Association between genetic variation at the APO AI-CIII-AIV gene cluster and familial combined hyperlipidaemia.

By using chemical cleavage mismatch analysis and the single strand conformation 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 apo AI-CIII-AIV gene cluster in affected individuals from eight FCHL families. A C1100-T transition in the wobble position of codon 14 in exon 3 and a T3206-G transversion 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 obtained using the affected pedigree member method of linkage analysis (overall T = -0.77 for f(p) = 1 [symbol: see text] p). The frequencies of T1100 and G3206 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 patients homozygous for the T1100 allele, levels of plasma triglyceride were 2.5-fold higher (868 mg/dl) than those homozygous for the C1100 allele (337 mg/dl), while patients heterozygous for the polymorphism had intermediate values (443 mg/dl) (p < 0.01). A similar association was seen in controls (p < 0.04). The three polymorphisms studied were in strong linkage disequilibrium in both the group of CHL patients and the unrelated 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 hyperlipidaemia, but fails to confirm co-segregation with FCHL, suggesting the role of other genetic or environmental factors in the aetiology of FCHL.