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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*
Lactobacillus fermentum FTDC 8312 combats hypercholesterolemia via alteration of gut microbiota

Lye HS, Kato T, Low WY, Taylor TD, Prakash T, Lew LC, et al.

J Biotechnol, 2017 Sep 19.
PMID: 28935567 DOI: 10.1016/j.jbiotec.2017.09.007

In this study, hypercholesterolemic mice fed with Lactobacillus fermentum FTDC 8312 after a seven-week feeding trial showed a reduction in serum total cholesterol (TC) levels, accompanied by a decrease in serum low-density lipoprotein cholesterol (LDL-C) levels, an increase in serum high-density lipoprotein cholesterol (HDL-C) levels, and a decreased ratio of apoB100:apoA1 when compared to those fed with control or a type strain, L. fermentum JCM 1173. These have contributed to a decrease in atherogenic indices (TC/HDL-C) of mice on the FTDC 8312 diet. Serum triglyceride (TG) levels of mice fed with FTDC 8312 and JCM 1173 were comparable to those of the controls. A decreased ratio of cholesterol and phospholipids (C/P) was also observed for mice fed with FTDC 8312, leading to a decreased number of spur red blood cells (RBC) formation in mice. Additionally, there was an increase in fecal TC, TG, and total bile acid levels in mice on FTDC 8312 diet compared to those with JCM 1173 and controls. The administration of FTDC 8312 also altered the gut microbiota population such as an increase in the members of genera Akkermansia and Oscillospira, affecting lipid metabolism and fecal bile excretion in the mice. Overall, we demonstrated that FTDC 8312 exerted a cholesterol lowering effect that may be attributed to gut microbiota modulation.

Matched MeSH terms: Apolipoprotein B-100
Fulltext Absence of Apo B R3500Q Mutation among Kelantanese Malays with Hyperlipidaemia

Kyi WM, Isa MN, Rashid FA, Osman JM, Mansur MA

Malays J Med Sci, 2000 Jan;7(1):16-21.
PMID: 22844210

Familial defective apolipoprotein B-100 (FDB) is an autosomal dominant genetic disorder associated with hypercholesterolaemia and premature coronary heart disease. FDB is caused by mutations in and around the codon 3500 of the apolipoprotein B (apo B) gene. Apo B R3500Q mutation is the first apo B mutation known to be associated with FDB and it is the most frequently reported apo B mutation in several different populations. The objective of the present study was to determine the association of apo B R3500Q mutation with elevated plasma cholesterol concentration in Kelantanese population in which both hypercholesterolaemia and coronary heart disease are common. Sixty-two Malay subjects with hyperlipidaemia, attending the lipid clinic at Hospital Universiti Sains Malaysia, Kelantan, were selected for this study. The DNA samples were analysed for the presence of apo B R3500Q mutation by polymerase chain reaction-based restriction fragment analysis method using mutagenic primers. This mutation was not detected in the subjects selected for this study. Apo B R3500Q mutation does not appear to be a common cause of hypercholesterolaemia in Kelantanese Malays.

Matched MeSH terms: Apolipoprotein B-100
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*
Lipid Metabolism Genes in Stroke Pathogenesis: The Atherosclerosis

Chow YL, Teh LK, Chyi LH, Lim LF, Yee CC, Wei LK

Curr Pharm Des, 2020;26(34):4261-4271.
PMID: 32534558 DOI: 10.2174/1381612826666200614180958

Stroke is the second leading cause of death and a major cause of disability worldwide. Both modifiable and non-modifiable risk factors can affect the occurrence of ischemic stroke at varying degrees. Among them, atherosclerosis has been well-recognized as one of the main culprits for the rising incidence of stroke-related mortality. Hence, the current review aimed to summarize the prominent role of lipid metabolism genes such as PCSK9, ApoB, ApoA5, ApoC3, ApoE, and ABCA1 in mediating ischemic stroke occurrence.

Matched MeSH terms: Apolipoprotein B-100
Fulltext Genetic researches among malaysian familial hypercholesterolaemic population

Al-Khateeb, A, Al-Talib, H

JUMMEC, 2016;19(2):1-11.
MyJurnal

Background:
Familial hypercholesterolaemia (FH) is one of the most frequent inherited metabolic disorders that can lead
to a risk of premature cardiovascular disease. Publications on FH are mainly from western patients as there is
little research on Asians, including Malaysians. The aim of this review is to provide an up-to- date information
on Malaysian studies on FH genotyping and its relation to the phenotype of the affected patients.
Method:
A search was conducted for data from online databases on FH in Malaysia.
Results:
The mutation spectrum for FH among Malaysian patients was extremely broad. The gene variants were located
mainly in the low-density lipoprotein receptor (LDLR) and apolipoprotein B-100 (APOB-100) genes rather than
in the proprotein convertase subtilisin kexin type 9 (PCSK9) gene. The exon 9 and 14 were the hotspots in the
LDLR gene. The most frequent mutation was p.Cys255Ser, at 12.5%, followed by p.Arg471Gly, at 11%, and the
most common single nucleotide polymorphism (SNP) was c.1060+7 T>C at 11.7%. The LDLR gene variants were
more common compared to the APOB-100 gene variants, while variants in the PCSK9 gene were very few.
Phenotype-genotype associations were identified. Subjects with LDLR and APOB-100 genes mutations had a
higher frequency of cardiovascular disease, a family history of hyperlipidaemia and tendon xanthoma and a
higher low-density lipoprotein cholesterol (LDL-C) level than non-carriers.
Conclusion:
Research on Malaysian familial hypercholesterolaemic patients by individual groups is encouraging. However,
more extensive molecular studies on FH on a national scale, with a screening of the disease-causing mutations
together with a comprehensive genotype-phenotype association study, can lead to a better outcome for
patients with the disease.

Matched MeSH terms: Apolipoprotein B-100
Fulltext Denaturing gradient-gel electrophoresis screening of familial defective apolipoprotein B-100 in a mixed Asian cohort: two cases of arginine3500-->tryptophan mutation associated with a unique haplotype

Choong ML, Koay ES, Khoo KL, Khaw MC, Sethi SK

Clin Chem, 1997 Jun;43(6 Pt 1):916-23.
PMID: 9191540

The Arg-to-Trp substitution at codon 3500 in the apolipoprotein (apo) B-100 gene is established as a cause of familial defective apo B-100 (FDB), a functional mutation, resulting in reduced LDL receptor binding and manifest hypercholesterolemia. In a search for similar mutations in 163 Malaysians, we screened the putative receptor-binding region (codons 3456-3553) of the apo B-100 gene by PCR amplification and denaturing gradient-gel electrophoresis. Four single-base mutations were detected and confirmed by DNA sequencing. Two females, a Chinese and a Malay, had the same CGG3500-->TGG mutation, resulting in an Arg3500-to-Trp substitution. This is the second published report of such an independent mutation involving the same codon as the established Arg3500-to-Gln mutation. The two other mutations detected, CTT3517-->CTG and GCC3527-->GCT, resulted in degenerate codons with no amino acid substitutions. All four mutations were associated with a unique apo B haplotype, different from those found in Caucasian FDB patients but concurring with that previously reported for two other Asians with FDB.

Matched MeSH terms: Apolipoprotein B-100