APO A-IV:

DEFECT: A substitution of histidine for glutamine at amino acid position 360 (also known as apo A-IV-2 allele). Another defect is a substitution of serine for threonine at amino acid position 347.

FREQUENCY: Among Caucasians of European descent, the frequencies of the His360 and Ser347 polymorphisms are about 15% and 33%, respectively. Among Hispanics, the frequency of the His360 allele is around 12%. These alleles are not prevalent in Asian populations.

MODE OF ACTION: Apo A-IV are synthesized by the small intestine during fat absorption. It is involved in the removal of cholesterol from peripheral tissues.

ASSOCIATED RISK: The A-IV-2 allele has been associated with a less atherogenic profile. In some studies, A-IV-1/2 heterozygotes have higher plasma HDL cholesterol and lower triglyceride levels than A-IV-1/1 homozygotes. In dietary intervention studies, A-IV-2 carriers are less responsive to dietary changes. On the other hand, carriers of A-IV-2 may develop a more atherogenic profile upon exposure to increased smoking and saturated fat intake, as compared to A-IV-1/1 homozygotes. Obese A-IV-2 carriers may also be more susceptible to heart disease than non-carriers. Carriers of the Ser347 allele have higher total cholesterol, LDL cholesterol and triglycerides. However, carriers have a greater decrease in total cholesterol when switched from a diet high in saturated fat to one with lower fat content.

METHOD OF DETECTION: Allele-specific PCR.

POSSIBLE CLINICAL UTILITY: Individuals at increased risk for coronary artery disease should be tested for this polymorphism, especially if they are exposed to other risk factors such as smoking, high saturated fat intake, diabetes and obesity.

References:

1. McCombs RJ, Marcadis DE, Ellis J, Weinberg RB; Attenuated hypercholesterolemic response to a high-cholesterol diet in subjects heterozygous for the apolipoprotein A-IV-2 allele. N Engl J Med 1994 Sep 15;331(11):706-10

The apo A-IV-2 allele attenuates the hypercholesterolemic response to the short-term ingestion of a very-high-cholesterol diet and may partially account for the heterogeneous response to dietary cholesterol. After subjects consumed a low-cholesterol diet during a two-week run-in period, daily cholesterol intake was then increased by the addition of four egg yolks per day. After three weeks of egg intake, the increase in mean plasma total cholesterol and low-density lipoprotein (LDL) cholesterol was significantly less in the apo A-IV-1/2 group than in apo A-IV-1/1 group. There were no changes in the plasma triglyceride or high-density lipoprotein cholesterol concentrations in either group.

2. Saha N, Wang G, Vasisht S, Kamboh MI; Influence of two apo A4 polymorphisms at codons 347 and 360 on non-fasting plasma lipoprotein-lipids and apolipoproteins in Asian Indians. Atherosclerosis 1997 Jun;131(2):249-55

Carriers of the Ser347 allele had significantly lower plasma total cholesterol and low density lipoprotein (LDL)-cholesterol levels than individuals homozygous for the Thr347 allele. The 2 allele at codon 360 was associated with marginally reduced plasma LDL-cholesterol and increased triglyceride levels compared to the 1 allele. The two uncommon haplotypes, Ser347 and A2, were associated with lower total cholesterol and LDL-cholesterol levels. The accentuated effect of apo A4 polymorphisms on non-fasting plasma cholesterol suggest that apo A-IV may play an important role in regulating the postprandial metabolism of lipoproteins.

3. Carmena-Ramon R, Ascaso JF, Real JT, Ordovas JM, Carmena R; Genetic variation at the apoA-IV gene locus and response to diet in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 1998 Aug;18(8):1266-74

The investigators studied the effect of 2 common apoA-IV genetic variants (Gln360-->His and Thr347-->Ser) on the lipid response to the National Cholesterol Education Program type I (NCEP-I) diet in familial hypercholesterolemia (FH) heterozygotes. Subjects were studied at baseline and after 3 months of consuming a low-fat diet. The APOA4-2 allele was associated with lower low density lipoprotein (LDL) cholesterol levels and apoB levels independent of diet effects. After consuming an NCEP-I diet, carriers of the APOA4-2 allele showed a significantly lower reduction in apoB concentration than 1/1 subjects. Although no significant differences were observed in baseline or post-NCEP-I diet values for Ser347 or Thr 347 groups in total, LDL, and high density lipoprotein cholesterol and plasma apoB levels, after dietary intervention, Thr347 homozygotes showed significant reductions in plasma triglyceride and very low density lipoprotein cholesterol levels; no changes were found in carriers of the Ser347 allele.

4. Fisher RM, Burke H, Nicaud V, Ehnholm C, Humphries SE; 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. J Lipid Res 1999 Feb;40(2):287-294

Control subjects who were carriers of Ser347 had significantly higher body mass indices (BMIs), waist:hip ratios, higher total, low density lipoprotein cholesterol and triacylglycerol (TG) concentrations than control subjects who were non-carriers, but these effects were not seen in the cases (offspring of fathers who suffered a myocardial infarction before age 55). Control subjects who were carriers of His360 had lower BMIs cholesterol and TG concentrations 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 had significantly reduced postprandial lipemia

5. Campos H, Lopez-Miranda J, Rodriguez C, Albajar M, Schaefer EJ, Ordovas JM; Urbanization elicits a more atherogenic lipoprotein profile in carriers of the apolipoprotein A-IV-2 allele than in A-IV-1 homozygotes. Arterioscler Thromb Vasc Biol 1997 Jun;17(6):1074-81

Lifestyles associated with an urban environment, such as increased smoking and saturated fat intake, elicit a more adverse plasma lipoprotein profile among Costa Rican carriers of the apoA-IV-2 allele than in apoA-IV-1 homozygotes. Urban compared with rural carriers of the apoA-IV-2 allele had significantly lower plasma HDL cholesterol and apoA-I, a significantly higher LDL/HDL cholesterol ratio, and significantly smaller LDL particles. In contrast, no significant rural-urban differences for these parameters were found in apoA-IV-1 homozygotes. A significant interaction between saturated fat intake and apoA-IV phenotype was found for HDL cholesterol and LDL/HDL cholesterol ratio. Increased saturated fat intake was significantly associated with 6% higher HDL cholesterol and no change (0.7%) in LDL/HDL cholesterol ratio in apoA-IV-1 homozygotes and with 19% lower HDL cholesterol and 37% higher LDL/HDL cholesterol ratio among carriers of the apoA-IV-2 allele. Smokers had significantly lower HDL cholesterol and apoA-I concentrations than nonsmokers, particularly among carriers of the apoA-IV-2 allele compared with apoA-IV-1. After taking these lifestyle characteristics into account, the areas of residence by phenotype interactions for plasma lipoprotein concentrations were no longer statistically significant.

6. Rewers M, Kamboh MI, Hoag S, Shetterly SM, Ferrell RE, Hamman RF; ApoA-IV polymorphism associated with myocardial infarction in obese NIDDM patients. The San Luis Valley Diabetes Study. Diabetes 1994 Dec;43(12):1485-9

The researchers investigated the association between MI risk and polymorphism at codon 360 in the apolipoprotein A-IV (apoA-IV) gene among patients with non-insulin-dependent diabetes mellitus (NIDDM) and controls . The risk of MI did not differ by apoA-IV phenotype in nondiabetic people; however, in NIDDM patients, those with the apoA-IV 1-2 phenotype had 2.8 higher MI risk than those with the 1-1 phenotype, adjusting for age, gender, ethnicity, hypertension, smoking, body mass index, fat centrality, and low-density lipoprotein and high-density lipoprotein cholesterol. The risk of MI was particularly high in obese NIDDM patients with the apoA-IV 1-2 phenotype: 5.1 times that in obese apoA-IV 1-1 NIDDM patients and 7.7 times that in lean nondiabetic people. The effect of apoA-IV 1-2 did not appear to be a part of the insulin-resistance syndrome nor was it dependent on diabetes duration or control. One half of the excess MI risk in the diabetic population studied was explained by the apoA-IV 1-2 phenotype.

7. Heilbronn LK, Noakes M, Morris AM, Kind KL, Clifton PM; 360His polymorphism of the apolipoproteinA-IV gene and plasma lipid response to energy restricted diets in overweight subjects. Atherosclerosis 2000 May;150(1):187-92

The researchers assessed the effects of an energy restricted diet for 12 weeks on weight loss and plasma lipids according to apoA-IV genotype in overweight/obese subjects. HDL-C increased in subjects with the apoA-IV-1/1 genotype with weight loss, but decreased in apoA-IV-1/2 subjects. This was more apparent when only the subjects with type 2 diabetes were analyzed. ApoA-IV genotype was not related to change in total cholesterol, LDL-C or triglyceride concentrations. Therefore, weight loss as a treatment to reduce CVD risk factors may be more effective in subjects with the apoA-IV-1/1 variant as compared to those with the apoA-IV-1/2 variant, especially in subjects with type 2 diabetes.

Back to Test Page