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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 associationsInternational meeting Glycogen Storage Diseases associationsMilan October 2Milan October 2ndnd 2010 2010
Luigi VaresioLuigi Varesio
54000 probsets54000 probsets
The chipThe chip
Gene expression Gene expression profile of GSD1a profile of GSD1a
liverliver
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.
GSD1aClinical manifestations hepatomegaly
hypoglycemiahyperuricemiahyperlipidemiagrowth retardation
Complicationslack of growthdelay of pubertygout juvenilepancreatitisarteriosclerosishepatomashypertensionadenomaskidney diseases
G6PaseG6Pase
sugars
fat
proteins
??
What causes complications?
What causes complications?
0
5
10
15
20
25
30
35
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22IL6 Control
patient
IL-6
IL6 in GSD1a patients
IL6 Control
IL6 GSD1a
GSD1a patients have higher levels of IL-6GSD1a patients have higher levels of IL-6
Possible state of chronic inflammationPossible state of chronic inflammation
CX3CL1 chemokine (C-X3-C motif) ligand 1
CCL2 chemokine (C-C motif) ligand 2
CMKOR1 chemokine orphan receptor 1
CXCR4 chemokine (C-X-C motif) receptor 4
CXCR4 chemokine (C-X-C motif) receptor 4
XCL1 chemokine (C motif) ligand 1
CCL14 chemokine (C-C motif) ligand 15
CCL3 chemokine (C-C motif) ligand 3
CCL4 chemokine (C-C motif) ligand 4
CXCL9 chemokine (C-X-C motif) ligand 9
CRLF3 cytokine receptor-like factor 3
SOCS3 suppressor of cytokine signaling 3
CISH cytokine inducible SH2-containing protein
IL17RC interleukin 17 receptor C
IL1RAPL1 interleukin 1 receptor accessory protein-like 1
IL1RN interleukin 1 receptor antagonist
IL8Homo sapiens interleukin 8 C-terminal variant (IL8) mRNA, complete cds.
IL10 interleukin 10
IL18RAP interleukin 18 receptor accessory protein
IL8RB interleukin 8 receptor, beta
IL1R2 interleukin 1 receptor, type II
IL6 interleukin 6 (interferon, beta 2)
IL10RA interleukin 10 receptor, alpha
IL1RL1LG interleukin 1 receptor-like 1 ligand
IL8 interleukin 8
ILF2 interleukin enhancer binding factor 2, 45kDa
GSD1a can be associated with an inflammatory state
GSD1a can be associated with an inflammatory state
IL-6 transgenic mice
0
10
20
30
1 14 28 42 56
Age (day)
Bo
dy
wei
gh
t (g
r)
Wild-type Transgenic
De Benedetti, J Clin Invest 1997
12 day-old littermates
GSD1aClinical manifestations hepatomegaly
hypoglycemiahyperuricemiahyperlipidemiagrowth retardation
Complicationslack of gowthdelay of pubertygout juvenilepancreatitisarteriosclerosishepatomashypertensionadenomaskidney diseases
sugars
fats
proteins
G6PaseG6Pase
InflammationInflammation
CytokinesIL-6, IL-8
Hypoxia in patho-physiological processesHypoxia in patho-physiological processesHypoxia in patho-physiological processesHypoxia in patho-physiological processes
HYPOXIA(pO2 0-20mm Hg)
Growing tumors
Cerebral ischemia Myocardial ischemia
Pulmonary hypertension
Rheumatoid arthritis
Diabetic retinopathy
Wound healing
PreeclampsiaIntrauterine growth
retardation
Energy metabolism
Cell proliferation/survival
Angiogenesis Cell survival
Cell migrationErytropoiesis
Microbial infections
Aherosclerosis
Hypoxia in the liver of GSD1a patients Hypoxia in the liver of GSD1a patients Hypoxia in the liver of GSD1a patients Hypoxia in the liver of GSD1a patients
NAMENAME
23 GENI OXP23 GENI OXP
HYPOXIA_REG_UPHYPOXIA_REG_UP
LINES_MYC_LEALINES_MYC_LEA
NB-HYPO_32 GENESNB-HYPO_32 GENES
L1L2_11PBSTL1L2_11PBST
HYPOXIA_RCC_NOVHL_UPHYPOXIA_RCC_NOVHL_UP
L1L2_M-L1L2_M-
V$HIF1_Q3V$HIF1_Q3
HYPOXIA_NORMAL_UPHYPOXIA_NORMAL_UP
HIF1_TARGETSHIF1_TARGETS
L1L2_M+L1L2_M+
TRP_U133TRP_U133
HYPOXIA_REVIEWHYPOXIA_REVIEW
V$HIF1_Q5V$HIF1_Q5
HYPOXIA_RCC_UPHYPOXIA_RCC_UP
LEA_C1_SET_TOPLEA_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
OO22
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
Necrotic foci, elevated chemokines and infiltrating neutrophils in the
liver of glycogen storage disease type Ia.
Kim DY et al, J Hepatol. 2008Necrotic foci, elevated chemokines and infiltrating neutrophils in the
liver of glycogen storage disease type Ia.
Kim DY et al, J Hepatol. 2008
What causes these effects?
What causes these effects?
Liver hypoxia canLiver hypoxia can
GSD1aClinical manifestations hepatomegaly
hypoglycemiahyperuricemiahyperlipidemiagrowth retardation
Complicationslack of gowthdelay of pubertygout juvenilepancreatitisarteriosclerosishepatomashypertensionadenomaskidney diseases
sugars
fats
proteins
G6PaseG6Pase
InflammationInflammation
CytokinesIL-6, IL-8
Liver Liver HypoxiaHypoxia
IL-6
IL-6Rgp130
sIL-6R
MRA (Tocilizumab)a humanized moAb to the IL-6R
YY
YYYY
MRA
gp130
CollaboratorsCollaboratorsCollaboratorsCollaborators
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
NationalNational Institutes of Health Institutes of Health (USA)(USA)• J.ChouJ.Chou• D. MunroeD. Munroe• S.K. AryaS.K. Arya
NationalNational Institutes of Health Institutes of Health (USA)(USA)• J.ChouJ.Chou• D. MunroeD. Munroe• S.K. AryaS.K. Arya
IST Genova IST Genova • O. BarbieriO. Barbieri
IST Genova IST Genova • O. BarbieriO. Barbieri
Clinical DepartmentsClinical Departments
Dr. M. Di RoccoDr. M. Di Rocco• G.Gaslini Institute (Genova)G.Gaslini Institute (Genova)
Dr. D. MelisDr. D. Melis
• Federico II University (Napoli) Federico II University (Napoli)
Dr. R.PariniDr. R.Parini
•S.Gerardo Hospital (Monza)S.Gerardo Hospital (Monza)
Dr. S. PaciDr. S. Paci
•S.Paolo Hospital (Milano)S.Paolo Hospital (Milano)
Dr. E. ProcopioDr. E. Procopio
•Meyer Hospital (Firenze)Meyer Hospital (Firenze)
Dr. C. DionisiDr. C. Dionisi
•Bambin Gesù Hospital (Roma)Bambin Gesù Hospital (Roma)
Clinical DepartmentsClinical Departments
Dr. M. Di RoccoDr. M. Di Rocco• G.Gaslini Institute (Genova)G.Gaslini Institute (Genova)
Dr. D. MelisDr. D. Melis
• Federico II University (Napoli) Federico II University (Napoli)
Dr. R.PariniDr. R.Parini
•S.Gerardo Hospital (Monza)S.Gerardo Hospital (Monza)
Dr. S. PaciDr. S. Paci
•S.Paolo Hospital (Milano)S.Paolo Hospital (Milano)
Dr. E. ProcopioDr. E. Procopio
•Meyer Hospital (Firenze)Meyer Hospital (Firenze)
Dr. C. DionisiDr. C. Dionisi
•Bambin Gesù Hospital (Roma)Bambin Gesù Hospital (Roma)
Associazione Associazione Italiana Italiana
GlicogenosiGlicogenosi