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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: Hyperlipoproteinemia Type II/blood; Hyperlipoproteinemia Type II/genetics
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: Hyperlipoproteinemia Type II
Low-density lipoprotein receptor gene mutations in a Southeast Asian population with familial hypercholesterolemia

Khoo KL, van Acker P, Defesche JC, Tan H, van de Kerkhof L, Heijnen-van Eijk SJ, et al.

Clin Genet, 2000 Aug;58(2):98-105.
PMID: 11005141 DOI: 10.1034/j.1399-0004.2000.580202.x

The aim of this study was to detect mutations in the genes coding for the low-density lipoprotein receptor and apolipoprotein B in patients of Southeast Asian origin with clinically diagnosed familial hypercholesterolemia (FH) and to relate these findings with the observed lower incidence of coronary heart disease in this part of the world. A total of 86 unrelated patients with FH were selected on clinical grounds, and complete DNA analysis of the low-density lipoprotein (LDL)-receptor and apolipoprotein B (apoB) genes by DGGE and DNA-sequencing was performed. In the majority (73%) of the cohort studied, no mutations could be detected, even after extensive analysis of the LDL-receptor and apoB genes. However, the 22 patients with a mutation had significantly more xanthomas and a higher incidence of coronary heart disease and levels of low-density lipoproteins were also significantly different. There was no correlation between the type of the mutation and lipoprotein levels or clinical signs of atherosclerosis. The fact that the majority of the FH patients studied had no detectable mutation and that this group had a significant milder phenotype, suggests the presence of a third gene in the Southeast Asian population, predominantly leading to a disorder resembling a milder form of FH. A similar, but less frequent, trait has recently been described in a number of European families.

Matched MeSH terms: Hyperlipoproteinemia Type II/ethnology; Hyperlipoproteinemia Type II/genetics*
Fulltext Genetic causes of familial hypercholesterolaemia in a Malaysian population

Khoo KL, Van Acker P, Tan H, Deslypere JP

Med J Malaysia, 2000 Dec;55(4):409-18.
PMID: 11221151

A total of 86 unrelated Malaysian patients with familial hypercholesterolaemia (FH) were studied for mutations in their low-density lipoprotein receptor (LDL-R) gene. Amongst them, 23 had a LDL-R gene mutation, while none having an Apolipoprotein B-3500 (Apo B-3500) mutation. Patients with the LDL-R gene defect appeared to have a higher level of low-density lipoprotein cholesterol (LDL-C), an increased incidence of xanthomas and coronary heart disease (CHD), but no relationships were found between the type of LDL-R gene mutations and their lipid levels or clinical signs of CHD. In contrast to Western data, our findings seemed to indicate a predominance of mutations in the ligand binding domain and an absence of Apo B-3500 gene mutation. The latter finding may offer a genetic basis as to why Asian patients with familial hypercholesterolaemia have lower LDL-C levels and less premature CHD than their Western counterparts.

Matched MeSH terms: Hyperlipoproteinemia Type II/blood; Hyperlipoproteinemia Type II/genetics*
Soluble intercellular adhesion molecule-1 and interleukin-6 levels reflect endothelial dysfunction in patients with primary hypercholesterolaemia treated with atorvastatin

Nawawi H, Osman NS, Annuar R, Khalid BA, Yusoff K

Atherosclerosis, 2003 Aug;169(2):283-91.
PMID: 12921980

Adhesion molecules and cytokines are involved in the pathogenesis of intimal injury in atherosclerosis but their relationship with endothelial function remains unclear. The objectives of this study were to examine the effects of atorvastatin on soluble adhesion molecules, interleukin-6 (IL-6) and brachial artery endothelial-dependent flow mediated dilatation (FMD) in patients with familial (FH) and non-familial hypercholesterolaemia (NFH). A total of 74 patients (27 FH and 47 NFH) were recruited. Fasting lipid profiles, soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular-cellular adhesion molecule-1 (sVCAM-1), E-selectin, IL-6 and FMD were measured at baseline, 2 weeks, 3 and 9 months post-atorvastatin treatment (FH--80 mg/day, NFH--10 mg/day). In both groups, compared to baseline, sICAM-1 levels were significantly reduced at 2 weeks, further reduced at 3 months and maintained at 9 months (P<0.0001). The IL-6 levels were significantly reduced at 3 months and 9 months compared to baseline for FH (P<0.005) and NFH (P<0.0001). In both groups, the FMD at 2 weeks was higher than baseline (P<0.005), with progressive improvement up to 9 months. FMD was negatively correlated with sICAM-1 and IL-6. In conclusion, both low and high doses of atorvastatin lead to early progressive improvement in endothelial function in patients with primary hypercholesterolaemia. sICAM-1 and IL-6 levels reflect endothelial dysfunction in these patients.

Matched MeSH terms: Hyperlipoproteinemia Type II/blood; Hyperlipoproteinemia Type II/drug therapy; Hyperlipoproteinemia Type II/physiopathology
Fulltext Measurement of intima-media thickness of common carotid arteries using ultrasound in patients with familial and non-familial hypercholesterolaemia and correlation of intima-media thickness to obesity

Nafikudin M, Nawawi H, Muid S, Annuar R, Yusoff K, Khalid BAK

Med J Malaysia, 2003 Dec;58(5):647-52.
PMID: 15190648

Ultrasonographic measurements of the intima-media thickness (IMT) of common carotid arteries (CCA) were taken in 50 patients with familial hypercholesterolaemia (FH) and 57 patients with non-familial hypercholesterolemia (NFH). The lipid profile, body mass index (BMI) and waist-hip ratio (WHR) of each patient were recorded. In FH patients, the IMT was significantly higher in overweight and elevated WHR subgroups compared to the normal with significant correlations between BMI and WHR to the IMT. In NFH patients, the IMT was significantly higher in the elevated WHR compared to the normal subgroup but the correlations between either BMI or WHR to IMT were insignificant. These suggest that the environmentally modified anthropometric indices may have an effect on atherosclerosis in genetically determined hypercholesterolaemia in FH patients.

Matched MeSH terms: Hyperlipoproteinemia Type II/complications; Hyperlipoproteinemia Type II/ultrasonography*
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: Hyperlipoproteinemia Type II/genetics*
Bilateral middle ear cholesterol granuloma in familial hypercholesterolemia

Masaany M, Siti HS, Nurliza I, Mazita A

Otolaryngol Head Neck Surg, 2008 Jun;138(6):803-4.
PMID: 18503863 DOI: 10.1016/j.otohns.2008.02.020

Cholesterol granuloma (CG) is a histologic description of foreign body giant cell formation toward cholesterol crystals. The majority of temporal bone CG is unilateral and most common in the petrous apex. Middle ear CG is usually the result of underlying ear diseases. Primary middle ear CG is very rare. Most reported CG has not been associated with familial hypercholesterolemia (FH). FH, an autosomal dominant disorder, manifests as high levels of serum cholesterol and low density lipoprotein (LDL) cholesterol. We report a rare case of FH and bilateral aggressive primary middle ear CG. This publication has been approved by the IRB, Hospital Alor Setar.

Matched MeSH terms: Hyperlipoproteinemia Type II/complications*; Hyperlipoproteinemia Type II/diagnosis; Hyperlipoproteinemia Type II/therapy
Fulltext Analysis of sequence variations in low-density lipoprotein receptor gene among Malaysian patients with familial hypercholesterolemia

Al-Khateeb A, Zahri MK, Mohamed MS, Sasongko TH, Ibrahim S, Yusof Z, et al.

BMC Med Genet, 2011;12:40.
PMID: 21418584 DOI: 10.1186/1471-2350-12-40

Familial hypercholesterolemia is a genetic disorder mainly caused by defects in the low-density lipoprotein receptor gene. Few and limited analyses of familial hypercholesterolemia have been performed in Malaysia, and the underlying mutations therefore remain largely unknown.We studied a group of 154 unrelated FH patients from a northern area of Malaysia (Kelantan). The promoter region and exons 2-15 of the LDLR gene were screened by denaturing high-performance liquid chromatography to detect short deletions and nucleotide substitutions, and by multiplex ligation-dependent probe amplification to detect large rearrangements.

Matched MeSH terms: Hyperlipoproteinemia Type II/complications; Hyperlipoproteinemia Type II/genetics*; Hyperlipoproteinemia Type II/epidemiology
Acute myocardial infarction in an adolescent

Muthupalaniappen L, Menon RK, Das S

Saudi Med J, 2012 Feb;33(2):197-200.
PMID: 22327763

Myocardial infarction (MI) is known to be common in adults. Interestingly, we report a case of a 15-year-old boy who presented with typical chest pain secondary to myocardial infarct attributable to a combination of familial hyperlipidemia and possible episode of Kawasaki disease in the past. The patient failed treatment and follow-up care, and died 2 years later. Although rare, this case demonstrates that MI should be considered as a diagnosis in adolescents presenting with typical chest pain as early detection, and management is vital for survival.

Matched MeSH terms: Hyperlipoproteinemia Type II/complications*
Differences in allele frequencies of autosomal dominant hypercholesterolemia SNPs in the Malaysian population

Alex L, Chahil JK, Lye SH, Bagali P, Ler LW

J Hum Genet, 2012 Jun;57(6):358-62.
PMID: 22534770 DOI: 10.1038/jhg.2012.34

Hypercholesterolemia is caused by different interactions of lifestyle and genetic determinants. At the genetic level, it can be attributed to the interactions of multiple polymorphisms, or as in the example of familial hypercholesterolemia (FH), it can be the result of a single mutation. A large number of genetic markers, mostly single nucleotide polymorphisms (SNP) or mutations in three genes, implicated in autosomal dominant hypercholesterolemia (ADH), viz APOB (apolipoprotein B), LDLR (low density lipoprotein receptor) and PCSK9 (proprotein convertase subtilisin/kexin type-9), have been identified and characterized. However, such studies have been insufficiently undertaken specifically in Malaysia and Southeast Asia in general. The main objective of this study was to identify ADH variants, specifically ADH-causing mutations and hypercholesterolemia-associated polymorphisms in multiethnic Malaysian population. We aimed to evaluate published SNPs in ADH causing genes, in this population and to report any unusual trends. We examined a large number of selected SNPs from previous studies of APOB, LDLR, PCSK9 and other genes, in clinically diagnosed ADH patients (n=141) and healthy control subjects (n=111). Selection of SNPs was initiated by searching within genes reported to be associated with ADH from known databases. The important finding was 137 mono-allelic markers (44.1%) and 173 polymorphic markers (55.8%) in both subject groups. By comparing to publicly available data, out of the 137 mono-allelic markers, 23 markers showed significant differences in allele frequency among Malaysians, European Whites, Han Chinese, Yoruba and Gujarati Indians. Our data can serve as reference for others in related fields of study during the planning of their experiments.

Matched MeSH terms: Hyperlipoproteinemia Type II/genetics*
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: Hyperlipoproteinemia Type II/genetics*
Fulltext Genetic polymorphisms in LDLR, APOB, PCSK9 and other lipid related genes associated with familial hypercholesterolemia in Malaysia

Lye SH, Chahil JK, Bagali P, Alex L, Vadivelu J, Ahmad WA, et al.

PLoS One, 2013;8(4):e60729.
PMID: 23593297 DOI: 10.1371/journal.pone.0060729

Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by elevations in total cholesterol (TC) and low density lipoprotein cholesterol (LDLc). Development of FH can result in the increase of risk for premature cardiovascular diseases (CVD). FH is primarily caused by genetic variations in Low Density Lipoprotein Receptor (LDLR), Apolipoprotein B (APOB) or Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) genes. Although FH has been extensively studied in the Caucasian population, there are limited reports of FH mutations in the Asian population. We investigated the association of previously reported genetic variants that are involved in lipid regulation in our study cohort. A total of 1536 polymorphisms previously implicated in FH were evaluated in 141 consecutive patients with clinical FH (defined by the Dutch Lipid Clinic Network criteria) and 111 unrelated control subjects without FH using high throughput microarray genotyping platform. Fourteen Single Nucleotide Polymorphisms (SNPs) were found to be significantly associated with FH, eleven with increased FH risk and three with decreased FH risk. Of the eleven SNPs associated with an increased risk of FH, only one SNP was found in the LDLR gene, seven in the APOB gene and three in the PCSK9 gene. SNP rs12720762 in APOB gene is associated with the highest risk of FH (odds ratio 14.78, p<0.001). Amongst the FH cases, 108 out of 141 (76.60%) have had at least one significant risk-associated SNP. Our study adds new information and knowledge on the genetic polymorphisms amongst Asians with FH, which may serve as potential markers in risk prediction and disease management.

Matched MeSH terms: Hyperlipoproteinemia Type II/genetics*; Hyperlipoproteinemia Type II/metabolism*; Hyperlipoproteinemia Type II/pathology
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: Hyperlipoproteinemia Type II/blood; Hyperlipoproteinemia Type II/diagnosis*; Hyperlipoproteinemia Type II/genetics*
Fulltext Homozygous familial hypercholesterolemia

Alicezah MK, Razali R, Rahman T, Hoh BP, Suhana NH, Muid S, et al.

Malays J Pathol, 2014 Aug;36(2):131-7.
PMID: 25194536 MyJurnal

We report a rare case of homozygous familial hypercholesterolemia (HoFH), a 22-year-old Malay woman who presented initially with minor soft tissue injury due to a cycling accident. She was then incidentally found to have severe xanthelasma and hypercholesterolemia (serum TC 15.3 mmol/L and LDL-C 13.9 mmol/L). She was referred to the Specialized Lipid Clinic and was diagnosed with familial hypercholesterolemia (FH) based on the Simon Broome (SB) diagnostic criteria. There was a family history of premature coronary heart disease (CHD) in that three siblings had sudden cardiac death, and of consanguineous marriage in that her parents are cousins. DNA screening of LDLR and APOB genes was done by Polymerase Chain Reaction (PCR), followed by Denaturing High Performance Liquid Chromatography (DHPLC). Homozygous mutation C255S in Exon 5 of her LDLR gene was found. There was no mutation was found in Exon 26 and Exon 29 of the APOB gene. This report is to emphasize the importance of identifying patients with FH and cascade screening through established diagnostic criteria and genetic studies in order to ensure early detection and early treatment intervention to minimize the risk of developing CHD and related complications.

Matched MeSH terms: Hyperlipoproteinemia Type II/genetics*
Integrated guidance on the care of familial hypercholesterolemia from the International FH Foundation

Watts GF, Gidding S, Wierzbicki AS, Toth PP, Alonso R, Brown WV, et al.

J Clin Lipidol, 2014 Mar-Apr;8(2):148-72.
PMID: 24636175 DOI: 10.1016/j.jacl.2014.01.002

Familial hypercholesterolemia (FH) is a dominantly inherited disorder present from birth that markedly elevates plasma low-density lipoprotein cholesterol and causes premature coronary heart disease. There are at least 20 million people with FH worldwide, but the majority remains undetected, and current treatment is often suboptimal. To address this major gap in coronary prevention we present, from an international perspective, consensus-based guidance on the care of FH. The guidance was generated from seminars and workshops held at an international symposium. The recommendations focus on the detection, diagnosis, assessment, and management of FH in adults and children and set guidelines for clinical purposes. They also refer to best practice for cascade screening and risk notifying and testing families for FH, including use of genetic testing. Guidance on treatment is based on risk stratification, management of noncholesterol risk factors, and the safe and effective use of low-density lipoprotein-lowering therapies. Recommendations are given on lipoprotein apheresis. The use of emerging therapies for FH is also foreshadowed. This international guidance acknowledges evidence gaps but aims to make the best use of contemporary practice and technology to achieve the best outcomes for the care of FH. It should accordingly be used to inform clinical judgment and be adjusted for country-specific and local healthcare needs and resources.

Matched MeSH terms: Hyperlipoproteinemia Type II/metabolism; Hyperlipoproteinemia Type II/pathology*; Hyperlipoproteinemia Type II/therapy*
Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation

Watts GF, Gidding S, Wierzbicki AS, Toth PP, Alonso R, Brown WV, et al.

Eur J Prev Cardiol, 2015 Jul;22(7):849-54.
PMID: 24776375 DOI: 10.1177/2047487314533218

Familial hypercholesterolaemia (FH) is a dominantly inherited disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL) cholesterol and causes premature coronary heart disease. There are at least 20 million people with FH worldwide, but the majority remains undetected and current treatment is often suboptimal.To address this major gap in coronary prevention we present, from an international perspective, consensus-based guidance on the care of FH. The guidance was generated from seminars and workshops held at an international symposium. The recommendations focus on the detection, diagnosis, assessment and management of FH in adults and children, and set guidelines for clinical purposes. They also refer to best practice for cascade screening and risk notifying and testing families for FH, including use of genetic testing. Guidance on treatment is based on risk stratification, management of non-cholesterol risk factors and safe and effective use of LDL lowering therapies. Recommendations are given on lipoprotein apheresis. The use of emerging therapies for FH is also foreshadowed.This international guidance acknowledges evidence gaps, but aims to make the best use of contemporary practice and technology to achieve the best outcomes for the care of FH. It should accordingly be employed to inform clinical judgment and be adjusted for country-specific and local healthcare needs and resources.

Matched MeSH terms: Hyperlipoproteinemia Type II/blood; Hyperlipoproteinemia Type II/diagnosis; Hyperlipoproteinemia Type II/genetics; Hyperlipoproteinemia Type II/therapy*
Ten years of lipoprotein apheresis for familial hypercholesterolemia in Malaysia: A creative approach by a cardiologist in a developing country

Khoo KL, Page MM, Liew YM, Defesche JC, Watts GF

J Clin Lipidol, 2016 05 13;10(5):1188-94.
PMID: 27678436 DOI: 10.1016/j.jacl.2016.05.006

BACKGROUND: Familial hypercholesterolemia (FH) leads to premature coronary artery disease and aortic stenosis, with undertreated severe forms causing death at a young age. Lipoprotein apheresis (LA) is often required for lowering low-density lipoprotein cholesterol levels in severe FH.
OBJECTIVES: The objective of this study was to present the first experiences with LA in Malaysia, between 2004 and 2014.
METHODS: We retrospectively collected data from patient records to assess the effectiveness, adverse effects, patient quality of life, and costs associated with an LA service for genetically confirmed homozygous and heterozygous FH.
RESULTS: We treated 13 women and 2 men aged 6 to 59 years, 10 with homozygous and 5 with heterozygous FH, all on maximally tolerated cholesterol-lowering drug therapy, for a total of 65 patient-years. Acute lowering of low-density lipoprotein cholesterol post apheresis was 56.3 ± 7.2%, with time-averaged mean lowering of 34.9 ± 13.9%. No patients experienced any cardiovascular events during the period of receiving LA. Patients receiving LA experienced few side effects and enjoyed reasonable quality of life, but inability to continue treatment was frequent because of cost.
CONCLUSION: LA for severe FH can be delivered effectively in the short term in developing nations, but costs are a major barrier to sustaining this mode of treatment for this high-risk group of patients. New drug therapies for FH, such as the proprotein convertase subtilisin/kexin type 9 inhibitors, microsomal triglyceride transfer protein inhibitors, and apolipoprotein-B100 antisense oligonucleotides may allow improved care for these patients, but costs and long-term safety remain as issues to be addressed.

Matched MeSH terms: Hyperlipoproteinemia Type II/therapy*
Fulltext Pooling and expanding registries of familial hypercholesterolaemia to assess gaps in care and improve disease management and outcomes: Rationale and design of the global EAS Familial Hypercholesterolaemia Studies Collaboration

EAS Familial Hypercholesterolaemia Studies Collaboration, Vallejo-Vaz AJ, Akram A, Kondapally Seshasai SR, Cole D, Watts GF, et al.

Atheroscler Suppl, 2016 Dec;22:1-32.
PMID: 27939304 DOI: 10.1016/j.atherosclerosissup.2016.10.001

The potential for global collaborations to better inform public health policy regarding major non-communicable diseases has been successfully demonstrated by several large-scale international consortia. However, the true public health impact of familial hypercholesterolaemia (FH), a common genetic disorder associated with premature cardiovascular disease, is yet to be reliably ascertained using similar approaches. The European Atherosclerosis Society FH Studies Collaboration (EAS FHSC) is a new initiative of international stakeholders which will help establish a global FH registry to generate large-scale, robust data on the burden of FH worldwide.

Matched MeSH terms: Hyperlipoproteinemia Type II/diagnosis; Hyperlipoproteinemia Type II/genetics; Hyperlipoproteinemia Type II/mortality; Hyperlipoproteinemia Type II/therapy*
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: Hyperlipoproteinemia Type II

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