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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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Evidence that peroxisome proliferator-activated receptor delta influences cholesterol metabolism in men.

https://arctichealth.org/en/permalink/ahliterature186424
Source
Arterioscler Thromb Vasc Biol. 2003 Apr 1;23(4):637-43
Publication Type
Article
Date
Apr-1-2003
Author
Josefin Skogsberg
Katja Kannisto
Tobias N Cassel
Anders Hamsten
Per Eriksson
Ewa Ehrenborg
Author Affiliation
Atherosclerosis Research Unit, King Gustaf V Research Institute, Karolinska Hospital, SE-171 76 Stockholm, Sweden.
Source
Arterioscler Thromb Vasc Biol. 2003 Apr 1;23(4):637-43
Date
Apr-1-2003
Language
English
Publication Type
Article
Keywords
5' Untranslated Regions - genetics
Adult
Alleles
Cholesterol - metabolism
Cholesterol, LDL - blood
Chromosomes, Human, Pair 6 - genetics
Cloning, Molecular
Cohort Studies
Exons - genetics
Gene Frequency
Genotype
Humans
Male
Middle Aged
Polymorphism, Genetic
Promoter Regions, Genetic - genetics
Receptors, Cytoplasmic and Nuclear - chemistry - genetics - metabolism - physiology
Sp1 Transcription Factor - metabolism
Structure-Activity Relationship
Sweden
Transcription Factors - chemistry - genetics - metabolism - physiology
Transfection
U937 Cells
Abstract
The objective of this work was to explore the role of peroxisome proliferator-activated receptor delta (PPARD) in lipid metabolism in humans.
PPARD is a nuclear receptor involved in lipid metabolism in primates and mice. We screened the 5'-region of the human gene for polymorphisms to be used as tools in association studies. Four polymorphisms were detected: -409C/T in the promoter region, +73C/T in exon 1, +255A/G in exon 3, and +294T/C in exon 4. The frequencies of the rare alleles were 4.2%, 4.2%, 1.2% and 15.6%, respectively, in a population-based group of 543 healthy men. Only the +294T/C polymorphism showed significant association with a metabolic trait. Homozygotes for the rare C allele had a higher plasma LDL-cholesterol concentration than homozygotes for the common T allele, which was verified in an independent cohort consisting of 282 healthy men. Transfection studies showed that the rare C allele had higher transcriptional activity than the common T allele. Electrophoretic mobility shift assays demonstrated that the +294T/C polymorphism influenced binding of Sp-1. An interaction with the PPAR alpha L162V polymorphism was also detected for several lipid parameters.
These findings suggest that PPARD plays a role in cholesterol metabolism in humans.
PubMed ID
12615676 View in PubMed
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Tissue-type plasminogen activator -7,351C/T enhancer polymorphism is associated with a first myocardial infarction.

https://arctichealth.org/en/permalink/ahliterature53790
Source
Thromb Haemost. 2002 Jan;87(1):105-9
Publication Type
Article
Date
Jan-2002
Author
Per Ladenvall
Lars Johansson
Jan-Håkan Jansson
Sverker Jern
Torbjörn K Nilsson
Anna Tjärnlund
Christina Jern
Kurt Boman
Author Affiliation
Cardiovascular Institute, Clinical Experimental Research Laboratory, Sahlgrenska University Hospital/Ostra, Göteborg University, Sweden.
Source
Thromb Haemost. 2002 Jan;87(1):105-9
Date
Jan-2002
Language
English
Publication Type
Article
Keywords
Apolipoprotein A-I - analysis
Binding Sites
Cardiovascular Diseases - epidemiology
Case-Control Studies
Enhancer Elements (Genetics) - genetics
Female
Genetic Predisposition to Disease
Health Surveys
Humans
Hypertension - epidemiology
Intervention Studies
Male
Middle Aged
Multivariate Analysis
Myocardial Infarction - epidemiology - genetics
Obesity - epidemiology
Odds Ratio
Plasminogen Activator Inhibitor 1 - analysis
Polymorphism, Genetic
Prognosis
Prospective Studies
Research Support, Non-U.S. Gov't
Risk
Risk factors
Sp1 Transcription Factor - metabolism
Sweden - epidemiology
Tissue Plasminogen Activator - genetics - secretion
Abstract
We recently identified a polymorphic Sp1 binding site in an enhancer at the tissue-type plasminogen activator (tPA) locus (tPA -7,351C/T), which was associated with vascular tPA release. Subjects homozygous for the -7,351C allele had twice the tPA release rate compared to subjects carrying the -7,351T allele. In this study we tested the hypothesis that the tPA -7,351C/T polymorphism is associated with myocardial infarction (MI). In a population-based prospective nested case-control study within northern Sweden, genotypes were determined among 61 MI cases and 120 controls. In a multivariate model, the tPA -7,351C/T polymorphism (OR 2.68 for T allele carriers; 95% CI 1.31-5.50), tPA antigen (OR 1.16; 95% CI 1.07-1.25) and apo A-I (OR, 0.997; 95% CI 0.995-0.999) were independently associated with a first MI. These findings suggest that genetic markers of local tPA release and circulating steady-state tPA levels carry independent prognostic information.
PubMed ID
11848437 View in PubMed
Less detail