Authors: Groenendijk, M.¹; Cantor, R. M.²; Funke, H.³; Dallinga-Thie, G. M.¹

Source: European Journal of Clinical Investigation, Volume 31, Number 10, October 2001 , pp. 852-859(8)

Publisher: Wiley-Blackwell

Abstract:

Background

We previously reported linkage and association of the apoAI-CIII-AIV gene region on chromosome 11 with familial combined hyperlipidaemia (FCHL). However, the observed epistasis resulting in an increased susceptibility to FCHL still remains unexplained. We hypothesize that the region between the apo AI and apo CIII genes may harbour functional mutations that might be in linkage disequilibrium with the already identified SstI and MspI polymorphisms, and provide an alternative explanation for the observed relationship. Methods

Using sequence analysis, we identified four new single nucleotide polymorphisms (SNPs) in the apo AI-CIII intergenic region. These four variants, T₃₂₁₃C, A₃₂₃₅C, T₃₂₈₇C and A₅₁₃₂C, were studied in 30 FCHL probands, 159 hyperlipidaemic relatives, 327 normolipidaemic relatives, and 218 spouses from the same families in which the original results were obtained. Results

The allele frequencies were significantly different between probands and spouses (P < 0·05). Transmission/disequilibrium test (TDT) analyses revealed more frequent transmission of the minor alleles to the affected offspring. The minor genotype was associated with elevated plasma cholesterol and triglyceride levels. The T₃₂₁₃C and MspI, and the A₃₂₃₅C and SstI SNPs 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-A₃₂₃₅C-T₃₂₈₇C-A₅₁₃₂C-SstI). Both haplotypes appear to predispose to FCHL independently, and account, together with the wild-type, for almost 90% of those occurring in these FCHL families, extending the high-risk combination of haplotypes that were reported previously. Conclusion

These newly identified additional intergenic SNPs therefore provide an alternative explanation for the observed association of the SstI and MspI polymorphisms to the increased susceptibility for FCHL.

Keywords: apolipoprotein CIII; familial combined hyperlipidaemia; lipids; lipoproteins

Document Type: Research article

Affiliations: 1: University Medical Center Utrecht, the Netherlands, 2: UCLA, USA, 3: University of Münster, Germany

Publication date: 2001-10-01

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