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50bp deletion in the promoter for superoxide dismutase 1 (SOD1) reduces SOD1 expression in vitro and may correlate with increased age of onset of sporadic amyotrophic lateral sclerosis.

https://arctichealth.org/en/permalink/ahliterature156293
Source
Amyotroph Lateral Scler. 2008 Aug;9(4):229-37
Publication Type
Article
Date
Aug-2008
Author
Wendy J Broom
Matthew Greenway
Ghazaleh Sadri-Vakili
Carsten Russ
Kristen E Auwarter
Kelly E Glajch
Nicolas Dupre
Robert J Swingler
Shaun Purcell
Caroline Hayward
Peter C Sapp
Diane McKenna-Yasek
Paul N Valdmanis
Jean-Pierre Bouchard
Vincent Meininger
Betsy A Hosler
Jonathan D Glass
Meraida Polack
Guy A Rouleau
Jang-Ho J Cha
Orla Hardiman
Robert H Brown
Author Affiliation
Day Neuromuscular Research Laboratory, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA. wendy.broom@gmail.com
Source
Amyotroph Lateral Scler. 2008 Aug;9(4):229-37
Date
Aug-2008
Language
English
Publication Type
Article
Keywords
Age of Onset
Amyotrophic Lateral Sclerosis - enzymology - epidemiology - genetics
Base Sequence
DNA Mutational Analysis
Female
Gene Expression
Genetic Predisposition to Disease
Genotype
Homozygote
Humans
Ireland - epidemiology
Male
Middle Aged
Phenotype
Polymorphism, Genetic
Promoter Regions, Genetic
Quebec - epidemiology
Risk factors
Scotland - epidemiology
Sequence Deletion
Sp1 Transcription Factor - metabolism
Superoxide Dismutase - genetics - metabolism
United States - epidemiology
Abstract
The objective was to test the hypothesis that a described association between homozygosity for a 50bp deletion in the SOD1 promoter 1684bp upstream of the SOD1 ATG and an increased age of onset in SALS can be replicated in additional SALS and control sample sets from other populations. Our second objective was to examine whether this deletion attenuates expression of the SOD1 gene. Genomic DNA from more than 1200 SALS cases from Ireland, Scotland, Quebec and the USA was genotyped for the 50bp SOD1 promoter deletion. Reporter gene expression analysis, electrophoretic mobility shift assays and chromatin immunoprecipitation studies were utilized to examine the functional effects of the deletion. The genetic association for homozygosity for the promoter deletion with an increased age of symptom onset was confirmed overall in this further study (p=0.032), although it was only statistically significant in the Irish subset, and remained highly significant in the combined set of all cohorts (p=0.001). Functional studies demonstrated that this polymorphism reduces the activity of the SOD1 promoter by approximately 50%. In addition we revealed that the transcription factor SP1 binds within the 50bp deletion region in vitro and in vivo. Our findings suggest the hypothesis that this deletion reduces expression of the SOD1 gene and that levels of the SOD1 protein may modify the phenotype of SALS within selected populations.
PubMed ID
18608091 View in PubMed
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Angiogenin levels and ANG genotypes: dysregulation in amyotrophic lateral sclerosis.

https://arctichealth.org/en/permalink/ahliterature139234
Source
PLoS One. 2010;5(11):e15402
Publication Type
Article
Date
2010
Author
Russell Lewis McLaughlin
Julie Phukan
William McCormack
David S Lynch
Matthew Greenway
Simon Cronin
Jean Saunders
Agnieska Slowik
Barbara Tomik
Peter M Andersen
Daniel G Bradley
Phil Jakeman
Orla Hardiman
Author Affiliation
Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland. mclaugr@tcd.ie
Source
PLoS One. 2010;5(11):e15402
Date
2010
Language
English
Publication Type
Article
Keywords
Alleles
Amyotrophic Lateral Sclerosis - genetics
Gene Frequency
Genetic Predisposition to Disease - genetics
Genotype
Haplotypes
Humans
Ireland
Linkage Disequilibrium
Poland
Polymorphism, Single Nucleotide
Ribonuclease, Pancreatic - blood - cerebrospinal fluid - genetics
Sweden
Abstract
To determine whether 5 single nucleotide polymorphisms (SNPs) associate with ALS in 3 different populations. We also assessed the contribution of genotype to angiogenin levels in plasma and CSF.
Allelic association statistics were calculated for polymorphisms in the ANG gene in 859 patients and 1047 controls from Sweden, Ireland and Poland. Plasma, serum and CSF angiogenin levels were quantified and stratified according to genotypes across the ANG gene. The contribution of SNP genotypes to variance in circulating angiogenin levels was estimated in patients and controls.
All SNPs showed association with ALS in the Irish group. The SNP rs17114699 replicated in the Swedish cohort. No SNP associated in the Polish cohort. Age- and sex-corrected circulating angiogenin levels were significantly lower in patients than in controls (p
Notes
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PubMed ID
21085671 View in PubMed
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Screening of hypoxia-inducible genes in sporadic ALS.

https://arctichealth.org/en/permalink/ahliterature156292
Source
Amyotroph Lateral Scler. 2008 Oct;9(5):299-305
Publication Type
Article
Date
Oct-2008
Author
Simon Cronin
Matthew J Greenway
Peter M Andersen
Orla Hardiman
Author Affiliation
Department of Neurology, Beaumont Hospital, Dublin, Ireland.
Source
Amyotroph Lateral Scler. 2008 Oct;9(5):299-305
Date
Oct-2008
Language
English
Publication Type
Article
Keywords
Aged
Amyotrophic Lateral Sclerosis - genetics
Anoxia - genetics
Female
Genetic Predisposition to Disease
Genetic Testing
Genotype
Humans
Ireland
Male
Middle Aged
Polymorphism, Single Nucleotide
Ribonuclease, Pancreatic - genetics
Sequence Analysis, DNA
Sweden
Vascular Endothelial Growth Factor A - genetics
Abstract
Genetic variations in two hypoxia-inducible angiogenic genes, VEGF and ANG, have been linked with sporadic amyotrophic lateral sclerosis (SALS). Common variations in these genes may reduce the levels or functioning of their products. VEGF and ANG belong to a larger group of angiogenic genes that are up-regulated under hypoxic conditions. We hypothesized that common genetic variation across other members of this group may also predispose to sporadic ALS. To screen other hypoxia-inducible angiogenic genes for association with SALS, we selected 112 tagging single nucleotide polymorphisms (tgSNPs) that captured the common genetic variation across 16 VEGF-like and eight ANG-like hypoxia-inducible genes. Screening for association was performed in 270 Irish individuals with typical SALS and 272 ethnically matched unrelated controls. SNPs showing association in the Irish phase were genotyped in a replication sample of 281 Swedish sporadic ALS patients and 286 Swedish controls. Seven markers showed association in the Irish. The one modest replication signal observed in the Swedish replication sample, at rs3801158 in the gene inhibin beta A, was for the opposite allele vs. the Irish cohort. We failed to detect association of common variation across 24 candidate hypoxia-inducible angiogenic genes with SALS.
PubMed ID
18608101 View in PubMed
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