TY - JOUR
T1 - New genetic variants in the apoA-I and apoC-III genes and familial combined hyperlipidemia
AU - Groenendijk, M.
AU - Cantor, R. M.
AU - de Bruin, T. W.
AU - Dallinga-Thie, G. M.
PY - 2001
Y1 - 2001
N2 - 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, C(317) -T in intron 2 of the apoA-I gene and C(1100)-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, C(317) -T; SstI, C(1100)-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
AB - 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, C(317) -T in intron 2 of the apoA-I gene and C(1100)-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, C(317) -T; SstI, C(1100)-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
M3 - Article
C2 - 11181747
SN - 0022-2275
VL - 42
SP - 188
EP - 194
JO - Journal of Lipid Research
JF - Journal of Lipid Research
IS - 2
ER -