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Genetic mutations of hyperlipidaemiaand acute pancreatitis
Wei Huang MD PhDSichuan Provincial Pancreatitis Centre
West China BiobanksIntegrated Traditional Chinese and Western Medicine
West China Hospital of Sichuan UniversityPancreasFest 2019 ・ Pittsburgh
Chengdu Global CenterWorld’s largest single building
Sun Bird- City SignB.C. 1300
Hot PotNo.1 in China
Giant PandaWorld’s largest Base of Giant Panda Breeding
Taikoo Li Chengdu2015 Global Award for Excellence (by Urban Land Institute)
Wu Hou ShrineFamous history site of Three Kingdoms period
Chengdu city
Shangjin Campus, 2012, 1170 beds
WCH
Tianfu New Zone Campus,2017-2018, 1500 beds
Leshan Campus, 2019-2020, 2000 beds
Jinjiang Campus, 2018, 1500 beds
Chengdu city
Main Campus,1892, 4300 beds
Omar L. Kilborn
A one-doctor clinicRenji and Cunren Hospital1892
Medical School of West China Union University1914
Wenjiang Campus, 2013, 200 beds
West China Hospital
> 10,000 beds
“Turning quantity into quality”
Pancreatic services in WCH
Pancreatic surgery: circa 1300 cases Necrosectomy: 400 Laparoscopic
pancreaticoduodenectomy: 190 Open pancreaticoduodenectomy: 280
Department of Integrated Traditional Chinese and Western Medicine
(218 beds)
Acupuncture Lung Disease Acute abdomens Anorectal Oncology
Bedsideservice 62 beds 75 beds 57 beds 24 beds
Pharmacology Laboratory of Traditional Chinese
Medicine
Laboratory of Integrated Traditional Chinese and
Western Medicine
Integrated Traditional Chinese and Western Medicine Clinical
Publications in recent 5 years:BMJ, Gut, Am J Gastroenterol, Intensive Care Med, Crit Care Med, Ann Surg, Brit J Surg, Theranostics, J Control Release, Cell Death Dis, Cell Prolif, Acta Pharm Sin B
Metabolic syndrome
Gurka MJ et al. Nutr Diabetes. 2018;8:14Langan SM et al. J Invest Dermatol 2012;132:556-62Li R et al. BMC Public Health 2016;16:296Rampal S et al. PLoS One 2012;7:e46365Nag T et al. Am J Hum Biol 2015;27:724–7SyRG LEJ et al. J Atheroscler Thromb 2014;21:S9–17OguomaVM et al. Public Health 2015;129:413–23de Carvalho VF et al. BMC Public Health 2013;13:1198Gundogan K et al. Arch Med Sci 2013;9:243–53Amirkalali B et al. Iran Red Crescent Med J 2015;17:e24723
Increased prevalence of central obesity and HTG in China
Abdominal obesity
HTG
Crude 7·7 (0·3) 24·8 (0·5)Men 1·7 (0·2) 24·9 (0·7)Women 13·9 (0·5) 24·6 (0·7)LocationNorth 11·0 (0·5) 26·5 (0·7)South 5·5 (0·3) 23·9 (0·6)Urban 10·1 (0·4) 32·3 (0·6)Rural 7·2 (0·3) 23·1 (0·6)
Types Sex No. of study Sample Pooled prevalence(95% CI) (%)
Central obesity Male 14 38,434 33.4 (25.3-41.5)Female 15 44,646 46.1 (37.0-55.2)
Hypertension Male 14 38,434 52.8 (45.3-60.4)Female 15 44,646 40.1 (32.2-48.0)
High FPG Male 14 38,434 31.5 (25.3-37.8)Female 15 44,646 26.3 (19.0-33.6)
HTG Male 14 38,434 32.9 (27.5-38.3)Female 15 44,646 27.7 (22.0-33.4)
Low HDL-C Male 14 38,434 27.4 (22.2-32.5)Female 15 44,646 40.4 (30.6-50.2)
Li R et al. BMC Public Health 2016;16:296Gu D et al. Lancet 2005;365:1398-405
Heterogenous definition for HTG
Carr et al. Pancreatol 2016;16:469-76
Guideline Definition TG levels (mmol/L)
TG levels (mg/dL)
2003 NCEP ATP III
Normal <1.7 <150 Borderline high
1.7–2.3 150–199
High 2.3–5.65 200–499 Very high >5.65 500
2011 ESC/EAS
Normal <1.7 <150 High 1.7–9.9 150-884
Severe ≥10 ≥8852012 Endocrine Society
Normal <1.7 <150 Mild 1.7–2.3 150–199 Moderate 2.3–11.2 200–999 Severe 11.2–22.4 1000–1999 Very severe ≥22.4 ≥2000
NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III; ESC = European Society of Cardiology; EAS = European Atherosclerosis Society
Berglund et al. J Clin Endocrinol Metab 2012;97:2969-89Hegele RA et al. The Lancet Diabetes & Endocrinol 2014;2:655-666
Classification of HTGPrimary HTG GeneticsFamilial chylomicronaemia (HLP type 1) Monogenic; autosomal recessive due to two mutant alleles of LPL, APOC2, APOA5,
LMF1, GPIHBP1, or GPD1Familial combined hyperlipidaemia (HLP type 2B) Polygenic; high GRS for HTG; excess of rare variants in HTG-associated genes; high
GRS for LDL cholesterolDysbetalipoproteinaemia (type 3) Polygenic; high GRS for HTG; excess of rare variants in HTG-associated genes; APOE
ε2/ε2 homozygosity, or heterozygous rare mutation in APOEPrimary or simple hypertriglyceridaemia (type 4) Polygenic; high GRS for HTG; excess of rare variants in HTG-associated genes
Primary mixed hypertriglyceridaemia (type 5) Polygenic; high GRS for HTG; excess of rare variants in HTG-associated genes, with higher burden of risk alleles than for hyperlipoproteinaemia type 4
Secondary HTGDiet with high positive energy-intake balance, and high fat, high glycaemic index and alcohol excess
Disorders of metabolism disease states: obesity, metabolic syndrome, diabetes (mainly type 2 diabetes), pregnancy (particularly in the third trimester), hypothyroidism, hypercortisolism, paraproteinaemiaOther disease states: Renal disease (nephrotic syndrome, renal failure), liver disease (acute hepatitis), systemic lupus erythematosus
Drugs (estrogen, second generation antipsychotic, antidepressants, isotretinoin, rosiglitazone, steroids, thiazides, beta-blockers, bile acid sequesterants, sirolimus, and antiretroviral therapy)
Hegele RA et al. Lancet Diabetes Endocrinol 2014;2:655-66
Official symbol Function Mutation Phenotypes
Approximate homozygote prevalence
LPL Encoding LPL, which catalyses hydrolysis of TG-
rich lipoproteins
LOF Type 1 HLP,
hyperapobetalipoproteinaemia
1 per million
APOA5 Encoding APOA5, which stabilises the
lipoprotein–LPL complex
LOF Familial HTG, familial type 5 HLP <10 families
APOC2 Encoding APOC2, which acts as an essential LPL
activator
LOF Apolipoprotein C2 deficiency <20 families
GPIHBP1 Encoding GPIHBP1, which mediates the
transmembrane transport and binding of LPL
LOF type ID HLP <5 families
LMF1 Encoding LMF1, which is involved in the folding
and expression of LPL
LOF Lipase deficiency combined <5 families
Genetics of HTG
LPL = lipoprotein lipase; TG = triglycerides; LOF = loss of function; APOA5 = apolipoprotein A5; HLP = hyperlipoproteinaemia;APOC2 = apolipoprotein C2; GPIHBP1 = glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1; LMF1 =lipase maturation factor 1
Hegele RA et al. Lancet Diabetes Endocrinol 2014;2:655-66; Khera AV et al. Nat Genet 2018;50:1219-1224
Complex genetic basis for HTG
Polygenic scores vs. monogenic mutations
Liu DJ et al. Nat Genet 2017;49:1758-1766
Protein-altering variants at novel loci
Genetics of pancreatitis
Modified from Mayerle J et al. Gastroenterol 2019; 156:1951-1968.e1951
• PRSS1
• CPA1
• CEL
• …
Trypsin-dependent
pathway
• PRSS1
• PRSS2 (protective)
• SPINK1
• CTRC
• …
• CFTR
• CASR
• CLDN2
• …
Mis-folding–dependent
pathway
Ductal pathways
Gene Mutation Phenotype Mechanism
PRSS1 p.R122C, p.R122H, p.N29I, pA16V, p.P17T, p.D19A, p.D21A, p.D22G, p.K23R, p.K23_I24insIDK
Autosomal dominant HP, familial pancreatitis, or sporadic CP
Trypsin-dependent
p.R116C, p.C139S,p.L104P, p.C139F, p.G208A, p. D100H, p. K92N, p.S124F
Sporadic or familial CP Mis-folding–dependent
c.-204C>A Protection against alcoholic CP Trypsin-dependent
PRSS2 p.G191R Protection against CP Trypsin-dependent
PRSS1-PRSS2 Copy Number Mutations Hereditary pancreatitis, idiopathic CP Trypsin-dependent
SPINK1 p.N34S, c.194þ2T>C Increased susceptibility for CP Trypsin-dependent
CTRC p.A73T, p.K247_R254del, p.R254W, p.V235I, p.G60=
Increased susceptibility for CP Trypsin-dependent
CTRB1-2 Locus inversion Protection against CP Trypsin-dependent
CPA1 p.N256K, p.S282P, p.R382W, p.R27X Sporadic and familial CP Mis-folding–dependentCEL Single-nucleotide deletions MODY8 Mis-folding–dependent
CEL-HYB1 Increased susceptibility for CP Mis-folding–dependentPNLIP p.T221M Increased susceptibility for CP Mis-folding–dependent
CRTR p.F508del, p.R117H Increased susceptibility for CP Ductal
CASR p.R990G, p.A986S, over-representation Increased susceptibility for CP? Ductal
CLDN2 CLDN2–MORC4 variants Increased susceptibility for CP Ductal
Susceptibility genes of pancreatitis
Pathway Gene
Inflammatory response IL-1β, IL-1, IL-1RN, IL-6, IL-8, IL-10, TNF-α, IL-23R, TLRs, CD14, RIPK2, NOD2, CCL2 (encodes MCP1), NFKB1, MIF, TNFAIP3, MBL2 HY/LX, DEFB1, HBDs
Oxidative stress GST family, iNOS, COX-2, HO-1
Apoptosis CASP7, CASP8, CASP9, CASP10, LTA, TNFRSF1B, TP53
Angiogenesis-related VEGFR-2, CXCR-2, PAR-1, EGF, TNF-β
Metabolism and enzyme ACE I/D, VEGFR-2/KDR, VDR, MMP, FXR
Blood system Thalassemia gene, HLA-DQA1–HLA-DRB1
Tight junction PARD3 and MAGI2, MYO9B: myosin IXB
Other Hydroxytryptamine (serotonin) receptor 2C, G protein-coupled (HTR2C), HSP70-2G, fibroblast growth factor receptor 4 (FGFR4)
Modifier genes of pancreatitis
Genetics of HTG and pancreatitis
Yang X et al. 2019 manuscript prepared
Pancreatitis HTG
Other risk factors
Genetics of HTG-AP
• No GWAS
• Case > cohort
• Novel mutation > reported mutation
• HTG risk genes > pancreatitis risk genes
• Gene-environment interaction
• PRSS1
• SPINK1
• CTRC
• CFTR
• LPL
• APOC2
• LMF1
• Alcohol
• Smoking
• Obesity
• Diabetes
• CASR
• CEL
• CPA1
• GPIHBP1
• APOA5
• GPD1
Pancreatitis
HTG
Genotype
Environment Other risk factors
Genotype
Environment Other risk factors
Petrov MS et al. Nat Rev Gastroenterol Hepatol 2019;16:175-184Sankaran SJ et al. Gastroenterol 2015;149:1490-1500.e1491
Yadav D et al. Gastroenterol 2013;144:1252-1261
Complex interactions
Disease continuum
Murphy M et al. JAMA Intern Med2013;173:162-164;Pedersen S et al. JAMA Intern Med2016;176:1834-1842;Wu BU et al. Dig Dis Sci2019;64:890-897
HTG increases risk of AP and RAP
HTG = hypertriglyceridemiaTG = triglycerides
Mukherjee R et al. Precis Clin Med 2019;2(2):81-86
Increased incidence of HTG-APHypertriglyceridemia-associated acute pancreatitis (HTG-AP)Incidence: 0.13 (95% CI: 0.1-0.17)
Baseline characteristics
Totaln=2145
MAPn=958
MSAPn=718
SAPn=469
Age, years* 45 (38-55) 44 (37-53) 45 (38-56) 46 (39-59)Male sex 1420 (66.2) 665 (69.4) 457 (63.6) 298 (63.5)Pre-existing comorbidity
Pulmonary 56 (2.6) 19 (2.0) 19 (2.6) 18 (3.8)Cardiovascular 368 (17.2) 142 (14.8) 115 (16.0) 111 (23.7)Liver 983 (45.8) 466 (48.6) 324 (45.1) 193 (41.5)Diabetes 420 (19.6) 168 (17.5) 161 (22.4) 91 (19.4)
AetiologyBiliary 650 (30.3) 295 (30.8) 228 (31.8) 127 (27.1)Hyperlipidaemic 657 (30.6) 280 (29.2) 206 (28.7) 171 (36.5)Alcohol excess 106 (4.9) 35 (3.7) 42 (5.8) 29 (6.2)Mixed 165 (7.7) 49 (5.1) 59 (8.2) 57 (12.2)Unknown or others 567 (26.4) 299 (31.2) 183 (25.5) 85 (18.1)
Shi N et al. Gut 2019 pii: gutjnl-2019-318241
HTG-associated AP in WCH
Serum TG > 1000 mg/dl is associated with more pancreatic necrosis
Nawaz H et al. Am J Gastroenterol 2015;110:1497–1503
Vipperla K et al. J Clin Gastroenterol 2017; 51: 586-59
HTG increases severity
Persistent respiratory failure 2.88 (1.61, 5.13)
Persistent renal failure 3.18 (1.92, 5.27)
Persistent shock 3.78 (1.69, 8.44)
Mortality 1.90 (1.05, 3.45)Wang Q et al. J Clin Gastroenterol 2017; 51:586-59
FFAs correlate with severityCE = cholesteryl ester
CER = ceramide
FFA = free fatty acid
HCER = hexosylceramide
LCER = lactosylceramide
LPE = lysophosphatidylethanolamine
PC = phosphatidylcholine
PE = phosphatidylethanolamine
PEO = ether-linked alkyl
phosphatidylethanolamine
PEP = ether-linked alkenyl
phosphatidylethanolamine
SM = sphingomyelin
TAG = triacylglycerol
TAKEN OUT
FFAs induce pancreatic toxicity
Werner J et al. Gastroenterol 1997;113:286-94Criddle DN et al. Gastroenterol 2006;130:781-93Navina S et al. Sci Transl Med 2011;107:107ra110Criddle DN et al. Proc Natl Acad Sci U S A2004;101:10738-43Huang W et al. Gut 2014;63:1313–1324Noel P et al. Gut 2016;65:100-111de Oliveira C et al. Gastroenterol 2019;156:735-747
Summary• HTG is associated with high
risk of AP
• Serum TG levels correlate with severity of AP
• HTG acerbates severity of AP caused by other aetiology
• HTG worsens long-term pancreatic exocrine and endocrine function
• HTG increases risk of RAP and possibly CP?
Unmet treatment! Mukherjee R et al. Precis Clin Med 2019;1:81-86
Acknowledgments• West China Pancreas Centre: Professors Qing Xia, Lihui Deng, Weimin Hu,
Xubao Liu, Yan Kang, Bin Song, Yu Cao and all multiple-disciplinary members
• State Key Laboratory of Biotherapy of Sichuan University: Professors Lu Chen and Xianghui Fu; colleagues from Nanjing, Nanchang and Shanghai
• International collaborators: Professors Robert Sutton (Liverpool), John A. Windsor (Auckland), Vikesh K. Singh (Baltimore), J Enrique Dominguez-Munoz (Santiago de Compostela)
• Invitation from Professor David C. Whitcomb (Pittsburgh) and PancreasFest
• Email address: [email protected]; wetchat: iPancreas