COMT Val158Met Polymorphism Modulates Huntington's Disease Progression

Abstract

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.

Fig 1. Structure of the latent class mixed models.

Red dashed line includes variables used for the linear mixed model part. Blue dashed line includes variables used for the beta transformation. Latent domain represents the non-observable motor, behavioral, functional or cognitive domains. Observed task performances are those measured using the UHDRS. The latent motor process was modeled using the TMS; the latent behavioral process was modeled using the UHDRS behavioral score; the latent functional process was modeled using the FAS and IS scores; The latent cognitive process was modeled using letter fluency at 1 minute, letter fluency at 2 minutes, SDMT, Stroop Color, Stroop Word and Stroop Word/Color interference.

Fig 2. Concordance between predicted and real age at onset.

Each point represents an individual patient. The observed age at onset is the one provided in the database. The predicted age at onset is the one calculated by the formula 21.54 + exp(9.556–0.146 x CAG). The gray line is the first bisector corresponding to the line of predicted = observed. The closeness of the points to the gray line indicates the extent to which predicted age at onset matches real age at onset. If predicted age at onset is greater than the observed age at onset, the points are located above the gray line. By contrast, if the predicted age at onset is below the real age at onset, the points are located below the gray line.

Fig 3. Curves of the impact of COMT polymorphism on the motor, behavioral, functional and cognitive domains, in a modeled cohort of a woman HD patients with 45 CAG repeats and 12-year education level.

We plotted the evolution of performance as a function of time for each task. Performance decrease was represented by a negative slope. 45 CAG repeats is the mean number in the cohort studied. The latent motor process was modeled using the UHDRS motor score; the latent behavioral process was modeled using the UHDRS behavioral score; the latent functional process was modeled using the FAS and IS scores; The latent cognitive process was modeled using letter fluency at 1 minute, letter fluency at 2 minutes, SDMT, Stroop Color, Stroop Word and Stroop Word/Color interference.

Fig 4. Curves of the impact of COMT polymorphism on each UHDRS score, in a modeled cohort of a female HD patient with 45 CAG repeats and 12-year education level.

We plotted the evolution of performance for each task. 45 CAG repeats is the mean number in the cohort studied. UHDRS motor score (A); UHDRS behavioral (B), IS: Independence Score (C); FAS: Functional Assessment Scale (D), cognitive (letter fluency 1’: at 1 minute (E); letter fluency 2’: at 2 minutes (F); SDMT: symbol digit modalities test (G); Stroop C: Stroop color (H); Stroop W: Stroop word (I); Stroop W/C: Stroop interference (J).

Fig 5. Schematic representation of the biphasic effect of COMT polymorphism in HD.

In the prefrontal cortex, DA levels are higher in Met/Met HD gene carriers at early stages and in HD gene carriers with premanifest disease than in controls. These levels subsequently decrease over time in both the Met/Met (in blue) and Val/Val groups (in red) [56]. The high levels of DA present in the PFC at early stages result in better cognitive performances. At late stages, higher levels of DA in the PFC in Met/Met HD gene carriers may be toxic, increasing atrophy [26, 51]. In both COMT groups, the level of striatal DA decreases over time.