COMT Val158Met Polymorphism Modulates Huntington’s Disease Progression.
PLoS ONE. 2016-09-22; 11(9): e0161106
DOI: 10.1371/journal.pone.0161106
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1. PLoS One. 2016 Sep 22;11(9):e0161106. doi: 10.1371/journal.pone.0161106.
eCollection 2016.
COMT Val158Met Polymorphism Modulates Huntington’s Disease Progression.
de Diego-Balaguer R(1)(2)(3)(4)(5)(6)(7), Schramm C(1)(2)(3), Rebeix I(8)(9),
Dupoux E(2)(10), Durr A(8)(11), Brice A(8)(11), Charles P(11), Cleret de
Langavant L(1)(2)(3)(12), Youssov K(1)(2)(3)(12), Verny C(13), Damotte V(8)(9),
Azulay JP(14), Goizet C(15), Simonin C(16)(17), Tranchant C(18), Maison
P(1)(2)(3)(19), Rialland A(19), Schmitz D(19), Jacquemot C(1)(2)(3), Fontaine
B(9)(11), Bachoud-Lévi AC(1)(2)(3)(12); French Speaking Huntington Group.
Author information:
(1)INSERM U955, Equipe 01 Neuropsychologie Interventionnelle, 94000, Créteil,
France.
(2)Département d’Etudes Cognitives, Ecole Normale Supérieure, PSL Research
University, 75005, Paris, France.
(3)Université Paris Est, Faculté de Médecine, 94000, Créteil, France.
(4)ICREA, 08010, Barcelona, Spain.
(5)Universitat de Barcelona, Departament de Cognició, Desenvolupament i
Psicologia de L’Educació, 08035, Barcelona, Spain.
(6)IDIBELL, Unitat de Cognició i Plasticitat Cerebral, 08907, L’Hospitalet de
Llobregat, Spain.
(7)Institut de Neurociència, Universitat de Barcelona, Barcelona, Spain.
(8)INSERM-UPMC-CNRS, UMR 7225-1127, Institut Cerveau Moelle-ICM, Hôpital
Pitié-Salpêtrière, 74013, Paris, France.
(9)Assistance Publique-Hôpitaux de Paris, Département des Maladies du Système
Nerveux, Hôpital Pitié-Salpêtrière, 74013, Paris, France.
(10)Laboratoire de Sciences Cognitives et Psycholinguistique, ENS-EHESS-CNRS,
Paris, 75005, France.
(11)Assistance Publique-Hôpitaux de Paris, Département de Génétique, Hôpital
Pitié-Salpêtrière, 74013, Paris, France.
(12)Assistance Publique-Hôpitaux de Paris, Centre de Référence Maladie de
Huntington, Service de Neurologie, Hôpital Henri Mondor-Albert Chenevier, 94000,
Créteil, France.
(13)CHU d’Angers, Centre de Référence des Maladies Neurogénétiques, Service de
Neurologie, 49933, Angers, France.
(14)CHU de Marseille-Hôpital de la Timone, Service de Neurologie et Pathologie du
Mouvement, 13385, Marseille, France.
(15)CHU de Bordeaux-GH Sud-Hôpital Haut-Lévêque, Service de Neurologie, 33604,
Pessac, France.
(16)CHRU de Lille, Service de Neurologie et Pathologie du Mouvement, 59000,
Lille, France.
(17)INSERM UMR-S 1172, JPArc, centre de recherche Jean-Pierre-Aubert
neurosciences et cancer, Université de Lille, 59000, Lille, France.
(18)CHU de Strasbourg-Hôpital de Hautepierre, Service de Neurologie, 67098,
Strasbourg, France.
(19)Assistance Publique-Hôpitaux de Paris, Hôpital Henri Mondor, Unité de
Recherche Clinique, 94000, Créteil, France.
Little is known about the genetic factors modulating the progression of
Huntington’s disease (HD). Dopamine levels are affected in HD and modulate
executive functions, the main cognitive disorder of HD. We investigated whether
the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene, which
influences dopamine (DA) degradation, affects clinical progression in HD. We
carried out a prospective longitudinal multicenter study from 1994 to 2011, on
438 HD gene carriers at different stages of the disease (34 pre-manifest; 172
stage 1; 130 stage 2; 80 stage 3; 17 stage 4; and 5 stage 5), according to Total
Functional Capacity (TFC) score. We used the Unified Huntington’s Disease Rating
Scale to evaluate motor, cognitive, behavioral and functional decline. We
genotyped participants for COMT polymorphism (107 Met-homozygous, 114
Val-homozygous and 217 heterozygous). 367 controls of similar ancestry were also
genotyped. We compared clinical progression, on each domain, between groups of
COMT polymorphisms, using latent-class mixed models accounting for disease
duration and number of CAG (cytosine adenine guanine) repeats. We show that HD
gene carriers with fewer CAG repeats and with the Val allele in COMT polymorphism
displayed slower cognitive decline. The rate of cognitive decline was greater for
Met/Met homozygotes, which displayed a better maintenance of cognitive capacity
in earlier stages of the disease, but had a worse performance than Val allele
carriers later on. COMT polymorphism did not significantly impact functional and
behavioral performance. Since COMT polymorphism influences progression in HD, it
could be used for stratification in future clinical trials. Moreover, DA
treatments based on the specific COMT polymorphism and adapted according to
disease duration could potentially slow HD progression.
DOI: 10.1371/journal.pone.0161106
PMCID: PMC5033325
PMID: 27657697
Conflict of interest statement: R. de Diego-Balaguer, C. Schramm, I. Rebeix, E.
Dupoux, A. Durr, A. Brice, P. Charles, L. Cleret de Langavant, K. Youssov, G.
Fénelon, C. Verny, V. Damotte, JP Azulay, C. Simonin, C. Tranchant, P. Maison, A.
Rialland, D. Schmitz, C. Jacquemot, B. Fontaine have nothing to disclose. A.C.
Bachoud-Lévi acted as a consultant once for Teva in 2014 and reports grants from
the National Reference Center for Huntington’s Disease from the Ministry of
Health and from the clinical research directorate (AP-HP). C. Goizet reports
grants from the European Huntington Disease Network and the Programme Hospitalier
de Recherche Clinique (PHRC) during the duration of the study; personal fees came
from Raptor Pharmaceutical France, Genzyme, and Actelion; grants from Genzyme,
Association Française contre les myopathies (AFM), Association Strumpell-Lorrain
(ASL), Connaître les Syndromes Cérébelleux (CSC), Union Nationale des Aveugles et
Déficients Visuels (UNADEV), Conseil Régional d’Aquitaine (CRA), Agence Nationale
pour la Recherche (ANR), Programme Hospitalier de Recherche Clinique (PHRC),
Genzyme, Actelion, and Biomarin, not covering the work submitted here. This does
not alter the authors’ adherence to PLOS ONE policies on sharing data and
materials.