Академический Документы
Профессиональный Документы
Культура Документы
Address: 1Schools of Pharmacy and Biomedical Sciences, University of Portsmouth, St. Michael's Building, White Swan Road, Portsmouth PO1
2DT, UK and 2Centre for Tropical Clinical Pharmacology and Therapeutics, University of Ghana Medical School. P.O. GP 4236, Accra, Ghana
Email: William Kudzi* - wkudzi@yahoo.com; Alexander NO Dodoo - alexooo@yahoo.com; Jeremy J Mills - Jeremy.mills@port.ac.uk
* Corresponding author
Abstract
Background: Genetic influences on drug efficacy and tolerability are now widely known.
Pharmacogenetics has thus become an expanding field with great potential for improving drug
efficacy and reducing toxicity. Many pharmacologically-relevant polymorphisms do show variability
among different populations. Knowledge of allelic frequency distribution within specified
populations can be useful in explaining therapeutic failures, identifying potential risk groups for
adverse drug reactions (ADRs) and optimising doses for therapeutic efficacy. We sought to
determine the prevalence of clinically relevant Cytochrome P450 (CYP) 2C8, CYP2C9, and CYP2C19
variants in Ghanaians. We compared the data with other ethnic groups and further investigated
intra country differences within the Ghanaian population to determine its value to
pharmacogenetics studies.
Methods: RFLP assays were used to genotype CYP2C8 (*2, *3, *4) variant alleles in 204 unrelated
Ghanaians. CYP2C9*2 and CYP2C19 (*2 and *3) variants were determined by single-tube tetra-
primer assays while CYP2C9 (*3, *4, *5 and *11) variants were assessed by direct sequencing.
Results: Allelic frequencies were obtained for CYP2C8*2 (17%), CYP2C8*3 (0%), CYP2C8*4 (0%),
CYP2C9*2 (0%), CYP2C9*3 (0%), CYP2C9*4 (0%), CYP2C9*5 (0%), CYP2C9*11 (2%), CYP2C19*2
(6%) and CYP2C19*3 (0%).
Conclusion: Allele frequency distributions for CYP2C8, CYP2C9 and CYP2C19 among the Ghanaian
population are comparable to other African ethnic groups but significantly differ from Caucasian
and Asian populations. Variant allele frequencies for CYP2C9 and CYP2C19 are reported for the first
time among indigenous Ghanaian population.
Page 1 of 6
(page number not for citation purposes)
BMC Medical Genetics 2009, 10:124 http://www.biomedcentral.com/1471-2350/10/124
Page 2 of 6
(page number not for citation purposes)
BMC Medical Genetics 2009, 10:124 http://www.biomedcentral.com/1471-2350/10/124
Table 1: Allele and Genotype frequencies for CYP2C8, CYP2C9 and CYP2C19 alleles observed in the Ghanaian population (%, 95% CI in
parenthesis)
CI, Confidence Interval. CYP2C8*3, *4, CYP2C9*2, *3 *4, *5 and CYP2C19*3 variant alleles were not detected in this study
The pairwise LD between each SNP analysed was per- higher in the Northern tribe (p = 0.025). CYP2C9 *11 var-
formed and the results expressed in Table 2. Three SNPs, iant was detected in only the Ewe and Ga tribes at frequen-
CYP2C9*3, CYP2C9*4 and CYP2C9*5 showed a strong cies of 5% and 3% respectively. The Ghanaian population
linkage disequilibrium. The major allele was defined as was found to a large extent to be genetically homogenous.
the most commonly occurring allele in the population.
CYP2C8*2 variant was the most frequent allele detected at The current study investigated three previously described
17%. CYP2C8*3 and CYP2C8*4 variant alleles were not polymorphisms of the CYP2C8 and the data was com-
detected in this study. Homozygous variant alleles were pared with other studies reported in published literature
detected in 3% of the study population while 29% of indi- (Table 3). The CYP2C8*2 variant allele was observed in
viduals carried at least one variant allele (Table 1). 17% of this study population consistent with data from
CYP2C9*2, CYP2C9*3, CYP2C9*4 and CYP2C9*5 variant an earlier study among the Ghanaian population (17%)
alleles were not detected in the present study. CYP2C9*11 [17] and other populations of African origin such as Afri-
variant allele frequency was 2% (Table 1). Homozygous can American (18%) [6,18], Burkina Faso (11.5%) [19]
CYP2C9*11 variant was found in one individual, while and Zanzibaris (14%) [20]. Conversely the CYP2C8*2
four individuals were heterozygous for the CYP2C9*11 variant is very infrequent in the Caucasian populations (0-
variant (Table 1). Carriers of the CYP2C19*2 variant allele 2%) [6,14,21,22] and absent in Asian populations [2].
were found in twenty individuals (6%) in this study pop- The CYP2C8*3 and CYP2C8*4 variant alleles were not
ulation; three of these individuals were homozygous for detected in this study population. These variant alleles
the CYP2C19*2 variant while 14 individuals were hetero- have rarely been reported in other African populations
zygous for CYP2C19*2 variant. The CYP2C19*3 variant [18-20,23]. CYP2C8*3 variant allele, however, has been
was not detected in the study population. reported between 9.5-17% within the Caucasian popula-
tion [2]. The CYP2C8*4 variant allele is rare among Cau-
Intra-population variations were determined for five casian populations (0-7.5%). CYP2C8*3 and CYP2C8*4
major tribes within the Ghanaian population were self- variant alleles have not been reported within Asian popu-
identified as Akan, Fanti, Ewe, Northern, and Ga tribes. lations [2]. The presence of CYP2C8*3 and CYP2C8*4
Intra-population data was similar for all the SNPs ana- variant alleles in Caucasians differs significantly from data
lysed except for CYP2C8*2 variant which was significantly from the present study.
Table 2: Analysis of linkage disequilibrium for a set of 10 SNPs in CYP2C locus in a Ghanaian population.
CYP2C8*2 CYP2C8*3 CYP2C8*4 CYP2C9*2 CYP2C9*3 CYP2C9*4 CYP2C9*5 CYP2C9*11 CYP2C19*2 CYP2C19*3
CYP2C8*2
CYP2C8*3 0
CYP2C8*4 0 0
CYP2C9*2 0.00001459 0 0
CYP2C9*3 0.0008986 0 0 0.0402
CYP2C9*4 0.0008986 0 0 0.0402 1
CYP2C9*5 0.0008986 0 0 0.0402 1 1
CYP2C9*11 0.001332 0 0 0.002015 0 0 0
CYP2C19*2 0.0134 0 0 0.0209 0.003165 0.003165 0.003165 0.001274
CYP2C19*3 0.00342 0 0 0.2237 0.1631 0.1631 0.1631 0.003538 0.0121
Pairwise LD represented as r2 (from 0 to 1) is expressed in each cell. SNPs with strong linkage disequilibrium are highlighted in gray
Page 3 of 6
(page number not for citation purposes)
BMC Medical Genetics 2009, 10:124 http://www.biomedcentral.com/1471-2350/10/124
Table 3: Allele frequencies of CYP2C8, CYP2C19 and CYP2C19 variants in a Ghanaian and other previously studied populations
CYP2C8*2 CYP2C8*3 CYP2C8*4 CYP2C9*2 CYP2C9*3 CYP2C9*4 CYP2C9*5 CYP2C9*11 CYP2C19*2 CYP2C19*3
African
Ghanaian 0.17 0 0 0 0 0 0 0.02 0.06 0
Ghanaian 0.17 [23] 0 [23] 0 [23]
Zanzibaris 0.14 [20] 0.02 [20] 0.006 [20]
Burkinabe 0.115 [19] 0.004 [19] 0 [19]
Beninese 0 [15] 0 [15] 0 [15] 0.02 [15] 0.03 [15] 0.13 [15] 0[15]
Ethiopian 0.043 [24] 0.023 [24] 0 [24]
Zimbabweam 0.13 [34] 0[34]
African 0.18 [6] 0.02 [6] 0.033 [18] 0.023 [18] 0 [18] 0.01 [18] 0.02 [18] 0.25 [33] 0 [33]
American
Caucasian § 0 - 0.004 0.095 - 0.17 0 - 0.075 [2] 0.08 - 0.191 0.03 - 0.17 0 - 0.004 0 [2] 0.09 [15] - 0
[2 ] [2] [2] [2] [15] 0.14 [42]
Asian § 0 [2] 0 [2] 0 [2] 0 - 0.001 [2] 0.011 - 0.068 0.23 [33] - 0.085 [43]
[2] 0.305 [43]
§ The lowest and the highest allele frequencies for Caucasian and Asian populations
CYP2C8*2 variant detected at 17% in this study and has quency within this study population. This frequency was
a reduced potential of metabolising paclitaxel and arachi- similar to data from Beninese (3%) and African American
donic acid. The CYP2C8*2 variant allele results in 15% (2%) populations [15,18]. This variant allele was rare
reduction in activity towards paclitaxel metabolism in among the Caucasian [15] and was not reported in the
vitro compared to the wild-type allele (CYP2C8*1) [6] Asian population.
while the CYP2C8*3 variant allele showed 50% reduction
in activity to paclitaxel metabolism [14]. CYP2C8*2 and CYP2C9*2 and CYP2C9*3 polymorphisms have been
CYP2C8*3 variant genotypes can lead to poor metaboliser shown to cause a decrease in enzymatic activity of 30%
(PM) phenotype which could potentially cause drug tox- and 80% respectively [25,26] and have been shown to
icity. Although CYP2C8*2 and CYP2C8*3 variant alleles have clinical implications for patients carrying these alle-
have been associated with reduced enzymatic activity only les [27]. The CYP2C9*3 variant allele has been reported to
the CYP2C8*2 variant was detected in the current study. cause the largest reduction in metabolic capacity for many
CYP2C9 substrates, followed by the CYP2C9*2 variant
Five pharmacologically relevant CYP2C9 variants were allele causing an intermediate reduction when compared
surveyed in the current study and the results compared to the wild-type allele (CYP2C9*1) [28]. Poor metabolis-
with other studies (Table 3). The CYP2C9*2 and ers, mostly CYP2C9*3/CYP2C9*3 carriers, may experience
CYP2C9*3 variant alleles were not found in this study severe toxicity when metabolising CYP2C9 substrates with
population and this was consistent with an earlier report narrow therapeutic index such as warfarin and phenytoin.
in a Beninese population [15]. This observation, however, Conversely, these PMs may not have an adequate drug
was different from frequencies obtained within the Afri- response and may experience therapeutic failure when
can American and Ethiopian populations. The CYP2C9*2 taking a pro-drug such as losartan and cyclophospha-
and CYP2C9*3 variant alleles were reported at 3.3% and mide, that requires bio-activation by CYP2C9 [21]. ADRs
2.3% respectively in African American populations [18] to CYP2C9 substrate drugs like warfarin and glipizide are
and at 4.3% and 2.3% in the Ethiopian population [24]. more evident in African/Afro-Caribbean populations than
In contrast, CYP2C9*2 variant allele has been reported at Caucasians, however, CYP2C9*2 and CYP2C9*3 poly-
8-19% and the CYP2C9*3 variant allele at 3.3-17% morphisms are not common in this ethnic group [29,30].
among the Caucasian population [2]. The CYP2C9*2 var-
iant allele was rarely seen in Asian populations while the CYP2C19*2 and CYP2C19*3 variant alleles are the most
CYP2C9*3 variant allele was prevalent at 1.1-6.8% within characterised alleles of the CYP2C19 gene [31,32]. The
the Asian populations [2]. CYP2C19*2 variant allele was the most common allele
found in the current study as in other studies (Table 3).
The CYP2C9*5 variant allele was not detected in the cur- Significant inter-ethnic difference has been reported for
rent study but has been reported at a low level in Beninese CYP2C19*2 variant allele in the published literature
(2%), but slightly higher than the Tanzanian (0.8%) and [15,33]. It occurred at a lower frequency of 6% within this
African American (1%) populations [15,18]. This variant study population compared to 13% in the Beninese [15]
allele is not reported among the Caucasian populations and Zimbabwean (13%) populations [34]. CYP2C19*2
[2]. The CYP2C9*11 variant allele was detected at 2% fre- variant allele has been reported at similar frequencies in
Page 4 of 6
(page number not for citation purposes)
BMC Medical Genetics 2009, 10:124 http://www.biomedcentral.com/1471-2350/10/124
Page 5 of 6
(page number not for citation purposes)
BMC Medical Genetics 2009, 10:124 http://www.biomedcentral.com/1471-2350/10/124
Beninese and Belgian populations. Br J Clin Pharmacol 2003, 35. Gaikovitch EA, Cascorbi I, Mrozikiewicz PM, Brockmoller J, Frotschl
56(6):653-657. R, Kopke K, Gerloff T, Chernov JN, Roots I: Polymorphisms of
16. Hersberger M, Marti-Jaun J, Rentsch K, Hanseler E: Two single-tube drug-metabolizing enzymes CYP2C9, CYP2C19, CYP2D6,
tetra-primer assays to detect the CYP2C19*2 and *3 alleles CYP1A1, NAT2 and of P-glycoprotein in a Russian popula-
of S-mephenytoin hydroxylase. Clin Chem 2001, 47(4):772-774. tion. Eur J Clin Pharmacol 2003, 59(4):303-312.
17. Rower SBU, Weise A, Lambertz U, Frost T, Otchwemah RN, Pfut- 36. Goldstein JA, de Morais SM: Biochemistry and molecular biol-
zner A, Mockkenhaupt F: High prevalence of the cytochrome ogy of the human CYP2C subfamily. Pharmacogenetics 1994,
P450 2C8*2 mutation in Northern Ghana. Tropical Medicine and 4(6):285-299.
International Health 2005, 10(12):1271-1273. 37. Fukushima-Uesaka H, Saito Y, Maekawa K, Ozawa S, Hasegawa R,
18. Dreisbach AW, Japa S, Sigel A, Parenti MB, Hess AE, Srinouanprach- Kajio H, Kuzuya N, Yasuda K, Kawamoto M, Kamatani N, et al.:
anh SL, Rettie AE, Kim H, Farin FM, Hamm LL, et al.: The Preva- Genetic variations and haplotypes of CYP2C19 in a Japanese
lence of CYP2C8, 2C9, 2J2, and soluble epoxide hydrolase population. Drug Metab Pharmacokinet 2005, 20(4):300-307.
polymorphisms in African Americans with hypertension. Am 38. Chowbay B, Cumaraswamy S, Cheung YB, Zhou Q, Lee EJ: Genetic
J Hypertens 2005, 18(10):1276-1281. polymorphisms in MDR1 and CYP3A4 genes in Asians and
19. Parikh S, Ouedraogo JB, Goldstein JA, Rosenthal PJ, Kroetz DL: the influence of MDR1 haplotypes on cyclosporin disposition
Amodiaquine metabolism is impaired by common polymor- in heart transplant recipients. Pharmacogenetics 2003,
phisms in CYP2C8: implications for malaria treatment in 13(2):89-95.
Africa. Clin Pharmacol Ther 2007, 82(2):197-203. 39. Grasmader K, Verwohlt PL, Rietschel M, Dragicevic A, Muller M,
20. Cavaco I, Stromberg-Norklit J, Kaneko A, Msellem MI, Dahoma M, Hiemke C, Freymann N, Zobel A, Maier W, Rao ML: Impact of pol-
Ribeiro VL, Bjorkman A, Gil JP: CYP2C8 polymorphism frequen- ymorphisms of cytochrome-P450 isoenzymes 2C9, 2C19 and
cies among malaria patients in Zanzibar. Eur J Clin Pharmacol 2D6 on plasma concentrations and clinical effects of antide-
2005, 61(1):15-18. pressants in a naturalistic clinical setting. Eur J Clin Pharmacol
21. Yasar U, Lundgren S, Eliasson E, Bennet A, Wiman B, de Faire U, Rane 2004, 60(5):329-336.
A: Linkage between the CYP2C8 and CYP2C9 genetic poly- 40. Einarson TR: Drug-related hospital admissions. Ann Pharmaco-
morphisms. Biochem Biophys Res Commun 2002, 299(1):25-28. ther 1993, 27(7-8):832-840.
22. Weise A, Grundler S, Zaumsegel D, Klotzek M, Grondahl B, Forst T, 41. Lazarou J, Pomeranz BH, Corey PN: Incidence of adverse drug
Pfutzner A: Development and evaluation of a rapid and relia- reactions in hospitalized patients: a meta-analysis of pro-
ble method for cytochrome P450 2C8 genotyping. Clin Lab spective studies. Jama 1998, 279(15):1200-1205.
2004, 50(3-4):141-148. 42. Bosch TM, Doodeman VD, Smits PH, Meijerman I, Schellens JH, Bei-
23. Rower S, Bienzle U, Weise A, Lambertz U, Forst T, Otchwemah RN, jnen JH: Pharmacogenetic screening for polymorphisms in
Pfutzner A, Mockenhaupt FP: Short communication: high preva- drug-metabolizing enzymes and drug transporters in a
lence of the cytochrome P450 2C8*2 mutation in Northern Dutch population. Mol Diagn Ther 2006, 10(3):175-185.
Ghana. Trop Med Int Health 2005, 10(12):1271-1273. 43. Adithan C, Gerard N, Vasu S, Rosemary J, Shashindran CH, Krishna-
24. Scordo MG, Aklillu E, Yasar U, Dahl ML, Spina E, Ingelman-Sundberg moorthy R: Allele and genotype frequency of CYP2C19 in a
M: Genetic polymorphism of cytochrome P450 2C9 in a Cau- Tamilian population. Br J Clin Pharmacol 2003, 56(3):331-333.
casian and a black African population. Br J Clin Pharmacol 2001,
52(4):447-450.
25. Crespi CL, Miller VP: The R144C change in the CYP2C9*2 Pre-publication history
allele alters interaction of the cytochrome P450 with The pre-publication history for this paper can be accessed
NADPH:cytochrome P450 oxidoreductase. Pharmacogenetics here:
1997, 7(3):203-210.
26. Takanashi K, Tainaka H, Kobayashi K, Yasumori T, Hosakawa M,
Chiba K: CYP2C9 Ile359 and Leu359 variants: enzyme kinetic http://www.biomedcentral.com/1471-2350/10/124/pre
study with seven substrates. Pharmacogenetics 2000, pub
10(2):95-104.
27. Schwarz UI: Clinical relevance of genetic polymorphisms in
the human CYP2C9 gene. Eur J Clin Invest 2003, 33(Suppl
2):23-30.
28. Lee CR, Goldstein JA, Pieper JA: Cytochrome P450 2C9 poly-
morphisms: a comprehensive review of the in-vitro and
human data. Pharmacogenetics 2002, 12(3):251-263.
29. Shorr RI, Ray WA, Daugherty JR, Griffin MR: Individual sulfonylu-
reas and serious hypoglycemia in older people. J Am Geriatr Soc
1996, 44(7):751-755.
30. White RH, Beyth RJ, Zhou H, Romano PS: Major bleeding after
hospitalization for deep-venous thrombosis. Am J Med 1999,
107(5):414-424.
31. De Morais SM, Wilkinson GR, Blaisdell J, Meyer UA, Nakamura K,
Goldstein JA: Identification of a new genetic defect responsible
for the polymorphism of (S)-mephenytoin metabolism in
Japanese. Mol Pharmacol 1994, 46(4):594-598. Publish with Bio Med Central and every
32. de Morais SM, Wilkinson GR, Blaisdell J, Nakamura K, Meyer UA,
Goldstein JA: The major genetic defect responsible for the pol- scientist can read your work free of charge
ymorphism of S-mephenytoin metabolism in humans. J Biol "BioMed Central will be the most significant development for
Chem 1994, 269(22):15419-15422. disseminating the results of biomedical researc h in our lifetime."
33. Goldstein JA, Ishizaki T, Chiba K, de Morais SM, Bell D, Krahn PM,
Evans DA: Frequencies of the defective CYP2C19 alleles Sir Paul Nurse, Cancer Research UK
responsible for the mephenytoin poor metabolizer pheno- Your research papers will be:
type in various Oriental, Caucasian, Saudi Arabian and
American black populations. Pharmacogenetics 1997, 7(1):59-64. available free of charge to the entire biomedical community
34. Dandara C, Masimirembwa CM, Magimba A, Sayi J, Kaaya S, Sommers peer reviewed and published immediately upon acceptance
DK, Snyman JR, Hasler JA: Genetic polymorphism of CYP2D6
and CYP2C19 in east- and southern African populations cited in PubMed and archived on PubMed Central
including psychiatric patients. Eur J Clin Pharmacol 2001, yours — you keep the copyright
57(1):11-17.
Submit your manuscript here: BioMedcentral
http://www.biomedcentral.com/info/publishing_adv.asp
Page 6 of 6
(page number not for citation purposes)