Influence of apoA-V gene variants on postprandial triglyceride metabolism: impact of gender
2008; Elsevier BV; Volume: 49; Issue: 5 Linguagem: Inglês
10.1194/jlr.m700112-jlr200
ISSN1539-7262
AutoresEstíbaliz Olano-Martin, Elizheeba C. Abraham, Rosalynn Gill-Garrison, Ana M. Valdes, Keith Grimaldi, Fiona Tang, Kim G. Jackson, Christine M. Williams, Anne Marie Minihane,
Tópico(s)Peroxisome Proliferator-Activated Receptors
ResumoAlthough 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 (−1131 T>C and S19W) and apoA-V haplotypes on fasting and postprandial lipid metabolism in adults in the United Kingdom (n = 259). Compared with the wild-type TT, apoA-V −1131 TC heterozygotes had 15% (P = 0.057) and 21% (P = 0.002) higher fasting TG and postprandial TG area under the curve (AUC), respectively. Significant (P = 0.038) and nearly significant (P = 0.057) gender × 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 = 0.047). Significant linkage disequilibrium was found between the apoA-V −1131 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 = 0.015). However, in linear regression analysis, a significant independent association with TG AUC (P = 0.007) was only evident for the apoA-V −1131 T>C SNP, indicating a greater relative importance of the apoA-V genotype. 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 (−1131 T>C and S19W) and apoA-V haplotypes on fasting and postprandial lipid metabolism in adults in the United Kingdom (n = 259). Compared with the wild-type TT, apoA-V −1131 TC heterozygotes had 15% (P = 0.057) and 21% (P = 0.002) higher fasting TG and postprandial TG area under the curve (AUC), respectively. Significant (P = 0.038) and nearly significant (P = 0.057) gender × 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 = 0.047). Significant linkage disequilibrium was found between the apoA-V −1131 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 = 0.015). However, in linear regression analysis, a significant independent association with TG AUC (P = 0.007) was only evident for the apoA-V −1131 T>C SNP, indicating a greater relative importance of the apoA-V genotype. Since its discovery in 2001 (1.Pennacchio L.A. Olivier M. Hubacek J.A. Cohen J.C. Cox D.R. Fruchart J.C. Krauss R.M. 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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 postprandial lipemia, with two conducted in Korean male cohorts and one in young adult Caucasian males (European Atherosclerosis Research Study 2) (32.Jang Y. Kim J.Y. Kim O.Y. Lee J.E. Cho H. Ordovas J.M. Lee J.H. The −1131 T→C polymorphism in the apolipoprotein A5 gene is associated with postprandial hypertriacylglycerolemia: elevated small, dense LDL concentrations; and oxidative stress in non-obese Korean men.Am. J. Clin. Nutr. 2004; 80: 832-840Crossref PubMed Scopus (90) Google Scholar, 33.Kim J.Y. Kim O.Y. Koh S.J. Jang Y. Yun S.S. Ordovas J.M. Lee J.H. Comparison of low-fat and high-fat meal on postprandial lipaemic response in non-obese men according to the −1131T>C polymorphism of the apolipoprotein A5 (apoA-V) gene (randomized cross-over design).J. Am. Coll. 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Genet. 2002; 11: 3039-3046Crossref PubMed Scopus (340) Google Scholar), the individual and interactive impact of other SNPs in this locus on postprandial TG metabolism were also considered. The participants included in the current analysis were taken from four individual studies designed to investigate the impact of chronic dietary fat manipulation on postprandial lipid (TG and NEFAs), glucose, and insulin metabolism. Here, we report on the impact of genotype on fasting and postprandial lipid responses, using the baseline data from 259 participants. At the time of the study, all participants were following their habitual diet and had not commenced the relevant chronic intervention study. All individuals were recruited using identical inclusion/exclusion criteria, and all underwent the same sequential meal postprandial protocol. Healthy adults in the United Kingdom aged 20–70 years, with fasting total cholesterol between 4.6 and 8.0 mmol/l and TG between 1.0 to 4.0 mmol/l, were recruited by a variety of means, including e-mailing staff at the university with a general description of the study, advertising in the local media, and through a database held at the Department of Clinical Pathology, Royal Berkshire Hospital, Reading, UK. Those interested in taking part were asked to contact the Hugh Sinclair Unit of Human Nutrition to complete a health and lifestyle questionnaire and to provide a screening blood sample. Exclusion criteria for participation in the study included the following: evidence of CVD, including angina; diagnosed diabetes or fasting glucose > 6.5 mmol/l; liver or other endocrine dysfunction; pregnancy or lactation; smoking of >15 cigarettes per day; exercising strenuously more than three times per week; body mass index (BMI) of 32 kg/m2; and hemoglobin < 130 g/l in men or 120 g/l in women. Individuals who were prescribed hyperlipidemic or anti-inflammatory medication, who took fatty acid or antioxidant supplements on a regular basis, who consumed sterol/stanol-containing spreads, or who consumed more than one portion of oily fish per week were excluded. The studies were approved by the University of Reading Ethics and Research Committee and the West Berkshire Health Authority Ethics Committees, and each volunteer gave written informed consent before participating. The day before their postprandial assessment, participants were asked to refrain from alcohol or organized exercise regimens and were provided with a relatively low-fat ( C (rs 662799), S19W (rs 3135506), ApoC3 3238 C>G (SstI, S1/S2, rs5128), apoA-IV S347T (rs675), and apoA-IV Q360H (rs 5510) gene variants was conducted using TaqMan PCR technology (7300 Instrument; Applied Biosystems, Warrington, UK) and Assay-on-Demand SNP genotyping assays (Applied Biosystems). Hitagene Gene Hunting System Software (Hitachi, Dublin, Ireland) was used to investigate the pair-wise strength of linkage disequilibrium (LD) between SNPs (with the LD between two SNPs estimated using D′) and estimated haplotype frequencies. Deviations from Hardy-Weinberg equilibrium were assessed using the exact test by the Markov chain modeling method as implemented by Genepop (www.genepop.curtin.edu.au). The ApoA-V*1, ApoA-V*2, and ApoA-V*3 haplotypes were defined by the presence of the apoA-V −1131T/56C, −1131C/56C, and −1131T/56G alleles, respectively (18.Mar R. Pajukanta P. Allayee H. Groenendijk M. Dallinga-Thie G. Krauss R.M. Sinsheimer J.S. Cantor R.M. de Bruin T.W. Lusis A.J. Association of the APOLIPOPROTEIN A1/C3/A4/A5 gene cluster with triglyceride levels and LDL particle size in familial combined hyperlipidemia.Circ. Res. 2004; 94: 993-999Crossref PubMed Scopus (87) Google Scholar). Furthermore, strong LD was observed between the apoA-V −1131T>C and apoC-III 3238C>G SNPs; therefore the combined impact of these SNPs was also considered. All biochemical outcomes are expressed as means and (SEM). The impact of genotype on fasting and postprandial (AUC and IAUC) lipid responses was determined using one-way analysis of co-variance (ANCOVA), with BMI, gender, and age as covariants. The significance of gender × genotype, age × genotype, and BMI × genotype interactions was established using multiple analysis of variance (MANOVA) with gender, age, and BMI entered into the model as independent variables. Because of the relatively small group sizes, full haplotype analysis was not conducted, but the independent contributions of individual SNPs or SNP × gender/age/BMI interactions to the lipid responses were established using stepwise regression analysis. Statistical analysis was carried out using the S-Plus 6.1 statistical package (Insightful Corp., Seattle, WA), with P < 0.05 taken as significant. A total of 262 individuals, 153 males and 109 females, underwent postprandial assessment, with complete postprandial data available for 259, which included 235 Caucasians and 24 non-Caucasians of South Asian or Afro-Caribbean origin. The mean age, BMI, and fasting plasma lipids, glucose, and insulin for the cohort as a whole and according to gender are presented in Table 1 .TABLE 1.Baseline characteristics of the study group as a whole and according to genderOutcomeAll (n = 262)Males (n = 153)Females (n = 109)PaIntergender differences tested using one-way ANOVA.Age (years)52.7 (0.7)53.0 (0.8)52.2 (1.1)0.560BMI (kg/m2)26.2 (0.2)27.3 (0.3)25.4 (0.3)<0.001Total cholesterol (mmol/l)5.76 (0.06)5.90 (0.08)5.55 (0.10)0.007LDL-C (mmol/l)3.71 (0.06)3.91 (0.08)3.42 (0.10)<0.001HDL-C (mmol/l)1.32 (0.03)1.11 (0.02)1.62 (0.04)<0.001% LDL352.1 (2.1)54.6 (2.8)47.1 (2.0)0.110TG (mmol/l)1.64 (0.05)1.97 (0.07)1.18 (0.04)<0.001NEFA (μmol/l)512 (11)499 (14.7)531 (18)0.160Glucose (mmol/l)5.16 (0.04)5.34 (0.05)4.89 (0.05) C, apoA-V S19W, apoA-IV T347S, apoA-IV Q360T, and apoC-III 3238C>G SNPs, respectively. Comparable rare allele frequencies of 0.13, 0.02, 0.13, 0.06, and 0.19 were evident in the non-Caucasian subgroup relative to the group as a whole. To determine the degree of LD in our study sample, standardized LD coefficients (D′) was calculated for all pairs of SNPs. The LDs between the individual variants were comparable to those reported previously (see supplementary Figure I), with significant LD between the two apoA-V SNPs (P = 0.024), the apoA-V −1131T>C and apoC-III 3238C>G variants (P = 0.000), and the apoA-V S19W and apoA-IV T347S SNPs (P = 0.013). No significant LD was evident between the apoA-IV and apoA-V variants. The two polymorphic sites in the apoA-V gene resulted in three observed haplotypes, as described in Table 2, which had frequencies of 85.6, 9.4, and 4.8% for apoA-V*1, apoA-V*2, and apoA-V*3, respectively, in our 259 unrelated participants. As the alleles are in strong LD, the apoA-V −1131C/56G haplotype is rare and was not observed in the present study. Based on these three haplotypes, four haplotype combinations were observed, with 189, 40, 25, and 3 participants having an apoA-V*1/apoA-V*1, apoA-V*1/apoA-V*2, apoA-V*1/apoA-V*3, and apoA-V*2/apoA-V*2, genotype, respectively, and no individuals presenting with the apoA-V*2/apoA-V*3 or apoA-V*3/ apoA-V*3 genotype (Table 3).TABL
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