Taq1B polymorphism of cholesteryl ester transfer protein (CETP) gene in primary combined hyperlipidaemia.

Background & objectives: Cholesteryl ester transfer protein (CETP) gene polymorphism is known to be associated with changes in lipid profiles. Primary hyperlipidaemia is considered to be a major risk factor for pancreatitis, atherosclerosis and coronary heart disease. We investigated the association of one common polymorphism in the CETP gene (Taq1B) with plasma lipid levels and CETP activity in Iranian subjects with and without primary combined hyperlipidaemia. Methods: The study included 102 patients with primary combined hyperlipidaemia and 214 health individuals. Polymerase chain reaction and restriction fragment length polymorphisms were used for genotype detection. To determine the relationship between Taq1B polymorphism and lipid levels, lipids and CETP activity were measured in primary combined hyperlipidaemic and normolipidaemic subjects, with and without Taq1B polymorphism. Results: Plasma CETP activity was significantly (P<0.001) higher in primary combined hyperlipidaemic individuals than in controls. Plasma HDL-C was higher in both groups, in the B2B2 genotype than in the B1B1 and B1B2 genotypes, whereas the serum TG concentrations and CETP activity were lower in B2B2 genotype compared with other genotypes (B1B1 and B1B2). The genotype and allelic frequencies for this polymorphism differed significantly between hyperlipidaemic and nonmolipidaemic individuals (P<0.05). In both groups, CETP Taq 1B polymorphism (presence of B2 allele) correlated significantly with HDL-cholesterol (HDL-C) (r=0.201 and r=0.452 in control and patient groups respectively) and CETP activity (r= -0.123 for controls and r= -0.192 for patients). Interpretation & conclusions: The results showed that Taq 1B polymorphism of CETP gene was associated with changes in lipids profile and plasma CETP activity in the selected population and might have a role in contributing to genetic risk of developing coronary artery disease.

Identification of loci conferring risk for premature CAD and heterozygous familial hyperlipidemia in the LDLR, APOB and PCSK9 genes

Heterogeneous familial hypercholesterolemia [HFH] partly underlies polymorphic changes in the low-density lipoprotein receptor [LDLR], apolipoprotein B [APOB] and protein convertase subtili-sin/kexin type 9 [PCS/C9], exhibiting intra-ethnical variations in its clinical features. Methods: We employed the Affymetrix whole genome scan 250 styl array to characterize possible geno-mic linkage to heterozygous familial hypercholesterolemia [HFH] and sequencing techniques to identify related mutations in the above three genes in a Saudi family of 11 individuals harbouring clinical features of FH. The propositus had early onset of coronary artery disease [CAD] and very significantly elevated cholesterol [Chol] level of 10.1 mmol/L and LDL-cholesterol [LDL-C] of 7.9 mmol/L as well as low HDL-C level of 0.51 mmol/L, while 4 siblings were affected with HFH.. Whole genome scan for the autosomal dominant model showed high homology for the affected individuals in several regions including chromosomes [chr] 1 and 2 which harbour PCSK9 and APOB, respectively. Subsequent sequencing of the coding regions of these two and LDLR identified 11 single nucleotide polymorphisms [SNPs] in the LDLR, 8 in the APOB and 6 in the PCSK9 genes. The propositus uniquely carried the homozygous mutant genotypes [haplotype] for all 11 LDLR SNPs, in direct contrast to the only normolipidemic sibling and a control who carried the homozygous wild type genotypes at these loci. Another set of 7 SNPs in the APOB also isolated with FH. Interestingly, all family members were heterozygous for all except the rs2228671 C > T of this gene, for which the mother shared the C/C genotype with the propositus, two other affected off-springs and a control, all of whom exhibited low HDL-C levels. A confirmation experiment involving 70 individuals harbouring low HDL-C revealed 74.3% of them as C/C carriers. Our study identified a haplotype in the LDLR as a marker for early onset of CAD, and rs2228671 C > T in the LDLR in association with a reduction in HDL-C concentrations in FH. The results also substantiate the notion of genetic heterogeneity in HFH, underlining the essence of recognizing ethnic-specific gene variability as a potential basis for appropriate management of FH