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

Linkage and association between the apolipoprotein (apo) A-I/C-III/A-IV gen e region on chromosome II and familial combined hyperlipidemia (FCHL) has b een observed previously. Using sequence analysis two new allelic variants w ere 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, 1 59 hyperlipidemic relatives, 327 normolipidemic relatives, and 218 spouses. The allele frequencies of both variants were significantly different in pr obands and spouses (P < 0.002 and P < 0.001, respectively), with increased frequency of the minor alleles in the probands, The minor genotypes (TL) we re associated with elevated plasma triglyceride and apoC-III. Both variants were in strong, although not complete, linkage disequilibrium with each ot her and with the MspI site in the promoter region of the apoA-I gene and th e SstI site in the 3' untranslated region of exon 4 of the apoC-III gene. H aplotypes based on these four variants were constructed and the distributio ns 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 proban ds 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.