Two polymorphisms in the apo A-IV gene and familial combined hyperlipidemia

Linkage and association of the apo AI-CIII-IV gene region to familial combi ned hyperlipidemia (FCHL) was reported previously, based on the presence of genetic variants in the apo CIII and apo AI gene. No data were available y et on the contribution of the apo A-IV locus. Two DNA variants in exon 3 of the apo A-IV gene, A (Thr)(347)T (Ser) and [CTGT](3-4) were characterized by sequencing the coding region of the apo A-IV gene and were analyzed in o ur Dutch FCHL cohort (30 probands, 159 affected relative, 317 unaffected re latives and 218 spouses). The genotype frequency of the A(347)T variant was different in probands and spouses. In probands no 2/2 carriers were found, resulting in a significant decreased frequency of the 2-allele (P < 0.05). This was suggestive for a protective role of the presence of the serine (T ) allele on the prevalence of FCHL. No difference in frequency distribution was found for the [CTGT](3-4) variant between the groups. Homozygous 4/4 c arriers in spouses had a more favorable lipid profile (LDL-cholesterol and apo B, P < 0.05). The absence of linkage disequilibrium of the A(347)T with other markers in the gene cluster, and the absence of linkage disequilibri um with [CTGT]3-4 marker and the MspI-AI marker in the apo A-I promoter sho wed that these two apo A-IV variants reside on different haplotypes from th e apo A-I and apo C-III markers. This was illustrated by extensive haplotyp e analysis. The present data on the contribution of DNA variants in the apo A-IV gene support our previous observations that the apo AI-CIII-AIV gene cluster has a complex genetic contribution to FCHL both by conferring susce ptibility and protection. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.