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Online Appendix for the following JACC article
TITLE: Clinical Application of Cardiovascular Pharmacogenetics
AUTHORS: Deepak Voora, MD, Geoffrey S. Ginsburg, MD, PHD
APPENDIX
Additional Loci for Statins
ABCB1
The ATP-binding cassette, sub-family B (MDR/TAP), member 1 (ABCB1) gene encodes
an apical membrane protein in enterocytes and hepatocytes and serves to reduce
bioavailability. All statins appear to be handled by this transporter and three SNPs—
C1236T (rs1128503), G2677T (rs2032582), C3435T (rs1045642)—capture the common
genetic variation at this locus. Individuals who carry a T allele at each SNPs (i.e., the TT-T haplotype) have higher systemic exposure to simvastatin and atorvastatin (1). In the
two largest studies each numbering over 1500 individuals, the T-T-T haplotype was
associated with reduced LDLc lowering, (2) (3) while smaller studies found an enhanced
LDLc lowering in carriers haplotype.(4 ) This conflicting evidence makes firm
conclusions difficult, however, the magnitude of the associations is likely small (i.e.,
<10% difference in LDLc lowering).
ABCG2
The ATP-binding cassette, sub-family G (WHITE), member 2 (ABCG2), is similar to
ABCA1 in location and function and a common variant (rs2231142) reduces its transport
capacity (5). Carriers of the A allele experience higher systemic exposure to
rosuvastatin{Keskitalo, 2009 #1376} or atorvastatin(6), but not pravastatin(7) or
simvastatin acid (simvastatin’s active metabolite)(7). Carriers of the A allele experience
a 5-7% greater reduction in LDLc with rosuvastatin compared to noncarriers{Bailey,
2010 #1820}. Although a recent GWAS did not identify this variant as a determinant of
atorvastatin reduction(8), whether this is due to a failure to replicate or statin-specific
effects is unknown.
Additional loci for clopidogrel
P2YR12
Using a candidate-gene approach, carriers of a common P2YR12 haplotype (rs6798347,
rs6787801, rs9859552, rs6801273, rs9848789, and rs2046934) experienced improved
platelet inhibition(9), though this has not been validated. Unlike the variants at
CYP2C19, those in P2RY12 have not been consistently linked to clinical outcomes(10,11)
(12).
CYP2C9
Despite initial reports of an association with decreased active metabolite production and
reduced platelet inhibition in carriers of CYP2C9*3 (rs1057910) (13), this initial
observation has not been validated (14,15) and only may relevant at the 300mg dose (16).
PON1
A common reduced function allele in PON1 (rs662), may be involved in clopidogrel
bioactivation (17), though this observation has not been validated by others(15,18-20).
Carriers of the minor allele of the rs662 variant in PON1 are overrepresented in one
series of ST cases on clopidogrel (17) though not in two others (18,19). Finally, carriers
of the minor allele of the rs662 variant in PON1 are overrepresented in one series of ST
cases on clopidogrel (17) though not in two others (18,19). Variants in PON1 have not
yet been assessed for their clinical or platelet function response to newer agents such as
prasugrel and ticagrelor.
Additional loci for warfarin
Most studies of warfarin pharmacogenetics were performed in Caucasians, however,
because of the lower allele frequencies of CYP2C9, VKORC1, and CYP4F2 variants in
individuals of African descent, these variants are not as informative in this population
(21). By resequencing CALU, which was originally identified in warfarin resistant rats,
VKORC1, and CYP2C9 several novel SNPs: rs2290228 in CALU, rs61162043 in
VKORC1, and rs7089580 in CYP2C9 (each prevalent in 15-40%% of African-
Americans) were each associated warfarin dose requirements in African-Americans
(22,23) Similarly, resequencing GGCX (the enzyme responsible for gamma
carboxylation of vitamin K dependent coagulation factors), identified rs11676382 as a
predictor of modest reductions in warfarin dose in several studies (24,25) though not all
(26).
References
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Keskitalo JE, Kurkinen KJ, Neuvoneni PJ, Niemi M. ABCB1 haplotypes
differentially affect the pharmacokinetics of the acid and lactone forms of
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Rudez G, Bouman HJ, van Werkum JW, et al. Common variation in the platelet
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2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel
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Harmsze A, van Werkum JW, Bouman HJ, et al. Besides CYP2C19*2, the variant
allele CYP2C9*3 is associated with higher on-clopidogrel platelet reactivity in
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implantation. Pharmacogenet Genomics 2010;20:18-25.
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Bouman HJ, Schomig E, van Werkum JW, et al. Paraoxonase-1 is a major
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Lewis JP, Fisch AS, Ryan K, et al. Paraoxonase 1 (PON1) gene variants are not
associated with clopidogrel response. Clin Pharmacol Ther 2011;90:568-74.
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Gage B, Eby C, Johnson J, et al. Use of pharmacogenetic and clinical factors to
predict the therapeutic dose of warfarin. Clin Pharmacol Ther 2008;84:326-31.
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Voora D, Koboldt DC, King CR, et al. A polymorphism in the VKORC1
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