The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients
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The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients. / Metzger, Silke; Walter, Carolin; Riess, Olaf; Roos, Raymund A C; Nielsen, Jørgen E; Craufurd, David; Nguyen, Huu Phuc; REGISTRY Investigators of the European Huntington’s Disease Network.
I: PLOS ONE, Bind 8, Nr. 7, 07.2013, s. e68951.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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
Y1 - 2013/7
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
VL - 8
SP - e68951
JO - PLoS ONE
JF - PLoS ONE
SN - 1932-6203
IS - 7
ER -
ID: 119642331