Common variant in GRN is a genetic risk factor for hippocampal sclerosis in the elderly

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

Background: Hippocampal sclerosis (HpScl) is common in elderly subjects with dementia, either alone or accompanied by other pathologic processes. It is also found in >70% of frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions (FTLD-TDP). TDP-43 inclusions are detected in >20% of Alzheimer disease (AD) and >70% of HpScl cases. The most common cause of FTLD-TDP is mutation in the progranulin gene (GRN). Recently, a common genetic variant in the 3′ untranslated region (3′UTR) of GRN (rs5848; c.*78C>T) located in a microRNA binding site regulated progranulin expression, and the T-allele was increased in FTLD-TDP compared to controls. Objective: The goal of this study was to determine if the 3′UTR variant in GRN was associated with TDP-43 immunoreactivity in AD with and without HpScl. Methods: 644 cases of pathologically confirmed AD, including 57 with HpScl, were screened for TDP-43 immunoreactivity and were genotyped at the GRN 3′UTR single-nucleotide polymorphism rs5848 using previously published methods. Results: There was a trend (p = 0.06) for TDP-43 immunoreactivity, but a very significant (p = 0.005) association of HpScl with the variant, with 72% of AD with HpScl carrying a T-allele, compared to 51% of AD without HpScl carrying a T-allele. Conclusion: The results suggest that a genetic variant in GRN leading to decreased levels of progranulin may be a risk factor for HpScl in AD, while its role in TDP-43 immunoreactivity in AD remains less certain.

Original languageEnglish (US)
Pages (from-to)170-174
Number of pages5
JournalNeurodegenerative Diseases
Volume7
Issue number1-3
DOIs
StatePublished - Apr 2010

Fingerprint

Sclerosis
Alzheimer Disease
Frontotemporal Dementia
3' Untranslated Regions
Alleles
Frontotemporal Lobar Degeneration
Pathologic Processes
MicroRNAs
Single Nucleotide Polymorphism
Dementia
Binding Sites
Mutation
Genes

Keywords

  • Alzheimer's disease
  • Hippocampal sclerosis
  • Immunohistochemistry
  • Progranulin gene

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology

Cite this

Common variant in GRN is a genetic risk factor for hippocampal sclerosis in the elderly. / Dickson, Dennis W; Baker, Matthew; Rademakers, Rosa V.

In: Neurodegenerative Diseases, Vol. 7, No. 1-3, 04.2010, p. 170-174.

Research output: Contribution to journalArticle

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abstract = "Background: Hippocampal sclerosis (HpScl) is common in elderly subjects with dementia, either alone or accompanied by other pathologic processes. It is also found in >70{\%} of frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions (FTLD-TDP). TDP-43 inclusions are detected in >20{\%} of Alzheimer disease (AD) and >70{\%} of HpScl cases. The most common cause of FTLD-TDP is mutation in the progranulin gene (GRN). Recently, a common genetic variant in the 3′ untranslated region (3′UTR) of GRN (rs5848; c.*78C>T) located in a microRNA binding site regulated progranulin expression, and the T-allele was increased in FTLD-TDP compared to controls. Objective: The goal of this study was to determine if the 3′UTR variant in GRN was associated with TDP-43 immunoreactivity in AD with and without HpScl. Methods: 644 cases of pathologically confirmed AD, including 57 with HpScl, were screened for TDP-43 immunoreactivity and were genotyped at the GRN 3′UTR single-nucleotide polymorphism rs5848 using previously published methods. Results: There was a trend (p = 0.06) for TDP-43 immunoreactivity, but a very significant (p = 0.005) association of HpScl with the variant, with 72{\%} of AD with HpScl carrying a T-allele, compared to 51{\%} of AD without HpScl carrying a T-allele. Conclusion: The results suggest that a genetic variant in GRN leading to decreased levels of progranulin may be a risk factor for HpScl in AD, while its role in TDP-43 immunoreactivity in AD remains less certain.",
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N2 - Background: Hippocampal sclerosis (HpScl) is common in elderly subjects with dementia, either alone or accompanied by other pathologic processes. It is also found in >70% of frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions (FTLD-TDP). TDP-43 inclusions are detected in >20% of Alzheimer disease (AD) and >70% of HpScl cases. The most common cause of FTLD-TDP is mutation in the progranulin gene (GRN). Recently, a common genetic variant in the 3′ untranslated region (3′UTR) of GRN (rs5848; c.*78C>T) located in a microRNA binding site regulated progranulin expression, and the T-allele was increased in FTLD-TDP compared to controls. Objective: The goal of this study was to determine if the 3′UTR variant in GRN was associated with TDP-43 immunoreactivity in AD with and without HpScl. Methods: 644 cases of pathologically confirmed AD, including 57 with HpScl, were screened for TDP-43 immunoreactivity and were genotyped at the GRN 3′UTR single-nucleotide polymorphism rs5848 using previously published methods. Results: There was a trend (p = 0.06) for TDP-43 immunoreactivity, but a very significant (p = 0.005) association of HpScl with the variant, with 72% of AD with HpScl carrying a T-allele, compared to 51% of AD without HpScl carrying a T-allele. Conclusion: The results suggest that a genetic variant in GRN leading to decreased levels of progranulin may be a risk factor for HpScl in AD, while its role in TDP-43 immunoreactivity in AD remains less certain.

AB - Background: Hippocampal sclerosis (HpScl) is common in elderly subjects with dementia, either alone or accompanied by other pathologic processes. It is also found in >70% of frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions (FTLD-TDP). TDP-43 inclusions are detected in >20% of Alzheimer disease (AD) and >70% of HpScl cases. The most common cause of FTLD-TDP is mutation in the progranulin gene (GRN). Recently, a common genetic variant in the 3′ untranslated region (3′UTR) of GRN (rs5848; c.*78C>T) located in a microRNA binding site regulated progranulin expression, and the T-allele was increased in FTLD-TDP compared to controls. Objective: The goal of this study was to determine if the 3′UTR variant in GRN was associated with TDP-43 immunoreactivity in AD with and without HpScl. Methods: 644 cases of pathologically confirmed AD, including 57 with HpScl, were screened for TDP-43 immunoreactivity and were genotyped at the GRN 3′UTR single-nucleotide polymorphism rs5848 using previously published methods. Results: There was a trend (p = 0.06) for TDP-43 immunoreactivity, but a very significant (p = 0.005) association of HpScl with the variant, with 72% of AD with HpScl carrying a T-allele, compared to 51% of AD without HpScl carrying a T-allele. Conclusion: The results suggest that a genetic variant in GRN leading to decreased levels of progranulin may be a risk factor for HpScl in AD, while its role in TDP-43 immunoreactivity in AD remains less certain.

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