ABSTRACT
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