Pharmacogenomics || Pharmacogenomics of Lipid-Lowering Agents

Abstract

Cardiovascular disease is the major cause of death in North America and Europe.As shown by several large placebo-controlled intervention studies, the correctionof dyslipoproteinemias with bile acid sequestrants, fibrates, niacin or 3-hydroxy-3-methylglutaryl coenzymeA reductase inhibitors substantially reduces the risk offuture coronary events. The response to these lipid-lowering drugs is modified bya number of factors like gender, age, concomitant disease, additional medication,and genetic determinants. Even among carefully selected patients of clinical trials,individual responses vary greatly. At the time being there are no established bio-chemical or clinical parameters to distinguish between responders, non-respond-ers, and patients who will develop adverse, potentially life-threatening events.Monogenetic disorders of the lipid metabolism such as familial hypercholesterole-mia or type III hyperlipoproteinemia can produce severe premature atherosclero-sis. Due to their low frequency, however, their contribution to the overall burdenof cardiovascular disease is small. On the other hand, polymorphisms in genes ofthe lipoprotein metabolism (e.g., apolipoprotein E) are associated with plasma li-poprotein concentrations, explaining a substantial fraction of the variance of lowdensity lipoprotein (LDL) or high density lipoprotein (HDL) in the general popula-tion. The recent advances in pharmacogenomics, e. g., the characterization of newvariants and haplotypes of lipoprotein-related genes, will deepen our understand-ing of lipid and lipoprotein metabolism and of the individual response to lipid-lowering drugs.

13.1Introduction

Changes in the concentrations of lipoproteins, in particular increases in low den-sity lipoproteins (LDL), triglyceride-rich lipoproteins, and decreases in high den-sity lipoproteins (HDL), are among the most important causes of atherosclerosis.Dyslipidemias result from the interaction of environmental risk factors and multi-ple predisposing genes. Among the genetic factors affecting lipoprotein metabo-

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13

Pharmacogenomics of Lipid-Lowering AgentsMichael M. Hoffmann, Bernhard R. Winkelmann, Heinrich Wieland

and Winfried März

Pharmacogenomics: The Search for Individualized Therapies.Edited by J. Licinio and M.-L. Wong

Copyright © 2002 Wiley-VCH Verlag GmbH & Co. KGaAISBNs: 3-527-30380-4 (Paper); 3-527-60075-2 (Electronic)

lism are monogenetic disorders producing severe clinical phenotypes, e.g., famil-ial hypercholesterolemia (due to mutations in the LDL receptor gene) or Tangierdisease (due to mutations in the ABC-A1 gene). Although some of these disordersbelong to the most frequent inborn errors of metabolism in humans, they are toorare to make significant contributions to the variance of LDL or HDL cholesterolconcentrations observed in the general population. In the last decade, populationstudies showed that polymorphisms of genes involved in lipoprotein metabolismdetermine a substantial fraction of the variance of concentrations of circulating li-poproteins. Although the benefits of lipid-lowering therapy have been shown inmany patient populations, the individual variation in response is large. In thecase of LDL lowering by statins, responses may vary from decreases by 10–70%[1]. It is reasonable to assume that these differences, at least in part, relate to thegenetic diversity.

13.2The Metabolism of Plasma Lipoproteins

There are three major routes of lipid transport in plasma: the exogenous, the en-dogenous and the reverse cholesterol transport pathway. The exogenous pathwayis fed by dietary lipids, which are incorporated into chylomicrons and subse-quently released into the intestinal lymph. These particles enter the bloodstreamvia the thoracic duct, thus by-passing the liver. Lipoprotein lipase (LPL), which re-sides on the lumenal surface of the capillary endothelium, hydrolyzes the trigly-ceride moiety of the chylomicrons. The liberated free fatty acids are taken up bytissues such as adipose, for storage, and muscle, for oxidation. As a result of thehydrolysis process, chylomicrons are converted to smaller remnant particles, ex-cess surface components (phospholipids and apolipoproteins) being transferred toHDL. The remnant particles become enriched in cholesterol and acquire apoEfrom HDL. apoE is needed as ligand for lipoprotein receptors in the liver, becauseapoB-48, the major apolipoprotein of chylomicrons, lacks the receptor binding do-main of apoB-100. In summary thus, there are two major steps in the catabolismof chylomicrons: hydrolysis of triglycerides in the circulation and receptor-mediated catabolism of cholesterol in the liver.

In the endogenous pathway the liver is the source of triglycerides and cholester-ol, which are secreted as components of VLDL. Like chylomicrons, VLDL undergolipolysis in the circulation to give rise to IDL. A significant portion of the IDL israpidly taken up by the liver. The remainder undergoes further lipolysis by LPLand another lipolytic enzyme, hepatic triglyceride lipase (HTGL), leading to theformation of LDL. LDL particles contain most of the cholesterol in blood. Theironly protein constituent is apoB-100. In the periphery, LDL is taken up via theLDL-r and provides cholesterol for the synthesis of cell membranes and steroidhormones. However, roughly two thirds of the LDL are catabolized by the liver.

The reverse cholesterol pathway is mediated by HDL. HDL is formed from pre-cursor particles originating from the intestine and the liver. In addition, surface

13 Pharmacogenomics of Lipid-Lowering Agents268

material derived from the catabolism of chylomicrons is a source of HDL parti-cles. Nascent HDL particles mobilize free cholesterol from peripheral cells. Thisprocess is mediated by several proteins, e.g., apoAI and transmembrane ATP-binding cassette molecules like ABC-A1. The HDL-associated enzyme leci-thin : cholesterol acyltransferase (LCAT) immediately esterifies the free cholesterol.The esterified cholesterol is then transferred to the pool of apoB-100 containing li-poproteins or delivered directly to the liver, a process which is mediated by the ac-tion of cholesterol ester transfer protein (CETP).

13.3Pharmacogenomics of Lipid-Lowering Agents

13.3.1Bile Acid Sequestrants (Resins)

Resins, like cholestyramine and colestipol, impede the recycling of bile acids bytrapping them in the lumen of the intestine [2]. As a consequence the hepaticconversion of cholesterol to bile acid is increased by up-regulation of the cholester-ol-7-�-hydroxylase (CYP7) [3], the rate-limiting enzyme of bile acid synthesis.CYP7 activity seems to be inversely correlated with plasma cholesterol levels [4].There exists at least one common polymorphism within the regulatory region ofthe CYP7 gene (C-278A [5] or A-204C [6]). Depending on the population studied,the C-278A polymorphism accounted for 1–15% of the variation of LDL cholester-ol [5, 6]. The effect of this SNP on the regulation of CYP7 has not been evaluatedin detail. It is, therefore, difficult to predict whether it will influence the lipid-low-ering effect of bile acid sequestrants or HMG-CoA reductase inhibitors. Empiricalevidence for this possibility has also not been provided so far. The apolipoproteinEgenotype, which has shown to influence the plasma cholesterol level (see statins),had no effect on the hypolipidaemic efficacy of colestipol [7].

13.3.2Fibrates

The most pronounced effects of fibrates are to decrease plasma triglyceride-rich li-poproteins. In addition, fibrates slightly reduce LDL cholesterol and substantiallyraise HDL cholesterol. Further, they reduce small dense LDL, a highly atherogenicsubfraction of LDL. Fibrates act on the transcription of genes involved in lipopro-tein metabolism by activating transcription factors belonging to the nuclear hor-mone receptor family, the peroxisome proliferator-activated receptors (PPARs) (forreview, see [8, 9]). PPAR� is predominantly expressed in tissues that metabolizehigh amounts of fatty acids [10], like liver, kidney, heart, and muscle.

The hypotriglyceridemic action of fibrates involves combined effects on LPL andapolipoproteinCIII (apo CIII). LPL is up-regulated [11], whereas apoCIII, an inhib-itor of LPL, is down-regulated [12], leading to enhanced hydrolysis of triglyceride-

13.3 Pharmacogenomics of Lipid-Lowering Agents 269

rich lipoproteins. Moreover, fibrates decrease apoB and VLDL production [13]. Inrodents, fibrates enhance intracellular fatty acid metabolism. Whether this mecha-nism plays a role in humans is still under investigation. In humans the expres-sion of apo A-I, apo AII and of ABC-A1 [14] is stimulated, providing an explana-tion for the raise in HDL cholesterol during fibrate therapy. Kinetic analyses haverevealed that fibrates increase the receptor-mediated clearance of LDL. This is,however, most likely due to changes in the composition of LDL towards more re-ceptor-active particles rather than to up-regulation of the LDL receptor itself [15].

No polymorphisms have been described within the PPAR responsive elements(PPRE) of the promoters of LPL, apoCIII, apoAI and apoAII, which might influ-ence directly the binding of these transcription factors. On the other hand thereare several possible polymorphisms in the target genes of PPAR�, which mightinteract with the action of fibrates action, e.g., LPL D9N, N291S and S447X. Car-riers of the truncated LPL variant S447X, which is associated with higher plasmaLPL activity, might have greater benefit, whereas carriers of LPL 9N and 291S,who have lower plasma LPL activity, might have a smaller benefit from fibratetherapy, but this has not been proven experimentally so far.

Several SNPs in the PPAR� gene have been published recently: a G/A transver-sion in intron 3, R131Q, and L162V [16–18]. In all studies the frequency of theminor allele was lower than 10%. There was no evidence that the mutations with-in the coding region of PPAR have a major role in type 2 diabetes, although theymight have a borderline impact on LDL cholesterol levels [16, 17]. In the SEND-CAP study, bezafibrate-treated V162 allele carriers (13 patients) showed a 2-foldgreater lowering of total cholesterol (–0.90 vs. –0.42 mmol L–1, p= 0.04] and non-HDL-C (–1.01 vs. –0.50 mmol L–1, p= 0.04) than L162 allele homozygotes (109 pa-tients) [17]. As bezafibrate is not PPAR�-specific, but also interacts with PPAR�and PPAR�/�, the effects of the V162 variation might even be greater in the caseof other, more specific fibrates. In view of the small number of V162 carriers,these results obviously need to be reproduced in other studies.

There are a few studies investigating the role of polymorphisms at the apolipo-proteinB gene in modulating the response to fibrates. Although the apoB XbaIand signal peptide insertion/deletion polymorphisms might influence the baselinelevel of LDL cholesterol, they do not influence the response to fibrate therapy[19, 20]. The reports concerning the apolipoproteinE locus are conflicting [21–25].It is important to note that all of these studies are very small (n = 63– 230) and,therefore, their power to detect an effect of the apo E genotype is low.

13.3.3Niacin (Nicotinic Acid)

Niacin reduces plasma LDL cholesterol, lipoprotein (a), triglycerides and raises HDLcholesterol in all types of hyperlipoproteinemia [26]. Although available on the mar-ket for more than 40 years, the mechanisms of action of niacin are poorly under-stood. Putative mechanisms are the activation of adipose tissue LPL, diminishedHTGL activity, a reduced hepatic production and release of VLDL, and composi-


tional changes in LDL leading to higher affinity to the LDL receptor. Potential can-didates for modulators of the action of niacin are LPL, HTGL, the apoAI-CIII-AIVgene cluster, LCAT, CETP, and MTP, but empirical data is lacking up to now.

13.3.4Probucol

Primarily sold as antioxidant probucol is serving as an efficient cholesterol-lower-ing agent, reducing both LDL and HDL cholesterol without affecting plasma tri-glyceride levels. The decrease in HDL, mainly a reduction in HDL2, is a directconsequence of increased CETP activity in plasma [27]. It is still a matter ofdebate whether this indicates an enhanced reverse cholesterol transport. Unfortu-nately, there is no data relating polymorphisms in the CETP gene to the efficacyof probucol therapy. Probucol lowers LDL cholesterol in homozygous LDL recep-tor deficiency [28], providing evidence that probucol may increase LDL receptor-in-dependent catabolism of LDL.

One of the first pharmacogenomic studies investigating lipid-lowering drugswas published by Nestruck et al. in 1987 [29], describing that carriers of at leastone apoE4 allele who received probucol showed the greatest cholesterol reductionin comparison to those without an apoE4 allele. These data were confirmed in asecond study by Eto et al. [30].

13.3.5HMG-CoA Reductase Inhibitors (Statins)

The most successful strategies to reduce the concentration of LDL in the circula-tion involve the up-regulation of the LDL receptor activity by depleting the regula-tory pool of cholesterol in the liver. Inhibitors of 3-hydroxy-3-methylglutaryl coen-zyme A (HMG-CoA) reductase constitute the most powerful single class of hypo-lipidemic drugs currently available. Their efficacy in reducing coronary morbidityand mortality has been established by large secondary and primary interventiontrials. The expression of the LDL-r gene is regulated by the intracellular cholester-ol pool through sterol-responsive element binding proteins (SREBPs) 1 and 2 (forreview, see [31, 32]). The precursors of SREBPs are anchored in the membrane ofthe endoplasmic reticulum. When the sterol content of a cell decreases, SREBPprocessing proteins including SREBP cleavage activating protein (SCAP), site1protease (S1P), and site1 protease (S2P) act synergistically to release the amino-terminal domain of SREBP by proteolysis. These active domains are subsequentlytransferred into the nucleus where they activate the transcription of the genes ofthe LDL-r and of enzymes involved in the biosynthesis of cholesterol. Beyond this,the SREBPs up-regulate genes involved in the production of free fatty acids, in-cluding acetyl-CoA carboxylase and fatty acid synthase [33, 34].

Inter-individual variability of the cholesterol-lowering efficacy may relate to themetabolic processing of the drugs themselves. Genetic polymorphisms of drug meta-bolizing enzymes give rise to three categories of biochemical phenotypes:


� extensive metabolism of a drug is characteristic of the normal population;� ultraextensive metabolism results in increased drug metabolism and is an auto-

somal dominant trait arising from gene duplication; and� poor metabolism is associated with the accumulation of specific drug substrates

and is typically an autosomal recessive trait requiring mutation/deletion of twoalleles.

Atorvastatin, cerivastatin, lovastatin, and simvastatin are all substrates of cyto-chrome P450 (CYP) 3A4 [35]. Cerivastatin is in addition metabolized by CYP2C8,while pravastatin is not significantly metabolized by any of the CYPs. Fluvastatinis metabolized by CYP2C9, which to a minor degree also contributes to the meta-bolism of lovastatin and simvastatin [35]. CYP2D6, a monooxygenase displayingseveral genetic variants [36, 37] has a minor role only in the metabolism of sta-tins. Current knowledge of the relationship between genetic variants of the cyto-chromeP450s and the clinical efficacy of statins is rather limited. Clinically, how-ever, such information will be of value, in particular in the identification of pa-tients susceptible to rare, but potentially life-threatening adverse events of statintherapy such as myositis and rhabdomyolysis.

Mutations within the SREBPs and the SREBP processing proteins (SCAP, S1P,S2P) have intensively been searched, especially in patients with familial hyperchol-esterolemia. So far, however, only four polymorphic sites within SCAP [38, 39],one within the promoter of SREBP-1a [40], and five mutations in SREBP-2 [41]have been published. Yet, the impact of these polymorphisms and mutations onthe response to statins has not been evaluated.

Familial hypercholesterolemia (FH) is an autosomal dominantly inherited diseasecaused by mutations in the gene for the LDL receptor. Up to now more than 680distinct mutations, distributed over the entire gene, have been described [42]. Het-erozygous FH individuals express only half the number of functional LDL-r and,therefore, have a markedly raised plasma cholesterol and usually present with pre-mature coronary artery disease. Homozygous FH individuals are more severely af-fected and may succumb before the age of maturity. The prevalence of heterozy-gous FH is approximately 1 in 500 in Caucasians.

Heterozygous FH subjects have successfully been treated with statins [43–45],and cholesterol lowering has also been observed in LDL-r negative, homozygouscarriers [46]. The type of the mutation has been shown to impact on the cholester-ol-lowering effect of statins [45]. Thus, although characterization of the moleculardefect in FH patients may not be relevant to their immediate clinical manage-ment, those with a particular mutation may need more aggressive lipid-loweringtreatment to reach LDL cholesterol levels recommended to reduce the risk of coro-nary heart disease.

Apolipoprotein AI (apo AI) is the major apolipoprotein of HDL and plays an im-portant role in the formation of mature HDL and the reverse cholesterol trans-port. HDL concentrations are largely determined by the rate of synthesis of apoAIin the liver. As a consequence deficiency of apoAI results in an almost completeabsence of HDL and in accelerated atherosclerosis. In the promoter of the apoAI


gene, a GA substitution at position –75 is common in the general population. Arecent meta-analysis has shown that the minor allele A is associated with mildlyelevated apo A-I levels in healthy individuals [47]. In a small study, 58 male sub-jects were treated with atorvastatin (40mg d–1) or placebo in a cross-over design.Carriers of the apoAI –75 A allele (n= 15) showed a smaller response to atorvasta-tin treatment in the fasting as well as in the postprandial state [48]. Larger studiesare needed to confirm these results. However, the overall effect of this polymorph-ism appears to be small.

Apolipoprotein AIV (apo AIV) is produced in the intestine and is found in chylo-microns, VLDL and HDL. It may modulate enzymes involved in lipoprotein meta-bolism and may serve as a saturation signal [49]. In a study with 144 participantsthe apo AIV His360Glu polymorphism showed no significant effect on cholesterollowering in response to statin therapy [50].

Apolipoprotein B is the only apolipoprotein of LDL particles and responsible forthe receptor-mediated uptake of LDL. Therefore, it is obvious that mutations andpolymorphisms of the apoB gene may modulate the lipid response to statins.Familial defective apo B-100 (FDB) is a group of autosomal dominantly inheriteddisorders, in which the cellular uptake of LDL from the blood is diminished dueto mutations within the apoB-100 receptor binding domain [51]. A number ofpoint mutations of the putative receptor binding domain of apo B-100 have beenidentified. Only three of these mutations have so far been proven to produce bind-ing-defective apoB-100. Apparently the most frequent one is apoB-100(arg3500�gln) [52]. We and others identified homozygous FDB patients [53, 54].Hypercholesterolemia was less severe in these subjects as compared to patientshomozygous for FH in whom the LDL receptor is defective. Using a stable iso-tope labeling technique, we studied the turnover in vivo of lipoproteins in the fast-ing state in our FDB homozygous patient [55]. As expected, the residence time ofLDLapoB-100 was prolonged 3.6-fold in homozygous FDB, but the productionrate of LDL apoB-100 was approximately half of normal. This resulted from anenhanced removal of apoE containing LDL precursors by LDL receptors, whichmay be up-regulated as a consequence of the decreased flux of LDL-derived chol-esterol into hepatocytes. The availability of apo E for the receptor-mediated re-moval of remnant particles may also explain why FDB patients, homozygous orheterozygous, similarly respond to statins compared to individuals with othertypes of hypercholesterolemia. Numerous frequent polymorphisms have beenidentified at the apoB locus. Among these, a (silent) polymorphic XbaI site has ex-tensively been examined. In most studies, presence of the XbaI cutting site wasassociated with moderately increased LDL cholesterol. One study addressing theimpact of this polymorphism on response to lovastatin treatment (20 or 40 mg d–1;n= 211) was negative [56].

Among known genetic variants of genes related to lipoprotein metabolism, theapolipoprotein E polymorphism determines the greatest fraction (around 5%) of thepopulation variance of LDL cholesterol [6]. In humans, there are three commonalleles designated �2, �3, �4, giving rise to three homozygous and three hetero-zygous genotypes (for review, see [57]). The polymorphism of apo E affects the


concentration of LDL by modifying the expression of hepatic LDL-r. By virtue ofits preferential association with triglyceride-rich lipoproteins and due to strongerbinding to lipoprotein receptors, apo E4 enhances the catabolism of remnants.Consequently, hepatic LDL-r are down-regulated and LDL plasma levels increase.For this reason, apo E4 is associated with increased LDL cholesterol and athero-sclerosis. The �2 allele exerts an opposite effect on lipoprotein levels. apo E2 is de-fective in binding to lipoprotein receptors. This decreases the flux of remnant-de-rived cholesterol into the liver, up-regulates hepatic LDL-r and lowers LDL choles-terol. Ultimately, apo E2 may thus confer protection against the development ofvascular disease. For yet unknown reasons, however, one out of twenty apo E2/2homozygotes develops type III hyperlipoproteinemia, a disorder characterized byaccumulation of excessive amounts of cholesterol-rich remnant lipoproteins de-rived from the partial catabolism of chylomicrons and very low-density lipopro-teins.

Reports on the effects of the apo E polymorphism on the efficacy of hypolipid-emic drugs are conflicting. There are several negative reports [25, 56, 58, 59] anda few publications, describing a lower cholesterol reduction in apo E4 carriers [7,50, 60, 61] (for review, see [58]). In view of the fact that the apoE polymorphismis a strong predictor of baseline LDL cholesterol, it is surprising that there is aweak interaction only, if any at all, between the apo E genotype and the change inthe LDL cholesterol concentration on statin treatment. On the other hand, mostof the studies addressing this issue included patients with severe forms of hyperli-poproteinemia in which the influence of apoE might be less than in polygenic hy-percholesterolemia.

In an elegant paper, Gerdes et al. [59] examined whether the risk of death or amajor coronary event in survivors of myocardial infarction (MI) was related to theapo E genotype and whether risk reduction brought about by simvastatin was dif-ferent between genotypes. They analyzed 5.5 years of follow-up data of 966 Dan-ish and Finish myocardial infarction survivors enrolled in the Scandinavian Sim-vastatin Survival Study and found that MI survivors with the apo E4 allele have anearly 2-fold increased risk of death, and that treatment with simvastatin abol-ished excess mortality. They concluded that the effect of apo E4 may involve mech-anisms unrelated to serum lipoproteins because� baseline lipid levels did not differ between apo E genotypes,� E4 carriers and patients with other genotypes were equally responsive to simvas-

tatin treatment in terms of LDL cholesterol lowering [59].

It would be very interesting to go back into the other cohorts, in which no differ-ence in cholesterol reduction between the genotypes has been seen and to exam-ine, whether the statin treatment also abolished excess mortality of apo E4 car-riers.

In 1998 the REGRESS group published data, which showed that the TaqIB poly-morphism in intron 1 of the cholesterol-ester transfer protein (CETP) gene predictswhether men with coronary artery disease would benefit from treatment with pra-vastatin or not [60]. Pravastatin therapy slowed the progression of coronary athero-


sclerosis in B1B1 carriers but not in B2B2 carriers who represented 16% of thepatients. In the meantime the effect of this polymorphic site on HDL cholesteroland CETP plasma levels was confirmed by other investigators [61], but at least inthe WOSCOPS (West of Scotland Coronary Prevention Study) study it was notpossible to confirm the interaction between TaqIB genotype and pravastatin treat-ment [62]. REGRESS was an angiography-based trial in men with pre-existing cor-onary disease, whereas WOSCOPS was a primary prevention study in men withelevated LDL cholesterol. Possibly the different populations and primary end-points of these studies are the reason for the inconsistent results.

Hepatic triglyceride lipase (HTGL) catalyzes the hydrolysis of triglycerides of HDLand remnant lipoproteins like IDL and LDL. Further it is involved in their uptakein the liver. Whether HTGL is pro- or antiatherogenic is still a matter of debate[63]. Recently, a CT polymorphism at position –514 (–480) in the promoter of theHTGL gene has been described which is in complete linkage disequilibrium withthree other polymorphic sites within the promoter (G-250A, T-710C, A-763G) [64].The common C allele is associated with higher HTGL activity and an atherogeniclipid profile, characterized by lower levels of HDL2-cholesterol and dense LDL par-ticles [65]. In a small study of 25 men with dyslipoproteinemia and establishedCAD, undergoing lipid-lowering therapy with 40 mg daily of lovastatin and colesti-pol, subjects with the CC genotype had the greatest decrease in HTGL activity, thegreatest improvement in LDL density, and the greatest increase in HDL2 choles-terol [66]. Consistently, the CC homozygous subjects had the greatest angio-graphic improvements. The authors concluded that the HTGL gene –514 CT poly-morphism predicts 16% of the change in coronary stenosis produced by lipid-low-ering therapy. There are several other polymorphisms within the coding region ofthe HTGL gene, which influence the activity of the lipase [67]. It would be inter-esting to see whether the effects of the C-514 allele could be reproduced for othervariants.

Lipoprotein (a) is an independent risk factor for coronary artery disease [68]. Itconsists of two components: an LDL particle and apolipoprotein (a) which arelinked by a disulfide bridge. Apo(a) reveals a genetically determined size poly-morphism, resulting from a variable number of plasminogen kringle IV-type re-peats [69]. Statins either do not affect Lp(a) or may even increase Lp(a) [70, 71]. Ina study of 51 FH patients, treated with 40 mg d–1 pravastatin, it has been shownthat the increase in Lp(a) was greatest in patients with the low molecular-weightapo(a) phenotypes [70].

Recently, within the stromelysin-1 promoter a functional 5A/6A polymorphismhas been described [72]. Stromelysin-1 is a member of metalloproteinases that de-grade extracellular matrix. In situ hybridization and histopathological studies sug-gest that stromelysin-1 activity is important in connective tissue remodeling asso-ciated with atherogenesis and plaque rupture. Patients homozygous for the 6A al-lele showed greater progression of angiographic disease than those with othergenotypes [72]. In the REGRESS study (Regression Growth Evaluation Study) pa-tients within the placebo group with the 5A6A or 6A6A genotype had more clini-cal events than patients with the 5A5A genotype. In the pravastatin group, the


risk of clinical events in patients with 5A6A or 6A6A genotypes was lower, com-pared with placebo [73]. Similar data were obtained for the incidence of repeat an-gioplasty. These beneficial changes were independent of the effects of pravastatinon the lipid level, raising the possibility that pravastatin exerts pleiotropic effectson stromelysin-1 expression or activity. Up to now there are two studies, one withgemfibrozil (LOCAT) [74] and the REGRESS study conducted with pravastatin[73], suggesting that the stromelysin-1 promoter polymorphism confers a geno-type-specific response to medication.

13.4Conclusion

Lipid-lowering pharmacotherapy is one of the most recent advances in the treat-ment of heart disease and atherosclerosis. Genetic variants of genes involved indrug metabolism and genes involved in the lipoprotein metabolism can modifythe response of plasma lipoproteins to these drugs. Research of the interaction ofgenetic factors and the efficacy of lipid-lowering agents, however, is at its very be-ginning. Publications on interactions between genotypes and the effects of lipid-lowering drugs on plasma lipoproteins and clinical outcomes are sporadic. Manystudies have methodical limitations because the influence of genetic determinantshas not been a pre-specified objective. The majority of the studies is not suffi-ciently powered to detect the effects of less frequent variants. In several cases ini-tial positive results have not been confirmed in other studies. One reason mightbe the different genetic background in these cohorts. The concept that one poly-morphism would provide sufficient information is probably too simplistic and de-terministic. Haplotypes, describing at the same time variations in both regulatoryelements and coding regions of a gene on the individual chromosome, mighthave the advantage of providing more information on genotype–phenotype rela-tionships than individual SNPs. To use this information in daily practice, novelanalytical tools are needed to make the results even of complex genetic profilesimmediately available to clinicians. Genetic information will then probably help toset up indications for lipid-lowering drug therapy and to choose between an ex-panding number of treatment options.


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