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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.

SUBMITTER: de Diego-Balaguer R

PROVIDER: S-EPMC5033325 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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COMT Val158Met Polymorphism Modulates Huntington's Disease Progression.

de Diego-Balaguer Ruth R Schramm Catherine C Rebeix Isabelle I Dupoux Emmanuel E Durr Alexandra A Brice Alexis A Charles Perrine P Cleret de Langavant Laurent L Youssov Katia K Verny Christophe C Damotte Vincent V Azulay Jean-Philippe JP Goizet Cyril C Simonin Clémence C Tranchant Christine C Maison Patrick P Rialland Amandine A Schmitz David D Jacquemot Charlotte C Fontaine Bertrand B Bachoud-Lévi Anne-Catherine AC

PloS one 20160922 9

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 s ...[more]

PMID: 27657697

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Project description:Math anxiety (MA) is a phobic reaction to math activities, potentially impairing math achievement. Higher frequency of MA in females is explainable by the interaction between genetic and environmental factors. The molecular-genetic basis of MA has not been investigated. The COMT Val158Met polymorphism, which affects dopamine levels in the prefrontal cortex, has been associated with anxiety manifestations. The valine allele is associated with lower, and the methionine allele with higher, dopamine availability. In the present study, the effects of sex and COMT Val158Met genotypes on MA were investigated: 389 school children aged 7-12 years were assessed for intelligence, numerical estimation, arithmetic achievement and MA and genotyped for COMT Val158Met polymorphism. The Math Anxiety Questionnaire (MAQ) was used to assess the cognitive and affective components of MA. All genotype groups of boys and girls were comparable regarding genotype frequency, age, school grade, numerical estimation, and arithmetic abilities. We compared the results of all possible genetic models: codominance (Val/Val vs. Val/Met vs. Met/Met), heterosis (Val/Met vs. Val/Val plus Met/Met), valine dominance (Val/Val plus Val/Met vs. Met/Met), and methionine dominance (Met/Met plus Val/Met vs. Val/Val). Models were compared using AIC and AIC weights. No significant differences between girls and boys and no effects of the COMT Val158Met polymorphism on numerical estimation and arithmetic achievement were observed. Sex by genotype effects were significant for intelligence and MA. Intelligence scores were higher in Met/Met girls than in girls with at least one valine allele (valine dominance model). The best fitting model for MA was heterosis. In Anxiety Toward Mathematics, heterozygous individuals presented MA levels close to the grand average regardless of sex. Homozygous boys were significantly less and homozygous girls significantly more math anxious. Heterosis has been seldom explored, but in recent years has emerged as the best genetic model for some phenotypes associated with the COMT Val158Met polymorphism. This is the first study to investigate the genetic-molecular basis of MA.

Dataset Information

COMT Val158Met Polymorphism Modulates Huntington's Disease Progression.

Publications

COMT Val158Met Polymorphism Modulates Huntington's Disease Progression.

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