Sultan Qaboos University Genetic Dyslipidemia and Cardiovascular Diseases Fahad AL Zadjali, PhD Fahadz@squ.edu.om We care 1 2/14/18
DISCLOSURE OF CONFLICT No financial relationships with commercial interests 2 2/14/18
Lipoprotein metabolism Genetic diseases: - LDL-cholesterol - HDL-cholesterol - Triglycerides - Combines
WHO / Fredrickson classification of primary hyperlipidaemias Familial hypercholestrolemia
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
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
Abetalipoproteinemia (ABL): deficiency of MTP Fat malabsorption Acanthocytosis Retinitis pigmentosa - Recessive disorder - Deficiency of all apob containing lipoproteins (chylomicrons, VLDL and LDL
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
Defects in HDL cholesterol levels Complete deficiency of HDL: APOAI LCAT ABCA1 Hyperalphalipoproteinemia HL CETP
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
ABCA1 deficiency (Tangier disease) APOA1 deficiency (Familial HypoAlpha Lipoproteinemia)
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
APOA1 deficiency (Familial Hypo-Alph Lipoproteinemia) Very low HDL-C levels (<10mg/dl) Premature CVD Positive Family History Corneal opacities
Hyper-Alpha-Lipoprotenemia HDL-C > 90th percentile CETP mutation, SR-B1 APOA1 overexpression
Copenhagen City Heart Study Johannsen et al JACC 2012; 60:2041
Isolated high triglyceride levels Familial Hypertriglyceridemia
Eruptive xanthomas Lipemia retinalis Palmar crease xanthomas
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
High TC and TG Familial Dysbetalipoproteinemia Type III Autosomal Recessive trait - Apo E mutation (E2/E2) - Rapid progressive atherosclerosis (PAD + CAD)
WHO / Fredrickson classification of primary hyperlipidaemias Familial hypercholestrolemia
Type IIA Familial Hypercholesterolemia LDLRAP1 Michael M Page, Aust Prescr 2016
Defects in LDLR Autosomal dominant hypercholesterolemia (ADH1) è classical FH Attributes to 60-90% of FH cases. Loss of function mutations
>1700 variants LDLR Home University College London www.ucl.ac.uk/ldlr
Population Specific Mutations
LDLR mutations in Saudi Arabia Alallaf F. et. al. Open Cardiovasc Med J. 2017
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
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
Amanda J 2004, clinical Chemistry 29 exons 2/3 of mutations are in exon 26 LDLR-binding domain
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
Mapping of common natural mutation of PCSK9 to the surface of the molecule. Eric N. Hampton et al. PNAS 2007;104:14604-14609 2007 by National Academy of Sciences
PCSK9 deficiency CHD Cohen JC. N Engl J Med. 2006;354:1264-72
Typical Features of FH Heterozygous FH Cholesterol 7.0-14 mmol/l One major genetic defect in LDL metabolism Arcus cornealis and Achilles tendon xanthomas often present CHD onset 30-60 years Most respond to drugs, but individual response variable Homozygous FH Cholesterol 10-28 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
Autosomal Recessive Hypercholesterolemia (ARH) LDLRAP1 Very rare Only patients with homozygous or compound heterozygous LDLRAP1 mutations are affected
Genetic testing for Familial dyslipidemia Next generation sequencing EDTA-blood tube Saliva sample
Spectrum of mutations in SQUH 20.5 LDLR 2.6 39.3 ApoB PCSK9 LDLRAP1 no mutation 37.6
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
Large deletion / duplication of LDLR Thoracic Key
Multiplex Ligation-dependent Probe amplification Run on samples with negative mutations from NGS and no double hit mutations
20% to 40% of individuals with clinical HeFH are mutationnegative in the 4 genes of FH.
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
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
Gene SNP Minor Allele Common Allele GLGC weight for score calculation CELSR2 rs629301 G T 0.15 ABCG8 rs4299376 G T 0.071 SLC22A1 rs1564348 C T 0.014 HFE rs1800562 A G 0.057 MYLIP rs3757354 T C 0.037 ST3GAL4 rs11220462 A G 0.050 NYNRIN rs8017377 A G 0 029 APOE rs429358 C T -- APOE rs7412 T C -- PCSK9 rs2479409 G A 0.052 APOB rs1367117 A G 0 10 LDLR rs6511720 T G 0.18 LDL-C-raising SNPs reported by GWAS
Futema M, Clin Chem 2015
Diagnostic workflow for cascade testing in patients with familial hypercholesterolemia Talmud PJ, The lancet 2013
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
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
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:10.1016/j.jacc.2015.02.020). Cannon CP, et al. AHA, November, 17 2014.
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.