Linked Life Data

18395529

Source:http://linkedlifedata.com/resource/pubmed/id/18395529

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
7-8
pubmed:dateCreated
2008-6-20
pubmed:abstractText
Plasma triglyceride (TG) and apoAV levels are reported to be positively correlated, yet SNPs defining haplotype APOA52 have consistently shown association with elevated plasma triglyceride (TG) but not plasma apoAV levels. We previously reported that individually -1131T>C, -3A>G and +1891T>C did not influence luciferase activity or in vitro translation efficiency. To investigate the combined effect of these SNPs additional constructs were examined. Compared to the wildtype -1131T/-3A/+1891T (TAT), the triple rare allele construct -1131C/-3G/+1891C (CGC) conferred 46% lower luciferase activity (p<0.0001), showing these SNPs are acting co-operatively. Although only these two combinations occur in vivo, we experimentally altered the TAT construct one site at a time; -3G (TGT) had the largest effect (94% lower luciferase), with lesser effects from CAT (-77%) and TAC (-70.3%) (all p<0.0001). Deletion constructs excluding one site at a time showed that -3G/1891C ( -GC) in combination, compared to -AT, was having the largest effect on luciferase activity (-59%, p=0.055). Using sequence homology and EMSA analysis no transcription factor binding at -1131 or +1891 was identified, though +1891 lies within a putative mRNA stability motif. Taken together, these data identify -3A>G in the Kozak sequence as functional, affecting translation initiation and driving the haplotype effects, while showing interaction with +1891T>C and to a lesser extent -1131T>C. A paradox arises since these results predict that APOA52 will lead to reduced apoAV with concomitant reduced LPL activation or lipoprotein-receptor interaction, resulting in higher plasma TG levels. We conclude that APOA5 expression, and not circulating plasma apoAV levels, is causatively associated with plasma TG levels.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:issn
0006-3002
pubmed:author
pubmed:issnType
Print
pubmed:volume
1782
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
447-52
pubmed:meshHeading
pubmed:articleTitle
The functional interaction on in vitro gene expression of APOA5 SNPs, defining haplotype APOA52, and their paradoxical association with plasma triglyceride but not plasma apoAV levels.
pubmed:affiliation
Division of Cardiovascular Genetics, Department of Medicine, University College London, 5 University Street, London WC1E 6JF, UK.
pubmed:publicationType
Journal Article, In Vitro, Research Support, Non-U.S. Gov't