Home >Documents >It’s all relative: Genetic dyslipidaemia. CVD risk factors, and especially lipid metabolism,...

It’s all relative: Genetic dyslipidaemia. CVD risk factors, and especially lipid metabolism,...

Date post:14-Dec-2015
Category:
View:213 times
Download:1 times
Share this document with a friend
Transcript:
  • Slide 1

Its all relative: Genetic dyslipidaemia Slide 2 CVD risk factors, and especially lipid metabolism, exemplify gene / environment interactions Mainly genetic Co-dominant mutations: Either genetic allele affected Recessive mutations: Both genetic alleles affected Polymorphisms and SNPs: A lleles consistent with normal and markers in proximity to significant genetic effects. Genome-wide association studies (GWAS). Mainly environmental or secondary to other disorders. Slide 3 A missing piece of the genetic puzzle Clinical Effect Gene Prevalence Common genes with small effect Autosomal dominant Autosomal recessive Uncommon genes with large effect Polymorphisms Pathogenic mutations Slide 4 Genetic hyper and hypo - cholesterolaemia Dominant Monogenic Hypercholesterolaemia Familial hypercholesterolemia (FH) Familial defective apo-100 (FDB-100) PCSK9 gain-of-function (FH-3) Hyperalphalipoproteinaemia (CETP deficiency, non-atherogenic?) Recessive Monogenic Hypercholesterolaemia Autosomal recessive hypercholesterolemia (ARH) Lysosomal acid lipase deficiency: Wolmans disease and Cholesterol ester storage disease Dominant Monogenic LDL deficiency PCSK9 loss-of-function Recessive Monogenic LDL deficiency Abeta and hypobeta lipoproteinaemia Chyomicron retention disease Slide 5 Familial Hypercholesterolaemia: What goes wrong? NORMALFH Slide 6 LPL LIVER INTESTINE B Chylomicrons CII LPL R E B CII LDL-R LRP -48 IDL B E VLDL B E CIII -100 B CIII HL B OxLDL O. AI AII E SR- B1 HDL Macrophage ABCA1 LCAT Other Tissues CE FC FH SR-A SR- B1 LDL AI Metabolic Defect in Familial Hypercholesterolemia DAVIGNON 2006 Slide 7 LPL LIVER INTESTINE B Chylomicrons CII LPL R E B CII LDL-R LRP -48 IDL B E VLDL B E CIII -100 B CIII HL B OxLDL O. AI Macrophage ABCA1 SR-A LDL AI AII E SR- B1 HDL LCAT Other Tissues CE FC SR- B1 AI Metabolic Defect in Familial Defective ApoB-100 FDB ApoB Defective apoB B DAVIGNON 2006 Slide 8 PCSK9 regulates the surface expression of LDLRs by targeting for lysosomal degradation 1. Qian YW, et al. J Lipid Res. 2007;48:1488-1498. 2. Horton JD, et al. J Lipid Res. 2009;50:S172-S177. 3. Zhang DW, et al. J Biol Chem. 2007;282:18602-18612. Slide 9 Gain-of-Function Mutations in PCSK9 Cause Familial Hypercholesterolaemia (FH) Associated with: High serum LDL-C 2 Premature CHD and MI 2 In vitro testing in many identified mutations show decreased levels of LDLRs 3 *For a full list of ADH mutations, please see refer to Abifadel reference. 1. Abifadel M, et al. Hum Gen. 2009;30:520-529. 2. Horton JD, et al. J Lipid Res. 2009;50:S172-S177. 3. Cameron J, et al. Hum Mol Genet. 2006;15:1551-1558. PCSK9 VariantPopulationClinical Characteristics D374Y British, Norwegian families, 1 Utah family Premature CHD Tendon xanthomas Severe hypercholesterolemia S127R French, South African, Norwegian families Tendon xanthomas; CHD, early MI, stroke R215HNorwegian family Brother died at 31 from MI; strong family history of CVD Slide 10 What is FH? What does it cause? FH is Co-dominant mutation of genes affecting formation or function of the LDL-receptor This causes metabolic and clinical consequences including precocious cardiovascular disease (CVD) Metabolic Increased LDL, Reduced clearance of remnants including LDLs precursor, IDL. Increased Lp(a)? Reduced HDL? Clinical Dominant: 50% of each generation. Risk 50:50 Premature CHD, CVD and PVD Aortic stenosis Tendon xanthomas (11%) specific? Corneal arcus (27%) non-specific > 40y? Xanthelasmas (12%) nonspecific No signs highly sensitive FH IS NOT JUST HIGH CHOLESTEROL IN A PATIENT AND THEIR RELATIVE(S) Slide 11 FH: Why is it important? 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 25-30 30-3535-40 40-4545-5050-5555-60 60-65 65-7070-75 75-80 80-8585-90 90+ Age Cumulative Probability of Clinical CAD Non-FH Women Non-FH Men FH Women FH Men MED PED Registry 2001. Slide 12 Why FH matters: Prevalence and Impact Prevalence: 0.2 0.5% (1 : 200-500) Atherosclerosis 173:55-68 > 8 x 10 6 affected world-wide. Seminars in Vasc Med 4:87-92 > 40,000 Australians Equal numbers of unaffected relatives Up to 1:60 in local groups with founder effect. Detection rates 0 44% Worlds best 20-40% World average (including Australia) < 5% Impact: 5 10% of CHD events under age 60. J Lipid Res 34:269-77 CVD death in >80% of FH cases. Absolute CVD risk differs from general population models. High risk profile from birth, Interaction differs (smoking, gender) Circulation 97:1837-47 Risk algorithms underestimate risk Eur Heart J 19:A2-11 Missed and misdiagnosed Molecular Medicine meets Public Health Slide 13 Clinical protocol Laboratory protocol Cascade Screening Clinical services Detecting index cases Genetic testing Management Diagnosis assessment Diagnostic criteria Children, Adolescents Adults Children, Adolescents Adults Process Optimal components Model of Care for FH Process LDL- Apheresis Case detection: Dutch Lipid Clinic Score? Slide 14 Severe triglyceride elevation due to recessive impairment of lipoprotein lipase Chylomicrons persist after fasting, massive levels of TG. Homozygous deficiency of Lipoprotein Lipase (LPL) Homozygous deficiency of the cofactor for L PL, Apo CII Impaired transport of LPL to site of action (endothelium) due to homozygous defect in ANGPTL or GPIHBP Combined overproduction and undercatabolism of triglyceride-rich lipoproteins sufficient to saturate LPL, eg in Apo AV mutations. Slide 15 LIVER INTESTINE B Chylomicrons CII LPL CR E B CII LDL-R LRP -48 IDL B E VLDL B E CIII -100 B LDL CIII HL B OxLDL O. Metabolic Defects affecting Lipoprotein Lipase Macrophage ABCA1 SR-A -48 Dietary fat TG TGTG ApoB-48 R LPL VLDLR AI DAVIGNON 2006 AIAII E SR- B1 HDL LCAT Other Tissues CE FC SR- B1 AI FFA + MG Slide 16 AV INTESTINE B Chylomicrons CII LPL CR E B CII LRP -48 IDL B E TG rich VLDL B E CIII -100 B CIII HL B OxLDL O. SR- B1 Metabolic defects saturating in LPL, eg Apo AV mutations Macrophage ABCA1 -48 Sugar fat calories LPL AI Overproduction of VLDL sdLDL ADIPOSE TISSUE GP + FFA TG Normal or reduced VLDL catabolism LDLR LOX-1 CD-36 SR-A SR-PSOX HSL CETP TG CE AV AIAII E HDL LCAT Other Tissues CE FC SR- B1 VLDLR DAVIGNON 2006 AI Slide 17 Normal Hypoalpha- lipoproteinemia Complete (FHC) or partial LPL deficiency associated with a secondary factor Complete LPL deficiency (FHC) Primary apoC- II deficiency Familial dysbeta- lipoproteinemia (type III) Hepatic lipase deficiency (Primary cause associated with a secondary factor) Apo B > 0.75 g/L Apo B < 0.75 g/L TC:Apo B > 6.2 TC:Apo B < 6.2 Familial hyperTG Partial LPL deficiency FH Polygenic FDB PCSK9 deficiency ARH deficiency CYP7A1 deficiency Hypoalphalipo- proteinemia FCH - Sitosterolemia NormalChylo + VLDLChylo Chylo + VLDL Remnants VLDLLDLVLDL + LDL NormoTG < 1.5 mmol/L TG:Apo B > 0.12 NormoApo B < 1.2 g/L TG:Apo B < 0.12 HyperTG > 1.5 mmol/L NomoTG > 1.5 mmol/L HyperApo B > 1.2 g/L Hyper TG > 1.5 mmol/L Primary Causes Algorithm for Diagnosis of Apo B Dyslipoproteinemias Abbreviations: apo, apolipoprotein; ARH, autosomal recessive hypercholesterolemia; CAPD, continuous ambulatory peritoneal dialysis; Chylo, chylomicrons; CP7A1, cytochrome P450 7A1; DM2, diabetes mellitus type 2; dysbeta; dysbetalipoproteinemia; FCH, familial combined hyperlipidemia; FDB, familial defective apoB; FH, familial hypercholesterolemia; FHC, familial hyperchylomicronemia; HAART, highly active antiretroviral therapy; LPL, lipoprotein lipase; PCOS, polycystic ovary syndrome; SLE, systemic lupus erythematosus; TC, total cholesterol; TG, triglyceride. de Graaf J et al. Nat Clin Pract Endocrinol Metab 2008;4:608- 18. Lipoproteins Slide 18 Autosomal recessive disorders have revealed HDL metabolism A-I FC A-I ABCA1 Macrophage Rapid catabolism LCAT Nascent HDL CE FC Homozygous (?heterozygous) Apo AI deficiency: Atherogenic Tangiers Disease: ABC-AI deficiency: Atherogenic? LCAT Deficiency: Non-atherogenic? Apo A1 Milano: Anti-atherogenic? + Slide 19 100 50 0 30 40 50 60 70 80 Age ( years) Event Free Survival ( % ) apoAI (L178P) carriers (n=54) family controls (n=147) p = 0.008 Carriers of the ApoAI Leu 178 Pro Variant Are at Increased Risk of Developing CAD Hovingh K et al. J Amer Coll Cardiol 44:1429, 2004 ApoAI 50% HDL-C 63% 18.9 x CAD risk DAVIGNON 2006 Slide 20 Normal ApoAI and ApoAI MILANO Dimer 1 25 35 66 121 165 209 220 243 187 143 99 Lipid Binding In Vivo Catabolism LCAT Activation Cholesterol Efflux Receptor Binding AI Franceschini G Eur J Clin Invest 26; 733, 1996 AI m /AI m 1 1 243 173 s s DAVIGNON 2006 Slide 21 Role of apolipoprotein E Apo E: ligand for hepatic removal of remnants. Apo E knockout model is atherogenic Apo E2 has lower binding affinity (E4>E3>E2). E2:E2 only critical if lipids increase for other reasons. Other roles for Apo E (CNS lipid transport and neural repair). CR E E AI CHYLOMICRON CIII TG OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO LPL LRP AII C E E E AI CE HDL B 48 B CII Lipolysis products C FC AI Slide 22 SR-B1 CE FC AI AII E CE AI FC AII E CE HL CE Kidney AI HDL 3 HDL 2 HL CE E CE AI HDL 3 LCAT FC/PL FC/PL AII AI Metabolic Defects in Remnant Dyslipidaemia Apo E2 homozygosity plus apo B overproduction or Hepatic Lipase deficiencyLIVER CELL ABCA1 VLDL to Remn B E CE CETP Chylo to ChyloRe B E LPL PLTP INTESTINE LDL B HL Degradation (catabolic) Formation (anabolic) CE TG LDLR TG Ox LDL B LRP Modified from Deeb SS et al. J Lipid Res 44:1279, 2003 Slide 23 Unspecified hereditary Dyslipoproteinemia Common: Lipoptotein (a) Rare: Familial Phytosterolemia DAVIGNON 2006 ABCG5 ABCG8 Micelle sPhytosterols Cholesterol Protease K V K IV Types 3-10 Apo(a) LDL Receptor Binding Site on apoB K IV Type 2 ApoB LDL particle K IV Type 1 C N -C -N DAVIGNON 2006 Slide 24 Genetic dyslipidaemias have motivated treatment discovery Clinical abnormalities represent real human problems Massive yield on research into genetic dyslipidaemia Familial H

Popular Tags:

Click here to load reader

Reader Image
Embed Size (px)
Recommended