Influence of apoA-V gene variants on postprandial triglyceride metabolism: impact of gendersâƒž

Although apolipoprotein A-V (apoA-V) polymorphisms have been consistently associated with fasting triglyceride (TG) levels, their impact on postprandial lipemia remains relatively unknown. In this study, we investigate the impact of two common apoA-V polymorphisms (21131 T.C and S19W) and apoA-V haplotypes on fasting and postprandial lipid metabolism in adults in the United Kingdom (n 5 259). Compared with the wild-type TT, apoA-V 21131 TC heterozygotes had 15% (P 5 0.057) and 21% (P 5 0.002) higher fasting TG and postprandial TG area under the curve (AUC), respectively. Significant (P 5 0.038) and nearly significant (P 5 0.057) gender 3 genotype interactions were observed for fasting TG and TG AUC, with a greater impact of genotype in males. Lower HDL-cholesterol was associated with the rare TC genotype (P 5 0.047). Significant linkage disequilibrium was found between the apoA-V 21131 T.C and the apoC-III 3238 C.G variants, with univariate analysis indicating an impact of this apoC-III single nucleotide polymorphism (SNP) on TG AUC (P 5 0.015). However, in linear regression analysis, a significant independent association with TG AUC (P 5 0.007) was only evident for the apoA-V 21131 T.C SNP, indicating a greater relative importance of the apoA-V genotype. — Olano-Martin, E. , E. C. Abraham, R. Gill-Garrison, A. M. Valdes, K. Grimaldi, F. Tang, K. G. Jackson, C. M. Williams, and A. M. Minihane. Influence of apoA-V gene variants on postprandial triglyceride metabolism: impact of gender. J. Lipid Res. 2008. 49: 945–953. Supplementary key words polymorphism & apolipoprotein A-V & apoA1/C3/A4/A5 gene locus & postprandial lipemia Since its discovery in 2001 (1), a number of key roles of apolipoprotein A-V (apoA-V) in lipoprotein, and in particular triglyceride-rich lipoprotein (TRL) metabolism have been described (2–6). Evidence for its role in TRL metabolism is provided by studies in apoA-V knockout or overexpressing rodents, in which 3to 4-fold higher and lower plasma triglyceride (TG) levels were observed, respectively (7). Furthermore, a number of publications reporting on the associations between polymorphisms in the gene locus and fasting TG levels (1, 8) support the importance of this newly defined apolipoprotein in whole body TRL handling. The apoA-V gene is located 27 kb distal to apoA-IV in the highly polymorphic apoA1/C3/A4/A5 gene cluster located on chromosome 11q23. Although reports are not fully consistent (9), significant associations between gene variants of the apoA-V gene locus and cardiovascular disease (CVD) and the metabolic syndrome/diabetes have been demonstrated repeatedly (10–15). Polymorphisms in the apoA-V site have also been associated with familial combined hyperlipidemia (FCH), with Ribalta and coworkers (16) suggesting that the apoA-V genotype may be responsible for 30% of the variation of TG levels in FCH families, an association that has been observed in subsequent studies (17–20). Common single nucleotide polymorphisms (SNPs) in the apoA-V gene, in particular the apoA-V 21131 T.C in the promoter region and the apoA-V S19W (56 C.T) coding region variant (which results in a serine-to-tryptophan amino acid change in the mature protein), have been associated with increased CVD risk and fasting TG levels. These two variants, which describe the apoA-V*1, apoAV*2, and apoA-V*3 haplotypes (21), have been shown to result in up to 70% higher fasting TG (8, 13, 22–27). In addition to fasting TG, an exaggerated postprandial lipemia is recognized as an independent predictor of CVD, associated with obesity and a loss of insulin sensitivity (28–31). Although the impact of apoA-V genotype on fasting TG has been relatively widely reported, to the best of our knowledge only three previous studies have investigated the impact of common apoA-V gene variants on Manuscript received 2 March 2007 and in revised form 31 July 2007 and in re-revised form 21 September 2007 and in re-re-revised form 22 January 2008 and in re-re-re-revised form 31 January 2008 and in re-re-re-re-revised form 6 February 2008. Published, JLR Papers in Press, February 8, 2008. DOI 10.1194/jlr.M700112-JLR200 1 To whom correspondence should be addressed. e-mail: a.m.minihane@reading.ac. uk The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of one figure. Copyright D 2008 by the American Society for Biochemistry and Molecular Biology, Inc. This article is available online at http://www.jlr. org Journal of Lipid Research Volume 49, 2008 945 This is an Open Access article under the CC BY license. postprandial lipemia, with two conducted in Korean male cohorts and one in young adult Caucasian males (European Atherosclerosis Research Study 2) (32–34). Here, we report on the impact of the 21131 T.C and S19W polymorphisms on postprandial TG metabolism in healthy males and females in the United Kingdom, with the data indicating that the impact of genotype may be gender-specific. Given the reported association between other gene variants in the apoA-I/C3/A4/A5 gene cluster and fasting TG levels (26, 27, 35–37), the individual and interactive impact of other SNPs in this locus on postprandial TG metabolism were also considered. SUBJECTS AND METHODS