Interactions among genetic variants from SREBP2 activating-related pathway on risk of coronary heart disease in Chinese Han population

Sterol regulatory element binding proteins (SREBPs), as a family of membrane-bound transcription factors, control the metabolism of cholesterol and fatty acids. We conducted a case-control study to investigate whether the common variants of genes from the SREBP2 activating-related pathway, involving SREBP2, SCAP, INSIG1 and INSIG2 genes, were associated with coronary heart disease (CHD) of Chinese Han population individually or interactively. Three, four and two single nucleotide polymorphisms (SNPs) from the INSIG1, INSIG2 and SCAP genes were chosen as haplotype-tagging SNPs (htSNPs), respectively, and one nonsynonymous coding SNP was selected from SREBP2. All of the SNPs were genotyped in 853 CHD cases and 948 unrelated control subjects. The interactions among SNPs of the four genes were evaluated with multifactor-dimensionality reduction (MDR) and logistic regression models (LRM). The results from MDR indicated that there existed the SNP-SNP interactive effect of INSIG1 gene on CHD (best prediction accuracy = 56.09%, p = 0.002 on 1000 permutations). The results from LRM also identified the 2-locus interaction model (adjusted p = 0.001 for interaction) as well as the 3-locus gene-gene interaction (adjusted p = 0.026 for interaction). Single polymorphism analysis showed that the rs4822063 of SREBP2 was associated with LDL-C in the controls. The genotype CC carriers had higher LDL-C than the major allele G carriers (3.44 + 0.90 mmol/L versus 3.17 + 0.84 mmol/L, adjusted p = 0.038). Our results suggested that the INSIG1 gene was associated with CHD; there might be potential interactive effect on CHD among genes from SREBP2 activating-related pathway; and the SREBP2 gene might be associated with plasma lipid level. (C) 2009 Elsevier Ireland Ltd. All rights reserved.