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Two newly identified SNPs in the APO AI‐CIII intergenic region are strongly associated with familial combined hyperlipidaemia
Author(s) -
Groenendijk M.,
Cantor R. M.,
Funke H.,
DallingaThie G. M.
Publication year - 2001
Publication title -
european journal of clinical investigation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.164
H-Index - 107
eISSN - 1365-2362
pISSN - 0014-2972
DOI - 10.1046/j.1365-2362.2001.00888.x
Subject(s) - genetics , linkage disequilibrium , haplotype , single nucleotide polymorphism , biology , minor allele frequency , allele , transmission disequilibrium test , genotype , gene
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 Sst I and Msp I 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, T 3213 C, A 3235 C, T 3287 C and A 5132 C, 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 T 3213 C and Msp I, and the A 3235 C and Sst I 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 ( Msp I‐T 3213 C‐A 3235 C‐T 3287 C‐A 5132 C‐ Sst I). 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 Sst I and Msp I polymorphisms to the increased susceptibility for FCHL.