Pharmacogenetics of cytochrome P450 (CYP) in the elderly

Ageing Research Reviews 9 (2010) 457–474

Contents lists available at ScienceDirect

Ageing Research Reviews journal homepage: www.elsevier.com/locate/arr

Review

Pharmacogenetics of cytochrome P450 (CYP) in the elderly Davide Seripa a,∗ , Andrea Pilotto b , Francesco Panza a , Maria Giovanna Matera a , Alberto Pilotto a a Geriatric Unit & Gerontology-Geriatrics Research Laboratory, Department of Medical Sciences, IRCCS Casa Sollievo della Sofferenza, Viale Cappuccini 1, 71013 San Giovanni Rotondo (FG), Italy b Department of Neuroscience, University of Padova, Italy

a r t i c l e

i n f o

Article history: Received 24 February 2010 Received in revised form 28 May 2010 Accepted 1 June 2010

Keywords: Cytochrome P450 Pharmacogenetics Haplotype Genotype Phenotype

a b s t r a c t The genetics of cytochrome P450 (CYP) is a very active area of multidisciplinary research, overlapping the interest of medicine, biology and pharmacology, being the CYP enzyme system responsible for the metabolism of more than 80% of the commercially available drugs. Variations in CYP encoding genes are responsible for inter-individual differences in CYP production or function, with severe clinical consequences as therapeutic failures (TFs) and adverse drug reactions (ADRs), being ADRs worldwide primary causes of morbidity and mortality in elderly people. In fact, the prevalence of both TFs and ADRs strongly increased in the presence of multiple pharmacological treatments, a common status in subjects aging 65 years and over. The present article explored some basic concepts of human genetics that have important implications in the genetics of CYP. An attempted to transfer these basic concepts to the genetic data reported by the Home Page of The Human Cytochrome P450 (CYP) Allele Nomenclature Committee was also made, focusing on the current knowledge of CYP genetics. The status of what we know and what we need to know is the base for the clinical applications of pharmacogenetics, in which personalized drug treatments constituted the main aim, in particular in patients attending a geriatric ward. © 2010 Elsevier B.V. All rights reserved.

1. Introduction The person-to-person variability in drug metabolism is a major problem in clinical practice, and the concept that genetic variation contributes to therapeutic failures (TFs) and adverse drug reactions (ADRs) is widely accepted and validated in many research settings (Roden et al., 2006). It was reported that only 25–60% of common drug therapies were successful (Wilkinson, 2005), and that ADRs caused 6.2–6.7% of all hospitalization, and caused death of 0.15–0.3% of all admission in U.S. and in Western countries (Ingelman-Sundberg and Rodriguez-Antona, 2005; Moore et al., 2007; Wilke et al., 2007). Drug use increased with advancing age, and in older patients it was associated with an increased prevalence of TFs and ADRs, being ADRs worldwide primary causes of morbidity and mortality in elderly people (Franceschi et al., 2008). The observation of inter-individual differences in the response to drug treatments was not a recent one. Early studies reported that the adverse reaction to the ingestion of fava beans, described by Pythagoras in VI century B.C., was attributable to a deficiency in the erythrocyte glucose 6-phosphate dehydrogenase enzyme activity, thus suggesting that this adverse reaction might be due to genetic factors (Carson et al., 1956). In the following years, sev-

∗ Corresponding author. Tel.: +39 0882 41 6260; fax: +39 0882 41 6264. E-mail address: [email protected] (D. Seripa). 1568-1637/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.arr.2010.06.001

eral inherited ADRs were elucidated (Kalow, 1956; Bönicke and Losboa, 1957), and Motulsky argued that otherwise innocuous genetic traits might underlie phenotypes resulted from variations in drug response among individuals (Motulsky, 1957). All these findings leaded Vogel to the introduction of the new term “pharmacogenetics” (Vogel, 1959).

2. Evolution of drug-metabolizing enzymes It was commonly accepted that plant–animal cohabitation played a pivotal role in the evolution of drug-metabolizing enzymes (Schuler, 1996). Plants continuously evolved their biosynthetic pathways, synthesizing metabolites to optimize their survival. About 400-to-300 million years ago, life became terrestrial, and animals started to eat plants. Plants responded by evolving new genes to synthesize new metabolites (Gonzalez and Nebert, 1990). In these chain reactions, diet gave the major selective pressure towards the evolution of drug-metabolizing enzymes in animals, with plant toxin playing a major role. This hypothesis was supported by the phylogenetic tree of the human cytochromes P450 (CYP). About 400-to-300 million years ago the occurrence of a large number of duplications in the CYP genes has been well documented (Ingelman-Sundberg et al., 1999). The discovery that CYP genes were aggregated in clusters further confirms the occurrence of CYP gene duplications (Fig. 1). It was remarkable that most of currently used drugs derived from natural plant metabolites, and

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Fig. 1. CYP clusters on chromosome 7 (cluster 3A), chromosome 10 (cluster 2C) and chromosome 22 (cluster 2D).

that these drugs were metabolized by the enzymes encoded by the CYP genes (Ingelman-Sundberg et al., 1999). This hypothesis about the evolution of CYP genes also well explained the high grade of polymorphisms showed by these genes. 3. Genetics of CYP The CYP enzymes are encoded by the CYP genes, all part of an highly polymorphic gene superfamily. These genes were categorized into families and subfamilies by the sequence similarities observed in their encoded proteins. Accordingly, genes encoding proteins showing similarity in their amino acid sequence greater than 40% were assigned to the same family, whereas genes encoding proteins showing similarity greater than 55% were assigned to the same subfamily. Humans have 18 CYP gene families, and 44 CYP gene subfamilies (Nelson, 2007). According to the Human Cytochrome P450 (CYP) Allele Nomenclature Committee (available at URL http://www.cypalleles.ki.se/) (Oscarson and Ingelman-Sundberg, 2002), the CYP gene superfamily includes the families, that are identified by a number (CYP1, CYP2, etc.), and classified into subfamilies, identified by a letter (CYP1A, CYP1B, etc.). Each subfamily includes the genes, identified by a number (CYP1A1, CYP1A2, etc.) and the allele families, identified by an asterisk followed by a number (CYP1A1*1, CYP1A1*2, etc.), in which the single alleles are indicated by a letter (CYP1A1*1A, CYP1A1*1B, etc.). It was well documented that CYP gene subfamilies lies in clusters of tightly linked genes widely scattered throughout the genome (Fig. 1) (Nelson et al., 1996), with the two main clusters being the cluster CYP3A on chromosome 7 (at locus 7q22.1) and the cluster CYP2C on chromosome 10 (at locus 10q23.33–10q24.1). A further cluster, the cluster CYP2D, was identified on chromosome 22 (at locus 22q13.2).

The high grade of polymorphism showed by these genes lead to an high variability in the activity of the encoded enzymes. Potentially the catalytic activity of each enzyme differed from each other (Daly et al., 1993; Ingelman-Sundberg et al., 1999; Evans and Relling, 1999). For this reason CYP enzymes play a major role in drug metabolism, determining drugs bioavailability, and thus the clinical response to pharmacological treatments (Tomalik-Scharte et al., 2008). These studies demonstrated that a similar variability was common, and may be observed throughout the populations. Up to date, it has been suggested that subjects of the general population might exhibit five metabolic phenotypes. Subjects with a normal enzyme activity, usually because they carried two functional gene copies, exhibited an extensive (or efficient) metabolizer (EM) phenotype (Caraco, 2004). These subjects were the wild-type (wt), and were the most common in the populations. As compared with this normal phenotype, subjects lacking of functional enzymes, usually because they were homozygotes for a defective allele, exhibit a poor metabolizer (PM) phenotype. Subjects with a reduced enzyme activity, usually because they were heterozygotes for a defective allele, exhibit an intermediate metabolizer (IM) phenotype. Subjects with an increased enzyme activity, usually because they carried more than two functional gene copies or carried mutations inducing an increased gene expression, exhibit a rapid or an ultrarapid metabolizer (RM or UM) phenotype, depending from their homozygote or heterozygote status. 4. The CYP haplotypes In an high-polymorphic gene system, such as the CYP system, each polymorphism contributed to the determination of the metabolic phenotypes throughout a number of different genetic mechanism acting at both single locus and genome levels (Tables 2 and 3) (Nebert, 2005; Daly et al., 1993; Nebert and

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Table 1 Present genetic and functional data available for the major CYP according to the Home Page of The Human Cytochrome P450 (CYP). Allele Nomenclature Committee (URL http://www.cypalleles.ki.se/). Gene

Allele family

Allele*

DNA change†

Protein change

In vivo E.A.‡

CYP3A4

*1

A B1

Reference

Wild-type None

–

Normal ?

C D E F G H J K L M N P Q R S T Hom. Hom. Hom. Hom. Hom. Hom. Hom. Hom. Hom. Hom.

None None None None None None None None None None None None None None None None None None None None None None None None None None

– – – – – – – – – – – – – – – – – – – – – – – – – –

Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported

Hom. Hom. Hom. A B A

None None None None None C15,603 → G

– – – – – Thr185 → Ser

Not reported Not reported Not reported Not reported Not reported Not reported

B

C15,603 → G

Thr185 → Ser

Not reported

*17 *18

Hom. A

*19 *20

B Hom. Hom.

T15,615 → C T20,070 → C T20,070 → C T20,070 → C None 25,889–25,890 ins A

Phe189 → Ser Leu293 → Pro Leu293 → Pro Leu293 → Pro – 488 Frameshift

Not reported Decreased2 Decreased2 Not reported Not reported Not reported

Gonzalez et al. (1988) Rebbeck et al. (1998) Westlind et al. (1999) Kuehl et al. (2001) Kuehl et al. (2001) Hamzeiy et al. (2002) Hamzeiy et al. (2002) Fukushima-Uesaka et al. (2004) Fukushima-Uesaka et al. (2004) Fukushima-Uesaka et al. (2004) Fukushima-Uesaka et al. (2004) Fukushima-Uesaka et al. (2004) Fukushima-Uesaka et al. (2004) Fukushima-Uesaka et al. (2004) Fukushima-Uesaka et al. (2004) Fukushima-Uesaka et al. (2004) Fukushima-Uesaka et al. (2004) Fukushima-Uesaka et al. (2004) Fukushima-Uesaka et al. (2004) Sata et al. (2000) Sata et al. (2000) Hsieh et al. (2001) Hsieh et al. (2001) Hsieh et al. (2001) Eiselt et al. (2001) Eiselt et al. (2001) Eiselt et al. (2001) Eiselt et al. (2001) Eiselt et al. (2001) Murayama et al. (2002) Eiselt et al. (2001) Eiselt et al. (2001) Lamba et al. (2002) Lamba et al. (2002) Hamzeiy et al. (2002) Lamba et al. (2002) Murayama et al. (2002) Murayama et al. (2002) Fukushima-Uesaka et al. (2004) Dai et al. (2001) Dai et al. (2001) Kang et al. (2009) Fukushima-Uesaka et al. (2004) Dai et al. (2001) Westlind-Johnsson et al. (2006)

A B C4 D6 E XN

Wild-type None None None None Gene duplication

– – – – N active genes

A7

None

–

Normal Normal3 Normal5 Not reported Not reported Increased Increased Normal8

B C

None None

– –

Not reported Not reported

D9 E10 F11 G12 H13 J K14 L15 M XN16

None None None None None

Not reported Not reported Not reported Not reported Not reported

None None None Gene duplication

– – – – – See CYP2D6*59 – – – N active genes

A18 B A19

2549delA 2549delA G1846 → A

259 Frameshift 259 Frameshift Splicing defect

None3 Not reported None3

*2 *3 *4 *5 *6 *7 *8 *9 *10 *11 *12 *13 *14 *15 *16

CYP2D6

*1

*2

*3 *4

Not reported Not reported Not reported Increased17

Kimura et al. (1989) Marez et al. (1997) Marez et al. (1997) Marez et al. (1997) Sachse et al. (1997) Dahl et al. (1995) Sachse et al. (1997) Johansson et al. (1993) Panserat et al. (1994) Raimundo et al. (2000) Sakuyama et al. (2008) Marez et al. (1997) Marez et al. (1997) Sachse et al. (1997) Marez et al. (1997) Marez et al. (1997) Marez et al. (1997) Marez et al. (1997) Marez et al. (1997) Marez et al. (1997) Gaedigk et al. (2005a) Gaedigk et al. (2005b) Johansson et al. (1993) Dahl et al. (1995) Aklillu et al. (1996) Kagimoto et al. (1990) Marez et al. (1997) Kagimoto et al. (1990)

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Table 1 (Continued ) Gene

Allele*

DNA change†

Protein change

In vivo E.A.‡

B

G1846 → A

Splicing defect

None3

C20 D E F G H J K L M

G1846 → A G1846 → A G1846 → A G1846 → A G1846 → A G1846 → A G1846 → A G1846 → A G1846 → A G1846 → A

Splicing defect Splicing defect Splicing defect Splicing defect Splicing defect Splicing defect Splicing defect Splicing defect Splicing defect Splicing defect

None None21 Not reported Not reported Not reported Not reported Not reported None Not reported Not reported

N22 X2

G1846 → A None

Splicing defect None

Not reported None

*5

Hom.23

Gene deletion

No protein

None3

*6

A24 B

1707delT 1707delT

118 Frameshift 118 Frameshift

None25 None3

*726 *827 *928

C D Hom. Hom. Hom.

1707delT 1707delT A2935 → C G1758 → T 2615–2617delAAG

118 Frameshift 118 Frameshift His324 → Pro Gly169 → Stop Lys281 del

None5 Not reported None5 None3 Decreased29

*10

A30

C100 → T

Pro34 → Ser

Decreased5

B31 C X2

C100 → T

Decreased17

None

Pro34 → Ser See CYP2D6*36 –

Decreased21

D

C100 → T

Pro34 → Ser

Not reported

Hom. Hom. Hom. A

G883 → C G124 → A Yes G1758 → A

Splicing defect Gly42 → Arg Frameshift Gly169 → Arg

None5 None5 None22 None17

B

G1758 → A

Gly169 → Arg

Not reported

*15 *1633 *1734

Hom. Hom. Hom.

137-138 insT Yes C1023 → T; C2850 → T

46 Frameshift Frameshift Thr107 → Ile; Arg296 → Cys

None22 None17 Decreased17

*1835

XN Hom.

None 4125–4133 dupGTGCCCACT

– 468–470 dupVal-Pro-Thr

Not reported None5

*2236 *2337 *2438 *2539 *2640 *2741

Hom. Hom. A B Hom. Hom. Hom. Hom. Hom. Hom.

2539–2542delAACT 1973–1974 insG 2573–2574 insC 2573–2574 insC None None None None None None

255 Frameshift 211 Frameshift 267 Frameshift 267 Frameshift – – – – – –

None None2 None None Not reported Not reported Not reported Not reported Not reported Not reported

*2842 *2943

Hom. Hom.

None None

– –

Not reported Decreased

*3044 *3145 *3246 *3347 *3448 *3549

Hom. Hom. Hom. Hom. Hom. Hom.

None None None None None None

– – – – – –

Not reported Not reported Not reported Normal5 Not reported Normal5

*36

X2 (A)50

No C100 → T

– Pro34 → Ser

Increased Negligible17

(B)51,52

C100 → T

Pro34 → Ser

Negligible17

Allele family

*1132 *12 *13 *14

*19 *20 *21

Reference Gough et al. (1990) Kagimoto et al. (1990) Hanioka et al. (1990) Yokota et al. (1993) Marez et al. (1997) Marez et al. (1997) Marez et al. (1997) Marez et al. (1997) Marez et al. (1997) Marez et al. (1997) Sachse et al. (1997) Shimada et al. (2001) Agúndez et al. (1997) Fuselli et al. (2004) Gaedigk et al. (2006) Gaedigk et al. (2006) Løvlie et al. (1997) Sachse et al. (1998) Gaedigk et al. (1991) Steen et al. (1995) Saxena et al. (1994) Evert et al. (1994) Daly et al. (1995) Marez et al. (1997) Marez et al. (1997) Evert et al. (1994) Broly et al. (1995) Tyndale et al. (1991) Broly and Meyer (1993) Yokota et al. (1993) Sakuyama et al. (2008) Johansson et al. (1994) Garcia-Barceló et al. (2000) Ji et al. (2002) Mitsunaga et al. (2002) Ishiguro et al. (2004) Ishiguro et al. (2004) Marez et al. (1995) Marez et al. (1996) Panserat et al. (1995) Wang et al. (1993) Wang et al. (1999) Sakuyama et al. (2008) Ji et al. (2002) Sakuyama et al. (2008) Sachse et al. (1996) Daly et al. (1996) Masimirembwa et al. (1996) Oscarson et al. (1997) Cai et al. (2006) Yokoi et al. (1996) Sakuyama et al. (2008) Marez et al. (1997) Marez-Allorge et al. (1999) Chida et al. (1999) Yamazaki et al. (2003) Marez et al. (1997) Marez et al. (1997) Marez et al. (1997) Marez et al. (1997) Marez et al. (1997) Marez et al. (1997) Sakuyama et al. (2008) Marez et al. (1997) Marez et al. (1997) Wennerholm et al. (2001) Wennerholm et al. (2002) Marez et al. (1997) Marez et al. (1997) Marez et al. (1997) Marez et al. (1997) Marez et al. (1997) Marez et al. (1997) Gaedigk et al. (2003a) Griese et al. (1998) Gaedigk et al. (2006) Sakuyama et al. (2008) Wang et al. (1993)

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461

Table 1 (Continued ) Gene

Allele family

*3753

CYP2C9

Allele*

DNA change†

Protein change

In vivo E.A.‡

*3854 *39

Hom. Hom. Hom.

None 2587–2590delGACT None

– 271Frameshift –

Not reported None Normal13

*40 *41

Hom. Hom.

1863–1864 ins(TTTCGCCCC)2 G2988 → A

174–175 ins(Phe-Arg-Pro)2 Splicing defect

None21 Decreased5

*42 *4355 *44 *45 *46 *47

Hom. Hom. Hom. A B Hom. Hom.

3259–3260ins(GT) None G2950 → C None None None C100 → T

365 Frameshift – Splicing defect – – – Pro34 → Ser

None Not reported None Not reported Not reported Not reported Not reported

*48

Hom.

None

–

Not reported

*49

Hom.

C100 → T

Pro34 → Ser

Not reported

*50

Hom.

None

–

Not reported

*51

Hom.

None

–

Not reported

*52 *53

Hom. Hom.

None None

– –

Not reported Not reported

*54

Hom.

None

–

Not reported

*55

Hom.

None

–

Not reported

*56 *5756

A B Hom.

C3201 → T C3201 → T None

Arg344 → Stop Arg344 → Stop –

Not reported Not reported Not reported

*58 *59

Hom. Hom.

None G2291 → A

– None

Not reported Not reported

*60 *61 *62 *63 *64 *65 *66 *67 *68 *69 *70 *71 *72 *73 *74 *75

Hom. Hom. Hom. Hom. Hom. Hom. Hom. Hom. Hom. Hom. Hom. Hom. Hom. Hom. Hom. Hom.

None None C4044 → T None None None None None None None None None None None None None

– – Arg441 → C – – – – – – – – – – – – –

Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Decreased Not reported Not reported Not reported Not reported Not reported Not reported

*1

*2

A B C D A

Wild-type None None None C3608 → T

– – – Arg144 → Cys

Normal Not reported Not reported Not reported Not reported

*3

B C A

C3608 → T C3608 → T A42,614 → C

Arg144 → Cys Arg144 → Cys Ile359 → Leu

Not reported Not reported Decreased

B

A42,614 → C

Ile359 → Leu

Decreased

Reference Johansson et al. (1994) Leathart et al. (1998) Marez et al. (1997) Leathart et al. (1998) Shimada et al. (2001) Sakuyama et al. (2008) Gaedigk et al. (2002) Raimundo et al. (2000) Raimundo et al. (2004) Toscano et al. (2006) Rau et al. (2006) Gaedigk et al. (2003b) Marez et al. (1997) Yamazaki et al. (2003) Gaedigk et al. (2005a) Gaedigk et al. (2005a) Gaedigk et al. (2005a) Soyama et al. (2004) Sakuyama et al. (2008) Soyama et al. (2004) Sakuyama et al. (2008) Soyama et al. (2004) Matsunaga et al. (2009) Sakuyama et al. (2008) Soyama et al. (2004) Sakuyama et al. (2008) Soyama et al. (2004) Sakuyama et al. (2008) Lee et al. (2009) Ebisawa et al. (2005) Sakuyama et al. (2008) Ebisawa et al. (2005) Sakuyama et al. (2008) Ebisawa et al. (2005) Sakuyama et al. (2008) Li et al. (2006) Gaedigk et al. (2007) Soyama et al. (2006) Sakuyama et al. (2008) – Marez et al. (1997) Toscano et al. (2006) Lee et al. (2009) Kramer et al. (2009) Klein et al. (2007) Kramer et al. (2009) Gaedigk and Coetsee (2008) Gaedigk and Coetsee (2008) Gaedigk and Coetsee (2008) – Kramer et al. (2009) Gaedigk et al. (2008) Matimba et al. (2009) Zhou et al. (2009) Matsunaga et al. (2009) – – Qin et al. (2008) Romkes et al. (1991) King et al. (2004) Shintani et al. (2001) King et al. (2004) Rettie et al. (1994) Crespi and Miller (1997) Takahashi et al. (2004) Sandberg et al. (2004) King et al. (2004) King et al. (2004) King et al. (2004) Sullivan-Klose et al. (1996) Haining et al. (1996) Aithal et al. (1999) Kidd et al. (1999) Takanashi et al. (2000) Shintani et al. (2001) King et al. (2004) Shintani et al. (2001)

462

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Table 1 (Continued ) Gene

CYP2C19

Allele family

Allele*

DNA change†

Protein change

In vivo E.A.‡

*4 *5

Hom. Hom.

None C42,619 → G

– Asp360 → Glu

Not reported Decreased (?)

*6

Hom.

10,601delA

273 Frameshift

None

*7 *8

Hom. Hom.

None G3627 → A

– Arg150 → His

Not reported Decreased

*9 *10 *11

Hom. Hom. A

None None C42,542 → T

– – Arg335 → Trp

Not reported Not reported Decreased

*12 *13

B Hom. Hom.

C42,542 → T C50,338 → T None

Arg335 → Trp Pro489 → Ser –

Not reported Not reported Decreased

*14

Hom.

G3552 → A

Arg125 → His

Not reported

*15

Hom.

None

–

Not reported

*16

Hom.

A33,497 → G

Thr299 → Ala

Not reported

*17

Hom.

None

–

Not reported

*18

Hom.

None

–

Not reported

*19

Hom.

None

–

Not reported

*20 *21 *22 *23 *24 *25 *26 *27 *28 *29 *30 *31 *32 *33 *34

Hom. Hom. Hom. Hom. Hom. Hom. Hom. Hom. Hom. Hom. Hom. Hom. Hom. Hom. Hom.

None None None None None None None None None None None None None None None

– – – – – – – – – – – – – – –

Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported

*1

*462 *563

A B C A57 B58 C59 D A60 B61 Hom. A

Wild-type None None G19,154 → A G19,154 → A G19,154 → A G19,154 → A G17,948 → A G17,948 → A A1 → G C90,033 → T

– – Splicing defect Splicing defect Splicing defect Splicing defect Trp212 → Stop Trp212 → Stop GTG initiation codon Arg433 → Trp

Normal Normal Normal None None Not reported Not reported None Not reported None None

*664 *7 *8 *9 *10 *11 *12 *13 *14 *15 *16 *17 *17 *18 *19 *20

B Hom. Hom. Hom. Hom. Hom. Hom. Hom. Hom. Hom. Hom. Hom. Hom. Hom. Hom. Hom. See CYP2C19*3B

C90,033 → T G12,748 → A T19,294 → A T12,711 → C G12,784 → A C19,153 → T None A90,209 → C None None None None C−806 → T C−806 → T None None

Arg433 → Trp Arg132 → Gln Splicing defect Trp120 → Arg Arg144 → His Pro227 → Leu – Stop491 → Cys (26 extra aa) – – – – – – – –

None None None None Not reported Not reported Not reported ? Not reported Not reported Not reported Not reported Increased Increased Not reported Not reported

*2

*3

Reference King et al. (2004) Imai et al. (2000) Dickmann et al. (2001) Allabi et al. (2004) Allabi et al. (2005) Kidd et al. (2001) Allabi et al. (2005) Blaisdell et al. (2004) Blaisdell et al. (2004) Allabi et al. (2005) Blaisdell et al. (2004) Blaisdell et al. (2004) Higashi et al. (2002) Blaisdell et al. (2004) King et al. (2004) Allabi et al. (2005) King et al. (2004) Blaisdell et al. (2004) Si et al. (2004) Guo et al. (2005a) Guo et al. (2005b) Zhao et al. (2004) Delozier et al. (2005) Zhao et al. (2004) Delozier et al. (2005) Zhao et al. (2004) Delozier et al. (2005) Zhao et al. (2004) Delozier et al. (2005) Zhao et al. (2004) Delozier et al. (2005) Zhao et al. (2004) Delozier et al. (2005) Zhao et al. (2004) Veenstra et al. (2005) Veenstra et al. (2005) Veenstra et al. (2005) Herman et al. (2006) Maekawa et al. (2006) Maekawa et al. (2006) Maekawa et al. (2006) Maekawa et al. (2006) Maekawa et al. (2006) Maekawa et al. (2006) Matimba et al. (2009) Matimba et al. (2009) Yin et al. (2008) Yin et al. (2008) Romkes et al. (1991) Richardson et al. (1995) Blaisdell et al. (2002) de Morais et al. (1994a) Ibeanu et al. (1998b) Fukushima-Uesaka et al. (2005) Lee et al. (2009) de Morais et al. (1994b) Fukushima-Uesaka et al. (2005) Ferguson et al. (1998) Xiao et al. (1997) Ibeanu et al. (1998a) Ibeanu et al. (1998a) Ibeanu et al. (1998b) Ibeanu et al. (1999) Ibeanu et al. (1999) Blaisdell et al. (2002) Blaisdell et al. (2002) Blaisdell et al. (2002) Blaisdell et al. (2002) Blaisdell et al. (2002) Blaisdell et al. (2002) Blaisdell et al. (2002) Morita et al. (2004) Sim et al. (2006) Rudberg et al. (2007) Fukushima-Uesaka et al. (2005) Fukushima-Uesaka et al. (2005)

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Table 1 (Continued ) Gene

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 * † ‡

Allele family

Allele*

DNA change†

Protein change

In vivo E.A.‡

Reference

*21 *22 *23 *24 *25 *26

See CYP2C19*2C Hom. Hom. Hom. Hom. Hom.

None None None None None

– – – – –

Not reported Not reported Not reported Not reported Not reported

Matimba et al. (2009) Zhou et al. (2009) Zhou et al. (2009) Zhou et al. (2009) Lee et al. (2009)

Also known as CYP3A4-V. As assessed by using the metabolic probe midazolam. As assessed by using the metabolic probes desbrisoquine and sparteine. Also known as M4. As assessed by using the metabolic probe sparteine. Also known as M5. Also known as CYP2D6L. As assessed by using the metabolic probes dextromethorphan, desbrisoquine and sparteine. Also known as M10. Also known as M12. Also known as M14. Also known as M16. Also known as M17 Also known as M21 Previously known as CYP2D6*41B. N = 2, 3, 4, 5 or 13. As assessed by using the metabolic probe desbrisoquine. Also known as CYP2D6A. Also known as CYP2D6B. Also known as K29-1. As assessed by using the metabolic probe dextromethorphan. Observed in a gene duplication. Also known as CYP2D6D. Also known as CYP2D6T. As assessed by using the metabolic probes desbrisoquine and dextromethorphan. Also known as CYP2D6E. Also known as CYP2D6G. Also known as CYP2D6C. As assessed by using the metabolic probes bufuralol, sparteine and desbrisoquine. Also known as CYP2D6J. Also known as CYP2D6Ch1. Also known as CYP2D6F. Also known as CYP2D6D2. Also known as CYP2D6Z. Also known as CYP2D6(J9). Also known as M2. Also known as M3. Also known as M6. Also known as M7. Also known as M8. Also known as M9. Also known as M11. Also known as M13 Also known as M15. Also known as M20 Also known as M19. Also known as CYP2D6*1C. Also known as CYP2D6*1D. Also known as CYP2D6*2B. Single gene. Gene duplication or tandem repeat. Also known as CYP2D6Ch2. Also known as CYP2D6*10D. Also known as N2. Also known as M1. In tandem with CYP2D6*10. Also known as m1 or m1A. Also known as m1B. Also called CYP2C19*21. Also known as m2. Also called CYP2C19*20. Also known as m3. Also known as m4. Also known as m5. Hom. indicate that the allele is homonym of the gene family name. DNA change indicates the dominant inherited mutation responsible of the observed phenotype. The enzymatic activity in vivo estimated by using metabolic probes.

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Vesell, 2004; Motsinger et al., 2007). Thus, a polymorphism could not be considered as a single entity, but in the genetic context of the other polymorphisms. The concept of haplotype, indicating the combination of the polymorphisms lying on a single chromosome, was the basis to understand these interactions. Considered a gene with several polymorphisms, the haplotype identified the sequential combination in which each polymorphism appeared along the chromosome. It was clear that, as well as two different alleles on the homologues that differed by one polymorphism encoded allelic forms of the same protein, also different haplotypes on the homologues encoded allelic forms of the same protein. For this reason the term “allele” was also used instead of “haplotype”, and all different haplotypes could be correctly considered alleles of the same gene. This was the case of the CYP alleles. A paradigmatic example was the common apolipoprotein E (APOE) polymorphism (Seripa et al., 2007). The APOE polymorphism showed three common alleles ␧2, ␧3 and ␧4, that indeed were the haplotypes resulted from the combination of the two SNPs rs429358 (C3937 → T) and rs7412 (C4075 → T) in exon 4 of the APOE gene. Thus, the T3937 –T4075 haplotype identified the ␧2 allele, the T3937 –C4075 haplotype identified the ␧3 allele, and the C3937 –C4075 haplotype identified the ␧4 allele. Nucleotides 3937 and 4075 corresponded to the first bases of two CGC codons which encoded arginine (Arg), and each C → T transition changed the first base in this codons, resulted in TGC codons encoded cysteine (Cys). Thus, the ␧2 allele encoded the E2 protein (Cys112 Cys158 ), the ␧3 allele encoded the E3 protein (Cys112 -Arg158 ), and the ␧4 allele encoded the E4 protein (Arg112 -Arg158 ). Exactly as the APOE proteins, the CYP enzymes were encoded by alleles determined by n-point haplotypes (n = number of gene variants), were for APOE n = 2 and for CYP n ≥ 1. 5. Informatic resources The main informatic resource, reference for the CYP description and nomenclature, was The Home Page of The Human Cytochrome P450 (CYP) Allele Nomenclature Committee (available at URL http://www.cypalleles.ki.se/). Accordingly, a polymorphism/mutation identifying a CYP allele was considered as a major alteration if it was responsible for the observed enzymatic activity in vivo (the metabolic phenotype). All gene names were reported in capital case according to the Human Gene Nomenclature Committee (HGNC) database of the Human Gene Organization (HUGO) (available at URL http://www.genenames.org/). All the other data were referred to the Entrez Gene database of the National Center for Biotechnology Information (NCBI) (available at URL http://www.ncbi.nlm.nih.gov), the GeneCards database (available at URL http://www.genecards.org/index.shtml) and the Geneatlas database (available at URL http://genatlas.medecine.univparwas5.fr/). In this review, we limited the description to the four most important CYP genes CYP3A4, CYP2D6, CYP2C9 and CYP2C19. 6. The CYP3A4 The gene cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) lied at locus 7q21.1, encompass 27,205 bases and is composed of 13 exons, encoding a protein of 503 amino acids. This gene is part of the CYP3A gene cluster (Fig. 1), including four genes (CYP3A4, CYP3A5, CYP3A7 and CYP3A43) and two pseudogenes (CYP3A5P1 and CYP3A5P2). The CYP3A4 enzyme is involved in the metabolism of approximately 50% of all drugs currently used in clinical practice. Overall, the CYP3A4 gene shows a total of 20 allele families, four of them showing multiple alleles, totally including 41 alleles, all summarized in Table 1. All these alleles were characterized

by different haplotypes. Thus, differences in the activities of the encoded enzymes may be observed. Notably, only in four allele families out of 20 (20.00%) major alterations were identified, and only in two alleles out of 41 (7.32%) the metabolic phenotypes were characterized. Thus, further studies were necessary to identify the missed metabolic phenotypes. Notably, in a pharmacogenetic study a genetic analysis discriminating among these alleles, and in particular among the variant alleles and the wt allele, was strongly recommended. 6.1. The CYP3A4 wt (CYP3A4*1A) The allele family *1 included the eighteen alleles A (Gonzalez et al., 1988), B (Rebbeck et al., 1998; Westlind et al., 1999), C and D (Kuehl et al., 2001), E and F (Hamzeiy et al., 2002), G, H, J, K, L, M, N, P, Q, R, S and T (Fukushima-Uesaka et al., 2004) (Table 1). Indeed, the allele A was considered the wt, encoding the enzyme with a normal activity in vivo, whereas the other alleles were considered variants. A normal activity was reported for the enzyme encoded by allele A, whereas no data were reported regarding the metabolic phenotype of alleles B-to-T. 6.2. The CYP3A4 alleles The allele families *2-to-*14 included one allele for each family (Sata et al., 2000; Eiselt et al., 2001; Hsieh et al., 2001; Murayama et al., 2002; Lamba et al., 2002) (Table 1). No major alterations identifying these families were reported and no data regarding the metabolic phenotypes of these alleles were available. The allele family *15 included the two alleles A (Lamba et al., 2002) and B (Hamzeiy et al., 2002) (Table 1). No major gene alteration identifying this family was reported, and no data regarding the metabolic phenotypes of these alleles were available. The allele family *16 included the two alleles A (Lamba et al., 2002; Murayama et al., 2002) and B (Murayama et al., 2002; Fukushima-Uesaka et al., 2004) (Table 1). This family was identified by the major alteration C15,603 → G (rs12721627), causing the amino acid change Thr185 → Ser. No data regarding the activity in vivo of the enzymes encoded by these alleles were available. The allele family *17 included one allele (Dai et al., 2001) (Table 1). This family was identified by the major alteration T15,615 → C (rs4987161) causing the amino acid change Phe189 → Ser. No data regarding the activity in vivo of the enzyme encoded by this allele were available. The allele family *18 included the two alleles A (Dai et al., 2001; Kang et al., 2009) and B (Fukushima-Uesaka et al., 2004) (Table 1). This family was identified by the major alteration T20,070 → C (rs28371759) causing the amino acid change Leu293 → Pro. A reduced enzyme activity in vivo was reported for allele A, whereas no data were available regarding the metabolic phenotype of allele B. The allele family *19 included one allele (Dai et al., 2001) (Table 1). No major alteration identifying this family was reported, and no data regarding the activity in vivo of the enzyme encoded by this allele were available. The allele family *20 included one allele (Westlind-Johnsson et al., 2006) (Table 1). This family was identified by the major alteration 25889–25890insA, causing a frameshift from codon 488 leading to a truncated non-functional protein. It resulted in a missing enzyme activity. No data were available regarding the metabolic phenotype of this allele. Notably, a number of further variants were recently described in the CYP3A4 gene (Solus et al., 2004; Suman et al., 2009). For these variants, however, no data were still available to classify them as CYP3A4 alleles.

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7. The CYP2D6 The CYP2D6 gene (cytochrome P450, family 2, subfamily D, polypeptide 6) lied at locus 22q13.1, encompasses 4408 bases and is composed of 9 exons, encoding a protein of 497 amino acids. This gene is part of the CYP2D cluster (Fig. 1), including one gene (CYP2D6) and two pseudogenes (CYP2D7P and CYP2D8P). The CYP2D6 gene is the most polymorphic CYP in the population, encoding enzymes responsible of PM phenotypes, and is responsible for the metabolism of approximately 20% of all drugs commonly prescribed in clinical practice. Overall, a total of 73 allele families are known for this gene, 13 of them showing multiple alleles, totally including 120 single alleles, all summarized in Table 1. All these alleles were characterized by different haplotypes. Thus, differences in the activities of the encoded enzymes may be observed. Notably, only in 31 allele families out of 73 (42.46%) were identified major alterations, and only in 46 alleles out of 120 (38.33%) the metabolic phenotypes were characterized. Thus, further studies were necessary to identify the missed metabolic phenotypes. Notably, in a pharmacogenetic study a genetic analysis discriminating among these alleles, and in particular among the variant alleles and the wt allele, was strongly recommended. 7.1. The CYP2D6 wt (CYP2D6*1A) The allele family *1 included the six alleles A (Kimura et al., 1989), B, C and D (Marez et al., 1997), E (Sachse et al., 1997) and *1XN, a gene duplication (Dahl et al., 1995; Sachse et al., 1997) (Table 1). Indeed, the allele A was considered the wt, whereas the other alleles were considered variants, although for alleles B and C a normal enzyme activity in vivo was also reported. No metabolic phenotypes were reported for alleles D and E. Notably, the allele *1XN showed an increased enzyme activity in vivo in which a doseeffect was expected, because to a gene duplication in which n gene with a normal activity were present. 7.2. The CYP2D6 alleles The allele family *2 included the thirteen alleles A (Johansson et al., 1993; Panserat et al., 1994; Raimundo et al., 2000; Sakuyama et al., 2008), B (Marez et al., 1997), C (Marez et al., 1997; Sachse et al., 1997), D, E, F, G, H (Marez et al., 1997), J (actually identified as the allele family *59), K (Marez et al., 1997), L (Gaedigk et al., 2005a), M (Gaedigk et al., 2005b) and XN (Johansson et al., 1993; Dahl et al., 1995; Aklillu et al., 1996) (Table 1). It was reported that alleles A and 2XN had a normal enzyme activity in vivo, despite no major gene alteration identifying this family was reported. In particular, allele 2XN showed an increased enzyme activity in vivo because to a gene duplication in which 2, 3, 4, 5 or 13 copies of the gene were present (Johansson et al., 1993; Dahl et al., 1995; Aklillu et al., 1996). Also in this case, a dose-effect was expected. No data regarding the metabolic phenotypes of alleles B-to-M were available. The allele family *3 included the two alleles A (Kagimoto et al., 1990) and B (Marez et al., 1997) (Table 1). This family was identified by the major alteration 2549delA (rs1057910) causing a frameshift from codon 259. It resulted in a truncated non-functional protein with a missing enzyme activity in vivo. This was reported for allele A, whereas no metabolic phenotype was reported for allele B. The allele family *4 included the fourteen alleles A (Kagimoto et al., 1990; Gough et al., 1990; Hanioka et al., 1990), B (Kagimoto et al., 1990), C (Yokota et al., 1993), D, E, F, G, H, J (Marez et al., 1997), K (Sachse et al., 1997), L (Shimada et al., 2001), M (Agúndez et al., 1997; Fuselli et al., 2004; Gaedigk et al., 2006), N (Gaedigk et al., 2006) and *4X2, a gene duplication (Løvlie et al., 1997; Sachse et al., 1998) (Table 1). This family was identified by the major alteration

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G1846 → A (rs3892097), causing a splicing defect. It resulted in a truncated non-functional protein with a missed enzyme activity. This was reported for alleles A, B, C, D, K and *4X2, whereas no metabolic phenotypes were reported for the alleles E, F, G, H, J, L, M and N. The allele family *5 included one allele (Gaedigk et al., 1991; Steen et al., 1995) (Table 1). The major alteration identifying this allele family was the gene deletion, resulting in a missed enzyme activity. The allele family *6 included the four allele A (Saxena et al., 1994), B (Evert et al., 1994; Daly et al., 1995), C and D (Marez et al., 1997) (Table 1). This family was identified by the major gene alteration 1707delT. It causes a frameshift from codon 118 leading to a truncated non-functional protein, resulting in a missed enzyme activity. This was reported for alleles A, B and C, whereas no metabolic phenotype was reported for allele D. The allele family *7 included one allele (Evert et al., 1994) (Table 1). This family was identified by the major alteration A2935 → C (rs105440243), resulting in the amino acid change His324 → Pro. It resulted in a missing enzyme activity. The allele family *8 included one allele (Broly et al., 1995) (Table 1). This family was identified by the major alteration G1758 → T, resulting in the conversion of the amino acid 169 (Gly) in a STOP codon, thus generating a truncated non-functional protein. It resulted in a missing enzyme activity. The allele family *9 included one allele (Tyndale et al., 1991; Broly and Meyer, 1993) (Table 1). This family was identified by the major alteration 2615 2617delAAG deleting Lys281 . It resulted in a reduced enzyme activity in vivo. The allele family *10 included the five alleles A (Yokota et al., 1993; Sakuyama et al., 2008), B (Johansson et al., 1994), C (also known as *36), D (Ishiguro et al., 2004) and *10XN (a gene duplication) (Garcia-Barceló et al., 2000; Ji et al., 2002; Mitsunaga et al., 2002; Ishiguro et al., 2004) (Table 1). This family was identified by the major alteration C100 → T (rs1065852), causing the amino acid changes Pro34 → Ser associated with a decreased enzyme activity in vivo. This metabolic phenotype was reported in alleles A, B and C. For allele D no data were available. The allele family *11 included one allele (Marez et al., 1995) (Table 1). This family was identified by the major alteration G883 → C, causing a splicing defect leading to a truncated nonfunctional protein. It resulted in a missing enzyme activity. The allele family *12 included one allele (Marez et al., 1996) (Table 1). This allele was identified by the major alteration G124 → A (rs5030862), causing the amino acid change Gly42 → Arg. It resulted in a missing enzyme activity. The allele family *13 included one allele (Panserat et al., 1995) (Table 1). Despite no major gene alteration was reported identifying this family, a frameshift was reported as primary effect of the formation of an hybrid between exons 2–9 of CYP2D6 and exon 1 of CYP2D7. It resulted in a truncated non-functional protein with a missing enzyme activity. The allele family *14 included the two alleles A (Wang et al., 1993, 1999; Sakuyama et al., 2008) and B (Ji et al., 2002; Sakuyama et al., 2008) (Table 1). This family was identified by the major alteration G1758 → A, causing the amino acid change Gly169 → Arg and resulting in a missed enzyme activity. It was reported in allele A. No metabolic phenotype was reported for allele B. The allele family *15 included one allele (Sachse et al., 1996) (Table 1). This family was identified by the major alteration 137–138insT, causing a frameshift from amino acid 46 leading to a truncated non-functional protein. It resulted in a missing enzyme activity. The allele family *16 included one allele (Daly et al., 1996) (Table 1). Despite no major gene alteration was reported identifying this allele, a frameshift was reported as primary effect of the

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formation of an hybrid between exons 8–9 of CYP2D6 and exons 1–7 of CYP2D7P. It resulted in a truncated non-functional protein with a missing enzyme activity. The allele family *17 included two alleles *17 (Masimirembwa et al., 1996; Oscarson et al., 1997) and *17XN, a gene duplication (Cai et al., 2006) (Table 1). This allele family was identified by the major alterations C1023 → T (rs28371706) and C2850 → T (rs16947), causing the amino acid changes Thr107 → Ile and Arg296 → Cys associated with a decreased enzyme activity in vivo. It was reported for allele *17 whereas no data regarding the metabolic phenotype of allele *17XN were available. The allele family *18 included one allele (Yokoi et al., 1996; Sakuyama et al., 2008) (Table 1). This family was identified by the major alteration 4125–4133dupGTGCCCACT, causing a duplication of the amino acids Val-Pro-Thr at codons 468–470. It resulted in a truncated non-functional protein with a missed enzyme activity. The allele family *19 included one allele (Marez et al., 1997) (Table 1). This family was identified by the major alteration 2539–2542delAACT, causing a frameshift from codon 255 leading to a truncated non-functional protein. It resulted in a missing enzyme activity. The allele family *20 included one allele (Marez-Allorge et al., 1999) (Table 1). This family was identified by the major alteration 1973–1974insG, causing a frameshift from amino acid 211 leading to a truncated non-functional protein. It resulted in a missing enzyme activity. The allele family *21 included the two alleles A (Chida et al., 1999) and B (Yamazaki et al., 2003) (Table 1). This family was identified by the major alteration 2573–2574insC, causing a frameshift from codon 267 leading to a truncated non-functional protein. It resulted in a missing enzyme activity. The allele families *22-to-*28 included one allele for each family (Marez et al., 1997; Sakuyama et al., 2008) (Table 1). No major alterations were reported identifying these families, and no data were reported regarding the metabolic phenotypes of these alleles. The allele family *29 included one allele (Marez et al., 1997; Wennerholm et al., 2001, 2002) (Table 1). Despite no major alteration was reported identifying this family, the activity in vivo of the enzyme encoded by this allele was described as decreased. The allele families *30-to-*32 included one allele for each family (Marez et al., 1997) (Table 1). No major gene alterations were reported identifying these families, and no data were reported regarding the metabolic phenotypes of these alleles. The allele family *33 included one allele (Marez et al., 1997) (Table 1). Despite no major alteration was described identifying this family, the activity in vivo of the enzyme encoded by this allele was reported as normal. The allele family *34 included one allele (Marez et al., 1997) (Table 1). No major alteration was reported identifying this family, and no data were reported regarding the metabolic phenotype of this allele. The allele family *35 included the two alleles *35 (Marez et al., 1997; Gaedigk et al., 2003a) and *35X2, a gene duplication (Griese et al., 1998) (Table 1). Despite no major alteration was reported identifying this family, the activity in vivo of the enzyme encoded by the *35 allele was reported as normal, whereas the activity in vivo of the enzyme encoded by the second allele *35X2, was reported as increased. The allele family *36 included two alleles (Gaedigk et al., 2006; Sakuyama et al., 2008; Wang et al., 1993; Johansson et al., 1994; Leathart et al., 1998), being a single gene (allele 1) or a gene duplication/tandem repeat (Table 1). This family was identified by the same major alteration identifying family *10. However, despite it was reported to confer a decreased enzyme activity in vivo in alleles *10A, *10B and *10C, a negligible activity in vivo was reported for these two alleles of this family.

The allele family *37 included one allele (Marez et al., 1997) (Table 1). No major alteration was reported identifying this family, and no data were reported regarding the metabolic phenotype of this allele. The allele family *38 included one allele (Leathart et al., 1998) (Table 1). This family was identified by the major alteration 2587–2590delGACT, causing a frameshift from amino acid 271 leading to a truncated non-functional protein. It resulted in a missing enzyme activity. The allele family *39 included one allele (Shimada et al., 2001; Sakuyama et al., 2008) (Table 1). No major alteration was reported identifying this family, and no data were reported regarding the metabolic phenotype of this allele. The allele family *40 included one allele (Gaedigk et al., 2002) (Table 1). It was identified by the major alteration 1863–1864ins(TTTCGCCCC)2 , causing the insertion 174–175ins(Phe-Arg-Pro)2 leading to a non-functional protein. It resulted in a missing enzyme activity. The allele family *41 included one allele (Raimundo et al., 2000, 2004; Toscano et al., 2006; Rau et al., 2006) (Table 1). It was identified by the major alteration G2988 → A, causing a splicing defect leading to an exon skipping, and thus in a non-functional protein. It resulted in a missing enzyme activity. The allele family *42 included one allele (Gaedigk et al., 2003a) (Table 1). It was identified by the major alteration 3259–3260insGT, causing a frameshift from amino acid 365 leading to a truncated non-functional protein. It resulted in a missing enzyme activity. The allele family *43 included one allele (Marez et al., 1997) (Table 1). No major alteration was reported identifying this family, and no data were reported regarding the metabolic phenotype of this allele. The allele family *44 included one allele (Yamazaki et al., 2003) (Table 1). It was identified by the major alteration G2950 → C, causing a splicing defect leading to an exon skipping, and thus to a non-functional protein. It resulted in a missing enzyme activity. The allele family *45 included the two alleles A (Gaedigk et al., 2005a) and B (Gaedigk et al., 2005a) (Table 1). No major gene alteration was reported identifying this family, and no data were reported regarding the metabolic phenotype of these alleles. The allele family *46 included one allele (Gaedigk et al., 2005a) (Table 1). No major gene alteration was reported identifying this family, and no data were reported regarding the metabolic phenotype of this allele. The allele family *47 included one allele (Soyama et al., 2004; Matsunaga et al., 2009; Sakuyama et al., 2008) (Table 1). This family was identified by the same major alteration of families *10 and *36. However, no data were reported regarding the metabolic phenotype of this allele. The allele family *48 included one allele (Soyama et al., 2004; Sakuyama et al., 2008) (Table 1). No major gene alteration was reported identifying this family, and no data were reported regarding the metabolic phenotype of this allele. The allele family *49 included one allele (Soyama et al., 2004; Matsunaga et al., 2009; Sakuyama et al., 2008) (Table 1). This family showed the same major alteration of families *10, *36 and *47. However, no data were reported regarding the metabolic phenotype of this allele. The allele families *50-to-*55 included one allele for each family (Soyama et al., 2004; Sakuyama et al., 2008; Lee et al., 2009; Ebisawa et al., 2005) (Table 1). No major alterations were reported identifying these families, and no data were reported regarding the activity in vivo of the enzymes encoded by these alleles. The allele family *56 included the two alleles A (Li et al., 2006) and B (Gaedigk et al., 2007) (Table 1). This family was identified by the major alteration C3201 → T converting the Arg344 in a STOP codon, thus producing a truncated non-functional protein.

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It resulted in a missing enzyme activity. No data were reported regarding the metabolic phenotypes of these alleles. The allele families *57 and *58 included one allele for each family (Soyama et al., 2006; Sakuyama et al., 2008) (Table 1). No major alterations were reported identifying these families, and no data were reported regarding the metabolic phenotypes of these alleles. The allele family *59 included one allele (Marez et al., 1997; Toscano et al., 2006) (Table 1). It was identified by the major alteration G2291 → A did not causing amino acid change. No data were available regarding the metabolic phenotype of this allele. The allele families *60 and *61 included one allele for each family (Lee et al., 2009; Kramer et al., 2009) (Table 1). No major alterations were reported identifying these families, and no data were reported regarding the metabolic phenotypes of these alleles. The allele family *62 included one allele (Klein et al., 2007) (Table 1). It was identified by the major alteration C4044 → T causing the amino acid change Arg441 → Cys. No data were reported regarding the metabolic phenotype of this allele. The allele families *63-to-*75 included one allele for each family (Gaedigk and Coetsee, 2008; Gaedigk et al., 2008; Qin et al., 2008; Kramer et al., 2009; Matimba et al., 2009; Matsunaga et al., 2009; Zhou et al., 2009) (Table 1). No major alterations identifying these families were reported, and no data regarding the metabolic phenotype of these alleles were available. Indeed, for the allele family *69, a decreased enzyme activity in vivo was reported. Notably, a number of further variants were recently described in the CYP2D6 gene (Solus et al., 2004; Matimba et al., 2009). For these variants, however, no data were still available to classify them as CYP2D6 alleles. 8. The CYP2C9 The gene cytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9) lied at locus 10q24.1, encompass 50,733 bases and is composed of 9 exons, encoding a protein of 490 amino acids. This gene is part of the CYP2C cluster, including four genes (CYP2C8, CYP2C9, CYP2C18 and CYP2C19). This enzyme is known to metabolize many xenobiotics. Overall, a total of 34 allele families are known for the CYP2C9 gene, including a total of 41 single alleles. All these alleles were characterized by different haplotypes. Thus, differences in the activities of the encoded enzymes may be observed. Notably, only in 9 allele families out of 34 (26.47%) were identified major gene alterations, and only in 5 alleles out of 41 (12.20%) the metabolic phenotypes were characterized. Thus, further studies were necessary to identify the missed metabolic phenotypes. Notably, in a pharmacogenetic study a genetic analysis discriminating among these alleles, and in particular among the variant alleles and the wt allele, was strongly recommended. 8.1. The CYP2C9 wt (CYP2C19*1A) The allele family *1 included the four alleles A (Romkes et al., 1991), B (King et al., 2004), C (Shintani et al., 2001; King et al., 2004) and D (King et al., 2004) (Table 1). All these alleles showed several gene variants that, however, were not classified as major alterations. Indeed, the allele A was considered the wt, encoding the enzyme with a normal activity, whereas the other three alleles were considered variants. No data were available regarding the metabolic phenotypes of the alleles B, C and D. 8.2. The CYP2C9 alleles The allele family *2 included the three alleles A (Rettie et al., 1994; Crespi and Miller, 1997; Takahashi et al., 2004; Sandberg et al., 2004; King et al., 2004), B (King et al., 2004) and C (King

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et al., 2004) (Table 1). This family was identified by the major alteration C3608 → T (rs1799853), causing the amino acid change Arg144 → Cys. However, no data reporting the metabolic phenotype of these alleles were available. The allele family *3 included the two alleles A (Sullivan-Klose et al., 1996; Haining et al., 1996; Aithal et al., 1999; Kidd et al., 1999; Takanashi et al., 2000; Shintani et al., 2001; King et al., 2004) and B (Shintani et al., 2001; King et al., 2004) (Table 1). This family was identified by the major alteration A42,614 → C (rs1057910), causing the amino acid change Ile359 → Leu, that has been associated with a decreased enzyme activity in vivo. The allele family *4 included one allele (Imai et al., 2000) (Table 1). No major alteration was reported identifying this family, and no data regarding the metabolic phenotype of this allele were available. The allele family *5 included one allele (Dickmann et al., 2001; Allabi et al., 2004, 2005) (Table 1). It was identified by the major alteration C42,619 → G (rs28371686), causing the amino acid change Asp360 → Glu. No data regarding the metabolic phenotype of this allele were available. The allele family *6 included one allele (Kidd et al., 2001; Allabi et al., 2005) (Table 1). It was identified by the major alteration 10,601delA, causing a frameshift from amino acid 273 and leading to a truncated non-functional protein. It resulted in a missing enzyme activity. The allele family *7 included one allele (Blaisdell et al., 2004) (Table 1). No major alteration was reported identifying this family, and no data regarding the metabolic phenotype of this allele were available. The allele family *8 included one allele (Blaisdell et al., 2004; Allabi et al., 2005). It was identified by the major alteration G3627 → A (rs7900194), causing the amino acid change Arg150 → His that has been associated with a decreased enzyme activity in vivo. The allele families *9 and *10 included one allele for each family (Blaisdell et al., 2004) (Table 1). No major alterations were reported identifying these families, and no data regarding the metabolic phenotypes of these alleles were available. The allele family *11 included the two alleles A (Higashi et al., 2002; Blaisdell et al., 2004; King et al., 2004; Allabi et al., 2005) and B (King et al., 2004). This allele family was identified by the major alteration C42,542 → T (rs28371685), causing the amino acid change Arg355 → Trp associated with a decreased enzyme activity in vivo. It was reported in allele A. No data were available regarding the metabolic phenotype of allele B. The allele family *12 included one allele (Blaisdell et al., 2004) (Table 1). It was identified by the major alteration C50,338 → T (rs9332239), causing the amino acid change Pro489 → Ser. No in vivo data regarding the activity of the enzyme encoded by this allele was available. The allele family *13 included one allele (Si et al., 2004; Guo et al., 2005a,b) (Table 1). Despite a decreased in vivo enzyme activity has been reported for this allele, no major alteration responsible for this metabolic phenotype was reported. The allele family *14 included one allele (Zhao et al., 2004; Delozier et al., 2005) (Table 1). It was identified by the major alteration G3552 → A, causing the amino acid change Arg125 → His. No metabolic phenotype was available for this allele. The allele family *15 included one allele (Zhao et al., 2004; Delozier et al., 2005) (Table 1). No major alteration identifying this family was described, and no data regarding the metabolic phenotype of this allele were available. The allele family *16 included one allele (Zhao et al., 2004; Delozier et al., 2005) (Table 1). It was identified by the major alteration A33,497 → G, causing the amino acid change Thr299 → Ala. However, no in vivo data regarding the

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activity of the enzyme encoded by this allele was available. The allele families *17-to-*34 included one allele in each family (Zhao et al., 2004; Delozier et al., 2005; Veenstra et al., 2005; Herman et al., 2006; Maekawa et al., 2006; Matimba et al., 2009; Yin et al., 2008) (Table 1). No major gene alterations were reported identifying these families, and no data regarding the metabolic phenotypes of these alleles were available. Notably, a number of further variants were recently described in the CYP2C9 gene (Solus et al., 2004; Maekawa et al., 2006; Kramer et al., 2009; Matimba et al., 2009; Goldstein et al., 2009). For these variants, however, no data were still available to classify them as CYP2C9 alleles. 9. The CYP2C19 The gene CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) lied at locus 10q24, encompass 90,637 bases and is composed of 9 exons, encoding a protein of 490 amino acids. This gene is part of the CYP2C cluster including four genes (CYP2C8, CYP2C9, CYP2C18 and CYP2C19). This enzyme is known to metabolize many xenobiotics. Overall, a total of 26 allele families were described for this gene. Indeed, the alleles initially called CYP2C19*20 and CYP2C19*21 were demonstrated to be CYP2C19*2C and CYP2C19*3B. Thus, whereas a total of 26 CYP2C19 alleles were categorized, only 24 allele families were really known. All these alleles were characterized by different haplotypes. Thus, differences in the activities of the encoded enzymes may be observed. These 24 allele families include a total of 32 single alleles. Notably, only in 10 families out of 24 (41.67%) were identified major gene alterations, and only in 13 alleles out of 32 (40.63%) the metabolic phenotypes were characterized. Thus, further studies were necessary to identify the missed metabolic phenotypes. Notably, in a pharmacogenetic study a genetic analysis discriminating among these alleles, and in particular among the variant alleles and the wt allele, was strongly recommended. 9.1. The CYP2C19 wt (CYP2C19*1A) The allele family *1 included the three alleles A (Romkes et al., 1991), B (Richardson et al., 1995) and C (Blaisdell et al., 2002) (Table 1), all encoding enzymes with a normal activity in vivo, despite no major alteration was reported identifying this family. Indeed, the allele A was considered the wt, whereas the other alleles B and C were considered variants. 9.2. The CYP2C19 alleles The allele family *2 included the four alleles A (also known with the trivial name m1 or m1A) (de Morais et al., 1994a), B (also known with the trivial name m1B) (Ibeanu et al., 1998a), C (also called CYP2C19*21) (Fukushima-Uesaka et al., 2005) and D (Lee et al., 2009) (Table 1). This family was identified by the major alteration G19,154 → A (rs71644820), causing a splicing defect resulting in an exon skipping, and thus in a non-functional protein with a missed enzyme activity. No data were available regarding the metabolic phenotypes of alleles C and D. The allele family *3 included the two alleles A (also known with the trivial name m2) (de Morais et al., 1994b) and B (also called CYP2C19*20) (Fukushima-Uesaka et al., 2005) (Table 1). This family was identified by the major alteration G17,948 → A (rs5586416), causing a STOP codon at amino acid 212 (Arg212 → STOP) leading to a premature termination of the protein. It resulted in a missing enzyme activity. No data regarding the metabolic phenotype of the allele B were available.

The allele family *4 included one allele (also known with the trivial name m3) (Ferguson et al., 1998) (Table 1). This family was identified by the major alteration A1 → G (rs28399504), causing a modification of the GTG initiation codon resulting in a missing of gene transcription, and thus in a lost enzyme activity. The allele family *5 included the two alleles A (also known with the trivial name m4) (Xiao et al., 1997; Ibeanu et al., 1998b) and B (Ibeanu et al., 1998a) (Table 1). This family was identified by the major alteration C90,033 → T (rs56337013), causing the amino acid change Arg433 → Trp. No enzyme activity in vivo was reported for these alleles. The allele family *6 included one allele (also known with the trivial name m5) (Ibeanu et al., 1998a) (Table 1). This family was identified by the major alteration G12,748 → A causing the amino acid change Arg132 → Gln, leading to a missed enzyme activity. The allele family *7 included one allele (Ibeanu et al., 1999) (Table 1). This family is identified by the major alteration T19,294 → A, causing a splicing defect resulting in an exon skipping. It resulted in a non-functional protein with a missing enzyme activity. The allele family *8 included one allele (Ibeanu et al., 1999) (Table 1). This family was identified by the major alteration T12,711 → C (rs41291556), causing the amino acid change Trp120 → Arg. It resulted in a non-functional protein with a missing enzyme activity. The allele family *9 included one allele (Blaisdell et al., 2002) (Table 1). This family is identified by the major alteration G12,784 → A (rs17884712), causing the amino acid change Arg144 → His. No data regarding the metabolic phenotype of this allele were available. The allele family *10 included one allele (Blaisdell et al., 2002) (Table 1). This family was identified by the major alteration C19,153 → T (rs6413438), causing the amino acid change Pro227 → Leu. No data regarding the metabolic phenotype of this allele were available. The allele family *11 included one allele (Blaisdell et al., 2002) (Table 1). No major alteration was reported identifying this family, and no data regarding the metabolic phenotype observed for this allele were available. The allele family *12 included one allele (Blaisdell et al., 2002) (Table 1). This family was identified by the major alteration A90,209 → C (rs55640102), converting the natural STOP codon at position 491 in a Cys (X491 → Cys) and causing the addition of 23 extra amino acid at the –COOH terminus of the protein. No data regarding the metabolic phenotype of this allele were available. The allele families *13-to-*16 included one allele for each family (Blaisdell et al., 2002; Morita et al., 2004) (Table 1). No major alterations were reported identifying these families, and no data regarding the metabolic phenotypes observed in these alleles were available. The allele family *17 included one allele (Sim et al., 2006; Rudberg et al., 2008) (Table 1). This family was identified by the major alteration C−806 → T (rs12248560), modifying the activity of the gene promoter, thus altering the transcriptional activity of the gene, being associated to an increased transcriptional activity in vivo. The allele families *18 and *19 (Fukushima-Uesaka et al., 2005), and *22-to-*26 (Lee et al., 2009; Matimba et al., 2009; Zhou et al., 2009) (Table 1) included one allele for each family. Families *20 and *21 were previously classified as alleles *3B and *2C, respectively. No major alterations identifying these families were reported. No data regarding the metabolic phenotypes observed in these families were available. Notably, six further variants were recently described in the CYP2C19 gene (Solus et al., 2004; Chen et al., 2008; Matimba et al., 2009; Lee et al., 2009). For these variants, however, no data were still available to classify them as CYP2C19 alleles.

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Table 2 Genetic factors, acting at single the locus, that at can contribute to an erroneous phenotype identification. Dominance

Haploinsufficiency Allelic heterogeneity Pleiotropy Genocopy Phenocopy Penetrance

Expressivity Intragenic complementation

The effects of the two allele of a gene on a phenotype. The phenotype may reflect the effects of one of the two allele (dominance) or the effect of both alleles (co-dominance or incomplete dominance). Similarly, we report about the two alleles as dominant, codominant and recessive. The situation in which one allele is absent, and the other allele is incapable to provide sufficient protein to assure normal function. Contribution of more than two alleles of a gene to the phenotype (multiple allelia). A gene that affects more than one phenotype. In particular, in an allelic serie, different alleles contribute to different phenotypes. The same phenotype due to different genetic causes. A phenotype that resembles to a genetic one, but has environmental rather than a genetic cause, and is not inherited. Proportion of individuals having a defined genotype who manifest the correspondent phenotype. May be complete (100% of subjects with the genotype manifested the phenotype) or non-complete (<100% of subjects with the genotype manifested the phenotype). Variation in the allelic expression when the allele is penetrant. As outcome we observed difference in the severity of the phenotype. The situation in which one allele encode a protein with a reduced function, and the other allele encode a protein with an increased function, giving a normal phenotype.

10. CYP2D6 and the metabolism of donepezil Donepezil is a potent and specific piperidine-based inhibitor of acetylcholinesterase (AChE), currently used for the symptomatic treatment of mild-to-moderate Alzheimer’s disease (AD) (Jann et al., 2002; Courtney et al., 2004; Cummings, 2004). The inhibition of AChE increases the concentration of acetylcholine (ACh) in the synaptic cleft, thus restoring the physiological effects of ACh within the central nervous system (Small et al., 1997; Doody et al., 2001; Cummings, 2004). After oral administration, more than 90% of donepezil undergoes to an extensive first-pass metabolism by the CYP2D6 enzyme (Tiseo et al., 1988), producing several metabolites. All these metabolites are clinically inactive because of their low plasma levels and their poor ability to cross the blood–brain barrier, with the exception of 6-O-desmethyldonepezil, the active metabolite (Tiseo et al., 1988; Jann et al., 2002). Several polymorphisms of the CYP2D6 play a role in the pharmacokinetics of donepezil, which may influence the efficacy of treatment in patients with AD (Varsaldi et al., 2006). Among the large number of allelic variants causing absent, decreased, or increased CYP2D6 enzyme activity, recent data demonstrated that the G allele of the SNP C−15,843 → G (rs1080985) was associated with a higher enzymatic activity in vivo as a consequence of a higher gene expression associated with the G allele (Gaedigk et al., 2003a; Zanger et al., 2001). It has been suggested that the presence of the G allele of rs1080985 was associated with a more rapid drug metabolism, probably due to an higher promoter activity in vivo associated with the A allele of the polymorphism G2988 → A, always in linkage disequilibrium with the G allele of rs1080985, and that the analysis of rs1080985 might be useful to ruled out the CYP2D6 poor metabolizer phenotype in Caucasians (Gaedigk et al., 2003a). It has been recently demonstrated that the analysis of rs1080985 in AD patients classified as responders/non-responders to donepezil treatment showed a significant difference in the overall distribution of the rs1080985 genotype between these patients (Pilotto et al., 2009). Notably, no information were available about the numerous polymorphisms described in the coding region of the CYP2D6 gene causing absence, decreased or increased CYP2D6 enzyme activity in these patients. Thus, an high-throughput genetic analysis may be recommended in the attempted to identify these polymorphisms to explored their possible influence on the efficacy of donepezil treatment in patients with mild-to-moderate AD. 11. CYP2C9 and the metabolism of nonsteroidal anti-inflammatory drugs (NSAID) Gastroduodenal bleeding associated with the use of nonsteroidal anti-inflammatory drugs (NSAID) is the most frequent ADR

responsible for high rates of both hospitalization and mortality in Western countries (Pilotto et al., 2005). Several NSAIDs are metabolized by CYP2C9 (Güzey and Spigset, 2004). In the CYP2C9 gene, as compared with the wt, the two most common gene variants are CYP2C9*2 (rs1799853) and CYP2C9*3 (rs1057910) (Table 1). Both in vitro and in vivo studies carried out with NSAID substrates reported that the CYP2C9*3 allele decreased the enzyme activity more than does CYP2C9*2 (Lee et al., 2002). An increased frequency of ADRs has been observed in CYP2C9*3 carriers treated with warfarin (Higashi et al., 2002) and possibly phenytoin (Soga et al., 2004), while the clinical consequences of CYP2C9 polymorphisms on NSAID-related gastroduodenal bleeding were still undefined (Kircheiner and Brockmoller, 2005). Recent data investigating these polymorphisms (Pilotto et al., 2007), showed that significantly higher frequencies of the CYP2C9*1/*3 genotypes were found in bleeding versus control patients. No significant differences were observed regarding the distribution of the heterozygotes CYP2C9*2/*3. Also in this case, an high-throughput genetic analysis may be recommended in the attempt to identify all the CYP2C9 functional polymorphisms and to exploring their possible role in influencing the efficacy of NSAIDs treatment. 12. Final remarks The CYP system is responsible for the metabolism of more than 80% of the commercially available drugs, and TFs and ADRs are the main functional consequences of CYP genetics (IngelmanSundberg, 2008). The aim of pharmacogenetics is the establishment of connections between pharmacology and genetics, in particular the establishment of connections between pharmacological phenotypes and genotypes, to predict different individual response to drug treatments (Al-Ghoul and Valdes, 2008). Notably, both TFs and ADRs strongly increase according to increasing concomitant therapies. For this reason the pharmacogenetic of CYP may have a wide application in the elderly. However, the establishment of connections between genotypes and phenotypes is not simple, requiring the unequivocal identification of genotypes and phenotypes. The “unequivocal identification of a genotype” and the “unequivocal identification of a phenotype” are two concepts introduced by Daly et al. (1993), Nebert (2005) and Nebert and Vesell (2004), and were defined as “the assignment of a genotype or a phenotype by scientific investigators without any room of error”. A complete review of the genetic factors affecting the unequivocal determination of a genotype both at single locus and at genome level were reported by Nebert (2005), Nebert and Vesell (2004) and Daly et al. (1993). Indeed, one of these factors known as epistasis were recently detailed (Motsinger et al., 2007).

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Table 3 Post-analysis factors, acting at multiple loci, that at can contribute to an erroneous genotype–phenotype association. Locus heterogeneity (or genetic heterogeneity) Epistasis

Modifier genes Intergenic complementation Epigenetics

Contribution of two or more genes to the same phenotype (polygenic phenotype). These two or more genes may show epistasis. Interaction between two or more genes to control a single phenotype. As outcome we can observed four epistatic interaction: (a) duplicate gene if the genes at locus 1 and at locus 2 are redundant (they duplicate each other), (b) complementary gene action if both genes at locus 1 and at locus 2 are required for the correct phenotype, (c) dominant epistasis if the presence of a dominant allele at locus 1 masks the effects of the dominant allele or the effect of the recessive allele at locus 2, (d) dominant suppression epistasis if the action of a dominant allele at locus 1 masks the gene at locus 2. Genes that have an effects on the level of expression of another gene. The situation in which to gene contributed to the same normal phenotype through two unbalanced gene products, i.e. one with a reduced function and one with an increased function. Regulatory effects on inheritance and gene expression that are not controlled by classical Mendelian genetics.

Notably, the metabolic phenotype may be quite different from the pharmacological phenotype observed in clinical practice, because it results from the interaction of metabolic phenotypes with a number of factors (Tables 2 and 3), including environmental ones. The concomitant assumption of substances stimulating or inhibiting the CYP enzyme activity may seriously affect drugs metabolism, thus changes the pharmacological phenotype. Accordingly, the pharmacological phenotype observed in clinical practice is far to being a direct consequences of the metabolic phenotype, and only highly stringent selective criteria permit the unequivocal identification of the metabolic phenotype. Notably, the genetic and phenotypic identification of the EMs is pivotal in studies investigating the response to drug treatments. These subjects show a normal enzyme activity, and are considered as a reference for the comparison of the other metabolic phenotypes. It must be also noted that the observed phenotype can be unequivocally referred to the genotype only in the homozygotes. It must be remembered that, if we are in presence of an equivocal phenotype or an equivocal genotype, the genotype–phenotype association may be seriously affected, and the pharmacogenetic study give false results. 13. Conclusions Drug treatments increase with advancing age, and the presence of concomitant therapies is common in elderly people. Accordingly, the prevalence of TFs and ADRs strongly increases in elderly people, being ADRs in the elderly a primary cause of morbidity and mortality worldwide. Since CYPs are responsible for the metabolism of more than 80% of the commercially available drugs, only a deep knowledge of CYP genetics let us to drastically predict and reduce the prevalence of TFs and ADRs in these subjects. It must be noted that the sole aim of pharmacogenetic studies was not a statistical association of a genotype with a given phenotype in a number of individuals, but the identification in a single individual of a unique genotype univocally responsible of the observed phenotype. This was the condition letting us to use CYP pharmacogenetics to set up an individualized therapy, and the starting point leading to a personalized medicine in elderly patients attending a geriatric ward. Acknowledgements This work was fully supported by “Ministero della Salute”, IRCCS Research Program, Ricerca Corrente 2009-2011, Linea n. 2 “Malattie complesse”. References Agúndez, J.A., Ramirez, R., Hernandez, M., Llerena, A., Benítez, J., 1997. Molecular heterogeneity at the CYP2D gene locus in Nicaraguans: impact of gene-flow from Europe. Pharmacogenetics 7, 337–340.

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