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J. Biol. Chem., Vol. 280, Issue 31, 28215-28220, August 5, 2005

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Determination of the Functionality of Common APOA5 Polymorphisms^*

Philippa J. Talmud, Jutta Palmen, Wendy Putt, Laurence Lins¶, and Steve E. Humphries

From the Division of Cardiovascular Genetics, Department of Medicine, Royal Free and University College Medical School, 5 University Street, London WC1E 6JF, United Kingdom and the ^¶Centre de Biophysique Moléculaire Numérique, Faculté des Sciences Agronomiques de Gembloux, 5030 Gembloux, Belgium

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°) at the lipid/water interface of Trp-19 SP compared with Ser-19 SP (40°), 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.

Received for publication, February 24, 2005 , and in revised form, May 11, 2005.

^* This work was supported by British Heart Foundation Grants PG/2000/057, PG/2000/134, RG2000/015, and PG/04/110/17827. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 44-207679-6968; Fax: 44-207679-6212; E-mail: p.talmud{at}ucl.ac.uk.

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