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Vol. 26. Issue 3.
Pages 137-142 (January 2011)
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Vol. 26. Issue 3.
Pages 137-142 (January 2011)
Original Article
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Influence of APOE gene polymorphisms on interferon-beta treatment response in multiple sclerosis
Influencia del polimorfismo del gen de la APOE en la respuesta al tratamiento con interferón beta en esclerosis múltiple
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A.L. Guerrero
Corresponding author
gueneurol@gmail.com

Corresponding author.
, M.A. Tejero, F. Gutiérrez, J. Martín-Polo, F. Iglesias, E. Laherran, J.I. Martín-Serradilla, S. Merino
Sección de Neurología, Complejo Asistencial de Palencia, Palencia, Spain
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Abstract
Objective

Clinical trials with interferon beta in relapsing remitting multiple sclerosis (RRMS) have demonstrated a reduction in the relapse rate. Nevertheless, not all patients respond to this treatment, although there is no consensus regarding the definition of response to therapy. The reasons for this failure are not known but genetic factors probably influence this, as has been previously shown with Interleukin 10 or Interferon gamma polymorphisms.

The role of apolipoprotein E (APOE) gene in MS has been investigated and does not appear to increase risk for MS or influence disease severity. Interestingly APOE variation influences response to cholinesterase inhibitor treatment in Alzheimer disease or to statins in hypercholesterolemia. This might have future implications for MS.

Material and methods

We retrospectively reviewed 38 RRMS patients (32 females and 6 males) treated with interferon beta (INFbeta) over at least two years. Criteria for treatment were uniform accordingly to an “Advisory Committee for the Treatment of Multiple Sclerosis”. We collected data variables including age, age of onset, clinical type or disease duration. Patients were classified, two years after the start of treatment, as responders and non-responders based upon clinical criteria available in the literature, which rely on the presence of relapses, increase of disability, or both. APOE genotype was determined from blood samples using validated polymerase chain reaction methods. Correlation between patient responding status with allele E2 or E4 was tested.

Results

A total of 20 patients (52.6%) received subcutaneous INFbeta1b (Betaferon®), 13 (34.2%) INFbeta1a intramuscular (Avonex®), and 5 (13.2%) subcutaneous INFbeta1a (Rebif®). We found 2 patients (5.2%) heterozygous for the E2 allele and 9 (23.7%) for the E4 allele. No patient was homozygous for E2 or E4. Comparison of patients with and without E2 or E4 allele showed no significant differences in any of the ten therapy response variables assessed.

Conclusion

Findings of a recent meta-analysis have not supported a role for APOE in MS susceptibility or severity. We have not found, in our data, any influence of this gene in the RRMS response to INFbeta. However, larger series would be required to validate these results.

Keywords:
Multiple sclerosis
Treatment response
Pharmacogenetics
APOE
Resumen
Objetivos

Los ensayos clínicos llevados a cabo con el interferón beta (INFB) en esclerosis múltiple remitente recidivante (EMRR) han mostrado que reducen la tasa de brotes. Sin embargo, no todos los pacientes responden a este tratamiento, si bien aún no hay un absoluto consenso a propósito de la definición de respuesta al tratamiento. Las razones para este fracaso terapéutico no son conocidas, y probablemente hay factores genéticos implicados, como se ha mostrado con los polimorfismos de los genes que codifican la interleuquina 10 o el interferón gamma. El papel del gen de la apolipoproteína E (APOE) en la EM ha sido investigado en los últimos años y no parece aumentar el riesgo de aparición de la enfermedad ni influir en su severidad. Variaciones en este gen influyen en la respuesta al tratamiento con inhibidores de la colinesterasa en la enfermedad de Alzheimer o a las estatinas en la hipercolesterolemia. Esto podría tener implicaciones futuras en la EM.

Material y métodos

Hemos revisado retrospectivamente 38 pacientes diagnosticados de EMRR (32 mujeres y 6 varones) tratados con INFB durante al menos dos años. Los criterios para llevar a cabo el tratamiento eran uniformes de acuerdo con las indicaciones del Comité asesor para el tratamiento de la EM. Recogimos datos acerca de la edad y tiempo de evolución de la enfermedad. Al cabo de dos años del inicio del tratamiento los pacientes fueron clasificados como respondedores o no-respondedores de acuerdo con los criterios clínicos disponibles, basados en la presencia de brotes, evolución de la discapacidad, o ambos. El genotipo APOE se determinó de muestras sanguíneas utilizando métodos validados de reacción en cadena de la polimerasa. Se estudió la correlación entre la condición de respondedor o no respondedor y la presencia de los alelos E2 o E4.

Resultados

Veinte pacientes (52,6%) recibían INFB1b subcutáneo (Betaferón®), 13 (34,2%) INFB1a intramuscular (Avonex®) y 5 (13,2%) INFB1a subcutáneo (Rebif®). Dos pacientes (5,2%) eran heterocigotos para el alelo E2 y 9 (23,7%) para el alelo E4. Ningún paciente era homocigoto para E2 o E4. La presencia o no de estos alelos no se correlacionó con la respuesta al tratamiento de acuerdo con las 10 variables estudiadas.

Conclusión

Tras los resultados de un metanálisis que no muestran influencia del gen APOE en la susceptibilidad o severidad de la EM, no hemos encontrado en nuestra serie influencia de este gen en la respuesta de pacientes con EMRR al INFB. En cualquier caso, series más extensas son necesarias para validar estos resultados.

Palabras clave:
Esclerosis múltiple
Respuesta al tratamiento
Farmacogenética
APOE
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Partially presented as a poster at the 17th Congress of the European Neurological Society (ENS). Rhodes, Greece, June 2007.

Copyright © 2011. Sociedad Española de Neurología
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