Two newly identified SNPs in the APO AI-CIII intergenic region are strongly associated with familial combined hyperlipidaemia

Background We previously reported linkage and association of the apoAI-CIII -AIV gene region on chromosome 11 with familial combined hyperlipidaemia (F CHL). However, the observed epistasis resulting in an increased susceptibil ity to FCHL still remains unexplained. We hypothesize that the region betwe en the apo AI and apo CIII genes may harbour functional mutations that migh t be in linkage disequilibrium with the already identified SstI and MspI po lymorphisms, and provide an alternative explanation for the observed relati onship. Methods Using sequence analysis, we identified four new single nucleotide p olymorphisms (SNPs) in the apo AI-CIII intergenic region. These four varian ts, T3213C, A(3235)C, T3287C and A(5132)C, were studied in 30 FCHL probands , 159 hyperlipidaemic relatives, 327 normolipidaemic relatives, and 218 spo uses from the same families in which the original results were obtained. Results The allele frequencies were significantly different between proband s and spouses (P < 0.05). Transmission/disequilibrium test (TDT) analyses r evealed more frequent transmission of the minor alleles to the affected off spring. The minor genotype was associated with elevated plasma cholesterol and triglyceride levels. The T3213C and MspI, and the A(3235)C and SstI SNP s were in complete linkage disequilibrium, resulting in two different major haplotypes 2-2-1-2-2-1 and 1-1-2-2-2-2 (MspI-T3213C-A(3235)C-T3287C-A(5132 )C-SstI). Both haplotypes appear to predispose to FCHL independently, and a ccount, together with the wild-type, for almost 90% of those occurring in t hese FCHL families, extending the high-risk combination of haplotypes that were reported previously. Conclusion These newly identified additional intergenic SNPs therefore prov ide an alternative explanation for the observed association of the SstI and MspI polymorphisms to the increased susceptibility for FCHL.