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Molecular description of familial defective APOB-100 in Malaysia

Al-Khateeb AR, Mohd MS, Yusof Z, Zilfalil BA

Biochem Genet, 2013 Oct;51(9-10):811-23.
PMID: 23775634 DOI: 10.1007/s10528-013-9609-6

Familial ligand-defective apolipoprotein B-100 is characterized by elevated plasma low-density lipoprotein levels and premature heart disease. This study aims to determine apolipoprotein B gene mutations among Malaysians with clinical diagnoses of familial hypercholesterolemia and to compare the phenotype of patients with apolipoprotein B gene mutations to those with a low-density lipoprotein receptor gene mutation. A group of 164 patients with a clinical diagnosis of familial hypercholesterolemia was analyzed. Amplicons in exon 26 and exon 29 of the apolipoprotein B gene were screened for genetic variants using denaturing gradient high-performance liquid chromatography; 10 variants were identified. Five novel mutations were detected (p.Gln2485Arg, p.Thr3526Ala, p.Glu3666Lys, p.Tyr4343CysfsX221, and p.Arg4297His). Those with familial defective apolipoprotein had a less severe phenotype than those with familial hypercholesterolemia. An apolipoprotein gene defect is present among Malaysian familial hypercholesterolemics. Those with both mutations show a more severe phenotype than those with one gene defect.

Matched MeSH terms: Apolipoprotein B-100/genetics*
Fulltext Use of the denaturing gradient gel electrophoresis (DGGE) method for mutational screening of patients with familial hypercholesterolaemia (FH) and Familial defective apolipoprotein B100 (FDB)

Azian M, Hapizah MN, Khalid BA, Khalid Y, Rosli A, Jamal R

Malays J Pathol, 2006 Jun;28(1):7-15.
PMID: 17694954 MyJurnal

Familial hypercholesterolaemia (FH) and Familial defective apolipoprotein B100 (FDB) are autosomal dominant inherited diseases of lipid metabolism caused by mutations in the low density lipoprotein (LDL) receptor and apolipoprotein B 100 genes. FH is clinically characterised by elevated concentrations of total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C), presence of xanthomata and premature atherosclerosis. Both conditions are associated with coronary artery disease but may be clinically indistinguishable. Seventy-two (72) FH patients were diagnosed based on the Simon Broome's criteria. Mutational screening was performed by polymerase chain reaction (PCR)-denaturing gradient gel electrophoresis (DGGE). Positive mutations were subjected to DNA sequencing for confirmation of the mutation. We successfully amplified all exons in the LDL receptor and apo B100 genes. DGGE was performed in all exons of the LDL receptor (except for exons 4-3', 18 and promoter region) and apo B100 genes. We have identified four different mutations in the LDL receptor gene but no mutation was detected in the apo B 100 gene. The apo B100 gene mutation was not detected on DGGE screening as sequencing was not performed for negative cases on DGGE technique. To our knowledge, the C234S mutation (exon 5) is a novel mutation worldwide. The D69N mutation (exon 3) has been reported locally while the R385W (exon 9) and R716G (exon 15) mutations have not been reported locally. However, only 4 mutations have been identified among 14/72 patients (19.4%) in 39 FH families. Specificity (1-false positive) of this technique was 44.7% based on the fact that 42/76 (55.3%) samples with band shifts showed normal DNA sequencing results. A more sensitive method needs to be addressed in future studies in order to fully characterise the LDLR and apo B100 genes such as denaturing high performance liquid chromatography. In conclusion, we have developed the DNA analysis for FH patients using PCR-DGGE technique. DNA analysis plays an important role to characterise the type of mutations and forms an adjunct to clinical diagnosis.

Matched MeSH terms: Apolipoprotein B-100/genetics*
Fulltext Phenotype-genotype analyses of clinically diagnosed Malaysian familial hypercholestrolemic patients

Al-Khateeb A, Al-Talib H, Mohamed MS, Yusof Z, Zilfalil BA

Adv Clin Exp Med, 2013 Jan-Feb;22(1):57-67.
PMID: 23468263

BACKGROUND: Familial hypercholesterolemia and familial defective apo lipoprotein B are genetic disorders caused by defects in the low-density lipoprotein receptor gene and apo lipoprotein B 100 genes, respectively. The clinical phenotype of both diseases is characterized by increased plasma levels of total cholesterol and low density lipoprotein cholesterol, tendinous xanthomata, and premature coronary heart disease.
OBJECTIVES: The aim of this study is to perform an association study between different gene sequence variants in low-density lipoprotein and apo lipoprotein B 100 genes to the clinical finding and lipid profile parameters of the study subjects.
MATERIAL AND METHODS: A group of 164 familial hypercholesterolemic patients were recruited. The promoter region, exon 2-15 of the low density lipoprotein gene and parts of exon 26 and 29 of apo lipoprotein B 100 gene were screened by Denaturating Gradient High Performance Liquid Chromatography.
RESULTS: For the apo lipoprotein B 100 gene, those with apo lipoprotein B 100 gene mutation have a significantly higher frequency of cardiovascular disease (P = 0.045), higher low density lipoprotein cholesterol and total cholesterol: high density lipoprotein cholesterol ratio than those without mutation (P = 0.03 and 0.02, respectively). For the low density lipoprotein gene defect those with frame shift mutation group showed the worst clinical presentation in terms of low density lipoprotein cholesterol level and cardiovascular frequency.
CONCLUSIONS: There was a statistically significant association between mutations of low density lipoprotein gene and apo lipoprotein B 100 genes and history of cardiovascular disease, younger age of presentation, family history of hyperlipidemia, tendon xanthoma and low density lipoprotein cholesterol level.
Study site: Cardiology Clinic, Hospital Universiti Sains Malaysia (HUSM), Kelantan, Malaysia

Matched MeSH terms: Apolipoprotein B-100/genetics
The impact of APOA5, APOB, APOC3 and ABCA1 gene polymorphisms on ischemic stroke: Evidence from a meta-analysis

Au A, Griffiths LR, Irene L, Kooi CW, Wei LK

Atherosclerosis, 2017 Oct;265:60-70.
PMID: 28865324 DOI: 10.1016/j.atherosclerosis.2017.08.003

BACKGROUND AND AIMS: Genetic studies have been reported on the association between APOA5, APOB, APOC3 and ABCA1 gene polymorphisms and ischemic stroke, but results remain controversial. Hence, this meta-analysis aimed to infer the causal relationships of APOA5 (rs662799, rs3135506), APOB (rs693, rs1042031, rs1801701), APOC3 (rs4520, rs5128, rs2854116, rs2854117) and ABCA1 rs2230806 with ischemic stroke risk.
METHODS: A systematic review was performed for all the articles retrieved from multiple databases, up until March 2017. Data were extracted from all eligible studies, and meta-analysis was carried out using RevMan 5.3 and R package 3.2.1. The strength of association between each studied polymorphism and ischemic stroke risk was measured as odds ratios (ORs) and 95% confidence intervals (CIs), under fixed- and random-effect models.
RESULTS: A total of 79 studies reporting on the association between the studied polymorphisms and ischemic stroke risk were identified. The pooled data indicated that all genetic models of APOA5 rs662799 (ORs = 1.23-1.43), allelic and over-dominant models of APOA5 rs3135506 (ORs = 1.77-1.97), APOB rs1801701 (ORs = 1.72-2.13) and APOB rs1042031 (ORs = 1.66-1.88) as well as dominant model of ABCA1 rs2230806 (OR = 1.31) were significantly associated with higher risk of ischemic stroke. However, no significant associations were observed between ischemic stroke and the other five polymorphisms, namely ApoB (rs693) and APOC3 (rs4520, rs5128, rs2854116 and rs2854117), under any genetic model.
CONCLUSIONS: The present meta-analysis confirmed a significant association of APOA5 rs662799 CC, APOA5 rs3135506 CG, APOB rs1801701 GA, APOB rs1042031 GA and ABCA1 rs2230806 GG with increased risk of ischemic stroke.

Matched MeSH terms: Apolipoprotein B-100/genetics*