Toward a clinical practice guide in pharmacogenomics testing for functional polymorphisms of drug-metabolizing enzymes. Gene/drug pairs and barriers perceived in Spain

The development of clinica lpractice recommendations or guidelines for the clinical use of biomarkers is an issue of great importance withr regard to adverse drug reactions.The poten-tial of pharmacogenomicbiomarkers has been extensively investigated in recent years.However,several barriers to implementing the use of pharmacogenomics testing exist.We conducted a survey among members of the Spanish Societies of Pharmacology and Clinical Pharmacology to obtain information about the perception of such barriers and to compare the perceptions of participants about the relative importance of majorgene/drug pairs.Of 11 potential barriers,the highest importance was attributed to lack of institutional support for pharmacogenomic stesting,and to the issues related to the lack of guidelines.Of the proposed gene/drug pairs the highest importance was assigned to HLA-B/abacavir, UGT1A1/irinotecan, and CYP2D6/tamoxifen.In this perspective article,we compare the relative importance of 29 gene/drugpairs in the Spanish study with that of the same pairs in the American Society for Clinical Pharmacology and Therapeutic sstudy,and we provide suggestions and areas of focus to develop a guide for clinical practice in pharmacogenomics testingThe work in the author’s laboratory is financed by Grants PS09/00943, PS09/00469, RETICS RIRAAF RD07/0064/0016, and CIBERehd from Instituto de Salud CarlosIII,Madrid, Spain, and by Grants GR10068 from Junta de Extremadura, Spain. Financed in part with FEDER funds from the European Unio

A 3’-UTR polymorphism in soluble epoxide hydrolase gene Is associated with acute rejection in renal transplant recipients

Antecedentes y finalidad: Los ácidos epoxyeicosatrienoic (EETs) son metabolitos del ácido araquidónico que desempeñan una función protectora contra procesos perjudiciales que pueden ocurrir después de re-oxigenación del injerto. Decidimos investigar si la presencia de polimorfismos funcionales en el gen que codifica el epóxido hidrolasa soluble (EPHX2), que metaboliza EETs a menos compuestos activos, pueden jugar un papel importante en el resultado del trasplante renal. Métodos En un grupo de 259 receptores caucásicos de trasplante renal y 183 donantes fallecidos, se determinó la presencia de tres EPHX2 común, a saber, los SNPs rs41507953 (K55R), rs751141 (R287Q) y rs1042032 A/G. Las asociaciones con los parámetros de la función del injerto y la incidencia de rechazo agudo fueron investigados retrospectivamente durante el primer año después del injerto mediante regresión logística, ajustándose a las variables clínicas y demográficas. Resultados Los portadores del genotipo rs1042032 GG muestran significativamente menor tasa de filtración glomerular estimada (eGFR) (38.15 ± 15.57 vs. 45.99 ± 16.05; p = 0,04) y mayores valores de creatinina sérica (1,57 ± 0,58 vs. 1,30 ± 0,47 g/dL; p=0.02) un año después del injerto, en comparación con los pacientes portadores del alelo A wildtype. El mismo genotipo GG también se asoció a un mayor riesgo de rechazo agudo. Curiosamente, esta asociación fue observada por el genotipo de ambos destinatarios [o =6.34 (1.35-29.90); p = 0,015] y donantes [OR = 5.53 (1.10 - 27.80); p=0,042]. Un modelo estadístico incluyendo ambos genotipos junto con otras variables demográficas y clínicas significativas se tradujo en un aumento de la importancia de la asociación con los receptores del genotipo [OR=8,28 (1.21-74.27); p=0,031]. Conclusiones Nuestros resultados indican que la variabilidad genética en el gen metabolizante de EETs, EPHX2, pueden tener un impacto significativo en los resultados del trasplante renal de donante fallecido.Background and Purpose: Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites that play a protective role against damaging processes that may occur after re-oxygenation of the graft. We aimed to investigate whether the presence of functional polymorphisms in the gene encoding soluble epoxy hydrolase (EPHX2), which metabolizes EETs to less active compounds, may play a role in the outcome of renal transplantation. Methods In a group of 259 Caucasian renal transplant recipients and 183 deceased donors, we determined the presence of three common EPHX2 SNPs, namely rs41507953 (K55R), rs751141 (R287Q) and rs1042032 A/G. Associations with parameters of graft function and the incidence of acute rejection were retrospectively investigated throughout the first year after grafting by logistic regression adjusting for clinical and demographic variables. Results Carriers of the rs1042032 GG genotype displayed significantly lower estimated glomerular filtration rate (eGFR) (38.15 ± 15.57 vs. 45.99 ± 16.05; p = 0.04) and higher serum creatinine values (1.57 ± 0.58 vs. 1.30 ± 0.47 g/dL; p=0.02) one year after grafting, compared to patients carrying the wildtype A-allele. The same GG genotype was also associated to increased risk of acute rejection. Interestingly, this association was observed for the genotype of both recipients [OR =6.34 (1.35-29.90); p = 0.015] and donors [OR = 5.53 (1.10- 27.80); p=0.042]. A statistical model including both genotypes along with other meaningful demographic and clinical variables resulted in an increased significance for the association with the recipients’ genotype [OR=8.28 (1.21-74.27); p=0.031]. Conclusions Our results suggest that genetic variability in the EETs-metabolizing gene, EPHX2, may have a significant impact on the outcome of deceased-donor renal transplantation.• Asociación para el Estudio y la Prevención de las Enfermedades Renales (ASEPER), Badajoz • Junta de Extremadura, Consejería de Economía, Comercio e Innovación: Proyecto GR10022 • Red de Investigación Renal - REDINREN (Instituto de Salud Carlos III – Fondo Europeo de Desarrollo Regional – FEDER) : Ayudas a Eliecer Coto García, Carmen Díaz Corte y Carlos López LarreapeerReviewe

Genetic variability in CYP3A4 and CYP3A5 in primary liver, gastric and colorectal cancer patients

<p>Abstract</p> <p>Background</p> <p>Drug-metabolizing enzymes play a role in chemical carcinogenesis through enzymatic activation of procarcinogens to biologically reactive metabolites. The role of gene polymorphisms of several cytochrome P450 enzymes in digestive cancer risk has been extensively investigated. However, the drug-metabolizing enzymes with the broader substrate specificity, CYP3A4 and CYP3A5, have not been analyzed so far. This study aims to examine associations between common CYP3A4 and CYP3A5 polymorphisms and digestive cancer risk.</p> <p>Methods</p> <p>CYP3A4 and CYP3A5 genotypes were determined in 574 individuals including 178 patients with primary liver cancer, 82 patients with gastric cancer, 151 patients with colorectal cancer, and 163 healthy individuals.</p> <p>Results</p> <p>The variant allele frequencies for patients with liver cancer, gastric cancer, colorectal cancer and healthy controls, respectively, were: <it>CYP3A4*1B</it>, 4.8 % (95% C.I. 2.6–7.0), 3.7 % (0.8–6.6) 4.3% (2.0–6.6) and 4.3% (2.1–6.5); <it>CYP3A5*3</it>, 91.8 % (93.0–97.4), 95.7% (92.6–98.8), 91.7% (88.6–94.8) and 90.8% (87.7–93.9). The association between <it>CYP3A4*1B </it>and <it>CYP3A5*3 </it>variant alleles did not significantly differ among patients and controls. No differences in genotypes, allele frequencies, or association between variant alleles were observed with regard to gender, age at diagnosis, tumour site or stage.</p> <p>Conclusion</p> <p>Common polymorphisms on <it>CYP3A4 </it>and <it>CYP3A5 </it>genes do not modify the risk of developing digestive cancers in Western Europe.</p