ASSOCIATION BETWEEN GENETIC-VARIATION AT THE APO AI-CIII-AIV GENE-CLUSTER AND FAMILIAL COMBINED HYPERLIPIDEMIA

By using chemical cleavage mismatch analysis and the single strand con formation polymorphism technique, DNA fragments of the apo CIII gene, including the 5' flanking region and all the exons, were screened for sequence changes underlying the observed association between familial combined hyperlipidaemia (FCHL) and the ape AI-CIII-AIV gene cluster i n affected individuals from eight FCHL families. A C-1100-T transition in the wobble position of codon 14 in exon 3 and a T-3206-G transvers ion in the non-translated region of exon 4 were identified, occurring in four and all probands, respectively. Using these variants and the G (-75)-A transition in the apo AI promoter, co-segregation of the gene cluster with hyperlipidaemia could be excluded in all eight families ( lod score -(infinity) at theta=0). No support for co-segregation was o btained using the affected pedigree member method of linkage analysis (overall T= -0.77 for f (p)=1 root p), The frequencies of T-1100 and G (3206) in a group of 55 patients with combined hyperlipidaemia were 0. 35 and 0.52, respectively, which were significantly higher compared to 360 controls (0.21, p<0.01 and 0.35, p<0.005 respectively). In patien ts homozygous for the T-1100 allele, levels of plasma triglyceride wer e 2.5-fold higher (868 mg/dl) than those homozygous for the C-1100 all ele (337 mg/dl), while patients heterozygous for the polymorphism had intermediate values (443 mg/dl) (p<0.01). A similar association was se en in controls (p<0.04). The three polymorphisms studied were in stron g linkage disequilibrium in both the group of CHL patients and the unr elated individuals. This study confirms the association between common variation in the gene cluster and differences in plasma lipid levels in the general population and in patients with combined hyperlipidaemi a, but fails to confirm co-segregation with FCHL, suggesting the role of other genetic or environmental factors in the aetiology of FCHL.