The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients

Silke Metzger; Carolin Walter; Olaf Riess; Raymund A C Roos; Jørgen E Nielsen; David Craufurd; Huu Phuc Nguyen; REGISTRY Investigators of the European Huntington’s Disease Network

doi:10.1371/journal.pone.0068951

The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients

Silke Metzger, Carolin Walter, Olaf Riess, Raymund A C Roos, Jørgen E Nielsen, David Craufurd, Huu Phuc Nguyen, REGISTRY Investigators of the European Huntington’s Disease Network

Medical Genetics Program

30 Citationer (Scopus)

Abstract

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the "REGISTRY" cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis.

Originalsprog	Engelsk
Tidsskrift	PLOS ONE
Vol/bind	8
Udgave nummer	7
Sider (fra-til)	e68951
ISSN	1932-6203
DOI	https://doi.org/10.1371/journal.pone.0068951
Status	Udgivet - 22 jul. 2013

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10.1371/journal.pone.0068951

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Metzger, S., Walter, C., Riess, O., Roos, R. A. C., Nielsen, J. E., Craufurd, D., Nguyen, H. P., & REGISTRY Investigators of the European Huntington’s Disease Network (2013). The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients. PLOS ONE, 8(7), e68951. https://doi.org/10.1371/journal.pone.0068951

Metzger, S, Walter, C, Riess, O, Roos, RAC, Nielsen, JE, Craufurd, D, Nguyen, HP & REGISTRY Investigators of the European Huntington’s Disease Network 2013, 'The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients', PLOS ONE, bind 8, nr. 7, s. e68951. https://doi.org/10.1371/journal.pone.0068951

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abstract = "The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the {"}REGISTRY{"} cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis.",

keywords = "Adolescent, Adult, Age of Onset, Aged, Autophagy, Child, Child, Preschool, Cohort Studies, Gene Frequency, Genotype, Humans, Huntington Disease, Italy, Middle Aged, Polymorphism, Single Nucleotide, Ubiquitin-Activating Enzymes, Young Adult",

author = "Silke Metzger and Carolin Walter and Olaf Riess and Roos, {Raymund A C} and Nielsen, {J{\o}rgen E} and David Craufurd and Nguyen, {Huu Phuc} and {REGISTRY Investigators of the European Huntington{\textquoteright}s Disease Network}",

year = "2013",

month = jul,

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doi = "10.1371/journal.pone.0068951",

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T1 - The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients

AU - Metzger, Silke

AU - Walter, Carolin

AU - Riess, Olaf

AU - Roos, Raymund A C

AU - Nielsen, Jørgen E

AU - Craufurd, David

AU - Nguyen, Huu Phuc

AU - REGISTRY Investigators of the European Huntington’s Disease Network

PY - 2013/7/22

Y1 - 2013/7/22

N2 - The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the "REGISTRY" cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis.

AB - The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the "REGISTRY" cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis.

KW - Adolescent

KW - Adult

KW - Age of Onset

KW - Aged

KW - Autophagy

KW - Child

KW - Child, Preschool

KW - Cohort Studies

KW - Gene Frequency

KW - Genotype

KW - Humans

KW - Huntington Disease

KW - Italy

KW - Middle Aged

KW - Polymorphism, Single Nucleotide

KW - Ubiquitin-Activating Enzymes

KW - Young Adult

U2 - 10.1371/journal.pone.0068951

DO - 10.1371/journal.pone.0068951

M3 - Journal article

C2 - 23894380

SN - 1932-6203

VL - 8

SP - e68951

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 7

ER -

The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients

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