Article (Scientific journals)
Determination Of The Functionality Of Common Apoa5 Polymorphisms
Talmud, Pj.; Palmen, J.; Putt, W. et al.
2005In Journal of Biological Chemistry, 280 (31), p. 28215-28220
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Abstract :
[en] Common variants of APOA5 have consistently shown association with differences in plasma triglyceride (TG) levels. These single nucleotide polymorphisms (SNPs) fall into three common haplotypes: APOA5*1, with common alleles at all sites; APOA5*2, with rare alleles of -1131T--> C, -3A--> G, 751G--> T, and 1891T--> C; and APOA5*3, distinguished by the c56C--> G (S19W). Molecular modeling of the apoAV signal peptide (SP) showed an increased angle of insertion (65 degrees ) at the lipid/water interface of Trp-19 SP compared with Ser-19 SP (40 degrees ), predicting reduced translocation. This was confirmed by 50% reduction of Trp-19-encoded SP.secretory alkaline phosphatase (SEAP) fusion protein secreted into the medium from HepG2 cells compared with the Ser-19.SEAP fusion protein (p < 0.002). Considering APOA5*2 SNPs, there was no significant difference in the relative luciferase expression in Huh7 cells transiently transfected with a -1131T construct compared with the -1131C (fragments -1177 to -516 or -1177 to -3). Similarly, for the -3A--> G in the Kozak sequence, in vitro transcription/translation assays and primer extension inhibition assays showed no alternate AUG initiation codon usage, demonstrating that -3A--> G did not influence translation efficiency. Although 1891T--> C in the 3'-untranslated region disrupts a putative Oct-1 transcription factor binding site, when inserted 3' of the luciferase gene the T--> C change demonstrated no significant difference in luciferase expression. Thus, association of APOA5*2 SNPs with TG levels is not due to the individual effects of any of these SNPs, although cooperativity between the SNPs cannot be excluded. Alternatively, the effect on TG levels may reflect the strong linkage disequilibrium with the functional APOC3 SNPs.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Talmud, Pj.
Palmen, J.
Putt, W.
Lins, Laurence  ;  Université de Liège - ULiège > Gembloux Agro-Bio Tech
Humphries, Se.
Language :
English
Title :
Determination Of The Functionality Of Common Apoa5 Polymorphisms
Publication date :
2005
Journal title :
Journal of Biological Chemistry
ISSN :
0021-9258
eISSN :
1083-351X
Publisher :
American Society for Biochemistry and Molecular Biology, United States - Maryland
Volume :
280
Issue :
31
Pages :
28215-28220
28215-20
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 07 July 2010

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