36 Personalized medicine in cardiovascular disease Flashcards
Genotyping HLA-B*57:01 is used for what drug adverse drug reactions in HIV?
The HLA-B*57:01 allele has been associated with hypersensitivity to abacavir, a highly effective nucleoside analog reverse-transcriptase inhibitor used to treat HIV infection and AIDS
Crizotinib, a TKI
1) Crizotinib is a receptor tyrosine kinase inhibitor (TKI) that blocks cell signaling by tyrosine kinases ALK, hepatocyte growth factor receptor (HGFR, c-Met) and Recepteur d’Origine Nantais (RON);
2) Crizotinib showed marked antitumor activity in patients with advanced ALK-positive non–small-cell lung cancer
Warfarin used in which diseases?
1) Warfarin is anticoagulant drug;
2) used in the prevention and treatment of venous thrombosis, pulmonary embolism, and the complications associated with atrial fibrillation and/or cardiac valve replacement;
3) Warfarin is sometimes prescribed to reduce the risk of stroke after a myocardial infarction (MI)
Which enzyme Warfarin inhibits?
1) Warfarin inhibits the enzyme VKORC1;
2) VKORC1catalyzes the conversion of vitamin K epoxide to the active reduced form of
vitamin K, vitamin K hydroquinone.
3) Vitamin K hydroquinone is an essential cofactor in the synthesis of several clotting factors—it promotes the synthesis of γ-carboxyglutamic
acid residues in the proteins essential for biological activity.
4) the decreased availability of
vitamin K hydroquinone leads to decreased activity of the clotting factors II, VII, IX, and
X, and the anticoagulant proteins C and S
Warfarin stable dose
WSD: 06 to 15.5 mg/day
what is VKORC1?
1) vitamin K epoxide reductase complex subunit 1;
2) Warfarin targets VKORC1, which catalyzes the rate limiting step of vitamin K cycle.
VKORC1 mutation may cause the need of lowered warfarin WSD
1) A common non-coding variant of VKORC1, -1639G>A, increased sensitivity to warfarin;
2) this SNP occurs in the promoter region of VKORC1 and alters a transcription factor binding site, leading to lower protein expression.
3) lowered WSD;
4) the −1639G>A allele frequency varies among different ethnic groups. It is the major allele
(around 90%) in Asian populations, and may be a contributing factor for lower warfarin
dosing requirements often observed in patients of Asian descent. It is also common in
Caucasians (around 40%) and African Americans (around 14%).
VKORC1 mutation associated with warfarin resistance
D36Y, rare, higher WSD needed
epigenetic regulation of VKORC1
microRNA: miR-133a, leads to decreased VKORC1 expression
Two isoforms of Warfarin
1) S-warfarin, more potent than R-warfarin;
2) R-warfarin
Main CYP450 isozymes involved in the metabolism of warfarin
CYP2C9, CYP3A4, CYP1A2;
CYP2C9 metabolizes S-warfarin;
CYP3A4, CYP1A2 metabolizes R-warfarin;
CYP2C9 alleles affecting warfarin metabolism
1) CYP2C91 : wild-type allele, normal enzyme activity, normal metabolizer phenotype.
2) CYP2C92 (Arg144Cys) and CYP2C9*3 (Ile359Leu): reduced enzyme activity, patients are more sensitive to warfarin, reduced WSD
CYP2C9*2 ethnic group distribution
Caucasian (10-20%) ;
Asian (1-3%);
African (0-6%);
CYP2C9*3 ethnic group distribution
CYP2C9*3 allele is less common (<10% in most populations), more in Caucasian, rare in others
In African Americans, which CYP2C9 variants contribute to the variability in patient response
to warfarin?
1) CYP2C9*5, *6, *8, and *11;
2) 20% of African-American carry at least one
CYP2C92 and CYP2C93 affect which warfarin isoform metabolism?
S-warfarin, need to decrease WSD
Genetic tests for CYP2C9 and VKORC1
The variants that are routinely
tested for are CYP2C92, CYP2C93, and −1639G>A.
These variants are used in the FDA table to guide therapy, and also in the International Warfarin Pharmacogenomics Consortium (IWPC) algorithm.
CYP2C9*2
CYP2C9*2: 430C>T; Arg144Cys
CYP2C9*3
CYP2C9*3: 1075A>C; Ile359Leu
CYP4F2 and variant affect warfarin WSD
1) CYP4F2 metabolizes reduced vitamin K to hydroxy-vit K;
2) novel mutation: 1397 G>A, needs higher WSD, observed more in Caucasian and Asian not in African-American.
Clopidogrel (Clo-pi-DOG-rel)
1) antiplatelet medication;
2) prevents platelets from sticking together, forming dangerous clots
Clopidogrel is metabolized by two main groups of enzymes.
1) Carboxylesterase (CES1): 85% of clopidogrel is hydrolyzed by hepatic CES1 to inactive form;
2) CYP system: 15% of clopidogrel is oxidized by CYPs to produce the active 5-thiol metabolite: CYP1A2, CYP3A4/5, CYP2B6, CYP2C9, CYP2C19.
Note: 5-thiol metabolite inhibits platelet purinergic P2Y12 receptor, preventing ADP-induced platelet aggregation.
Main CYP enzyme for clopidogrel conversion to its active form.
CYP2C19 is the principle enzyme responsible for converting clopidogrel into its active metabolite
4 main CYP2C19 gene alleles and clopidogrel metabolism
1) CYP2C191: wild type, normal CYP2C19 function, normal metabolism;
2) CYP2C192: 681G>A, no or reduced or loss CYP2C19 function, intermediate or poor metabolism;
3) CYP2C193: 636G>A, no or reduced or loss CYP2C19 function, intermediate or poor metabolism;
4) CYP2C1917: -806C>T, gain of CYP2C19 function, rapid or ultra-rapid metabolism
5 main CYP2C19 genotype and phenotype of clopidogrel metabolism
1) CYP2C191/1: normal clopidogrel metabolizer;
2) CYP2C191/2, 1/3: intermediate clopidogrel metabolizer;
3) CYP2C192/2, 2/3: poor clopidogrel metabolizer;
4) CYP2C191/17: rapid clopidogrel metabolizer;
5) CYP2C1917/17: ultra-rapid clopidogrel metabolizer
Carboxylesterase 1
CES1;
Hydrolyzes clopidogrel to release an inactive metabolite clopidogrel carboxylic acid (CCA)
1) Mutation of CES1 and clopidogrel metabolism
CES1 G143E is associated with increased clopidogrel active metabolite levels and greater clopidogrel response.
may increase bleeding by reducing the ADP-induced platelet aggregation.
2) Mutation of CES1 and clopidogrel metabolism
1) CES1 A2: A(-816)C;
2) an SNP in the promoter region;
3) increased CES1 transcription;
4) increased ex vivo platelet reactivity;
5) increased clopidogrel metabolism and elimination
miRNA-223 may repress platelet P2Y12 mRNA expression, decrease platelet reactivity in patients with P2Y12 inhibitors such as clopidogrel
Patients with CYP2C19 intermediate or poor metabolizer can use alternative drugs of clopidogrel
Prasugrel;
Ticagrelor
Statins
1) Statins are used to treat high cholesterol;
2) Statins are hypolipidemic drugs;
3) Statins are Hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors
Adverse drug reactions (ADRs) of statins
1) myalgias;
2) severe myopathies with increased creatine kinase levels;
3) potential fatal rhabdomyolysis;
4) rare autoimmune-mediated necrotizing myositis
SLCO1B1 gene
1) encodes organic anion transporting polypeptide 1B1, or OATP1B1;
2) OATP1B1 is found in liver cells; it transports compounds from the blood into the liver so that they can be cleared from the body.
3) OATP1B1 is the major uptake protein for statin into the liver.
SLCO1B1c.521T>C causes muscle ADRs in patients using statins
1) SLCO1B1 c.521T>C, common in Asians and Caucasians, CC homozygous reduce nonrenal clearance, causing muscle ADRs;
2) SLCO1B1 c.521T>C decreased OPTP1B1 expression on the cell surface, total protein is not affected though.
3) c.521T > C, p.Val174Ala
SLCO1B1c.388A>G causes muscle ADRs in patients using statins
1) SLCO1B1c.388A>G increases OATP1B1 expression;
2) Asparagine to Aspartic acid at 130 position: p.Asn130Asp;
3) SLCO1B1c.388A>G is common is African-Americans than in Caucasians
4 distinct OATP1B1 haplotypes for statin metabolism
1) OATP1B15: 388A/521C, impaired hepatic uptake, increased statin exposure systemically;
2) OATP1B115: 388G/521C, impaired hepatic uptake, increased statin exposure systemically;
3) OATP1B11B: 388G/521T, increased statin hepatic uptake, reduced statin exposure systemically;
4) OATP1B11A: 388A/521T, normal allele, wild type
Rotor syndrome
1) an affected individual must have mutations in both the SLCO1B1 and the SLCO1B3 gene;
2) an autosomal recessive ;
3) The SLCO1B1 and SLCO1B3 gene mutations that cause Rotor syndrome, lead to abnormally short, nonfunctional OATP1B1 and OATP1B3 proteins or an absence of these proteins;
4) characterized by conjugated hyperbilirubinemia, strongly reduced liver uptake of many compounds, jaundice.
OATP1B1, 521T>C
1) statin ADRS are seen with simvastatin and atorvastatin, but not associated with pravastatin;
2) gender also plays a role
Bucindolol
Bucindolol is a non-selective beta–adrenoreceptor (b-AR) inhibitor, also weakly inhibits alpha1-AR.
Mutations in genes affecting bucindolol function
1) ADRB1 Arg389Gly;
2) ADRA2C Ins322-325Del polymorphism
ADRB1 Arg389Gly homozygotes
and
any ADRA2C Ins322-325Del
enhance bucindolol effect
ADRB1 Arg389Gly carriers (heterozygotes)
and
any ADRA2C Ins322-325Ins homozygotes
intermediate bucidolol effect
ADRB1 Arg389Gly carriers (heterozygotes)
and
any ADRA2C Del22-325 carriers
No bucindolol effect
