pharmacogenetic tactics and strategies

Pharmacogenetic Tactics and StrategiesImplications for Paediatrics

Wendell W. Weber

Department of Pharmacology , University of Michigan, Ann Arbor, Michigan, USA

Abstract Genetic diversity exerts profound effects on variation in human drug responsein adults, but comparatively little research that specifically relates to geneticallyabnormal responses in infancy and childhood has been reported. Specific geneticchanges in human enzymes, receptors and other proteins that are implicated indrug response and their associated phenotypic correlates provide needed data forconstruction of profiles individualised to predict susceptibility to adverse drugreactions. If therapy adheres to such guidelines, failure to respond to drug therapyand drug toxicity among genetically susceptible persons can be greatly minimisedor averted.

LEADING ARTICLE Paediatr Drugs 2001; 3 (12): 863-8811174-5878/01/0012-0863/$22.00/0

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Physicians are accustomed to view life as con-secutive periods of growth and development, matur-ity and senescence. In practice, they rely on drugsto exert characteristic, reproducible responses in thetreatment of specific diseases, but they also knowthat responses to a particular drug are, in fact, at-tributable to the physiological and biochemical attri-butes of cells that are targeted by their receptors.When physiological factors controlling the dispo-sition of drugs (absorption, distribution and elimin-ation) remain relatively constant, as during the rela-tively lengthy period extending from early childhoodinto senescence, responses of individual patients tothese agents also tend to remain relatively constant.

The realm of paediatrics deals mainly with theperiod from birth to maturity, which is marked byseveral recognisable stages of rapid growth and de-velopment. Within each of these stages, physiolog-ical and biochemical attributes of cells vary to amuch greater extent than at any later stage of life.Typically, notable differences in the magnitude andtiming of these attributes occur in different tissues

and in different parts of the body. When variationis large, averages tend to lose their significance andnorms are better expressed as a range of values. Forcertain attributes, separatenorms are needed for malesand females and at certain stages of childhood, suchas the onset of adolescence, a profusion of physiolog-ical changes occur with such rapidity that the grossattributes of a person (bodyweight, age) are of littleuse as scales of reference; thus, it is not surprisingthat profound differences in responses to drugs arean established part of infancy and childhood.

The first attempts to assess pharmacogenetics asit applies specifically to children and paediatric prac-tice was published about 30 years ago.[1] Most ofthe older studies of pharmacogenetic abnormalitiesdiscussed there were conducted mainly in adults;however, in studies of family members of patientswho had adverse drug reactions, a number of chil-dren were shown to have the same propensity toreact adversely as the adults when challenged withthe drug in question. Despite the remarkable prog-ress made since then in understanding the basic mole-

cular processes that result in unexpected responsesto drugs in genetically susceptible persons, compara-tively little pharmacogenetic research that specifi-cally relates to children has been reported.[2-4] Never-theless, where information to the contrary is lacking,it is not unreasonable to assume that mutations rel-evant to drugs used in paediatric populations arelikely to be important, even if investigated in adults.

Leeder and Kearns,[3] and Rane[4] summarise thepharmacogenetic traits that are generally acknow-ledged as the most important in the adult clinicalarena with the intent of acquainting the practicingpaediatrician with the developmental changes dur-ing infancy and childhood. Important clinical im-plications of some of the more well-known meta-bolic traits of pharmacogenetic interest, such as theinfluence of concurrent infectious disease on vari-ation in human drug response, and of particularlife-threatening drug interactions that have beenobserved in children, are discussed.

However, several reviews[5-12] as well as a num-ber of comprehensive sources on pharmacogenet-ics are available.[13-15] Additionally, the proceed-ings of a recent conference brings together a greatdeal of information on new directions on pharma-cogenetics and ecogenetics[16] that will be of inter-est to paediatricians. The scarcity of publicationsin paediatric pharmacogenetics is probably ex-plained by the greater complexity and difficulty inconducting a proper pharmacogenetic study in in-fants and children compared with adults,[14] ratherthan lack of interest or concern. There are not onlya greater number of variables that contribute to var-iation in drug response in infants and children thanin adults, but the difficulty is compounded furtherbecause of greater methodological problems in in-fants and children and greater ethical constraints inpaediatric clinical investigation.

1. Historical Parallels in Biology and Pharmacogenetics

Genetics has scored a number of extravagantlyambitious successes recently. The initial sequenc-ing and analysis of the human genome now com-

plete is a signal achievement in the history of biol-ogy.[17-19] The insights gained from this extraordin-ary trove of information about human development,physiology, medicine and evolution is the most re-cent step in the quest into the nature of heredity.The growth of biology[18-20] and of pharmacogene-tics[21,22] since Mendel’s discovery of the funda-mental laws of inheritance have been recounted else-where, but if we examine historical perspectives inunderstanding the nature of heredity and variationin human drug response for insights to the future,some interesting parallels emerge (table I).

Research in these endeavours can be roughlydivided into four periods, the first of which beginswith the rediscovery of Mendel’s laws at the begin-ning of the 20th century. During this period, Garrodset forth his concept of the chemical individualityof humans to explain the heritability of inborn er-rors of metabolism, and chromosomes were estab-lished as the cellular basis of heredity. On the phar-macological side, insights into the cellular basis ofmodern pharmacology were gained by the demon-stration of ‘drug receptors’ that explained why ac-tions of chemicals in individuals are localised totissues, and physiological mechanisms that ena-bled humans exposed to exogenous toxins to meta-bolise and excrete them harmlessly. Garrod leapedfar ahead of his contemporaries when he foresawenzymes as agents responsible for detoxification ofexogenous chemicals and that such a mechanismmight fail in persons who lacked the required de-toxifying enzyme.

The second period began toward the middle ofthe 20th century when the DNA was shown to bethe hereditary material and the double helix ofDNA was established as the molecular basis of he-redity. Shortly thereafter, protein polymorphism, aphenomenon initially associated with the occur-rence of haemoglobin in multiple forms, was estab-lished to be of much broader biological signifi-cance, and two human pathological states, Downssyndrome and chronic myelogenous leukaemia,were found to be associated with chromosomal ab-errations: an extra chromosome 21 in Downs syn-

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drome, and the chimeric Philadelphia chromosomein chronic myelogenous leukaemia. This periodalso marked the true beginning of pharmacogenet-ics as an experimental science when the founda-tions for hereditary variation in the structural andbiochemical properties of enzymes, receptors andother proteins affecting human drug response wereestablished.

The third period was initiated in the 1960s andextended through the 1980s. During this period,the informational basis of heredity was revealedthrough discovery of the mechanism by whichcells read the information encoded in the gene andthe invention of technologies for cloning, sequenc-ing, and expression of genes. Recombinant DNAand allied technologies enabled DNA polymor-phism to be established and the proteins encodedby the genes to be expressed. Steady progress inpharmacogenetics was recorded when these tech-niques were used to establish direct relationships

between individual variation in human drug re-sponsiveness and genetic variation of enzymes, re-ceptors and other proteins. This period also contri-buted immensely to the clarification of mechanismsthat explained lack of clinical response to drugtherapy and drug toxicity, as well as unwanted re-sponses to other exogenous substances, among gen-etically susceptible individuals.

We have now entered a fourth period. We havealready seen genetics become more firmly fixed inthe foundations of biology and pharmacogenetics.Whereas allelic variants of genes could only beinferred by classical genetic techniques one geneat a time, the advent of molecular genetics enablesus to directly describe variant forms of many genessimultaneously in many individuals and popula-tions. Consequently, a strong case was made for largescale, structural and functional analysis of singlegene polymorphisms and genomic diversity aimed atproducing a complete catalogue of human genomic

Table I. Historical parallels in biology and pharmacogenetics

Biology Pharmacogenetics

Discovery (1865) and rediscovery (1900) of Mendel’s laws

I. Cellular foundationChemical individuality of man defined Chemical individuality of man defined

Chromosomes identified as the locus of heredity Drug receptors identified

Metabolism of exogenous chemicals demonstrated

II. Molecular foundationDNA identified as the hereditary material and double helix of DNAis described

Heritable human drug metabolising enzyme variants discovered

Protein polymorphism found to be of broad biological significance Phase I and Phase II drug metabolism proposed

Pathological states (Downs syndrome, chronic myelogenousleukaemia) associated with chromosomal aberrations

Heritable drug receptor-related traits discovered

III. Informational foundationRecombinant DNA technologies developed and DNA polymorphismestablished

DNA polymorphisms of enzymes and receptors established

IV. Genomics

Paramount need:

Large scale, high throughput technologies and bioinformatics foranalysis of DNA, RNA and proteins

Large scale, high throughput capacity for genotyping andphenotyping of genetic polymorphisms of pharmacogenomicinterest

Next challenge:

Completing the catalogue of structural and functional human genomicdiversity (SNPs, insertions, deletions, repeats and rearrangements)

Construction of risk profiles for individual susceptibility to drugsand other exogenous chemicals

Ultimate goal:

Association of genomic diversity with diseased susceptibility Better therapies and personalised medicine

Pharmacogenetics in Paediatrics 865


diversity [SNPs (for a full list of common abbre-viations and acronyms see Appendix I)], insertion/deletions, repeats and rearrangements. By pinningdown the functions of the natural and variant pro-teins encoded in the human genome, we expect toestablish associations between the genetic makeupof individuals and individual susceptibility to dis-ease. Similarly, by establishing associations withresponsiveness to specific drugs, foods and otherexogenous substances, we expect to discover bettertherapies and improve prospects for personalisedmedicine.

2. Innovative Technologies

Molecular technology has evolved rapidly in theface of numerous applications in medicine and re-search that require quantification of the number ofspecific targets within a test specimen.[23-28] Forexample, the determination of changes in tumourburden or prognosis, obtained in response to inter-vention with anticancer therapy, is of clinical im-portance while the analysis of functional states ofcells, as mirrored by tissue-specific expression pro-files obtained through quantitative measurement ofmRNA profiles, is of research interest. PCR-basedtechniques allow genetic information to be obtainedthrough specific amplification of the nucleic acidtarget sequences of interest, but PCR reactions arecharacterised by a logarithmic increase in PCRcopies of target sequences. The amount of specificDNA product obtained at the end of a PCR run isunrelated to the number of copies present in the ori-ginal test sample. Until recently, a number of obsta-cles have retarded the development of quantitativePCR techniques but now powerful new methods todissect heterogeneous tissues[29,30] combined withadvances in PCR technology[31] have set the stage fordetailing the quantitative analysis of target nucleicacids, mostly performed as quantitative PCR or re-verse transcriptase PCR.

3. Pharmacogenetic Predictors ofHuman Drug Response

Pharmacogenetic evidence accumulated betweenthe 1960s and mid 1980s clearly establishes gen-etic diversity as a key element in human variationin response to drugs, nutrition and other environ-mental chemicals. More than 100 human polymor-phic traits of pharmacogenetic interest were identi-fied during this period[32] and now the total probablyexceeds that estimate by a considerable margin.Most traits that have been studied initially focusedon polymorphic isoforms of drug metabolising en-zymes, but with the advent of molecular geneticsin the mid 1980s, many enzymes (other than thoseinvolved in drug metabolism), receptors, as well asother types of proteins that participate in responsesof cells to exogenous agents, are clearly of pharma-cogenetic importance. The sample of traits that isincluded below is intended to represent the broadrange (but does not define the limits) of proteinvariation that physicians may encounter in prac-tice.

3.1 Genetically Polymorphic ProteinsExplain Many Pharmacogenetic Traits

Hereditary differences in response to exogenouschemicals are attributable to genetic variants ofproteins that play a role in the disposition and elim-ination of these agents. Broadly speaking, threetypes of genetic variants account for these traits: (i)those associated with altered transport, distributionand elimination of an agent; (ii) those resulting inadverse effects of the agent; and (iii) those associ-ated with genetic variation in the drug target. How-ever, if the molecular or biochemical character ofa given trait is identified, it can also be categorisedmore logically according to the type of geneticallyvariant protein responsible for expression of thetrait. Most pharmacogenetic traits can be dividedinto those attributable to genetic variants of en-zymes or receptors. Enzymatic traits are further di-visible into those that involve variants of drug me-tabolising enzymes and nondrug metabolisingenzymes, whereas receptor-related traits are divis-

866 Weber


ible into those resulting from variants of nuclear(cytoplasmic) or cell surface receptors. Protein vari-ants such as clotting factors, oncogenic and tumoursuppressor proteins, immune response proteins,etc, that do not fit readily into either of these groupsmay be considered separately.

3.2 Enzymatic Traits

Most enzymatic traits are attributable to high orlow (null) isoforms of polymorphic human drugmetabolising enzymes. By altering the levels andpharmacokinetic properties of drugs and other en-vironmental chemicals prior to elimination, theymay alter the therapeutic effectiveness or toxicityof these substances (table II). Of the many cyto-chrome (CYP)-450 enzymes (Phase I) that havebeen identified in human cells (>50), only about ahalf dozen are pharmacogenetically important. Theseare CYP1A2, 2A6, 2C19, 2D6, 2C9, 2B6, 2E1 and3A4. Among these, CYP3A4 is the primary clear-ance mechanism for >50% of all drugs, followedby CYP2D6 (>20%). Acontinuously updated data-base where information about old and new P450alleles encoding human CYP450 enzymes is col-lected, has also been established.[33,34]

Serum cholinesterase and paraoxonase are twoadditional Phase 1 enzymes of pharmacogeneticimportance. These esterases have been implicatedin succinylcholine sensitivity[14] and susceptibility toorganophosphate toxicity and atherosclerosis,[49-51]

respectively.Several conjugating (Phase 2) enzymes are also of

pharmacogenetic interest. These include, but are notlimited to, the glucuronosyltransferases (UDPGTs),glutathione S-transferases (GSTs), sulfotransfer-ases, thiopurine methyltransferase (TPMT), and N-acetyltransferases (NATs).[14]

Genetic variants of nondrug metabolising enzy-mes may also confer, or be associated with, adverseeffects of environmental agents. α1-Antitrypsindeficiency, glucocorticoid remediable hyperten-sion and pyridoxine-deficient anaemia are traits inpoint of this fact. Extraordinary responses to foodsand dietary constituents further attest to the broadscope of genetically variant enzymes in pharmaco-genetics. The fish malodour syndrome is a partic-ularly interesting example of such a trait (see be-low) that stems from a defective form of flavinmono-oxygenase III.[52] Other examples of food-related disorders include liquorice-induced aldo-steronism[14] and fructose intolerance.[53]

Table II. Clinically relevant effects associated with genetically defective enzymesa

Defective enzyme Year of genediscovery

Clinical effect References

CYP2D6 poor metabolisers (missense mutations) 1988 Drug toxicity (affects >50 drugs) 35

Aldehyde dehydrogenase (missense mutations) 1988 Protects against alcoholism 36

Aldolase B (missense mutations) 1988 Fructose intolerance 37

Aldosterone synthase (chimeric gene) 1992 Glucocorticoid remediable hypertension 38

CYP2D6 ultra rapid metabolisers (gene duplications) 1993 Lack of clinical response to >50 drugs 39

CYP2C9 (missense mutations) 1994 Bleeding (warfarin), hypoglycaemia(tolbutamide, glipizide), phenytoin toxicity,losartan (diminished antihypertensive effect)

40,41

5-Aminolevulinate synthase (missense mutation) 1994 Pyridoxine-responsive anaemia 42

Thiopurine methyltransferase (missense mutations) 1995 Fatal myelosuppression 43

Glucuronosyl transferase (promoter repeat mutations) 1995-6 Explains Gilbert’s syndrome 44,45

Flavin mono-oxygenase (FMO) III (missense mutation) 1997 Fish malodor syndrome 46

Alcohol dehydrogenase (ADH2*3) 1997 Isoform protects against alcohol-relatedbirth defects

47

5-Lipoxygenase (ALOX5) [promoter repeat mutations] 1999 Implicated in anti-asthmatic therapy 48

a Unless otherwise noted, the polymorphic enzyme is due to multiple mutations.



The characteristics of several pharmacogenetictraits are summarised below. The summaries con-tain information about the genetics of the trait, itsmolecular basis and medical or biological signifi-cance. The traits chosen are not meant to cover thewhole topic but were selected with a view towardpossible interests of paediatricians to illustrate thediverse nature of unusual hereditary responses todrugs and environmental chemicals. More detaileddescriptions of these and many other traits are pre-sented elsewhere.[14,15,54]

3.2.1 CYP2D6 Debrisoquine/Sparteine Oxidation PolymorphismThis trait affects the metabolism of >50 medi-

cally used drugs. Although it was originally namedfor debrisoquine (an antihypertensive) and sparte-ine (an antispasmodic of the uterus), neither agentis in common use. To test for this drug-metabolisingenzyme polymorphism, the ratio of dextromethor-phan to dextrorphan (the product of oxidative de-methylation) is a marker of CYP2D6 activity. Threeseparable phenotypes can be identified in manypopulations by this technique (table III): ‘poor me-tabolisers (PMs)’ have relatively high ratios, ‘ex-tensive metabolisers (EMs)’or ‘normal metabolisers’have lower ratios, and ‘ultra rapid metabolisers(URMs)’ have extremely low ratios.

Although phenotyping reveals three classes ofindividuals, genetic studies show further varia-tions. At least 30 different defective CYP2D6 al-leles and about 55 CYP2D6 variants have been des-cribed;[33] however, the six most common defectivealleles will predict the phenotype with 95 to 99%certainty. It should be noted that genotyping forduplicated or amplified alleles explains only 10 to30% of the ultra rapid metaboliser phenotypes ob-served in Caucasians.[57]

PM phenotypes are at increased risk of toxicityfrom CYP2D6 substrate drugs given at ‘usual’dos-ages. They are also more likely to exhibit interactionbetween drugs that are subject to CYP2D6 polymor-phism. Drug substrates administered to URM pheno-types may not reach therapeutic levels because du-plicated genes (2- to 12-fold) produce an increasedamount of enzyme which is responsible for increasedmetabolism. Several times the ‘usual’ dosage mayhave to be given to achieve a therapeutic response.

An interesting point about the CYP2D6 poly-morphism is that quinidine, which is not a CYP2D6substrate, strongly inhibits the enzyme. EMs receiv-ing quinidine plus a CYP2D6 substrate may respondas PMs, and PMs receiving quinidine would have aneven greater probability of toxicity from CYP2D6drugs.

Table III. Ethnic specificity of genetically polymorphic human drug metabolising enzymes[55,56] a

Polymorphic gene Phenotype or genotype Population Phenotypefrequency (%)

CYP2C19 Poor metabolisers Caucasian 2-5

CYP2C19 Poor metabolisers Asian 13-23

CYP2C19 Poor metabolisers Melanesian 70.8

CYP2D6 Poor metabolisers Caucasian 5-10

CYP2D6 Poor metabolisers Japanese <1

CYP2D6 Ultra rapid metabolisers Caucasian 1-2

CYP2D6 Ultra rapid metabolisers Hispanic 7

CYP2D6 Ultra rapid metabolisers Ethiopian 13

Glutathione S-transferase M1 (null) genotype Caucasian 49 b

Glutathione S-transferase M1 (null) genotype African 35b

Glutathione S-transferase M1 (null) genotype Indian 5b

N-Acetyltransferase Slow acetylators Caucasian and African 40-65

N-Acetyltransferase Slow acetylators Asian 10-20

a Unless otherwise noted, the polymorphic gene is due to multiple mutations.

b Frequencies are for the homozygous null genotype.

868 Weber


3.2.2 CYP2C19 Mephenytoin PolymorphismThis trait affects the metabolism of mephenytoin

(anticonvulsant) and several other drugs.[58] Meph-enytoin is a racemic mixture of R and S enantiomers.In most individuals S-mephenytoin is hydroxy-lated and eliminated more efficiently than R-mephenytoin. The R/S ratio of 4-OH-mephenytoinin urine is a determinant of CYP2C19 phenotypes,called EMs and PMs. PMs are found to have highconcentrations of the parent drug for a given doseand are more susceptible to acute adverse effects(drowsiness) and chronic toxicity (skin rash, fever,blood dyscrasias). Other drugs metabolised byCYP2C19 and subject to mephenytoin polymor-phism include omeprazole and its congeners, pro-guanil, and some barbiturates.

CYP2C19 polymorphism shows marked differ-ences in ethnic specificity (table III). The PM fre-quency in Caucasians is about 2 to 5%, but inAsians it is about 13 to 23%. This difference isreflected in the 6-fold higher frequency of adverseeffects from mephobarbital in Japanese comparedwith Caucasians. An unusually high PM frequency(70.8%) has been observed in Melanesians.[59,60]

The ability to test for CYP2C19 alleles has raisedquestions about the association of CYP2C19 withsusceptibility to disease. Tentative associations havebeen identified, but most of these early efforts havebeen hampered by the absence of defined mecha-nisms to relate such variations to any disease pro-cess.[45]

3.2.3 CYP2C9 PolymorphismCYP2C9 metabolises a wide variety of clini-

cally important drugs including warfarin, tolbuta-mide, phenytoin, glipizide, fluoxetine, losartan andvarious NSAIDs.[61] Three alleles of the CYP2C9gene have been identified with amino acid changes inthe coding region (Arg144/Ile359, Cys144/Ile359;Arg144/Leu359). In Caucasians, their frequenciesrange from 0.79 to 0.86, 0.08 to 0.125 and 0.03 to0.85. The Cys144 allele has not been detected inChinese and Japanese and its frequency is reportedto be very low (0.01) in African-Americans.

The enzyme is inducible, notably by rifampicin(rifampin). Numerous clinically significant inhib-itory drug interactions involving 2C9 substrateshave been described.[61] Individuals homozygousfor the Leu359 variant have markedly diminishedcapacity to metabolise most CYP2C9 substrates.CYP2C9 does not appear to be expressed in fetaltissue but is detectable in neonatal liver. The rateof whole body elimination (half-life) of phenytoinis shorter and steady-state plasma concentrationsare lower in children than adults; however, whetherthese age-related differences are attributable to dif-ferences in 2C9 is not known. Individualisation ofdose is essential for CYP2C9 substrates with a nar-row therapeutic index.

3.2.4 Succinylcholine SensitivityDiscovery of low pseudocholinesterase in two

Cypriot brothers that resulted in prolonged apnoeaafter succinylcholine (‘succinylcholine sensitiv-ity’) first suggested that the enzyme deficiency wasfamilial and possibly hereditary.[14] Succinylchol-ine sensitivity is inherited as a relatively rare (1/2500Caucasians), codominant autosomal trait. Personshomozygous for the mutant atypical form of serumcholinesterase gene have an impaired serum cholin-esterase and are susceptible to this disorder. Atleast six other hereditary variants have been iden-tified in association with succinylcholine sensitivity.

3.2.5 Glucuronosyl Transferase PolymorphismsGlucuronosyl transferases are microsomal enzy-

mes that catalyse the glucuronidation of numerousendogenous and exogenous substrates. A numberof recent findings about the genetic multiplicity andregulation of glucuronosyl transferases recentlyhighlighted some important features of this enzymesystem.[62] Defects in glucuronidation enzymes(UGTs) of long-standing interest to paediatrics arecharacterised by unconjugated hyperbilirubinae-mia. The clinically relevant polymorphisms relatedto genetic abnormalities are those associated withfamilial hyperbilirubinaemic syndromes such as Gil-bert’s syndrome and the rare Crigler-Najjar syn-dromes Type I (CN-I) and II (CN-II). Both of thesesyndromes are determined by defects in UGT1A1.



Gilbert’s syndrome is a relatively mild, nonpatho-genic, often undiagnosed disorder that occurs inup to 19% of individuals. This disorder is usuallyassociated with a homozygous insertion in theTATAA promoter of UGT1A1 leading to a mutated(TA)7TAAsequence instead of (TA)6TAA. The mu-tated promoter results in reduced UGT1A1 expres-sion and activity. Patients with CN syndromes haveabsent (CN-I) or reduced (CN-II) UGT1A1 withcorrespondingly elevated levels of unconjugatedbilirubin.[63]

UGT1A1 polymorphism also plays a role in themetabolic elimination of irinotecan, a prodrug usedin the treatment of metastatic colorectal cancer. Irin-otecan is an ester that is biotransformed to a toxicmetabolite, SN-38, by a carboxylesterase.[63] SN-38requires glucuronidation by UGT1A1 for efficientdetoxication and elimination. Failure of UGT1A1to detoxify SN-38 enables it to remain in the gastro-intestinal tract, whereupon prolonged diarrhoea re-sults. Decreased SN-38 glucuronidation activity isfound in the liver of individuals carrying the (TA)7

allele. A clinical trial is now in progress to demon-strate the predictive significance of UGT1A1genotyping for susceptibility to irinotecan toxicity.

The frequency of TA repeats (TA5 to TA8) ap-pears to vary remarkably in different populationswith Asian and American Indian populations show-ing highest frequencies; however, information isinsufficient at this time to characterise the allelefrequencies in any population.

3.2.6 Fish Malodor SyndromeThis trait is an example of person-to-person vari-

ation in response to foods that yield trimethylamineas a breakdown product.[52] Limited studies sug-gest that the hereditary form of the trait is transmit-ted by autosomal recessive (or codominant) inher-itance.[52] Affected persons exude the odour of rottingfish in sweat, breath and urine. They are subject toextreme social difficulties including severe depres-sion and suicide. Its molecular basis is a defective formof the flavin mono-oxygenase (FMOIII).[46] Manage-ment remains empirical. The usual recourse is to re-

duce the ingestion of eggs, liver, marine fish andother trimethylamine precursors.

3.2.7 Hereditary Fructose IntoleranceThis disorder refers to severe abdominal pain,

vomiting and other effects including hypoglycae-mia that may be fatal on ingesting fructose.[14] Thisdisorder is a rare (1/20 000) autosomal recessivetrait that is attributable to mutation of the aldolaseB gene located on chromosome 9q21.3-22.2. Thetrait is widely distributed in European populations.Absence of consanguinity in most parents of af-fected persons suggests that mutant alleles for al-dolase B may be relatively common in populationsat large. Recognition of this disorder is importantbecause exclusion of fructose and related sugarsfrom the diet usually leads to dramatic recoveryfrom foods that provoke symptoms. Continued in-gestion of fructose or its congeners is required toestablish the disease, but the widespread distribu-tion of these sugars in human foods places geneti-cally susceptible persons at constant risk to anavoidable nutritional disorder.

3.2.8 Thiopurine Methyltransferase DeficiencyTPMT deficiency is attributable to metabolic

polymorphism that has been observed in Cauca-sians, Africans and Asians.[64] Inheritance is by co-dominant autosomal expression of two mutant al-leles at a single locus. A series of single nucleotidepolymorphisms that result in low levels of TPMTactivity as well as a polymorphic variable tandemrepeat in the TPMT gene that modulates the levelof TPMT activity have been described. Three mu-tant alleles (TPMT*2, TPMT*3A, TPMT*3C) ac-count for most mutant alleles that occur in all hu-man populations. Significant ethnic specificitiesoccur in the frequencies of these alleles.[43]

TPMT deficiency is associated with serious acuteand delayed intolerance to immunosuppression fromantileukaemic drugs (mercaptopurine, thioguan-ine, azathioprine), and with hypopro-thrombinaemiaand bleeding from cephalosporin antibiotics [lata-moxef (moxalactam), cefamandole]. Metabolismof mercaptopurine is catalysed by TPMT and someother pathways. One of these leads to thioguanine

870 Weber


metabolites which at high concentrations (lowTPMT) may cause toxicity (myelosuppression) andat low concentrations (high TPMT) may bring aboutfailure to respond to therapy. Elimination of mercap-topurine, thioguanine and azathioprine by methyl-ation of an ‘SH’group is impaired in TPMT deficientpersons.[33] The number of clinically important ap-plications of TPMT molecular genetics is increas-ing; from children with acute leukaemia to currentinterest in TPMT phenotyping/genotyping of trans-plant patients, patients afflicted by Crohn’s disease,systemic lupus erythematosus, nonbullous inflam-matory dermatoses and other autoimmune disea-ses.[43,65] Mercaptopurine and azathioprine havebeen used to advantage in the management of inflam-matory bowel disease in young patients. Knowl-edge of mercaptopurine metabolite levels and TPMTgenotype is of clinical value in optimising thera-peutic response to these drugs and identifying indivi-duals at increased risk for drug-induced toxicity.[66,67]

3.3 Receptor Polymorphisms

Formany years, thepharmacogenetics of receptor-related traits lagged well behind that of enzyme phar-

macogenetics, but when techniques of cloning, se-quencing and site-directed mutagenesis becamemore widely employed, an enormous amount ofinformation on the nature and diversity of recep-tors and the origin of receptor-related disordersemerged. Investigations of human receptor poly-morphisms increased by almost six times (1453/249)from 1987 to 1998, and in 1987 to 1989 versus 1996to 1998, the proportion of human polymorphismsstudied compared with those in all species in-creased appreciably from 78% (249/321) to 92%(1453/1581).[54]

Based on their cellular location and mechan-isms of action, receptors and their subtypes wereclassed as either nuclear (cytoplasmic) or cell sur-face receptors. Defective forms of both types ofreceptors explain instances of therapeutic drugfailure, adverse and paradoxical drug responsesand susceptibility (or resistance) to infectious dis-ease. Nuclear receptors are best represented by thesuperfamily of regulatory proteins that interactwith steroidal hormones and drugs such as dexa-methasone, beclamethasone, steroidal contraceptivesand vitamins. Among these, substantial progress has

Table IV. Clinically relevant effects associated with genetically defective receptors a

Defective receptor Year of genediscovery

Clinical effect Reference

Vitamin D (various mutations) 1988 Vitamin D resistant rickets 68

Insulin (various mutations) 1988-93 Insulin-resistant diabetes 69,70

CFTRΔ508 (deletion) 1989 Pancreatic failure, intestinal obstruction,pulmonary infection

71,72

Potassium channels and subunits, one sodium channel(various mutations)

1991-99 Stress- and drug-induced cardiac arrhythmias 73

AVPR2 (various mutations) 1992 Vasopressin resistance; diabetes insipidus 14

Ryanodine (missense mutations) 1992 Malignant hyperthermia 74

β2 adrenergic (missense mutations) 1993-95 Nocturnal asthma, altered anti-asthmatic therapy 75,76

Estrogen (various mutations) 1994 Tall stature, unfused epiphyses, osteoporosis,infertility

77

Sulfonylurea (deletions, splice site and missense mutations) 1995 Infantile hyperinsulinism, type I diabetes 78

CCR5Δ32 (32bp deletion) 1996 AIDS resistance 79-81

Sulfate and iodide transporters (missense and nonsensemutations)

1997-98 Congenital hypothyroidism, Pendred’s syndrome 82

f-MLP (missense mutations) 1999 Localised juvenile periodontitis 83

Mineralocorticoid (missense mutation) 2000 Early onset and pregnancy-related hypertension 84

Multidrug resistance protein (MDR) [missense mutation] 2000 Higher plasma levels of digoxin are associatedwith the variant isoform

85

a Unless otherwise noted, the defective receptor is due to multiple mutations.



been recorded in elucidating syndromes of resis-tance to vitamin D, androgens, glucocorticoids,retinoic acid, and estrogen (table IV).

Cell surface receptors are pharmacologically in-teresting because they initiate and transmit cellularresponses to biogenic amines, protein and polypep-tide hormones, autocoids, neurotransmitters, andenvironmental chemicals including drugs. Cell sur-face receptors are usually subclassified as: (i) ionchannels and ion channel transporters; (ii) G-pro-tein coupled receptors (GPCRs) that act by an en-zymatic cascade such as adenylate cyclase or thephosphoinositol cascade; and (iii) those that act viaa tyrosine kinase, an integral component of the re-ceptor.

The following sections describe how geneticpolymorphisms of nuclear and cell surface recep-tors have clarified the genetic causes of susceptibilityto disease, and individual variation in the pharma-codynamics of human drug response.

3.3.1 Malignant HyperthermiaMalignant hyperthermia is a rare, clinically het-

erogeneous disorder that was first recognised some40 years ago to be associated with a high frequencyof anaesthetic-related deaths. The disorder is inher-ited as an autosomal dominant condition. This traitis characterised by elevated temperatures, hyper-metabolism and muscle rigidity. Some cases ap-pear to be attributable to a point mutation resultingin a defective ryanodine (calcium release channel)receptor which renders the muscle susceptible todisturbances in calcium regulation.[74] Recently, anovel ryanodine receptor mutation has been iden-tified in a large New Zealand Maori pedigree whichappears to be the first mutation in the receptor C-terminal region associated solely with malignanthyperthermia.[86] If therapy is not administered im-mediately, the patient may die within minutes fromventricular fibrillation or a few hours later from pul-monary oedema and renal failure. The introductionof dantrolene, a muscle relaxant, as a prophylacticor therapeutic agent dramatically improves the out-come.

3.3.2 Long QT SyndromeThis is a rare familial congenital disorder that is

characterised by QT prolongation on the electro-cardiogram (a sign of abnormal cardiac repolari-sation), syncope, seizures and sudden death fromventricular arrhythmias. Genetically, the long QTsyndrome is a complex disorder whose molecularbasis has not been fully elucidated. Molecular stud-ies reveal point mutations on 4 chromosomes inmultiple genes, all encoding cardiac channels. Thesedefects affect two potassium α-subunits, two potas-sium β-subunits, and one sodium channel.[73] Muta-tions in the KCNQ1 gene cause both the autoso-mal dominant Romano-Ward (RW) syndrome andthe recessive Jervell and Lange-Nielsen (JLN) syn-drome. JLN presents with cardiac arrhythmias andcongenital deafness, and heterozygous carriers ofJLN mutations exhibit a mild cardiac phenotype.Despite the phenotypic differences between heter-ozygotes with RW and those with JLN mutations,both classes of variant protein fail to produce K+

currents in cultured cells.[87]

Persons with hereditary long QT may die sud-denly during excitement or stress. Sudden deathoccurred at an average age of 16 in 9 persons of oneaffected family over a 30 year period. Affected per-sons are also highly susceptible to ventricular ar-rhythmias induced by certain drugs (quinidine,chlorpromazine, tricyclic antidepressants and H-1antihistaminics). Theantihistamines terfenadine andastemizole have produced such a response in suscep-tible persons.

3.3.3 Chemokine Receptor (CCR5) andSusceptibility to HIV-1 InfectionEvidence has recently emerged for the requirement

of chemokine receptor (CCR5) for HIV-induced in-fection.[88] The CCR5 gene encodes a 7 transmem-brane GPCR that binds several HIV-suppressive β-chemokines. Identification of a naturally occurring32-base pair deletion (Δ32 allele) in the CCR5 geneexplains in part the genetic basis for resistance toHIV-induced disease.[63-65] Adult homozygotes forCCR5Δ32 are highly protected from HIV infection

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and progression of the disease is slowed in adultheterozygotes for the deletion.

The CCR5Δ32 allele displays differences in eth-nic specificity. In Caucasians and in populations inWestern Europe its frequency is about 0.10, reach-ing 0.20 in some populations. An extensive surveyrevealed a cline of CCR5Δ32 allele frequencies of0 to 14% across Europe and Asia, whereas the vari-ant was absent among native African and East-Indianethnic groups.[89] The geographic cline frequenciesare consistent with a strong selective event such asan epidemic of a pathogen that, like HIV-1, usesCCR5, driving its frequency upward in ancestralCaucasian populations.[90]

The effects of chemokine and chemokine recep-tor polymorphisms associated with HIV-1 transmis-sion and/or rate of progression have been analysedmainly in adults, but they are less well-defined inchildren. Mangano and colleagues[91] found that an-other receptor allele, CCR2-64I, plays a protectiverole in mother-to-infant HIV-1 transmission anddelays HIV-1 progression after infection. How-ever, CCR5Δ32 and the 3′A variant of stromal de-rived factor 1 (SDF1-3′A) did not modify the rateof HIV-1 transmission or disease progression inHIV-1 infected children.

3.3.4 Localised Juvenile PeriodontitisThis disease emerges around puberty and leads

to rapid, localised destruction of teeth and support-ing tissue.[83] A strong familial pattern of inheri-tance supports the hypothesis that a genetic factoris involved in its aetiology. Molecular studies in-dicate that affected persons possess point muta-tions of the G-protein coupled f-MLP receptor thatis involved in the activation and response of neu-trophils to chemotactic stimuli. These molecularalterations are believed to play a role in the decreasedchemotactic activity reported in some patients withlocalised juvenile periodontitis and may account,in part, for the increased susceptibility of these pa-tients to infections by periodontal organisms.

3.3.5 Familial Persistent Hyperinsulinaemia and Hypoglycaemia of InfancyThis complex metabolic disorder is defined by

elevations of serum insulin, profound hypoglycae-mia, brain damage and death.[78] This syndrome isassociated with mutations (deletions, splice site, mis-sense) in the sulfonylurea receptor gene that causeseverely truncated, nonfunctional forms of the re-ceptor. The sulfonylurea receptor gene is classedas a member of the B-cell ATP-binding cassettesuper family of receptors owing to the presence oftwo nucleotide-binding folds in its consensus se-quence. Patients with combined variants of the sul-fonylurea gene exhibit normal serum C-peptideand insulin responses but 50% reduction in seruminsulin secretion on tolbutamide injection.

3.3.6 Familial Interstitial Lung DiseaseInterstitial lung diseases are a heterogeneous

group of diseases that are poorly understood. Re-ports of familial cases and a recent case history ofdesquamative interstitial pneumonitis of infan-cy[92] suggest a possible genetic basis for this con-dition. A family history of a full-term newbornbaby girl who developed respiratory distress at 6weeks of age, revealed the infant’s maternal grand-father had died from life-long lung disease. Hermother had been diagnosed as having desquamativelung disease at 1 year of age and had been treatedwith glucocorticoids until she was 15 years of age.The mother’s lung disease worsened after deliveryand she died from respiratory failure.

Deficiency of pulmonary surfactant is the prin-cipal cause of respiratory distress in infancy, par-ticularly in premature infants. A test of the hypoth-esis that mutations of the gene encoding surfactantprotein C (SP-C), a hydrophobic, lung-specific pro-tein, in the 6-week-old girl and her mother, revealeda mutant form of this protein. An SP-C mutationwas identified on only one allele in genomic DNAfrom the infant and her mother, as is consistent withthe dominant pattern of inheritance. The mutationresulted in deletion of exon 4 plus 37 amino acidsfrom the C-terminus of precursor SP-C protein.Since deletions in this domain have been shown to



disrupt intracellular transport, the authors specu-late that the aberrant precursor may have beenmistargeted to its final cellular destination or thatit may have folded improperly resulting in proteinaggregation, secondary cellular injury and local in-flammation.[92] They suggest that agents which en-hance intracellular processing and transport ofmisfolded proteins may have a role in the therapyof interstitial lung disease.

3.3.7 Early-Onset Hypertension Exacerbated by PregnancyDuring the past decade, hypertension research has

shifted strongly toward the search and identifica-tion of the molecular genetic basis of several mono-genic hypertensive syndromes. By 1996 at least 10genes had been shown to alter blood pressure, mostof which were rare mutations imparting large quan-titative effects to either raise or lower blood pres-sure.[93] One of those resulting in disrupted enzymeregulation is mentioned above (see glucocorticoidremediable hypertension, table II). Recently, allelicvariants in the genes for angiotensiogen, α-adducin,the β2-adrenergic receptor, the G-protein β3-subunit,and the T594M mutation in the B-subunit of theepithelial sodium channel have been identified.[94]

Still more recently, a new Mendelian form of hyper-tension featuring early-onset hypertension that isexacerbated in pregnancy has been described.[84]

A 15 year old boy with severe hypertension, sup-pressed plasma renin activity, low serum aldoste-rone and no other underlying cause was found tobe heterozygous for a missense mutation resultingin substitution of leucine for serine at codon 810 ofthe mineralocorticoid (ML) receptor.[84] When 23of his relatives were tested, 11 had the mutation andall of these had been diagnosed with severe hyper-tension before the age of 20 years. This mutationresults in constitutive ML receptor activity that al-ters receptor specificity, such that progesterone andother corticosteroids lacking 21-hydroxyl groups(normally MR antagonists) becoming agonists.

About 6% of pregnancies are complicated by hy-pertension. Progesterone levels normally increase100-fold in pregnancy, reaching concentrations of

500nM, suggesting that females with the 810L iso-form of the ML receptor might develop severe hy-pertension. Two ML carriers of the pedigree men-tioned above had undergone five pregnancies, allof which were complicated by exacerbation of hy-pertension.[84] There were no proteinuria, oedema,or neurological changes excluding pre-eclampsia.

There is, as yet, no approach to treat patientswho harbour this mutant ML, although structuraland biochemical studies indicate that the mutationresults in an interaction within the receptor (be-tween helix 5 and helix 3) that substitutes for inter-action of the 21-hydroxy group with helix 3. Thehelix 5-helix 3 interaction is highly conserved amongdiverse nuclear hormone receptors, suggesting itsgeneral role in receptor activation; thus, a drug tar-geted to interfere with such interactions might showclinical efficacy in controlling the resulting hyper-tension.

3.3.8 Genetic Diversity and Response toAnti-Asthma TherapySeveral reports have shown that certain β2-adren-

oceptor receptor haplotypes correlate with asthmaticphenotypes[95] or response to β2-adrenoceptor recep-tor agonist therapy[96] in instances where individualSNPs do not. A study of the β2-adrenoceptor recep-tor, expressed in the heart and lungs, which is in-volved in the pathophysiology of asthma[97,98] andcongestive heart failure illustrates this concept.[98]

The β2-adrenoceptor receptor was cloned, se-quenced and mapped in 1987, and molecular stud-ies have revealed a total of 13 SNPs organised into12 haplotypes.[96] The gene encoding the receptorcontains 3 nonsynonymous SNPs that affect recep-tor affinity and abundance, or regulation. The genealso contains multiple SNPs in the promoter regionthat affect receptor expression. Investigation ofseveral populations (Caucasians, African-American,Asian and Hispanic-Latino) revealed >20-fold dif-ferences in the frequencies of the four major hap-lotypes. The in vivo responses to the bronchodi-lator, salbutamol (albuterol), of persons with themost common β2-adrenoceptor haplotypes (deter-mined by haplotype pair) showed that mean haplo-

874 Weber


type responses differed by >2-fold. The mean res-ponse was significantly related to haplotype, butwas unrelated to individual SNPs.[96,98] This is thefirst study to examine the effect of combinations ofSNPs (haplotypes) on variation in response to aspecific drug.

However, genetic analysis in families indicatesthat asthma is likely to be a genetically heteroge-neous disorder influenced by only a few genes withmoderately strong effect rather than many genesof small effect;[99] thus, asthmatic patients of iden-tical phenotype may develop airway obstructionby distinct mechanisms. Additionally, while asthmain adults is generally recognised as a chronic in-flammatory disease, this association is not as well-established in childhood asthma.[100]

The cysteinyl leukotrienes are potent broncho-constrictor agents derived from the metabolism ofarachadonic acid via the 5-lipoxygenase (ALOX5)pathway. In adults with asthma, clinical trials dem-onstrated that various antileukotriene drugs (zafir-lukast, montelukast, zileuton) improve pulmonaryfunction, decrease asthma symptoms and decreasethe need for other anti-asthma drugs. Patients withasthma possessing polymorphic forms of the 5-lipoxygenase gene (ALOX5) also vary in their res-ponse to anti-asthmatic treatment (table II).[48] Onemight anticipate that mutations in the promoter re-gion of ALOX5 might cause ‘natural inhibition’ ofthe ALOX5 pathway and patients harbouring suchmutations would be expected to exhibit a dimin-ished response to exogenous ALOX5 inhibitors. Ina recent study, an uncommon ALOX5 genotypewas identified which was associated with a dimin-ished response to treatment with an ALOX5 inhibi-tor (ABT-761).[48] This pharmacogenetic experimentprovides evidence that leukotrienes play a role inthe pathogenesis of asthma, and that by blockingthe effects of these mediators, antileukotriene agentsmay help to manage asthma. Further clinical evalu-ation is needed on how agents that have the poten-tial to affect childhood development will be em-ployed in the management of asthma in childrenand to test their tolerability in children.

3.4 Other Pharmacogenetic Traits

3.4.1 Thrombophilia (Factor V Leiden)Thrombophilia (also known as Factor V Leiden)

is associated with susceptibility to deep vein throm-bosis, a common disease that causes morbidity inindividuals by myocardial infarction, stroke, pul-monary embolism and other embolic events.[14]

Transmission is as an autosomal dominant trait.Thrombophilia is associated with a point mutationin coagulation factor V. The defect is not accompa-nied by a change in plasma levels of factor V, butit can be detected by an ‘activated partial pro-thrombin times (APPT)’ test. Clinical samples canalso be routinely genotyped for this trait withoutthe need for PCR amplification, enzyme digestion,gel electrophoresis by the Invader assay (see sec-tion 2).[101]

Factor V Leiden causes a 7-fold increase in indi-vidual susceptibility to deep vein thrombosis, es-pecially at younger ages, during pregnancy and thepuerperium.[102] Information on ethnic variation sug-gests that the prevalence of the carrier frequencyof factor V Leiden is greater among Caucasians(5.27%) than among minority Americans (0.45%in Asian-Americans, 1.23% in African Americans,1.25% in Native Americans, 2.21% in HispanicAmericans).[103] Persons who harbour the mutantprotein may never develop thrombosis. Neverthe-less, they may be lifelong candidates for anticoagu-lant therapy and its attendant risks, a fact that mustbe weighed against the benefits of avoiding throm-botic attacks (which may be infrequent).

Carriers of both factor V Leiden combined withthe G20210A prothrombin SNP have increasedrisk of thrombosis after the first episode. They arealso candidates for lifelong anticoagulation.[104]

3.4.2 α1-Antitrypsin DeficiencyPersons with a deficiency of α1-antitrypsin are

predisposed to abnormally rapid degradation of thelung, liver, joints, kidneys and vasculature.[14] α1-Antitrypsin deficiency is inherited as an autosomalcodominant trait. α1-Antitrypsin forms a tight com-plex with serine proteases (such as elastase) to in-activate them. Susceptibility of homozygotes to



lung disease is believed to be caused by inadequateplasma levels of the point mutant Z variant of α1-antitrypsin, permitting the destruction of lung elas-tin by neutrophil elastase. Smoking is particularlydetrimental to the lungs of affected persons, predis-posing them at an early age to lung disease andemphysema. Survival for α1-antitrypsin-deficientsmokers was 22% compared with 83% for non-smokers. The high frequency of proteinase inhibi-tor MZ heterozygotes (PiMZ genotype, where M isthe predominant allele and Z is clinically the mostsignificant deficiency allele) in many populations(2 to 5%) is also of pharmacogenetic interest be-cause PiMZ smokers show some loss of elastic re-coil. The loss for heterozygote smokers is aboutequal that of homozygous nonsmokers.

3.4.3 Aminoglycoside Antibiotic-Induced DeafnessAminoglycoside antibiotic-induced deafness

(AAID) is a form of nonsyndromic hearing lossthat is a major cause of deafness in persons receiv-ing antibiotics such as streptomycin and gentami-cin.[14,105,106] A point mutation in the mitochondrialgenome is associated with this defect in Chineseand Arab-Israeli pedigrees. Because the mutationis transmitted maternally, the most immediate clin-ical significance is to avoid aminoglycosides forany maternal relative with maternally inheritedAAID. The protein variant that is responsible forAAID has not been identified.

4. Ethnic Variation

Population frequencies of many polymorphicgenes of pharmacogenetic interest depend on raceor ethnic specificity.[55,56,107] Knowledge of ethnicspecificity can suggest a starting point for furtherstudy, assist in tailoring drug therapy to individualpatients and aid in the design of new rational drugdiscovery and in smaller, more efficient clinical tri-als.

It is evident from data about ethnic specificityin human drug metabolising enzymes such asCYP2C19, CYP2D6, glutathione S-transferase,and N-acetyltransferase that extrapolation acrossdifferent populations is unwise (table III). This

kind of information cannot only provide a fullerunderstanding of a trait but it may also help guidediagnosis and improve clinical care. For instance,experience indicates that 5 to 10% of African, Med-iterranean and Oriental males are susceptible tohaemolysis from glucose 6-phosphate dehydroge-nase (G6PD) deficiency (primaquine sensitivity)from many (>200) oxidant drugs. Though this traitis rare in Caucasians, additional studies have shownthat several agents (e.g. trinitrotoluene, quinidine,nitrofurazone) can elicit haemolytic reactions ofgreater severity and longer duration among G6PDdeficient Caucasians compared with Blacks whoare deficient.

A recent study of genetic polymorphisms in al-cohol dehydrogenase (ADH2) and CYP2E1 as riskfactors for alcohol-related birth defects has inter-esting ethnic overtones. Both enzymes make im-portant metabolic contributions to ethanol elimina-tion.[35,94] A recent population study demonstratedthe frequency of the ADH2*3 isozyme is unique toAfrican Americans. The presence of ADH*3 affordsprotection against alcohol-related birth defects, aneffect which is attributed to its high capacity to eli-minate ethanol at high concentrations associated withmaternal drinking during pregnancy. The same in-vestigators have also described an insertion in theCYP2E1 regulatory region that enhances the meta-bolic capacity on CYP2E1 (based on enhanced meta-bolism of the probe substrate, chloroxazone)[108] inthe presence of alcohol or obesity. The frequency ofthis mutation varies across ethnic groups, occurringin about 30% of African Americans and 7% of Cau-casians. Both of these polymorphisms are likely tobe determinants of alcohol risk to offspring.

It is not unusual these days for physicians to seea mix of ethnicities among their patients. Say, forexample, a Hispanic patient exhibits an unexpectedlack of response to nortriptyline,[109] or an unex-pected exaggerated response to codeine.[110] Themetabolism and elimination of both of these drugsare subject to the CYP2D6 polymorphism. Hence,such responses would be expected to occur morefrequently among Hispanics or African patients

876 Weber


compared with Caucasians or Asian patients be-cause of the greater frequency of CYP2D6 ultrarapid metabolisers among Hispanics and Africans.The well-informed physician will know that ahigher proportion of Hispanics and Africans areCYP2D6 ultra rapid metabolisers than Caucasiansor Asians. This should prompt him to ask whetherhis patient should be genotyped to determine whe-ther he is an ultra rapid metaboliser.[97] Also, sincenortriptyline and codeine are but two of more than50 drugs that are subject to CYP2D6 polymor-phism, he would also be alerted to the unwantedeffects of other drugs to which his patients mightbe exposed (see table I).[111]

5. Genetic Profiles of Drug Susceptibility

The ultimate purpose of pharmacogenetics is touse knowledge of human genetic diversity for pre-dictive purposes to select better therapies that willimprove clinical outcomes and reduce toxicity. Ifselective treatment is guided by profiles indivi-dualised for susceptibility to specific drugs, it fol-lows that the occurrence of unwanted responsesamong genetically susceptible persons might beminimised or averted.

Pharmacogenetics is in an excellent position toconstruct risk profiles from knowledge of mono-genic traits attributable to polymorphisms of hu-man enzymes, receptors and other variant proteinssuch as those described in the previous section.Many monogenic traits are useful prognostic indi-cators of responses to drug therapy, but as thesetraits are examined in greater depth, it may turn outthat few phenotypic outcomes will be reliably pre-dicted from genetic analyses at a single locus. Nev-ertheless, we expect that the legacy of pharmaco-genetics can provide the starting point for theconstruction of extended, improved profiles suita-ble for medical practice. Future pharmacogenetictesting will likely rely on a broad individual geno-typing capability as a guide to rational therapeuticstrategies, but the full potential of such testing willonly be realised when this capability is combined

with bioinformatic methods to analyse large, com-plex sets of biological data.

Risk profiles for drug susceptibility would serveas stepping-stones from the molecular foundationsof pharmacogenetics to attain better therapies andpersonalised medicine (table I). Even though wellover 100 pharmacogenetic traits have been charac-terised, molecular studies indicate that such traitsare usually associated with only a limited numberof important variants. This raises the prospect thatthe structural diversity of genes of pharmacogen-etic interest and related haplotypes may be cata-logued relatively soon for many populations.

For a complete picture of a genetic drug suscep-tibility profile, however, we also need to know thefunctional consequences of structural genomic di-versity. This means that the relationship of the in-dividual’s genotype (or haplotype) to the expressedphenotype must be established. Pharmacologistsusually think of an altered drug response as a con-sequence of an alteration in either the drug’s phar-macokinetics or its pharmacodynamics. Put simply,one usually suspects a defect in either the mecha-nisms that control the drug concentration (absorp-tion, distribution, elimination), or those that regu-late the receptor that mediates the drug response.Defective pharmacokinetic mechanisms are easilyidentified, but knowledge of receptor-mediated di-versity in drug response is comparatively rudimen-tary; thus, establishing genotype-phenotype rela-tionships, especially for pharmacodynamic diversity,is the next major challenge to be met and one thatis likely to require more than technical develop-ment.

6. Conclusions

The initial sequencing phase of the Human Ge-nome Project has been completed and with it, muchhas been learned about the human genome; how-ever, much less is known about the structural ge-nomic variation and the functional consequencesof this variation. Now attention is turning to the nextgreat challenge in pharmacogenetics - the determi-nation of the structures and cellular locations of



proteins encoded by the human genome and howproteins interact in pathways and networks to guidecellular responsiveness to drugs and other exoge-nous chemicals.

Acknowledgements

No sources of funding were used in the preparation of thismanuscript and the authors acknowledge there are no con-flicts of interest.

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Appendix I. Common abbreviations and acronyms

AAID Aminoglycoside antibiotic-induceddeafness

ADH Aldehyde dehydrogenase

ALOX5 5-arachadonic acid lipoxygenase

CCR2-641 A variant form of chemokine receptorassociated with AIDS infection

CCR5 A chemokine receptor associated withAIDS infection

CCR5Δ32 Variant of CCR5 with a 32-base pair deletion

cDNA Complementary DNA

CN-1 and CN-11 Crigler-Najjar syndromes types I and II

CYP, CYP450, andCYP2C19, 2D6,2C9, etc

Cytochrome P450 families and subfamilies

EMs Extensive metabolisers

fMLP A receptor involved in immune defence

FMOIII Flavin monoxygenase type III

FRET Fluorescence resonance energy transfer

G6PD Glucose 6-phosphate dehydrogenase

GPCRs G-protein coupled receptors

GSTs Glutathione S-transferases

HIV-1 Human immunodeficiency virus, type 1

KCNQ1 Potassium channel implicated in cardiacarrhythmias

MALDI/TOF Matrix assisted laser desorption/ionisationtime of flight

ML Mineralocorticoid

NATs N-acetyltransferases

NSAIDs Nonsteroidal anti-inflammatory drugs

PCR Polymerase chain reaction

PMs Poor metabolisers

R and S enantiomers Optical isomers

SN-38 Toxic metabolite of irinotecan

SNPs Single nucleotide polymorphisms

SP-C Surfactant protein C

TPMT Thiopurine methyltransferase

UDPGTs or UGTs Glucuronosyl transferases

URMs Ultra rapid metabolisers

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Correspondence and offprints: Dr Wendell W. Weber, Room1301b MSRB III, Department of Pharmacology , Universityof Michigan, 1150 W. Medical Center Drive, Ann Arbor, MI48109-0632, USA.E-mail: [email protected]



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