Effect of 360His mutation in apolipoprotein A-IV on plasma HDL-cholesterol response to dietary fat

The response of serum lipids to dietary changes is to some extent an innate characteristic. One candidate genetic factor that may affect the response of serum lipids to a change in cholesterol intake is variation in the apolipoprotein A4 gene, known as the APOA4-1/2 or apoA-IVGln360His polymorphism. However, previous studies showed inconsistent results. We therefore fed 10 men and 23 women with the APOA4-1/1 genotype and 4 men and 13 women with the APOA4-1/2 or -2/2 genotype (carriers of the APOA4-2 allele) two diets high in saturated fat, one containing cholesterol at 12.4 mg/MJ, 136.4 mg/day, and one containing cholesterol at 86.2 mg/MJ, 948.2 mg/day. Each diet was supplied for 29 days in crossover design. The mean response of serum low density lipoprotein cholesterol was 0.44 mmol/l (17 mg/dl) in both subjects with the APOA4-1/1 genotype and in subjects with the APOA4-2 allele [95% confidence interval of difference in response, ؊ 0.20 to 0.19 mmol/l ( ؊ 8 to 7 mg/ dl)]. The mean response of high density lipoprotein cholesterol was also similar, 0.10 mmol/l (4 mg/dl), in the two APOA-4 genotype groups [95% confidence interval of difference in response, ؊ 0.07 to 0.08 mmol/l ( ؊ 3 to 3 mg/dl)]. Thus, the APOA4-1/2 polymorphism did not affect the response of serum lipids to a change in the intake of cholesterol in this group of healthy Dutch subjects who consumed a background diet high in saturated fat. Knowledge of the APOA4-1/2 polymorphism is probably not a generally applicable tool for the identification of subjects who respond to a change in cholesterol intake. -Weggemans, R. M., P. L. Zock, S. Meyboom, H. Funke, and M. B. Katan. Apolipoprotein A4-1/2 polymorphism and response of serum lipids to dietary cholesterol in humans.

Section: Discussioncontrasting

confidence: 99%

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confidence: 99%

Apolipoprotein A4-1/2 polymorphism and response of serum lipids to dietary cholesterol in humans

Weggemans¹,

Zock²,

Meyboom³

et al. 2000

“…This allele encodes a Q360H substi-tution (33) that significantly increases the lipid affinity (34), lecithin:cholesterol acyltransferase activation (34), and plasma residence time (35) of the apoA-IV-2 isoprotein. Recently, several studies have observed that the A-IV-2 allele affects the plasma lipoprotein response to dietary fat and cholesterol (36)(37)(38)(39), and may also modulate the efficiency of intestinal cholesterol absorption (40).…”

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confidence: 99%

Effect of the apolipoprotein A-IV Q360H polymorphism on postprandial plasma triglyceride clearance

Hockey

Anderson

Cook

et al. 2001

Apolipoprotein (apo)A-IV is synthesized in the small intestine during fat absorption and is incorporated onto the surface of nascent chylomicrons. In circulation, apoA-IV is displaced from the chylomicron surface by high density lipoprotein-associated C and E apolipoproteins; this exchange is critical for activation of lipoprotein lipase and chylomicron remnant clearance. The variant allele A-IV-2 encodes a Q360H polymorphism that increases the lipid affinity of the apoA-IV-2 isoprotein. We hypothesized that this would impede the transfer of C and E apolipoproteins to chylomicrons, and thereby delay the clearance of postprandial triglyceride-rich lipoproteins. We therefore measured triglycerides in plasma, S f Ͼ 400 chylomicrons, and very low density lipoproteins (VLDL) in 14 subjects heterozygous for the A-IV-2 allele (1/2) and 14 subjects homozygous for the common allele (1/1) who were fed a standard meal containing 50 gm fat per m 2 body surface area. All subjects had the apoE-3/3 genotype. Postprandial triglyceride concentrations in the 1/2 subjects were significantly higher between 2-5 h in plasma, chylomicrons, and VLDL, and peaked at 3 h versus 2 h for the 1/1 subjects. The area under the triglyceride time curves was greater in the 1/2 subjects (plasma, P ‫؍‬ 0.045; chylomicrons, P ‫؍‬ 0.027; VLDL, P ‫؍‬ 0.063). A posthoc analysis of the frequency of the apoA-IV T347S polymorphism suggested that it had an effect on triglyceride clearance antagonistic to that of the A-IV-2 allele. We conclude that individuals heterozygous for the A-IV-2 allele display delayed postprandial clearance of triglyceride-rich lipoproteins. -Hockey, K.

“…One study has evaluated these polymorphisms in relation to non-fasting lipid parameters and found significant associations with total and low density lipoprotein (LDL)-cholesterol and TG concentrations, suggesting an important role for apoA-IV in regulating post prandial lipoprotein metabolism (30). The response of total and LDL-cholesterol to changes in dietary intake of fat has been associated with Thr347Ser genotype (31), whilst HDL-C and apoA-I response was associated with Gln360His status (32). Kinetic studies showed that the His360 isoform had a slower fractional catabolic rate compared to the Gln360 isoform (33).…”

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confidence: 99%

Effect of variation in the apo A-IV gene on body mass index and fasting and postprandial lipids in the European Atherosclerosis Research Study II

Fisher

Burke

Nicaud

et al. 1999

The aims of the study were to investigate associations of the apolipoprotein (apo) A-IV polymorphisms Thr347Ser and Gln360His with anthropomorphic measurements and fasting and postprandial lipids in subjects participating in the European Atherosclerosis Research Study II (EARS II). The allelic frequencies of Ser347 and His360 were 0.185 and 0.067, respectively, in the sample as a whole. There were no significant differences in rare allele frequency between cases (offspring of fathers who suffered a myocardial infarction before the age of 55 years) and controls. Control subjects who were carriers of Ser347 had significantly higher body mass indices (BMIs), waist:hip ratios, total and low density lipoprotein cholesterol and triacylglycerol (TG) concentrations (all P Յ 0.02) than control subjects who were non-carriers, but these effects were not seen in the cases. Control subjects who were carriers of His360 had lower BMIs ( P ϭ 0.04), cholesterol and TG concentrations (both P Յ 0.07) compared to non-carriers, but these effects were not seen in the cases. After consumption of an oral fat load, carriers of His360 who were most obese (subjects in the third tertile of BMI) had significantly reduced postprandial lipemia ( P Ͻ 0.03, as assessed by area under the curve).-Fisher, R. M., H. Burke, V. Nicaud, C. Ehnholm, and S. E. Humphries. Effect of variation in the apoA-IV gene on body mass index and fasting and postprandial lipids in the European Atherosclerosis Research Study II. J.