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Original article
Allelic and phenotypic characterization of CYP2D6 and its encoded P450 cytochrome enzyme in a serie of Spanish type 1 Gaucher disease patients
Caracterización alélica y fenotípica del gen y la enzima Cyp2d6 en una cohorte de pacientes españoles con enfermedad de Gaucher tipo 1
Laura López de Frutosa,b,
Corresponding author
llopezdefrutos.uit@gmail.com

Corresponding author.
, Pilar Alfonsoa, Carlos Lahoza,b, Pilar Irúnc, Pilar Giraldob
a Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain
b Fundación para el Estudio y la Terapéutica de la Enfermedad de Gaucher y Otras Lisosomales (FEETEG), Zaragoza, Spain
c Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), IIS Aragón, Zaragoza, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The pharmacodynamics is one of the most important characteristics to know the safety and efficacy of drugs used in clinical practice&#46; It is regulated by its absorption&#44; distribution and elimination process&#46; Drug metabolism includes their oxidation by cytochrome enzymes&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">1</span></a> Cytochrome P450 superfamily is a group of oxidases involved in drug metabolism and many other cellular pathways&#46; There are 18 mammalian cytochrome P450 families&#44; which includes 57 human genes&#44; but eleven enzymes are the most important ones for metabolizing drugs&#44; including cytochrome P450 2D6 and 3A4&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The cytochrome P450 2D6 &#40;<span class="elsevierStyleUnderline">CYPIID6</span>&#59; Uniprot code P10635&#41; is an oxidase&#44; member of P450 cytochrome superfamily&#44; involved in the hepatic clearance of approximately 20&#37; of the most common drugs&#44; including codeine or paracetamol&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">1</span></a> This enzyme is encoded by <span class="elsevierStyleItalic">CYP2D6</span> gene &#40;MIM&#42;608902&#41;&#44; it is a highly polymorphic gene with 146 alleles according to the pharmacogene variation consortium &#40;PharmVar&#41;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">3</span></a> which presents a differential allele distribution among populations&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">4</span></a> Point mutations&#44; deletions&#44; insertions&#44; gene rearrangements&#44; and duplication or deletion of the entire gene are responsible for different metabolizer phenotypes&#46; According to the enzyme activity these fall into four categories&#58; poor metabolizers &#40;PM&#41; without enzymatic activity&#59; intermediate metabolizers &#40;IM&#41; those with a non-functional allele in combination with a normal activity one&#59; extensive or normal metabolizers &#40;NM&#41; with a normal activity on both alleles&#59; and ultra-rapid metabolizers &#40;UM&#41; those with more than two functional alleles&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">5&#44;6</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Nowadays this classification is being replaced by an activity score &#40;AS&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">7</span></a> Those alleles that encode a protein without enzymatic activity obtain a 0 score&#44; those for enzymes with reduced activity are punctuated with 0&#46;5 and the normal activity encoders obtain 1 point&#46; The subject alleles sum provided the AS between 0 &#40;two null alleles&#41; and &#62;3 &#40;subjects with at least three normal alleles&#41;&#46; The consensus among experts is clear to define AS<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0 as PM&#44; AS<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;5 as IM&#44; AS<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;5 or 2 as NM and AS<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>3 as UM&#44; but the classification of 1 and 2&#46;5 scores is not clear and experts are divided&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">5</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Gaucher disease &#40;GD&#41;&#44; the most frequent lysosomal storage disorder&#44; has been classically subdivided into three clinical phenotypes&#44; being type 1 phenotype the most commonly found &#40;GD1&#59; MIM&#35;230800&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">8</span></a> GD is an inherited autosomal recessive disease&#44; that arises from damaging variants in the <span class="elsevierStyleItalic">GBA1</span> gene &#40;MIM&#42;606463&#41;&#46; The gene includes 11 exons and it is located on chromosome 1 &#40;1q21-22&#41;&#46; On July&#8217;18 the professional &#8220;Human Gene Mutation Database&#8221; included 472 pathogenic variants related to the disease&#44; but only 4 of them are responsible over 90&#37; of GD1 patients in Ashkenazi Jews and over 50&#37; in non-Jewish patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">8&#44;9</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">GBA1</span> gene encodes a lysosomal enzyme named acid &#946;-glucosidase&#44; responsible for glucosylceramide &#40;Gb1&#41; hydrolysis&#46; Enzymatic malfunction induces Gb1 accumulation in the macrophagic mononuclear system cells which are the responsible for the most frequent or common clinical manifestations of GD&#58; splenomegaly&#44; hepatomegaly&#44; growth delay and bone disease&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">8</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The treatment with recombinant enzyme began in 1991&#46; Nowadays it consists of intravenous infusions with a 2-week frequency&#46; Despite not being curative&#44; it has been proved that it is a safe and efficient treatment and improves patients life quality&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">10</span></a> Another treatment option is the substrate reduction therapy &#40;SRT&#41;&#44; based on the inhibition of the enzyme glucosylceramide synthase with the purpose of reducing the Gb1 synthesis&#46; There are two drugs approved for GD and based on SRT&#44; the first approved in 2004 is an iminosugar &#40;Miglustat&#44; Zavesca&#174;&#41;&#44; and its analogy with the glucosyl group allows it to inhibit the enzyme by mimetic competition&#44;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">11</span></a> and the second one is a ceramide analogous &#40;Eliglustat&#44; Cerdelga&#174;&#41; approved in 2015 as GD1 treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">12</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Eliglustat&#44; a tartrate salt analogous to 1-phenyl-2-decanoylamino-3-morpholino-1-propanol is one of the drugs metabolized through CYPIID6 enzyme&#46; It is a glucosylceramide synthase inhibitor that induces a glucosylceramide production reduction&#44; avoiding its accumulation&#46; It is therefore approved by the European Union and the United States as a SRT to manage type 1 Gaucher disease &#40;GD1&#41; patients<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">13</span></a> and&#44; it is mandatory to genotype <span class="elsevierStyleItalic">CYP2D6</span> to determinate its metabolizing status before start any treatment with it&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">14</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Despite non-inductors for CYPIID6 have been described&#44; it is necessary to identify functional differences in the cytochrome activity to avoid clinical issues due to pharmacological interactions&#44;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">1&#44;15</span></a> as well as avoid high drug doses such that the patient cannot metabolize properly&#46; The aim of this project is to analyze the allelic status of <span class="elsevierStyleItalic">CYP2D6</span> and the corresponding phenotype on CYPIID6 on a Spanish GD1 patients&#8217; population&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Patients</span><p id="par0045" class="elsevierStylePara elsevierViewall">We have studied 109 patients &#40;GD-S group&#41;&#44; older than 18 years of age&#44; with confirmed enzymatic and genetic diagnosis of GD&#44; and a clinical classification for type 1 included in the Spanish Gaucher disease Registry&#46; The study design was approved by the institutional board of FEETEG foundation&#46; All individuals were provided with the written informed consent and the study was conducted in accordance with the principles stated in the Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects&#44; Helsinki&#44; Finland&#44; 1964&#44; and as amended in Fortaleza&#44; Brazil&#44; 2013&#46; The exclusion criteria were the inclusion on the clinical trial ENCORE&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095"><span class="elsevierStyleItalic">GBA1</span> sequencing</span><p id="par0050" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">GBA1</span> gene was amplified according to the previously published&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">16</span></a> To summarize it&#44; a long-chain PCR using specific primers of the functional <span class="elsevierStyleItalic">GBA1</span> gene and subsequent nested PCR of each exonic region were performed&#46; Products were sequenced by capillary electrophoresis and analyzed with the Variant Report v&#46;1 software&#46; Results were compared to the reference sequence available in the GeneBank database &#40;NG&#95;009783&#46;1&#41;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100"><span class="elsevierStyleItalic">CYP2D6</span> genotyping</span><p id="par0055" class="elsevierStylePara elsevierViewall">The allele identification of the <span class="elsevierStyleItalic">CYP2D6</span> gene &#40;GeneBank database reference&#58; NG&#95;008376&#46;3&#41; was done according to the xTAG&#174;CYP2D6v3 &#40;Luminex Corporation&#44; Texas&#44; USA&#41; manufacturer instructions&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">This kit analyzes 19 genetic variants and the presence of genetic deletions or duplications that allowed us to identify 17 alleles and establish a metabolizer phenotype for all evaluated patient&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Briefly&#44; DNA was first isolated and purified from whole blood using a commercial extraction kit&#44; and according to the manufacturer instructions&#46; A UV 260&#47;280 ratio purity of at least 1&#46;5 is necessary to perform the genotyping assay&#46; Gene duplication and 19 SNPs were amplified by multiplex PCR and cleaned by enzymatic purification&#46; Multiplex allele-specific primer extension was then performed&#44; followed by a bead hybridization&#46; Finally&#44; a reporter molecule was added&#44; washed and analyzed on xMAP&#8482; equipment&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">All reactions included a negative control and a control sample for each metabolizer status&#46; All patients with gene duplication were analyzed twice&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105"><span class="elsevierStyleItalic">CYP2D6</span> genotype&#8211;phenotype correlation</span><p id="par0075" class="elsevierStylePara elsevierViewall">The correlation between genotype and phenotype has been made by the allelic correlation&#44; establishing 4 activity groups&#58; NM&#44; PM&#44; IM and UM phenotypes and&#44; according to the activity score &#40;AS&#41; published by Gaedigk in 2008&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">6&#44;7</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Each allele has an assigned score between 0 and 2&#44; and the sum of both alleles provides an AS that allow us to classify the patients between 0 predicting poor metabolizers&#44; and &#62;2 predicting ultra-rapid metabolizers&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">The correlation between the AS and the classical phenotype assignation has been done defining poor metabolizer as those with AS<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44; intermediate metabolizer with AS<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;5&#44; normal metabolizer as those with AS between 1 and 2 and ultra-rapid metabolizers as those with activity score<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>3&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Control data analysis</span><p id="par0090" class="elsevierStylePara elsevierViewall">Three control dataset were obtained from the literature&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">The first one &#40;Control group 1&#59; CG1&#41; was obtained from the Spanish reports included on the Pharmgkb Database &#40;<a href="https://www.pharmgkb.org/page/cyp2d6RefMaterials">https&#58;&#47;&#47;www&#46;pharmgkb&#46;org&#47;page&#47;cyp2d6RefMaterials</a>&#41;&#46; This database includes 11 papers published between 2004 and 2017&#44; but only 5 of them analyze all the alleles&#44; so only these have been considered to prepare our control population dataset&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">17&#8211;21</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">The second one &#40;Control group 2&#59; CG2&#41; was obtained from one of the most recent papers about the genotypes and phenotypes CYP2D6 frequencies&#46; This report includes 6060 healthy subjects&#44; 1537 of them Iberian &#40;1081 Spanish population&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">22</span></a> As this report does not analyze &#42;9 allele and it is characterized by one specific variant&#44; its general frequency has been obtained from the Spanish Variant Server&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">23</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">The third group &#40;Control group 3&#59; ENCORE&#41; was obtained from clinical trial ENCORE published data&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">24</span></a> This group only includes metabolizer status information because allelic and AS information is not available&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Statistical analysis</span><p id="par0110" class="elsevierStylePara elsevierViewall">The AS&#44; metabolizer phenotype and allele frequency variability with the control groups were analyzed by chi-square test&#44; considering statistically significant those <span class="elsevierStyleItalic">p</span>-values<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#46; All statistics were analyzed by IBM SPSS statistics v22 software&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Results</span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Genotype and phenotype description on GD-S patients</span><p id="par0115" class="elsevierStylePara elsevierViewall">We analyzed 109 subjects&#44; with a gender proportion of 1&#58;1 &#40;55 females and 54 males&#41;&#46; The most common damaging variant of <span class="elsevierStyleItalic">GBA1</span> is NM&#95;000157&#58;c&#46;1226A&#62;G &#40;NP&#95;000148&#58;p&#46;Asn409Ser&#41;&#44; it was found on 53&#46;0&#37; of patients&#44; followed by NM&#95;000157&#58;c&#46;1448T&#62;C &#40;NP&#95;000148&#58;p&#46;Leu483Pro&#41; with a frequency of 18&#46;0&#37;&#46; All other found variants presented a low frequency between 2&#46;8 and 0&#46;5&#37; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">All patients were classified according to their CYPIID6 metabolizer status&#44; 87 are NM&#44; 14 IM&#44; 6 PM and only 2 are UM &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A&#41; and according to their activity score&#58; 6 are AS<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44; 13 are AS<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;5&#44; 25 are AS<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#44; 18 are AS<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;5&#44; 45 subjects are AS<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2 and only 2 patients have an AS<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>2 &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>B&#41;&#46; There are no significant differences in phenotype or allele distributions among patients depending on their gender&#46; No relationship has been observed between <span class="elsevierStyleItalic">GBA1</span> and <span class="elsevierStyleItalic">CYP2D6</span> genotypes &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0125" class="elsevierStylePara elsevierViewall">Six subjects have an allele duplication&#44; but in 3 cases it is combined with &#42;4 allele &#40;it codifies for a null enzyme&#41; and the other case is in combination with alleles that encode enzymes with reduced activity&#44; so they cannot be considered UM despite the duplication&#46; A total of 5 subjects show a deletion &#40;carriers for &#42;5 allele&#41;&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">The most frequent genetic variant is NG&#95;008376&#46;3&#58;g&#46;8381G&#62;C &#40;NM&#95;000106&#46;5&#58;c&#46;1547G&#62;C&#41;&#44; the minor allele frequency for this variant on this study is 51&#46;8&#37; and it is not related to a metabolizer phenotype&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">The most frequent allele in our project is the wild-type form &#40;39&#46;00&#37;&#41;&#44; followed by the null &#42;4 allele &#40;19&#46;0&#37;&#41; and the normal function &#42;2 allele &#40;17&#46;0&#37;&#41;&#46; The &#42;7&#44; &#42;8&#44; &#42;11&#44; &#42;15 alleles&#44; that encode for non-functional proteins and &#42;29 which encodes a reduced activity protein&#44; are not present in our population &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0140" class="elsevierStylePara elsevierViewall">At least one allele encoding for a non-functional protein is found in 53 subjects &#40;48&#46;6&#37;&#41; and at least one for a reduced function protein in 15 patients &#40;13&#46;8&#37;&#41;&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">The most common genetic variant related with a non-functional protein is NM&#95;000106&#46;5&#58;c&#46;506-1G&#62;A which defines the &#42;4 allele founded in 19&#46;00&#37; of cases&#44; while the most common for a reduced functional protein is NM&#95;0001065&#58;c&#46;841delAAG&#44; defining the &#42;9 allele founded in 5&#46;00&#37; of cases &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Comparison with control groups</span><p id="par0150" class="elsevierStylePara elsevierViewall">The source used to design CG1 and ENCORE datasets does not allow us to classify these groups according to the activity score&#44; so we are not able to make this comparison&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">The comparison study of the distribution of the metabolizer phenotype between our GD-S population and the CG1 showed significant statistically differences on the frequency of the IM phenotype &#40;<span class="elsevierStyleItalic">p</span>-value<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;028&#41;&#44; being this phenotype much more common in our GD-S population than in the CG1 &#40;12&#46;8&#37; vs 7&#46;2&#37;&#41;&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">The allele frequencies also showed an alteration on the distribution&#44; the frequency of &#42;2 allele is lower than expected &#40;16&#46;1&#37; vs 27&#46;8&#37;&#41;&#44; the opposite was found for the &#42;35 allele which is higher than expected &#40;3&#46;7&#37; vs 1&#46;7&#37;&#41;&#46; That differences are statistically significances &#40;<span class="elsevierStyleItalic">p</span>-value<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001 and 0&#46;044&#44; respectively&#41;&#46; In addition&#44; alleles that encodes for a protein with a reduced function shown an unexpected distribution being the frequency of &#42;6 and &#42;41 alleles on GD-S patients higher than in the CG1 &#40;1&#46;4&#37; vs 0&#46;3&#37; and 8&#46;3&#37; vs 4&#46;1&#37; respectively&#41;&#46; Those differences are&#44; again&#44; statistically significant &#40;<span class="elsevierStyleItalic">p</span>-value<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;045 and 0&#46;044&#44; respectively&#41;&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">When GD patients are compared with the CG2 we obtain similar results&#46; In this case we could analyze the activity score frequency&#44; and we observed than AS<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;5 showed statistically significant differences between both groups &#40;<span class="elsevierStyleItalic">p</span>-value<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;003&#41;&#44; being its frequency double on GD patients than in the control group &#40;11&#46;93&#37; vs 5&#46;56&#37;&#41;&#46; As expected&#44; due to the AS distribution&#44; the frequency of the IM phenotype was higher on GD patients than in CG2 &#40;12&#46;84&#37; vs 5&#46;56&#37;&#59; <span class="elsevierStyleItalic">p</span>-value<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; On this group the allelic distribution showed statistically significant differences in relation with the reduced activity enzyme encoders &#42;6 and &#42;9 alleles&#44; being those higher on GD patients than on CG2 &#40;1&#46;4&#37; and 4&#46;6&#37; vs 0&#46;6&#37; and 1&#46;5&#37;&#44; respectively&#41; with <span class="elsevierStyleItalic">p</span>-values<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;045 and 0&#46;001&#44; respectively&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Comparison with other GD population&#44; the worldwide population included on the ENCORE clinical trial&#44; do not show statistically significant differences between the metabolizer phenotypes distribution and our GD-S group &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; but shows it when compared with IM frequency in general Spanish population &#40;CG1 <span class="elsevierStyleItalic">p</span>-value<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;028 and&#44; CG2 <span class="elsevierStyleItalic">p</span>-value<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;007&#41;&#46;</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Discussion</span><p id="par0175" class="elsevierStylePara elsevierViewall">This is the first paper describing the genotypic and phenotypic frequency for <span class="elsevierStyleItalic">CYP2D6</span> and CYPIID6 on Gaucher disease population&#44; previously only phenotypic frequencies has been reported in one paper&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">24</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">The metabolizer phenotype frequency on this study showed differences with the previously published data for Spanish and Iberian population&#44; observing and increased frequency on IM &#40;12&#46;8&#37; vs 7&#46;2&#37; or 5&#46;6&#37;&#44; respectively&#41; or the equivalent AS<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;5 &#40;11&#46;9&#37; vs 5&#46;6&#37;&#41;&#46; Differences on UM frequencies are not statistically significant &#40;<span class="elsevierStyleItalic">p</span>-value<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; but show a tendency to be lower in the GD-S population than the Spanish or Iberian populations used as control groups &#40;1&#46;8&#37; vs 3&#46;3&#37; and 5&#46;0&#37;&#44; respectively&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">22&#44;25</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">The analysis of allelic frequencies of the different groups according to the encoded protein activity does not match with data recently published&#44; with a decreased frequency for normal encoders alleles and an increased one for the reducer encoders &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41;&#46; A possible explanation is the reduced frequency of &#42;2 allele in our population&#44; but we do not have any explanation to justify this reduction&#46; This can be important due to the use of concomitant therapies with drugs metabolized by the same cytochrome pathway&#44; as antihistaminic or antiarrhythmic drugs&#44; as well as substances capable of inhibiting this metabolic pathway&#44; which can affect harder than in other populations&#44; raising the drug toxicity&#46; Usually&#44; drug administration does not take in consideration the genotype or regroup the four metabolizer phenotypes in three groups&#58; PM with reduced doses&#44; UM not available for the treatment and IM&#43;NM with the standard doses&#46; But it is necessary to consider the huge range of CYP2D6 activities included on the last group&#44; with an AS range from 0&#46;5 to 2&#46; The interpretation of <span class="elsevierStyleItalic">CYP2D6</span> genotypes beyond the metabolizer phenotype extrapolation is important to understand possible drug-drug interactions and to understand and&#44; finally prevent&#44; adverse reactions&#46; So&#44; it is necessary to increase the information about patients&#8217; response to CYP2D6 metabolized therapies with every-day clinical practice reports to elucidate the importance of our results&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">A tendency&#44; although not statistically significant&#44; has been observed on the allele duplications frequency&#46; This is higher than previously published&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">26</span></a> However&#44; due to the higher frequency of alleles that encode null or reduced functional proteins&#44; this increase is not reflected on the UM frequency&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">Our results were compared with the recently published data for Ashkenazi Jews&#44; a population with a high frequency of damaging variants on <span class="elsevierStyleItalic">GBA1</span>&#46; It is remarkably the difference between the &#42;5 allele frequency &#40;2&#46;3&#37; vs 1&#46;1&#37;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; as well as the higher frequency in our population for &#42;6 and &#42;9 alleles &#40;1&#46;4&#37; vs 0&#46;8&#37;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;028 and 4&#46;6&#37; vs 0&#46;4&#37;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001 respectively&#41;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">27</span></a> finding a higher percentage of alleles that encodes for a null o reduced activity protein in our population than in the Jewish population&#46; This is the same difference that we found with the published Spanish population&#46; In contrast with these results&#44; is remarkable the concordance between our results in GD-S population and the other published GD patient&#39;s data &#40;ENCORE clinical trial&#41;&#44; encouraging our believe that there is any relation between GD disease and alleles that encodes for reduced activities CYP2D6 enzymes&#46; Despite this&#44; no correlation between <span class="elsevierStyleItalic">GBA1</span> damaging variants distribution and <span class="elsevierStyleItalic">CYP2D6</span> genotypes were found in our study as expected due to the genomic location for both genes&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Conclusions</span><p id="par0200" class="elsevierStylePara elsevierViewall">In conclusion&#44; this is the first publication that describes the genotype profile of CYP2D6 in Spanish GD population and shows some differences according to the <span class="elsevierStyleItalic">CYP2D6</span> variants distribution&#44; comparing with general Spanish population&#46; As these differences that were not previously observed in comparison with GD patients on ENCORE clinical trial &#40;data not shown&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">24</span></a> it is necessary to increase the analyzed series and perform more studies to confirm a correlation between GD and <span class="elsevierStyleItalic">GYP2D6</span> genotype&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">We can confirm the independence between allele frequency and gender or <span class="elsevierStyleItalic">GBA1</span> genotype&#44; but we found some disagreements with previously published data in relation to the second most frequent allele or the allele duplication frequency as well as the frequency for reduced activity encoder&#39;s alleles&#46; This is a relevant information to consider due to the importance of this cytochrome on drug metabolism and to prevent the drug interferences&#44; knowing that the risk of adverse effects by them is higher on patients with the lowest CYPIID6 activity&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Conflict of interest</span><p id="par0210" class="elsevierStylePara elsevierViewall">The authors declare that they have no financial disclosures or conflict of interest&#46;</p></span></span>"
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              "titulo" => "GBA1 sequencing"
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              "titulo" => "CYP2D6 genotyping"
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              "titulo" => "CYP2D6 genotype&#8211;phenotype correlation"
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              "titulo" => "Genotype and phenotype description on GD-S patients"
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              "titulo" => "Comparison with control groups"
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            0 => "Type 1 Gaucher disease"
            1 => "<span class="elsevierStyleItalic">CYP2D6</span> gene"
            2 => "P450 cytochrome"
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            0 => "CYPIID6"
            1 => "PharmVar"
            2 => "NM"
            3 => "IM"
            4 => "PM"
            5 => "UM"
            6 => "AS"
            7 => "GD"
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            0 => "Enfermedad de Gaucher tipo 1"
            1 => "Gen <span class="elsevierStyleItalic">CYP2D6</span>"
            2 => "Citocromo P450"
            3 => "CYP450 genotipo poblaci&#243;n espa&#241;ola"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Cytochrome p450 is the main drug metabolic pathway&#46; <span class="elsevierStyleItalic">CYP2D6</span> is a highly polymorphic gene that encodes a cytochrome p450 enzyme with three activity levels&#58; null&#44; reduced and normal&#46; Apart from another type of mutations <span class="elsevierStyleItalic">CYP2D6</span> can suffer duplications and deletions of the entire gene&#46; This is the pathway to metabolize one of the Gaucher disease treatments&#44; whose dose administration is regulated according to the metabolizer phenotype&#44; this being one of the administration limitations&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Objectives</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">The aim of this paper is to evaluate the allelic frequencies and the metabolizer status of Gaucher type 1 patients in the Spanish population and compare it with the general Spanish population and other Gaucher disease groups&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">In this study&#44; 109 type 1 Gaucher disease patients were analyzed with the xTAG&#174;CYP2D6 kit to identify the <span class="elsevierStyleItalic">CYP2D6</span> gene alleles&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">We observed that eighty-seven patients could be classified as extensive&#44; 14 as intermediate&#44; 6 as poor and 2 as ultra-rapid metabolizers&#46; The allelic duplication frequency is 5&#46;5&#37; and deletion is 4&#46;5&#37;&#46; The most common allele is wild-type and the second is the null &#42;4 allele&#46; Intermediate phenotype frequency is higher than expected &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">0</span>&#46;05&#41;&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusions</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Our Spanish GD series shows an unexpected distribution of some alleles and phenotypic metabolizer status&#44; in contrast to that previously reported in the Spanish population&#46;</p></span>"
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        "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Introducci&#243;n</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">La superfamilia citocromo P450 es la principal v&#237;a de metabolizaci&#243;n de f&#225;rmacos&#46; Uno de los genes que la componen&#44; <span class="elsevierStyleItalic">CYP2D6&#44;</span> es altamente polim&#243;rfico y puede producir enzimas con 3 niveles de actividad&#58; nula&#44; reducida o normal&#46; Adem&#225;s de presentar variantes puntuales&#44; este gen puede sufrir duplicidad o deleci&#243;n&#46; <span class="elsevierStyleItalic">CYP2D6</span> es la principal v&#237;a de metabolizaci&#243;n del &#250;ltimo tratamiento aprobado para la enfermedad de Gaucher&#44; cuya administraci&#243;n y dosificaci&#243;n depende del estado metabolizador de <span class="elsevierStyleItalic">CYP2D6&#46;</span></p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Objetivos</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">El objetivo de este trabajo es evaluar la frecuencia al&#233;lica y la distribuci&#243;n de fenotipos metabolizadores en una serie de pacientes espa&#241;oles con enfermedad de Gaucher&#44; y compararla con los datos publicados para poblaci&#243;n espa&#241;ola general y con otros grupos de pacientes de Gaucher&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">M&#233;todos</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Se han genotipificado 109 pacientes con enfermedad de Gaucher tipo 1 mediante el sistema xTAG&#174; CYP2D6&#46;</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Resultados</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Nuestra poblaci&#243;n se distribuye en 87 pacientes con un fenotipo metabolizador normal&#44; 14 intermedios&#44; 6 lentos y 2 ultrarr&#225;pidos&#46; La frecuencia de la duplicaci&#243;n y deleci&#243;n del gen es del 5&#44;5 y 4&#44;5&#37;&#44; respectivamente&#46; El alelo m&#225;s com&#250;n es la forma nativa de la prote&#237;na y el segundo el alelo &#42;4 que codifica para una prote&#237;na inactiva&#46; La frecuencia de fenotipos intermedios es superior a la esperada en poblaci&#243;n general &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#41;&#44; principalmente a causa de un incremento en la frecuencia de los alelos que codifican enzimas con actividad reducida &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#41;&#46;</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conclusiones</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">El grupo espa&#241;ol de pacientes con enfermedad de Gaucher muestra una distribuci&#243;n al&#233;lica y fenot&#237;pica diferente a la esperada para la poblaci&#243;n espa&#241;ola&#46;</p></span>"
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Metabolizer phenotype distribution&#46; &#40;A&#41; Observed frequency for each metabolizer phenotype in the studied population&#46; EM<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>87 patients&#59; IM<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>14 patients&#59; PM<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6 patients and UM<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2 patients&#46; The distribution is the expected according with the literature for the Spanish population&#46; &#40;B&#41; Observed activity score frequency in the studied population&#46; AS<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0 6 patients&#59; AS<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;5 13 patients&#59; AS<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1 25 patients&#59; AS<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;5 18 patients&#59; AS<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2 45 patients and AS<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3 2 patients&#46;</p>"
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Allele frequency distribution of CYP2D6 in 109 GD1 patients&#46; Observed allele distribution in the studied population&#46; Alleles that encodes for normal activity are in dark grey&#44; the reduced activity alleles are in grey and the null activity encoder alleles are soft grey coloured&#46; The &#42;7&#44; &#42;8&#44; &#42;11&#44; &#42;15 and &#42;29 alleles are not found in our population&#44; so they are not represented on the figure&#46;</p>"
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                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2464336.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">GBA1</span> genotypes in our sample&#46; GBA1 genotype frequency&#46; Compound heterozygous with the variants NM&#95;000157&#46;3&#58;c&#46;1226A&#62;G and c&#46;1448T&#62;C is the most common&#44; follow by the homozygous state for the variant NM&#95;000157&#46;3&#58;c&#46;1226A&#62;G&#46; Other 30 variants have been found on combination with the c&#46;1226A&#62;G&#44; half of it only has been observed in one patient&#46;</p>"
        ]
      ]
      3 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at2"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Frequency &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">CYP2D6 genetic variants &#40;NM&#95;000106&#46;5&#41;</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Duplication&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;75&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#42;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Deletion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;29&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#42;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;-1584C&#62;G&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">44&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&#46;18&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#42;35&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;31G&#62;A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;67&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#42;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;100C&#62;T&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">47&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">21&#46;56&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;124G&#62;A&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;00&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#42;15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;137&#95;138insT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;00&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#42;11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">c&#46;181-1G&#62;C&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;00&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#42;17&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;320C&#62;T&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;92&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#42;29&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">c&#46;406G&#62;A&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;00&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">c&#46;408G&#62;C&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">51&#46;38&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#42;6&nbsp;\t\t\t\t\t\t\n
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Article information
ISSN: 23870206
Original language: English
DOI:10.1016/j.medcle.2020.01.018
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