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Journal of Lipid Research, Vol. 42, 188-194, February 2001
Copyright © 2001 by Lipid Research, Inc.

Original Article

New genetic variants in the apoA-I and apoC-III genes and familial combined hyperlipidemia

Correspondence to: Geesje M. Dallinga-Thie, To whom correspondence should be addressed., g.m.dallingathie{at}digd.azu.nl (E-mail)

Linkage and association between the apolipoprotein (apo) A-I/C-III/A-IV gene region on chromosome 11 and familial combined hyperlipidemia (FCHL) has been observed previously. Using sequence analysis two new allelic variants were identified, C₃₁₇ -T in intron 2 of the apoA-I gene and C₁₁₀₀-T in exon 3 of the apoC-III gene. These variants were studied in 30 FCHL probands, 159 hyperlipidemic relatives, 327 normolipidemic relatives, and 218 spouses. The allele frequencies of both variants were significantly different in probands and spouses (P < 0.002 and P < 0.001, respectively), with increased frequency of the minor alleles in the probands. The minor genotypes (TT) were associated with elevated plasma triglyceride and apoC-III. Both variants were in strong, although not complete, linkage disequilibrium with each other and with the MspI site in the promoter region of the apoA-I gene and the SstI site in the 3' untranslated region of exon 4 of the apoC-III gene. Haplotypes based on these four variants were constructed and the distributions of haplotype combinations were significantly different (P < 0.0001). Two distinct haplotypes predisposing to FCHL were found: 2-2-1-2 and 1-2-2-2 (MspI, C₃₁₇ -T; SstI, C₁₁₀₀-T). The haplotype combinations carrying one of these high risk alleles are associated with elevated lipid levels in probands and in spouses.

While these effects can be attributed to the presence of the M2 and S2 minor alleles, these results suggest that the importance of specific allelic haplotypes may be greater than single genotypic effects. — Groenendijk, M., R. M. Cantor, T. W. A. De Bruin, and G. M. Dallinga-Thie. New genetic variants in the apoA-I and apoC-III genes and familial combined hyperlipidemia. J. Lipid Res. 2001. 42: 188;–194.

Supplementary key words: haplotypes, polymorphism, apolipoproteins

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