APO A1:

DEFECT: G to A transition 75 bp upstream from the start of transcription creates a site for MspI (this polymorphic site has been variably denoted as -75 bp, -76 bp or -78 bp in different studies). Another MspI APO AI polymorphism is due to a C to T transition (+83 bp) and/or a G to A transition (+84 bp) within the first intron. The presence of the MspI cutting site (MspI+) is common allele. MspI- is the rarer allele.

FREQUENCY:Among Caucasians of European descent, the reported frequency of the -75 bp G to A transition is ~20%; among those of Chinese descent, the frequency is ~45%. The frequency of the other MspI- (+83 bp or +84) polymorphism is ~4%.

MODE OF ACTION: Apolipoprotein (apo) AI, the major protein found in high density lipoproteins (HDL), is synthesized in the liver and small intestine. It is involved in the esterification of cholesterol by acting as the main activator of the enzyme lecithin cholesteryl acyl transferase (LCAT) and thus plays a major role in the removal of cholesterol from peripheral cells and in the reverse cholesterol transport process.

ASSOCIATED RISK: Plasma apo AI and HDL-C levels are higher in carriers of the -75 bp A allele, as compared with homozygotes for the G allele. Thus, the A allele has a protective effect against CAD. In contrast, among patients with coronary artery disease (CAD), subjects with the rare APO AI (+83 bp) MspI- allele showed decreased HDL-C levels.

METHOD OF DETECTION: Allele-specific PCR.

POSSIBLE CLINICAL UTILITY: Tests for APO AI should be done on people who are concerned about their lipid profile.

NOTE: Some studies have associated the -75 bp A and the rare +83 bp Msp I- alleles with CAD. We have not included these studies in the list of references. If you would like to review these publications, please and we will send you copies of these articles.

References:

1. Kamboh MI, Aston CE, Nestlerode CM, McAllister AE, Hamman RF; Haplotype analysis of two APOA1/MspI polymorphisms in relation to plasma levels of apo A-I and HDL-cholesterol. Atherosclerosis 1996 Dec 20;127(2):255-62

Single site RFLP analysis revealed an independent and significant effect associated with each polymorphism (-75 bp MspI polymorphism G/A and +83 bp MspI polymorphic site +/-) on plasma apo A-I variation but not on HDL-C variation. Compared to the most common haplotype (G+), the A+ (-75 bp MspI +) and G- (+83 bp MspI-) haplotypes were associated with increased plasma apo A-I in non-smoking men and women.

2. Reguero JR, Cubero GI, Batalla A, Alvarez V, Hevia S, Cortina A, Coto E; Apolipoprotein A1 gene polymorphisms and risk of early coronary disease. Cardiology 1998 Dec;90(3):231-5

The frequency of carriers of the rare allele at the -75 bp site G Msp I- (M1-) was significantly higher among patients with angina and myocardial infarction than in controls. Male patients with a diagnosis of coronary artery disease and age less than 50 years showed a higher frequency of the M1- allele. No difference in the frequencies for carriers of the rare allele at the +83-bp polymorphism (M2) was observed among patients with angina or myocardial infarction. Patients carrying the rare M2- allele, however, had a lower concentration of total cholesterol compared to those without this allele. HDL cholesterol was also lower among patients carrying the M2- allele.

3. Jeenah M, Kessling A, Miller N, Humphries S; G to A substitution in the promoter region of the apolipoprotein AI gene is associated with elevated serum apolipoprotein AI and high density lipoprotein cholesterol concentrations. Mol Biol Med 1990 Jun;7(3):233-41

The A substitution at -75 bp was associated with higher serum apo AI concentrations in healthy men. Men with the A allele had significantly higher serum concentrations of apo AI, high density lipoprotein (HDL) cholesterol and HDL2 than those with the G allele. In this population, variation associated with the G to A substitution accounted for 6% and 4.6% of the total variance in apo AI and HDL cholesterol concentrations, respectively.

4. Talmud PJ, Ye S, Humphries SE; Polymorphism in the promoter region of the apolipoprotein AI gene associated with differences in apolipoprotein AI levels: the European Atherosclerosis Research Study. Genet Epidemiol 1994;11(3):265-80

Individuals with one or more A allele had significantly higher plasma apo AI levels (P < 0.05) than individuals homozygous for the G allele. In females, those with one or more A allele had significantly higher apo AI levels (P = 0.05) than individuals homozygous for the G allele, and this raising effect of the A allele was greater in healthy offspring (cases) of fathers who had suffered premature myocardial infarction (MI) before age 55 years than in age- and sex-matched controls for both apo AI and HDL. In males, the A allele was associated with higher levels of apo AI and HDL, but the effect was much smaller and the differences did not reach statistical significance. In the females, where the effect of the A allele was strongest, the effect on apo AI associated with genotype was most evident in non-smokers, However, in the female smokers the raising effect of the A allele was greatly reduced. Thus genetic variation in the promoter region of the apo AI gene is associated with differences in apo AI and HDL levels in healthy individuals throughout Europe, but the effect is modulated by gender, environmental factors such as smoking, and a family history of MI.

5. Sigurdsson G Jr, Gudnason V, Sigurdsson G, Humphries SE; Interaction between a polymorphism of the apo A-I promoter region and smoking determines plasma levels of HDL and apo A-I. Arterioscler Thromb 1992 Sep;12(9):1017-22

In the men who were nonsmokers, a guanine (G) to adenine (A) (G/A) substitution 75 bp upstream from the start of transcription of the apo A-I gene was associated with elevated levels of HDL-C and apo A-I, with those carrying the A allele having levels of HDL-C and apo A-I roughly 10% higher than those with only the G allele. This genotype effect was abolished in the men who smoked and absent in the sample of women. Based on the reported protective effect associated with elevated levels of apo A-I and HDL-C, men carrying the A allele would have roughly a 20% lower relative risk of CAD compared with those without the A allele, but only if they remained nonsmokers.

6. Saha N, Tay JS, Low PS, Humphries SE; Guanidine to adenine (G/A) substitution in the promoter region of the apolipoprotein AI gene is associated with elevated serum apolipoprotein AI levels in Chinese non-smokers. Genet Epidemiol 1994;11(3):255-64

The frequency of the A allele in the Chinese was significantly higher than that reported in Caucasians. In men, the A allele was associated with 20% higher apo AI; this association was completely absent in women. Furthermore, in men this association was only observed in those who had never smoked, and was absent in smokers. The G/A substitution explained 9% (P < 0.02) of the sample variance of apo AI in non-smoking men.

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