Genetic Study of Low-Density Lipoprotein Receptor Gene and Apolipoprotein B-100 Gene among Malaysian Patients with Familial Hypercholesterolaemia

Background: Autosomal dominant hypercholesterolaemia (ADH) is a genetic disorder that is mainly resulted from defects in the low-density lipoprotein receptor (LDLR) and apolipoprotein B-100(APOB-100) genes. Few studies of familial hypercholesterolaemia (FH) have been conducted in Malaysia, that makes the underlying main defect remains not well understood.Objectives: This study was aimed to describe the molecular aspects of FH among Malaysian subjects.Methods and Findings: We studied a group of 74 familial hypercholesterolaemic patients and 77 healthy control subjects. The promoter region and the 18 exons of the low-density lipoprotein receptor gene were screened by denaturing high-performance liquid chromatography (DHPLC) to detect small deletions, insertions  and nucleotide substitutions, while DNA sequencing was applied to look for gene variants in amplicons  of exon 26 and 29 in the APOB -100 gene. A total of five gene sequence variants in the LDLR gene were reported in 54.1% of the studied patients. P.Arg471Arg variant has the highest frequency of 20.3% among the study subjects. One intronic mutation (c.313+1G>A) and one missense mutation (p.Arg 385Try) were found to be pathogenic, while the other three variants were reported to be non-pathogenic by the in silico analyses. Nine variants were reported in the APOB-100 gene among familial hypercholesterolaemic patients with a non-significant difference in their frequency from the control subjects.Conclusions: five LDLR gene sequence variants were reported. However, nine polymorphisms were stated in the APOB -100 gene. However they were not associated with FH phenotype among this cohort. These findings suggested that LDLR gene mutation is the major genetic cause for FH among Malaysians. The results offer information on the genetic spectrum of FH among Malaysian cohort which can serve as a platform for further genetic studies.