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Pharmacogenomics

POR*28 SNP is associated with lipid response to atorvastatin in children and adolescents with familial hypercholesterolemia Background: In children and adolescents with familial hypercholesterolemia (FH) pharmacotherapy with statins is the cornerstone in the current regimen to reduce low-density lipoprotein cholesterol (LDLc) and premature coronary heart disease risk. There is, however, a great interindividual variation in response to therapy, partially attributed to genetic factors. The polymorphic enzyme POR transfers electrons from NADPH to CYP450 enzymes including CYP3A, which metabolize atorvastatin. POR*28 polymorphism is associated with increased CYP3A enzyme activity. We analyzed the association of POR*28 allele with response to atorvastatin. Materials & methods: One hundred and five FH children and adolescents treated with atorvastatin at doses 10–40 mg were included in the study. Total cholesterol (TChol) and LDLc were measured at baseline and after 6 months of treatment. POR*28 allele was analyzed with TaqMan assay. CYP3A4*22, CYP3A5*3 and SLCO1B1 521T>C and 388A>G genotypes were also determined with TaqMan or PCR-RFLP methods. Results: POR*28 carriers had significantly lower percent mean reduction of TChol (33.1% in *1/*1, 29.8% in *1/*28 and 25.9% in *28/*28 individuals, p = 0.045) and of LDLc (43.9% in *1/*1, 40.9% in *1/*28 and 30.8% in *28/*28 individuals, p = 0.013). In multivariable linear regression adjusted for confounding factors, POR*28 genotypes, additionally to baseline cholesterol level, accounted for an estimated 8.3% and 7.3% of overall variability in % TChol and LDLc reduction (β: 4.05; 95% CI: 1.73–6.37; p = 0.001 and β: 5.08; 95% CI: 1.62–8.54; p = 0.004, respectively). CYP3A4*22, CYP3A5*3 and SLCO1B1 521T>C and 388A>G polymorphisms were not associated with lipid reductions and did not modify the effect of POR*28 on atorvastatin response. Conclusion: In children with FH, carriage of POR*28 allele is associated with reduced effect of atorvastatin on TChol and LDLc and therefore identifies FH children that may require higher atorvastatin doses to achieve full therapeutic benefits. Additional studies in different populations are needed to replicate this association.

Euridiki Drogari1, Georgia Ragia2,3, Vasiliki Mollaki1, Laure Elens 4,5, Ron HN Van Schaik4 & Vangelis G Manolopoulos*,2,6 Unit of Metabolic Diseases, 1st Department of Pediatrics, Choremio Research Laboratory, Aghia Sophia Children’s Hospital, Medical School, University of Athens, Athens, Greece 2 Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece 3 DNALEX S.A., Leontaridou 2, Alexandroupolis, Greece 4 Department of Clinical Chemistry, Erasmus MC, Rotterdam, The Netherlands 5 Louvain Centre for Toxicology & Applied Pharmacology, Catholic University of Louvain, Brussels, Belgium 6 Clinical Pharmacology Unit, Academic General Hospital of Alexandroupolis, Alexandroupolis, Greece *Author for correspondence: Tel.: +30 25510 30523 emanolop@ med.duth.gr 1

Original submitted 2 June 2014; Revision submitted 22 September 2014 Keywords:  atorvastatin • children • hypercholesterolemia • P450 oxidoreductase • pharmacogenomics • POR*28

Familial hypercholesterolemia (FH) is, mainly, an autosomal dominant disorder characterized by severely elevated levels of low-density lipoprotein (LDL) cholesterol (LDLc) leading to atherosclerosis and premature coronary heart disease (CHD) and death [1] . Both the heterozygous and homozygous forms of FH require aggressive cho-

10.2217/PGS.14.138 © 2014 Future Medicine Ltd

lesterol-lowering therapy. According to FH management recommendations from the National Lipid Association Expert Panel on FH, statins are the cornerstone in the current regimen [2] . In children with FH there is broad consensus that statin therapy is the treatment of choice, and it should be commenced by the

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Research Article  Drogari, Ragia, Mollaki, Elens, Van Schaik & Manolopoulos age of 10 years, after initiation of diet and physical activity management [3–6] . The American Academy of Pediatrics (AAP) has recommended that statins should be started as early as 8 years of age. Atorvastatin, simvastatin and pravastatin are among statins that have been approved by FDA for hypercholesterolemia treatment in children aged 10 years or more [7] . There is a wide interindividual variation in lipidlowering response and part of it may be due to genetic factors [8] . Study of genetic variation in association with statin response focuses on genes involved in statins pharmacokinetics and pharmacodynamics, as well as on genes that are involved in the underlying disease condition or intermediate phenotype [9] . Atorvastatin produces LDLc reductions of 40–60% at doses of 10–80 mg, respectively, and larger reductions of cholesterol and triglycerides (TGL) compared with other drugs in this class. It has also been shown to reduce the levels of small dense LDL and inter­mediate density lipoprotein (IDL). Atorvastatin undergoes extensive first-pass metabolism by cytochrome P450 3A enzymes in the liver; CYP3A4 is the primary metabolizing enzyme, while CYP3A5 has only a minor contribution to its metabolism [10] . Genetically determined interindividual variability in CYP3A4 expression has been suggested to be associated with the differences found in response to several drugs, including atorvastatin. However, the majority of CYP3A4 functional SNPs is infrequent and accounts only for a small portion of the observed CYP3A4 interindividual variability. Recently, a polymorphism in the POR gene was associated with increased CYP3A activity and can potentially explain the CYP3A expression variability. POR transfers electrons from NADPH to microsomal CYP450 enzymes, enabling their activity [11,12] . More than 40 SNPs have been identified in the POR gene, however the allele frequency of most of these is T SNP (POR*28) introduces an amino acid substitution at position 503 (alanine>valine) in the FAD-binding domain and it is both functional and common in the general population [13,14] . Conformational alterations induced by the POR*28 SNP probably modify primarily the POR–cytochrome interaction, leading to specific cytochrome-dependent changes in enzymatic activity. Homozygous POR*28 carriers have an increased in vivo CYP3A activity as demonstrated by a 1.6-fold increased midazolam metabolic ratio, compared with POR*1/*1 carriers [15] . In clinical setting, POR*28 allele has been investigated in terms of dose requirements and clinical response to the immunosuppressant tacrolimus. POR*28 carriers present significantly lower levels of tacrolimus exposure [16] and need additional increases in early tacrolimus dose requirements in renal

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recipients also expressing CYP3A5 [17] . This raises the probability that POR*28 carriers may exhibit different response to atorvastatin. Because the POR*28 allele is associated with increased in vivo CYP3A activity, the objective of this study was to assess whether the POR*28 poly­ morphism is associated with the hypocholesterolemic effect of atorvastatin in a cohort of children and adolescents with FH. Materials & methods A total of 123 nonrelated children and adolescents (61 males and 63 females) aged 13.3 ± 3.3 years clinically diagnosed with FH were initially included in the study group. LDLR molecular analysis was performed in 95 of the 123 patients by direct DNA sequencing of the whole gene. A mutation was identified in 74 patients, whereas 21 patients had no LDLR mutation. Six participants refused to take statin treatment while one patient stopped therapy during the first month. The remaining 117 participants were treated with atorvastatin at doses of 10, 20 and 40 mg. The dose of atorvastatin was adjusted according to the National Cholesterol Education Program Pediatric Panel Guidelines treatment goal for LDL-C based on risk category [18] . Three participants were also treated with ezetimibe 10 mg, after their expert doctor carefully examined their lipid profile and risk category. Total cholesterol (TChol), LDLc, high-density lipoprotein cholesterol (HDLc) and TGL were measured before initiation of therapy and after 6 months of treatment with atorvastatin. Twelve patients did not return on 6 months and were excluded from the study. Thus, data from a total of 105 FH atorvastatin treated children and adolescents (53 males and 52 females) aged 13.4 ± 3.3 years were included in the study. A mutation was identified in 64 patients whereas 17 patients had no LDLR mutation. All patients were referred to the ‘Aghia Sophia’ Children’s Hospital in Athens, Greece. When possible, three generation family screening was performed. The diagnosis of heterozygous FH was based on a uniform protocol including: an autosomal dominant mode of inheritance of hypercholesterolemia in the family; the presence of primary hypercholesterolemia (total cholesterol [TChol] ≥200 mg/dl) in the proband, siblings, parents, grandparents and great grandparents; plasma or serum LDLc ≥130 mg/dl; presence of tendon and cutaneous xanthomas at an early age with hypercholesterolemia; family history of coronary artery disease at G by use of methods already described ­elsewhere  [20–22] . Statistical analyses

All quantitative data are presented as mean ± SD. Continuous data were tested for normality using Kolmogorov–Smirnov test of normality. Comparisons for normally distributed continuous variables between two or more groups were performed with independent t-test or one-way ANOVA, respectively. Non-normally distributed continuous variables were compared by Mann–Whitney test or Kruskal–Wallis test as appropriate. Efficacy of statins in terms of mean reduction of TChol and LDLc from baseline was assessed using paired samples t-test. Comparisons for categorical data between two groups were conducted using χ 2 test.

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Demographic and baseline characteristics of our study population are shown in Table 1. For the entire cohort population, levels of TChol and LDLc before initiation of atorvastatin treatment were 262.5 mg/dl (±45.9) and 187.0 mg/dl (±45.8), respectively. After 6 months of atorvastatin treatment, the mean reductions from baseline of TChol and LDLc were 84.6 mg/dl (±35.1) and 80.4 mg/dl (±35.6), which corresponds to 31.4% (±9.1) and 41.9% (±12.1) reductions, respectively. Also, baseline levels of HDLc and TGL were 59.8 mg/dl (±12.6) and 66.1 mg/dl (±27.1), respectively, and were reduced to 57.4 mg/dl (±12.9) and 60.3mg/dl (±28.6), respectively, on 6 months of therapy. Atorvastatin treatment was associated with statistically significant mean reduction from baseline of TChol and LDLc (p G SNPs) which facilitates atorvastatin hepatic uptake might confound these results, we have replicated all analyses after further adjusting for CYP3A4*22, CYP3A5*3 and SLCO1B1 521T>C and 388A>G potential effects. We have found that none of the analyzed polymorphisms was independently associated with atorvastatin response (data not shown) and that the results regarding the association of POR*28 genotypes with % reduction of TChol and LDLc in multivariable linear regression did not change (Table 3) .

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Discussion In the present study, we investigated the association of POR*28 allele and all derived genotypes with atorvastatin response in children and adolescents diagnosed with FH clinically, molecularly, or both. The genetic polymorphism examined has been suggested to explain a proportion of CYP3A variability, since POR regulates CYP3A enzyme activity. To the best of our knowledge this is the first study to assess the association of POR*28 allele with atorvastatin response in a FH population. Our results show that POR*28 allele is associated with lower reductions in TChol and LDLc in a cohort of atorvastatin-treated FH children and adolescents after 6 months of atorvastatin therapy. Prevalence of POR*28 allele in the studied population of FH-children (25.2%) is in agreement with the frequency previously reported for the adult Greek population (27.6–28.7%) [25,26] , the reported global allele minor allele frequency of 28.8% annotated by 1000 Genomes, and within the minor allele frequency range 25.0–31.7% described for European populations [27] . POR transfers electrons from NADPH to microsomal CYP450 enzymes thus enabling their activity. Even though more than 40 SNPs have been identified in the POR gene, only recently their impact on

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POR*28 SNP & lipid response to atorvastatin in children & adolescents with familial hypercholesterolemia 

0.00

p = 0.045

-10.00 -20.00 -30.00 -40.00 -50.00 *1*1

*1*28 POR genotypes

*28*28

vastatin, such as SLCO1B1 521T>C and 388A>G. Adjustment of the multivariate regression models for these polymorphisms rather increases the association of POR*28 with reduced percent lowering of TChol and LDLc (Table 3) . In our study cohort, the studied population consists of children and adolescents diagnosed clinically or molecularly or both with FH. The age of our population limits the existence of comorbidities that could interfere with therapeutic response. Furthermore, the participants of our study are solely on atorvastatin monotherapy, with the exception of three participants who were also treated with ezetimibe. Therefore, drug interactions that may also interfere with therapeutic response to atorvastatin in adult populations are not present in this population. The studied population was treated with different doses of atorvastatin as decided based upon the baseline lipids and according to current treatment guidelines, however, it appears that this did not affect the results since all applied models were adjusted for atorvastatin dose. As a consequence, the presented results on the association of POR*28 allele with lipid response to atorvastatin and the proportion of variability attributed to this gene poly­morphism cannot be masqued by factors other than those included in the analyses models. Treatment with statins in children and adolescents with FH is crucial for reduction of CHD risk. However, a great interindividual variability exists in statin users. Pharmacogenomic analyses can shed light in cholesterol reduction response variability. Hitherto, pharmacogenomic cohorts in individuals with mole­cularly defined FH are scarce and mainly focus on the impact of LDLR

Percentage LDLc reduction from baseline

Percentage TChol reduction from baseline Mean percentage decrease TChol in last 6 months

drug pharmacokinetics has started to be investigated. POR*28 allele has emerged as a determinant of CYP450 enzymes expression. POR*28 carriage has a differential effect on CYP450 enzymes expression; it is associated with slightly decreased activity of CYP1A2 (85%) [13] and CYP2D6 (85% with EOMCC (2H-1-benzopyran3-carbonitrile,7-(ethoxy-methoxy)-2-oxo-(9Cl)), 62% with dextromethorphan and 53% with bufuralol) [28] , and with increased activity of CYP2C19 (113%) [13] and CYP2C9 (140–170%) [25,29] . In the case of CYP3A enzymes, POR*28 carriers have an increased in vivo hepatic CYP3A activity [15,30] . The ability of POR*28 variant to support the catalytic activity of CYP3A4 varies depending on the substrate and also depends on both the size and the chemical structure of each substrate and this appears to result from substrate-induced conformational changes in CYP3A4 [31] . In our study, carriers of POR*28 allele had significantly lower percent reductions in TChol and LDLc after 6 months of atorvastatin treatment. This effect can be attributed to the overall increased expression of CYP3A4 conferred by POR*28 allele. The additional effect of POR*28 genotypes on percent reduction of TChol and LDLc was estimated at 8.3 and 7.3%, respectively. Together with levels of cholesterol before the start of therapy, POR*28 genotypes predict 36.7 and 22.1% of variability in percent reduction of TChol and LDLc, respectively. Additionally, it appears that the effect of POR*28 genotypes on lipid-lowering response to atorvastatin in FH children and adolescents is independent of other gene polymorphisms in CYP3A locus, such as CYP3A4*22 and CYP3A5*3, or of polymorphisms in molecules that affect the hepatic transport of ator-

Research Article

0.00

p = 0.013

-10.00 -20.00 -30.00 -40.00 -50.00 -60.00 *1*1

*1*28

*28*28

POR genotypes

Figure 1. Reduction in cholesterol levels. Percentage reduction in (A) serum total cholesterol levels from baseline and (B) serum LDLc levels from baseline in patients on 6 months of atorvastatin therapy by POR*28 genotypes. Bars represent mean ± standard deviation. LDLc: Low-density lipoprotein cholesterol; TChol: Total cholesterol.

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Research Article  Drogari, Ragia, Mollaki, Elens, Van Schaik & Manolopoulos gene mutations on cholesterol-lowering response to statin therapy and statin dosage [32] . Other genes studied for their potential effect on lipid-lowering response to statins include CETP [33] , MTP [34] and apoE [35] . To the best of our knowledge, POR*28 gene poly­ morphism in relation to atorvastatin has only been assessed in our recent study in adults with primary hypercholesterolemia where no effect was found potentially due to uncontrolled factors such as comorbidities and polypharmacy [26] . Pharmacogenomic studies of atorvastatin have mainly focused on gene poly­morphisms affecting either drug pharmaco­kinetics or pharmacodynamics. At pharmacokinetic arm, even though CYP3A4 primarily metabolizes atorvastatin, most CYP3A4 functional SNPs are infrequent and account for only a small portion of the observed CYP3A4 enzyme content and/ or activity variability. Thus, they cannot be major contributors to interindividual variability to atorvastatin response. Given the fact that there is a strong correlation between statin dose, blood drug concentration, and lipid response, reduced atorvastatin levels due to POR*28 gene polymorphism that results in increased atorvastatin metabolism may lead to a variable efficacy and/or toxicity of therapy. Therefore, genotyping for this polymorphism can potentially identify individuals that require higher atorvastatin doses to achieve greater lipid levels reductions and is of increased validity in the studied population of children and adolescents, since early management of TChol and LDLc can lead to ­prevention of CHD.

Conclusion POR has emerged as a molecule that affects pharmaco­ kinetics of drug substrates of CYP3A through its functional role of enabling CYP3A activity. In the present study, we report that POR*28 polymorphism is associated with lower reductions in TChol and LDLc in response to atorvastatin in a FH population of children and adolescents. Therefore, the POR*28 allele appears as a novel promising marker of altered atorvastatin pharmacokinetics and lipid-lowering response (Figure 1).

Disclosure These results were partly presented at the 1st International Conference on Familial Hypercholesterolaemia in Children and Adolescents, Athens, Greece, June 2012.

Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research The authors state that they have obtained appropriate institutional review board approval or have followed the principles

Executive summary • Heterozygous and homozygous forms of familial hypercholesterolemia (FH) require aggressive cholesterol-lowering therapy. • In children with FH, statin therapy is the treatment of choice, and it should be commenced by the age of 10 years. • POR*28 allele is associated with increased in vivo CYP3A activity and may affect the hypocholesterolemic effect of atorvastatin.

Materials & methods • POR*28 allele was genotyped in children and adolescents with FH receiving atorvastatin. • Lipid profile measurements were assessed before initiation of therapy and after 6 months of treatment with atorvastatin.

Results • POR*28 carriers had significantly lower percent mean reduction of total cholesterol (TChol) and of low-density lipoprotein cholesterol (LDLc). • In multivariate linear regression adjusted for confounding factors, POR*28 genotypes account for an estimated 8.3 and 7.3% of overall variability in percent TChol and LDLc reduction.

Discussion • POR*28 allele is associated with lower reductions in TChol and LDLc in a cohort of atorvastatin-treated FH children and adolescents after 6 months of atorvastatin therapy. • POR*28 allele appears to be a novel promising marker of atorvastatin pharmacokinetics and lipid-lowering response.

Conclusion • POR*28 allele genotyping identifies children with FH that may require higher atorvastatin doses to achieve full therapeutic benefits.

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POR*28 SNP & lipid response to atorvastatin in children & adolescents with familial hypercholesterolemia 

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outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations in-

volving human subjects, informed consent has been obtained from the participants involved.

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POR*28 SNP is associated with lipid response to atorvastatin in children and adolescents with familial hypercholesterolemia.

In children and adolescents with familial hypercholesterolemia (FH) pharmacotherapy with statins is the cornerstone in the current regimen to reduce l...
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