Abstract
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.
Highlights
Linkage and association between the apolipoprotein A-I/C-III/A-IV gene region on chromosome 11 and familial combined hyperlipidemia (FCHL) has been observed previously
Several studies have suggested that variations in the apolipoprotein A-I/C-III/A-IV gene cluster on chromosome 11 are associated with altered lipid and lipoprotein levels [4,5,6,7,8,9,10,11,12], other studies were unable to confirm these findings [13,14,15,16,17]
The minor T-allele had a significantly higher frequency in FCHL patients compared with control subjects and a genedosage effect was observed with plasma triglyceride levels [20] and significantly elevated plasma apoA-I, apoC-III, and triglyceride levels were observed in Spanish FCHL patients carrying the T1100 allele [21]
Summary
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. The minor genotypes (TT) were associated with elevated plasma triglyceride and apoC-III Both variants were in strong, 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 3Ј untranslated region of exon 4 of the apoC-III gene. Singlestrand conformation polymorphism (SSCP) analysis revealed the presence of a C317-T variant in the apoA-I gene and a C1100-T variant in the apoC-III gene They were tested in 30 FCHL families, including 30 probands, 159 hyperlipidemic relatives, 327 normolipidemic relatives, and 218 spouses, to assess association with FCHL
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