Haplotypes of the cholesteryl ester transfer protein gene predict lipid-modifying response to statin therapy

Abstract

Cholesteryl ester transfer protein (CETP) plays a central role in high-density lipoprotein (HDL) metabolism. Single nucleotide polymorphisms (SNPs) and haplotypes in the CETP gene were determined in 98 patients with untreated dyslipidemias and analyzed for associations with plasma CETP and plasma lipids before and during statin treatment. Individual CETP SNPs and haplotypes were both significantly associated with CETP enzyme mass and activity. However, only certain CETP haplotypes, but not individual SNPs, significantly predicted the magnitude of change in HDL cholesterol (HDL-C) and triglycerides. After adjusting for covariates and multiple testing, the TTCAAA haplotype showed a gene-dose effect in predicting the HDL-C increase (P¼0.03), while the TTCAAAGGG and AAAGGG haplotypes predicted a decrease in triglycerides (P¼0.04 both). This is the first study to demonstrate that SNP haplotypes derived from allelic SNP combinations in the CETP gene were more informative than single SNPs in predicting the response to lipid-modifying therapy with statins. The Pharmacogenomics Journal (2003) 3, 284-296, doi:10.1038/sj.tpj.6500195Keywords: cholesteryl ester transfer protein; HDL-cholesterol; triglycerides; haplotype; single nucleotide polymorphism; statin INTRODUCTION Cholesteryl ester transfer protein (CETP) mediates the transfer of neutral lipids between lipoproteins and plays a central role in high-density lipoprotein (HDL) metabolism. CETP transfers cholesteryl esters associated with HDL to triglyceride-rich lipoproteins, facilitating the clearance of cholesteryl esters from plasma. 1 Although the potential contribution of CETP to reverse cholesterol transport suggests an antiatherogenic mode of action, knowledge of the physiologic role of CETP in lipoprotein metabolism remains incomplete. The overall effect of CETP on atherogenesis may vary depending on both metabolic context and molecular variation in the CETP gene. 2 Investigations of associations between genetic variants in CETP and cardiovascular phenotypes are numerous, but often conflicting in their findings. The Taq1B polymorphism of the CETP gene has been associated with plasma levels of CETP and HDL cholesterol (HDL-C) and with the risk of coronary heart disease (CHD). 3,4 The Taq1B polymorphism has also been shown to serve as a marker of lipoprotein response to dietary intervention. 5,6 Other studies have demonstrated a link between the CETP I405V gene polymorphism and HDL-C, but not with response to diet. 7,8 Several other single nucleotide polymorphisms (SNPs) in the

Alternative Splicing of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Is Associated With Plasma Low-Density Lipoprotein Cholesterol Response to Simvastatin

“…In addition, when age, race, smoking status, and body mass index are added to the model, the combination of these parameters accounts for 24% of the variation in LDL-C response, 29% of the variation in apoB response, and 8% of the variation in triglyceride, with HMGCRv_1 gene expression the most significant predictor of response in all 3. Because previous studies of genetic variation associated with statin response have explained Ͻ2% to 7.5% of the variation in LDL-C and HDL-C, 8,27 our findings point to a pathway that has much more substantial impact than previously identified SNPs. This finding is the first to establish a substantial contribution of a biological process to variation in statin efficacy.…”

The Association of XRCC1 Haplotypes and Chromosomal Damage Levels in Peripheral Blood Lymphocyte among Coke-Oven Workers

“…Theoretically, a haplotype has a higher level of heterozygosity than single SNP and the association study based on the haplotype may have an increased power to detect disease associations (10-12) compared with SNP-based analysis, which has been evidenced in association studies between the haplotypes of the cholesteryl ester transfer protein gene and lipid-modifying response to statin therapy (13) and between the haplotypes of h 2 -adrenergic receptor gene and receptor expression and in vivo responsiveness (14). Recently, four haplotype-tagging SNPs (htSNP), including Arg 194 Trp, Arg 280 His, Arg 399 Gln, and Gln 632 Gln, have been reconstructed based on the resequencing data of the XRCC1 gene from the NIH DNA Polymorphism Discovery Resource (15) and five common (>5%) haplotypes were inferred in this mixed population group.…”

SNPs identification in swine leptin 5’ flanking region and transcriptional activity of naturally occurring promoter haplotypes

“…In our case, the analyzed construct contained many mutated bases that could potentially affect the binding of more transcription factors and could, therefore, lead to thinner regulation of transcriptional promoter activity. Moreover, some authors have indicated that the unique interactions of multiple SNPs within a haplotype can affect the biological phenotype while single polymorphisms within the haplotype may have poor predictive power (Drysdale et al, 2000;Winkelmann et al, 2003).…”