kim DY et al, J Hepatol What causes these effects? Liver hypoxia can

18 GSD1a Clinical manifestations h epatomegaly hypoglycemia hyperuricemia hyperlipidemia growth retardation Complications lack of gowth delay of puberty gout juvenile pancreatitis arteriosclerosis hepatomas hypertension adenomas kidney diseases sugars fats proteins G6Pase Inflammation Cytokines IL-6, IL-8 Liver Hypoxia

19 IL-6 IL-6R gp130 sIL-6R MRA (Tocilizumab) a humanized moAb to the IL-6R Y Y Y Y Y Y MRA gp130

20 CollaboratorsCollaborators Molecular Biology Gaslini Molecular Biology Gaslini R. LavieriR. Lavieri A. EvaA. Eva P. FardinP. Fardin R.ResazR.Resaz L. VaresioL. Varesio Molecular Biology Gaslini Molecular Biology Gaslini R. LavieriR. Lavieri A. EvaA. Eva P. FardinP. Fardin R.ResazR.Resaz L. VaresioL. Varesio National Institutes of Health (USA) J.ChouJ.Chou D. MunroeD. Munroe S.K. AryaS.K. Arya National Institutes of Health (USA) J.ChouJ.Chou D. MunroeD. Munroe S.K. AryaS.K. Arya IST Genova O. BarbieriO. Barbieri IST Genova O. BarbieriO. Barbieri Clinical Departments Dr. M. Di Rocco Dr. M. Di Rocco G.Gaslini Institute (Genova) G.Gaslini Institute (Genova) Dr. D. Melis Dr. D. Melis Federico II University (Napoli) Federico II University (Napoli) Dr. R.Parini Dr. R.Parini S.Gerardo Hospital (Monza)S.Gerardo Hospital (Monza) Dr. S. Paci Dr. S. Paci S.Paolo Hospital (Milano)S.Paolo Hospital (Milano) Dr. E. Procopio Dr. E. Procopio Meyer Hospital (Firenze)Meyer Hospital (Firenze) Dr. C. Dionisi Dr. C. Dionisi Bambin Gesù Hospital (Roma)Bambin Gesù Hospital (Roma) Clinical Departments Dr. M. Di Rocco Dr. M. Di Rocco G.Gaslini Institute (Genova) G.Gaslini Institute (Genova) Dr. D. Melis Dr. D. Melis Federico II University (Napoli) Federico II University (Napoli) Dr. R.Parini Dr. R.Parini S.Gerardo Hospital (Monza)S.Gerardo Hospital (Monza) Dr. S. Paci Dr. S. Paci S.Paolo Hospital (Milano)S.Paolo Hospital (Milano) Dr. E. Procopio Dr. E. Procopio Meyer Hospital (Firenze)Meyer Hospital (Firenze) Dr. C. Dionisi Dr. C. Dionisi Bambin Gesù Hospital (Roma)Bambin Gesù Hospital (Roma) Associazione Italiana Glicogenosi


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