Genetic Dyslipidemia and Cardiovascular Diseases

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1 Sultan Qaboos University Genetic Dyslipidemia and Cardiovascular Diseases Fahad AL Zadjali, PhD We care 1 2/14/18

2 DISCLOSURE OF CONFLICT No financial relationships with commercial interests 2 2/14/18

3 Lipoprotein metabolism Genetic diseases: - LDL-cholesterol - HDL-cholesterol - Triglycerides - Combines

4 WHO / Fredrickson classification of primary hyperlipidaemias Familial hypercholestrolemia

5 Genetics defects in ApoB: synthesis and truncated apob Familial hypobetalipoproteinemia (FHBL) VLDL B MTP & lipid B VLDL TG CE B TG CE ApoB synthesis B TG CE LDL

retinitis pigmentosa Heterozygotes have decreased levels

6 Familial hypobetalipoproteinemia LDL-C very low in homozygotes and fat malabsoprion Acanthocytosis retinitis pigmentosa Heterozygotes have decreased levels of LDL-C and apob usually asymptomatic and have a decreased risk of CVD

7 Abetalipoproteinemia (ABL): deficiency of MTP Fat malabsorption Acanthocytosis Retinitis pigmentosa - Recessive disorder - Deficiency of all apob containing lipoproteins (chylomicrons, VLDL and LDL

8 Familial Combined Hypolipidemia - Mutation in Angiopoietin-like protein 3 (ANGPTL3) - increased activity of lipoprotein lipase - Increase clearance of VLDL LDL and HDL - Low TG and low T.Cholesteorl - No evidence of atherosclerosis

9 Defects in HDL cholesterol levels Complete deficiency of HDL: APOAI LCAT ABCA1 Hyperalphalipoproteinemia HL CETP

10 Lecithin:Cholesterol Acyl Transferase Deficiency (LCAT) - Convert cholesterol into cholesterol ester in HDL - deficiency results in accumulation of free cholesterol: corneal opacities Anemia Renal failure Atherosclerosis

11 ABCA1 deficiency (Tangier disease) APOA1 deficiency (Familial HypoAlpha Lipoproteinemia)

12 ATP-binding cassette transporter ABCA1 deficiency (Tangier Disease) Mediates efflux of cholesterol to newly formed HDL. Chol. esters accumulation in macrophages: Orange tonsils Corneal deposits Hepatomegaly/Splenomegaly Peripheral neuropathy Premature CVD

13 APOA1 deficiency (Familial Hypo-Alph Lipoproteinemia) Very low HDL-C levels (<10mg/dl) Premature CVD Positive Family History Corneal opacities

14 Hyper-Alpha-Lipoprotenemia HDL-C > 90th percentile CETP mutation, SR-B1 APOA1 overexpression

15 Copenhagen City Heart Study Johannsen et al JACC 2012; 60:2041

16 Isolated high triglyceride levels Familial Hypertriglyceridemia

18 Eruptive xanthomas Lipemia retinalis Palmar crease xanthomas

19 High TC and TG Familial Combined hyperlipidemia increase in TC/TG in at least two members of the same family intra-individual and intrafamilial variability of the lipid phenotype increased risk of premature coronary heart disease (CHD) Increased production of ApoB and VLDL (high LDL, TG and low HDL) Genetic loci: apoai-ciii-aiv USF1 TXNIPgene

20 High TC and TG Familial Dysbetalipoproteinemia Type III Autosomal Recessive trait - Apo E mutation (E2/E2) - Rapid progressive atherosclerosis (PAD + CAD)

21 WHO / Fredrickson classification of primary hyperlipidaemias Familial hypercholestrolemia

22 Type IIA Familial Hypercholesterolemia LDLRAP1 Michael M Page, Aust Prescr 2016

23 Defects in LDLR Autosomal dominant hypercholesterolemia (ADH1) è classical FH Attributes to 60-90% of FH cases. Loss of function mutations

24 >1700 variants LDLR Home University College London

25 Population Specific Mutations

26 LDLR mutations in Saudi Arabia Alallaf F. et. al. Open Cardiovasc Med J. 2017

27 Oman LDLR mutations: Novel cdna c.g1145t c.1214_1216del c.1319_1332del c.711delc c.c1502t c.t1054c c.271delg c.504_510del c.g1171a c.g1027a c.g1285a c.g397a Protein p.g382v p.405_406del p.r440fs p.r237fs p.a501v p.c352r p.g91fs p.d168fs p.a391t p.g343s p.v429m p.d133n

28 Apo B 100 gene defects Autosomal dominant hypercholesterolemia 2 (ADH 2) or Familial defective apob100 (FDB) Attributes to about 5% of FH cases Loss of function mutations Amanda J 2004, clinical Chemistry

29 Amanda J 2004, clinical Chemistry 29 exons 2/3 of mutations are in exon 26 LDLR-binding domain

30 Proprotein convertase subtilisin/kexin type 9 (PCSK9) Autosomal dominant hypercholesterolemia 3 (ADH 3) Gain of function mutations ( around 50) attributes to 1-3% of FH cases. Promotes degradation of LDLR

31 Mapping of common natural mutation of PCSK9 to the surface of the molecule. Eric N. Hampton et al. PNAS 2007;104: by National Academy of Sciences

32 PCSK9 deficiency CHD Cohen JC. N Engl J Med. 2006;354:

33 Typical Features of FH Heterozygous FH Cholesterol mmol/l One major genetic defect in LDL metabolism Arcus cornealis and Achilles tendon xanthomas often present CHD onset years Most respond to drugs, but individual response variable Homozygous FH Cholesterol mmol/l Two major genetic defects in LDL metabolism Tendon and cutaneous xanthomas often before age 10 years CHD onset in childhood Poorly responsive to drugs; apheresis often indicated

34 Autosomal Recessive Hypercholesterolemia (ARH) LDLRAP1 Very rare Only patients with homozygous or compound heterozygous LDLRAP1 mutations are affected

35 Genetic testing for Familial dyslipidemia Next generation sequencing EDTA-blood tube Saliva sample

36 Spectrum of mutations in SQUH 20.5 LDLR ApoB PCSK9 LDLRAP1 no mutation 37.6

37 Double heterozygous mutation è Homozygous FH normal HeFH HeFH HoFH X X X X X 2 normal LDLR 1 normal 1 defective LDLR 1 normal 1 defective LDLR 2 defective LDLR

38 Large deletion / duplication of LDLR Thoracic Key

39 Multiplex Ligation-dependent Probe amplification Run on samples with negative mutations from NGS and no double hit mutations

40 20% to 40% of individuals with clinical HeFH are mutationnegative in the 4 genes of FH.

41 Polygenic Hypercholesterolemia Individuals with elevated LDL-C similar to HeFH No Mutation detected in the 4 known genes, No deletion/duplication of LDLR. Identification is important as it will comprise the efficiency of cascade screening

42 Meta-analysis of plasma lipid concentrations in >100,000 individuals of European descent 12 SNPs è genotype and quantify LDL-C polygenic score Teslovich TM et. al. Nature 2010

43 Gene SNP Minor Allele Common Allele GLGC weight for score calculation CELSR2 rs G T 0.15 ABCG8 rs G T SLC22A1 rs C T HFE rs A G MYLIP rs T C ST3GAL4 rs A G NYNRIN rs A G APOE rs C T -- APOE rs7412 T C -- PCSK9 rs G A APOB rs A G 0 10 LDLR rs T G 0.18 LDL-C-raising SNPs reported by GWAS

44 Futema M, Clin Chem 2015

45 Diagnostic workflow for cascade testing in patients with familial hypercholesterolemia Talmud PJ, The lancet 2013

46 Cardiologists Neurologists Intenists Opthalmologists Dermatologists Pediatricians GPs Clinical chemists Recognize and Identify Index case Raise awareness Genetic field workers Clinical pathologists Laboratory workers Cascade genetic screening process & Genetic and lipid profile testing & Send referral letter with report Cardiologists Neurologists Intenists Opthalmologists Dermatologists Pediatricians GPs Clinical chemists Start lipid lowering therapy & Prevent CVD / death

47 COST-EFFECTIVNESS OF GENETIC CASCADE SCRENEING e.g Spanish National Program for FH (NPFH) 9000 FH cases with 10 years follow-up data: 1- prevented 847 coronary events & 203 deaths per year 2- gain of 29,608 Euros per quality-adjusted life years 19,691,492 EUROS Lazaro, P et. al. J clinic. lipid. 2017

48 Log-Linear Effect of Lower LDL-C on CHD Cumulative Effect of Lifelong LDL-C Ference, BA et al. J Am Coll Cardiol 2015;doi: /j.jacc ). Cannon CP, et al. AHA, November,

49 Conclusion FH is caused by mutation of 4 genes LDLR, apob100, PCSK9, LDLRAP1 Identified mutations è apply cascade screening for 1 st degree relatives Genetic cascade screening and cost-effective measure.

ATP III (Adult Treatment Panel III) CLASSIFICATION C IN ADULTS

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