APO C-III (Sst I allele):

DEFECT: The restriction length fragment polymorphism (RLFP) SstI polymorphism, arising from a cytosine to guanosine substitution in the 3' untranslated region of the APO C-III gene, distinguishes between two alleles: S1 (common) and S2 (rare).

FREQUENCY: About 5-10% of the general population have the S2 allele.

MODE OF ACTION: APO C-III protein is found in HDL, LDL, and VLDL particles. It is expressed in the liver and intestine. APO C-III inhibits the lypolysis of TG-rich lipoproteins. Poorly lipolyzed APO C-III-containing lipoprotein particles may accumulate in plasma because of their lower binding affinity to receptors.

ASSOCIATED RISK: The APO C-III S2 allele has been consistently associated with hypertriglyceridemia, a disorder that have been associated with atherosclerosis, myocardial infarction, and premature death. Healthy carriers of the S2 allele have higher plasma APO C-III levels compared to non-carriers. A positive correlation has been observed between plasma levels of APO C-III and elevated levels of plasma triglycerides (TG) and VLDL-TGs.

POSSIBLE CLINICAL UTILITY: Individuals concerned about their lipid profile should be tested for this polymorphism to determine their risk for coronary artery disease (CAD).

References:

1. Surguchov AP, Page GP, Smith L, Patsch W, Boerwinkle E; Polymorphic markers in apolipoprotein C-III gene flanking regions and hypertriglyceridemia. Arterioscler Thromb Vasc Biol 1996 Aug;16(8):941-7

The S2 Sst I polymorphism was significantly associated with hypertriglyceridemia, with an odds ratio of 4. The frequency of the S2 allele was 0.14 in those with high triglyceride levels and 0.05 in those with low triglyceride levels in a US Caucasian population.

2. Shoulders CC, Harry PJ, Lagrost L, White SE, Shah NF, North JD, Gilligan M, Gambert P, Ball MJ; Variation at the apo AI/CIII/AIV gene complex is associated with elevated plasma levels of apo CIII. Atherosclerosis 1991 Apr;87(2-3):239-47

This study shows in the healthy "English" population that the S2 allele is associated with elevated plasma apo CIII levels but not with low apo AI levels. In addition, it shows that the allele is associated with elevated plasma levels of apo B in men. Regression analysis shows in both men and women that apo CIII levels are positively correlated with plasma triglyceride levels and moreover that they are a stronger predictor of this parameter than apo AI, B or AIV. Apo CIII levels are also an independent predictor of total plasma cholesterol and HDL-cholesterol levels in males and females, respectively. Taken together, the data suggest that a genetic predisposition to develop elevated plasma levels of apo CIII, alone or in combination with elevated plasma apo AIV levels, is the primary defect responsible for the association of the S2 allele with hyperlipidemia and/or premature CHD.

3. Hoffer MJ, Sijbrands EJ, De Man FH, Havekes LM, Smelt AH, Frants RR; Increased risk for endogenous hypertriglyceridaemia is associated with an apolipoprotein C3 haplotype specified by the SstI polymorphism. Eur J Clin Invest 1998 Oct;28(10):807-12

Hypertriglyceridaemia is a common metabolic disorder frequently found in patients with coronary heart disease. The S2 allele was associated with an increased risk for severe hypertriglyceridaemia. The SstI polymorphism is found five times more frequently among patients with endogenous hypertriglyceridaemia (odds ratio of 5.28).

4. Wick U, Witt E, Engel W; Restriction fragment length polymorphisms at the apoprotein genes AI, CIII and B-100 and in the 5' flanking region of the insulin gene as possible markers of coronary heart disease. Clin Genet 1995 Apr;47(4):184-90

Carriers of the S2 allele have significantly higher serum levels of cholesterol and triglycerides than non-carriers in this German population. In addition, significantly higher levels of triglycerides were found within the heterozygous patients P1P2 (APO A-I) and S1S2 (APO C-III) than in the homozygotes P1P1 and S1S1.

5. Dallinga-Thie GM, van Linde-Sibenius Trip M, Rotter JI, Cantor RM, Bu X, Lusis AJ, de Bruin TW; Complex genetic contribution of the Apo AI-CIII-AIV gene cluster to familial combined hyperlipidemia. Identification of different susceptibility haplotypes. J Clin Invest 1997 Mar 1;99(5):953-61

In this study, combinations of haplotypes of three restriction enzyme polymorphisms: XmnI, and MspI sites 5' of the apo AI gene and SstI site in the 3' untranslated region of exon 4 of the apo CIII gene were analyzed their effect on severe hyperlipidemia in familial combined hyperlipidemia (FCH) subjects. A specific combination of haplotypes with one chromosome carrying the X1M1S2 (1-1-2) haplotype and the other the X2M2S1 haplotype (2-2-1) was significantly more frequent in hyperlipidemic relatives than in normolipidemic relatives and spouses. Associated with this combination of haplotypes were significantly elevated plasma cholesterol, triglycerides, and apo CIII levels when compared to the wild type combination of haplotypes 1-1-1/1-1-1. The present findings confirm that the apo AI-CIII-IV gene cluster contributes to the FCH phenotype, but this contribution is genetically complex.

6. Price WH, Morris SW, Kitchin AH, Wenham PR, Burgon PR, Donald PM; DNA restriction fragment length polymorphisms as markers of familial coronary heart disease. Lancet 1989 Jun 24;1(8652):1407-11

Men with a family history of CHD were twice as likely to have CHD themselves, compared with those without such a family history. At least 75% of the difference was accounted for by CHD in men with minor alleles of 4 restriction fragment length polymorphisms (RFLPs) in the region of the apolipoprotein (apo) AI and apo CIII genes. The RFLPs were identified with the restriction enzymes XmnI, PstI, MspI, and SacI. Each polymorphism has two alleles (major and minor), designated X1 and X2, P1 and P2, M1 and M2, and S1 and S2, respectively. In men with any one of the minor alleles, a family history of CHD was associated with a 234% increase in CHD prevalence. The association between the minor RFLP alleles and polymorphic gene variants (the apo AI, apo CIII, or both genes) which enhance liability to CHD accounted for almost 20% of total CHD in this population.

7. Sijbrands EJ, Hoffer MJ, Meinders AE, Havekes LM, Frants RR, Smelt AH, De Knijff P; Severe hyperlipidemia in apolipoprotein E2 homozygotes due to a combined effect of hyperinsulinemia and an SstI polymorphism. Arterioscler Thromb Vasc Biol 1999 Nov;19(11):2722-9

More than 90% of patients with type III hyperlipoproteinemia are homozygous carriers of the apolipoprotein (apo) E*2 allele. The great majority of these apoE2(Arg158-->Cys) homozygotes in the general population, however, are normolipidemic. Apparently, expression of the hyperlipidemic state requires additional genetic and/or environmental factors, suggesting a multifactorial etiology. In the hyperinsulinemic group, the carriers of the SstI polymorphism (S2) in the APOC3 gene displayed severely elevated VLDL cholesterol and VLDL triglyceride and low levels of HDL. These data provide the first evidence for a combined effect of hyperinsulinemia and the SstI polymorphism on the expression of hyperlipidemia in apoE2 homozygotes.

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