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Aim. To assess biochemical and genetic markers associated with the level of oxidized low density lipoproteides (oxLDL).Material and methods. Patients with various cardiovascular risk according to the SCORE scale were included in this study. Biochemical parameters were measured in blood serum with automatic analyzer Architect C8000 (Abbott, USA). OxLDL level was measured with the hard-phase immune-enzyme assay Oxidized LDL ELIsA (Mercodia, sweden). Genotyping was performed via the Cardio-MetaboChip microarrays (Illumina, USA). Seventeen single-nucleotide polymorphisms (SNP) of the APOB gene were included into analysis: rs676210, rs1042034, rs6728178, rs6754295, rs673548, rs6711016, rs11902417, rs10184054, rs6544366, rs4564803, rs7557067, rs2678379, rs533617, rs679899, rs1801695, rs1367117, rs1042031. The association study between SNP and oxLDL level was performed by the ROC-analysis. Based on results, the group of SNP was selected. According to this group, the total SCORE (TS) showing the level of genetic susceptibility to an increased oxLDL level was calculated.Results. The present study included 717 patients ranging from 28 to 84 years old (with the median of 57), 204 men (28.45%). The oxLDL level varied from 21,03 to 163,72 U/dL (median 68,5) and correlated with the levels of total cholesterol (TC), triglycerides (TG), low density cholesterol (LDL-C), C-reactive protein (C-RP) and apolipoprotein B-100 (ApoB-100). The highest coefficients of correlations (p3 (p

Purpose of the Review Identification of loci and common single-nucleotide polymorphisms (SNPs) that have modest effects on plasma lipids have been used to confirm or refute the causal role of lipid traits in the development of coronary heart disease (CHD), and as tools to identify individuals with polygenic hypercholesterolemia. Recent Findings Several groups have reported on the use of SNP scores in distinguishing individuals with a clinical diagnosis of familial hypercholesterolemia (FH) with a monogenic or polygenic etiology. We review evidence that those with monogenic FH have worse prognosis and discuss the possible mechanisms for this and their management. Summary Individuals with a clinical phenotype of FH and a monogenic cause are at greater risk of CHD than those where no causative mutation can be found. The patients with polygenic hypercholesterolemia would not require elaborate cascade screening or secondary care input for their management.

Introdução: O fígado gordo não alcoólico, a principal causa de doença hepática crónica na criança, é definida por infiltração de gordura hepática em >5% dos hepatócitos, na ausência de ingestão alcoólica excessiva, evidência de doença vírica, autoimune ou induzida por drogas. Doenças genéticas raras são condições a considerar no seu diagnóstico diferencial. Caso Clínico: Apresentam-se os casos de dois irmãos do sexo masculino, e de uma criança do sexo feminino, todos com excesso de peso e esteatose hepática. Um dos irmãos e a criança do sexo feminino apresentavam também elevação das transaminases; todos os casos associados a baixos níveis de colesterol total, lipoproteínas de baixa densidade e lipoproteínas de muito baixa densidade, hipotrigliceridemia e baixos níveis de apolipoproteina B. A biópsia hepática realizada num dos irmãos com citólise confirmou a presença de esteatohepatite e o estudo molecular do gene da apolipoproteina B mostrou a presença de uma nova mutação em homozigotia (c.9353dup p.Asn3118Lysfs17). Os doentes com citólise perderam peso, no􀀁 entanto, a esteatose hepática manteve-se. Conclusão: A doença hepática não-alcoólica poderá ser uma consequência da hipobetalipoproteinemia. A evidência científica é escassa, dado o baixo número de casos descritos.

Familial hypercholesterolemia (FH) is a monogenic dominant inherited disorder of lipid metabolism characterized by elevated low-density lipoprotein levels, and is mainly attributable to mutations in low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proportein convertase subtilisin/kexin type 9 (PCSK9) genes. Next-generation and exome sequencing studies have primarily involved genome-wide association analyses, and meta-analyses and next-generation studies examined a few single-nucleotide polymorphisms (rs151009667 and Val2095Glu) in the ApoB gene. The present study was conducted to investigate the association of APOB and patients with FH in a Saudi population. We genotyped 100 patients with FH and 100 controls for 2 polymorphisms in APOB using polymerase chain reaction-restriction fragment length polymorphism, followed by 3% agarose gel electrophoresis. The strength of the association between the genotype and allele frequencies with the risk of developing FH was evaluated. Clinical details and genotype analysis results were recorded. For the rs151009667 polymorphism, 18% of the CT genotypes were observed only in patients with FH. There was a positive association between CT and CC (odds ratio [OR] 45.07 [95% conflict of interest (CI), 2.67–759.1]; P = .0001) and between T and C (OR 87.8 [95% CI, 5.34–144.2]; P

Background: Familial hypobetalipoproteinemia type 1 (FHBL-1) is a codominant disorder characterized by greatly reduced plasma levels of total cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B. Rare exonic pathogenic variants of APOB gene (nonsense variants, minute deletions/insertions and nonsynonymous variants) have been frequently reported in subjects with FHBL-1. Also, rare intronic variants of APOB located at intron/exon junctions and assumed to affect splicing have been reported. However, the pathogenicity of most of these intronic variants remains to be established. Objective: The objective of this study was the in vitro functional characterization of six splicing variants of APOB gene identified in seven putative FHBL-1 heterozygotes. Methods: ApoB minigenes harboring each variant were expressed in COS-1 cells and their transcripts were sequenced. Results: Four novel variants (c.237+1G>A, c.818+5G>A, c.3000-1G>T, and c.3842+1G>A), predicted in silico to obliterate splice site activity, were found to generate abnormal transcripts. The abnormal transcripts were generated by the activation of cryptic splice sites or exon skipping. All these transcripts harbored a premature termination codon and were predicted to encode truncated apoBs devoid of function. The predicted translation products were: i) p.(Lys41Serfs*2) and p.(Val80Ilefs*10) for c.237+1G>A; ii) p.(Asn274*) for c.818+5G>A; iii) p.(Leu1001Alafs*10) for c.3000-1G>T, and iv) p.(Ser1281Argfs*2) for c.3842+1G>A. Two previously annotated rare variants (c.905-15C>G and c.1618-4G>A) with uncertain effect in silico were found to generate only wild-type transcripts. Conclusions: These in vitro minigene expression studies support the assignment of pathogenicity to four novel splice site variants of APOB gene found in FHBL-1.

Oxidatively modified low-density lipoproteins (oxLDL) play an important role in the occurrence and progression of atherosclerosis. To identify the genetic factors influencing the oxLDL levels, we have genotyped 776 DNA samples of Russian individuals for 196,725 single-nucleotide polymorphisms (SNPs) using the Cardio-MetaboChip (Illumina, USA) and conducted genome-wide association study (GWAS). Fourteen common variants in the locus including APOB gene were significantly associated with the oxLDL levels (P < 2.18 × 10-7). These variants explained only 6% of the variation in the oxLDL levels. Then, we assessed the contribution of rare coding variants of APOB gene to the oxLDL levels. Individuals with the extreme oxLDL levels (48 with the lowest and 48 with the highest values) were selected for targeted sequencing of the region including APOB gene. To evaluate the contribution of the SNPs to the oxLDL levels we used various statistical methods for the association analysis of rare variants: WST, SKAT, and SKAT-O. We revealed that both synonymous and nonsynonymous SNPs affected the oxLDL levels. For the joint analysis of the rare and common variants, we conducted the SKAT-C testing and found a group of 15 SNPs significantly associated with the oxLDL levels (P = 2.14 × 10-9). Our results indicate that the oxLDL levels depend on both common and rare variants of the APOB gene.

The RNA interference pathway (RNAi) is a specific and powerful biological process, triggered by small non-coding RNA molecules and involved in gene expression regulation. In this work, we explored the possibility of increasing the biological stability of these RNA molecules by replacing their natural ribose ring with an acyclic L-threoninol backbone. In particular, this modification has been incorporated at certain positions of the oligonucleotide strands and its effects on the biological properties of the siRNA have been evaluated. In vitro cellular RNAi assays have demonstrated that the L-threoninol backbone is well tolerated by the RNAi machinery in both double and single-stranded fashion, with activities significantly higher than those evinced by the unmodified RNAs and comparable to the well-known phosphorothioate modification. Additionally, this modification conferred extremely strong resistance to serum and 3′/5′-exonucleases. In view of these results, we applied this modification to the knockdown of a therapeutically relevant human gene such as apolipoprotein B ( ApoB). Further studies on the activation of the innate immune system showed that L-threoninol-modified RNAs are slightly less stimulatory than unmodified RNAs., This study was supported by the European Union (MULTIFUN, NMP4-LA-2011-262943), the Spanish Ministry of Education (CTQ2010-20541), Generalitat de Catalunya (2009/SGR/208). CIBER-BBN is an initiative funded by the VI National R&D&i Plan 2008-2011, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions and financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund. We are indebted to Elisa Pedone for her helpful advice and for providing technical assistance.

Ana Catarina Alves, colaboradora do grupo de investigação cardiovascular do Departamento da Promoção da Saúde e Prevenção de Doenças Não Transmissíveis do INSA, IP e aluna de doutoramento da Faculdade de Ciências da Universidade de Lisboa recebeu com este estudo, no dia 2 de junho de 2014, o Prémio Jovem Investigador atribuído pela Sociedade Europeia de Aterosclerose. Familial hypercholesterolaemia (FH) is characterized by increased circulating low-density lipoprotein (LDL) cholesterol leading to premature atherosclerosis and coronary heart disease. Although FH is usually caused by mutations in LDLR, mutations in APOB and PCSK9 also cause FH but only a few mutations have been reported, APOB p.R3527Q being the most common. However, 30-80% of clinical FH patients do not present an identifiable mutation in any of the described genes. To identify the genetic cause of the hypercholesterolaemia in 65 patients without mutations in LDLR, PCSK9 or in fragments of exon 26 and 29 of APOB currently analysed, we performed whole sequencing of APOB by pyrosequencing. A total of 10 putative mutations in APOB were identified. Flow cytometry with fluorescently labelled LDL from patients and relatives showed that p.Arg1164Thr (exon 22) and p.Gln4494del (exon 29) presented a 40% decrease in internalization in lymphocytes and HepG2 cells, very similar to APOB3527. The proliferation assays with U937 cells showed reduced growth for both cases. The variant p.Tyr1247Cys was found to be neutral and other three alterations were considered polymorphisms. Our results emphasize the need to study the whole APOB in routine protocols to improve patient identification and cardiovascular risk assessment.

Background The most frequent monogenic causes of low plasma cholesterol are familial hypobetalipoproteinemia (FHBL1) because of truncating mutations in apolipoprotein B coding gene (APOB) and familial combined hypolipidemia (FHBL2) due to loss-of-function mutations in ANGPTL3 gene. Objective A direct comparison of lipid phenotypes of these 2 conditions has never been carried out. In addition, although an increased prevalence of liver steatosis in FHBL1 has been consistently reported, the hepatic consequences of FHBL2 are not well established. Methods We investigated 350 subjects, 67 heterozygous carriers of APOB mutations, 63 carriers of the p.S17* mutation in ANGPTL3 (57 heterozygotes and 6 homozygotes), and 220 noncarrier normolipemic controls. Prevalence and degree of hepatic steatosis were assessed by ultrasonography. Results A steady decrease of low-density lipoprotein cholesterol levels were observed from heterozygous to homozygous FHBL2 and to FHBL1 individuals, with the lowest levels in heterozygous FHBL1 carrying truncating mutations in exons 1 to 25 of APOB (P for trend

Background: Non-alcoholic fatty liver disease, the leading cause of chronic liver disease in children, is defined by hepatic fat infiltration >5% of hepatocytes, in the absence of excessive alcohol intake, evidence of viral, autoimmune or drug-induced liver disease. Conditions like rare genetic disorders must be considered in the differential diagnosis. Case Report: Two male brothers, and a non-related girl, all overweight, had liver steatosis. One of the brothers and the girl had elevated transaminases; all three presented with low total cholesterol, low density lipoproteins and very low density lipoproteins cholesterol levels, hypotriglyceridemia and low apolipoprotein B. A liver biopsy performed in the brother with citolysis confirmed steatohepatitis and the molecular study of apolipoprotein B gene showed a novel homozygous mutation (c.9353dup p.Asn3118Lysfs17). Patients with cytolysis lost weight, however liver steatosis persists. Conclusion: Fatty liver disease might be a consequence of hypobetalipoproteinemia. Evidence is scarce due to low number of reported cases. Introdução: O fígado gordo não alcoólico, a principal causa de doença hepática crónica na criança, é definida por infiltração de gordura hepática em >5% dos hepatócitos, na ausência de ingestão alcoólica excessiva, evidência de doença vírica, autoimune ou induzida por drogas. Doenças genéticas raras são condições a considerar no seu diagnóstico diferencial. Caso Clínico: Apresentam-se os casos de dois irmãos do sexo masculino, e de uma criança do sexo feminino, todos com excesso de peso e esteatose hepática. Um dos irmãos e a criança do sexo feminino apresentavam também elevação das transaminases; todos os casos associados a baixos níveis de colesterol total, lipoproteínas de baixa densidade e lipoproteínas de muito baixa densidade, hipotrigliceridemia e baixos níveis de apolipoproteina B. A biópsia hepática realizada num dos irmãos com citólise confirmou a presença de esteatohepatite e o estudo molecular do gene da apolipoproteina B mostrou a presença de uma nova mutação em homozigotia (c.9353dup p.Asn3118Lysfs17). Os doentes com citólise perderam peso, no entanto, a esteatose hepática manteve-se. Conclusão: A doença hepática não-alcoólica poderá ser uma consequência da hipobetalipoproteinemia. A evidência científica é escassa, dado o baixo número de casos descritos.

Role of theAPOBGene Polymorphism (c.12669G>A, p. Gln4154Lys) in Coronary Artery Disease in the Indian Punjabi PopulationHigh concentration of apolipoprotein B (apoB) is a risk factor for coronary artery disease (CAD). The association of theAPOBgene polymorphism c.12669G>A, p. Gln4154Lys with the risk of CAD varies considerably in different populations. The present study represents the first investigation regarding the role of thisAPOBgene polymorphism with CAD in the Indian Punjabi population. We have studied theAPOBgene polymorphism c.12669G>A, p. Gln4154Lys and its relationship with lipid, apoB, low-density lipoprotein (LDL) heterogeneity and oxidation in subjects suffering from CAD. The study was conducted on 87 patients with CAD; 75 healthy subjects served as controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to determine the DNA polymorphism in theAPOBgene. Frequency of R-(mutant) allele was significantly high (pAPOBgenotypes were insignificant (p>0.05). However, serum apoB levels were significantly raised (pAPOBgenotype. Coronary artery disease patients had raised significantly raised (pAPOBgenotype as compared to controls. Carriers of the R- allele are at higher risk of CAD, probably because of elevated serum apoB levels in the Indian Punjabi population. Overall, it may be concluded that the R- allele might be associated with increased susceptibility towards CAD development in the Indian Punjabi population, and one of the linking factor is the elevation in serum apoB levels. However, this association needs further evaluation in a larger population. Secondly, the robust mechanism behind the positive association of the R- allele with raised serum apoB levels needs to be explored, which might be helpful in the strengthening the observed results.

Background Familial hypercholesterolemia (FH) is a monogenic disorder of lipoprotein metabolism leading to an increased risk of premature cardiovascular disease. Genetic testing for FH is not commonly used in Asian countries. We aimed to define the genetic spectrum of FH in Hong Kong and to test the feasibility of cascade genetic screening. Methods Ninety‐six Chinese subjects with a clinical diagnosis of FH were recruited, and family‐based cascade screening incorporating genetic testing results was performed. Results Forty‐two distinct mutations were identified in 67% of the index FH cases. The majority of causative mutations were in the LDLR gene. The three commonest mutations in the LDLR gene were NM_000527.4(LDLR): c.1241 T>G, NM_000527.4(LDLR): c.1474G>A, and NM_000527.4(LDLR): c. 682G>A, and nine novel variants were identified. The NM_000384.2(APOB): c.10579 C>T variant of the APOB gene was found in 5% of the index subjects. The presence of causative mutation significantly increased the odds of successful family recruitment for screening with an OR of 3.7 (95% CI: 1.53–9.11, p = 0.004). Conclusion Approximately two‐third of the subjects in this clinically ascertained sample of patients with FH had a discrete genetic basis. Genetic identification improves the response rate and efficiency of family screening.

Background Homozygous familial hypercholesterolemia is a rare clinical phenotype with a variable expression, which is characterized by extremely elevated plasma low-density lipoprotein (LDL), tendon and skin xanthomas, and a progressive atherosclerosis. In 95% of patients, homozygous familial hypercholesterolemia is due to mutations in low-density lipoprotein receptor ( LDLR ) gene, which abolish (receptor-negative) or greatly reduce (receptor-defective) LDLR function. Objective The objective of the study was the molecular and phenotypic characterization of 4 siblings with severe hypercholesterolemia. Methods The major LDL-related genes ( LDLR , APOB , PCSK9 , ANGPTL3 , APOE , and APOC3 ) were sequenced. LDLR messenger RNA, isolated from leukocytes, was reverse transcribed and sequenced. Results The index cases were 24-year-old identical twin sisters with long-standing tendon xanthomas and high low-density lipoprotein cholesterol (LDL-C ∼10 mmol/L) but no coronary heart disease. They were carriers of 2 LDLR mutations: (1) a previously reported mutation [p.(G335S)] inherited from the mother who had LDL-C level within normal range; (2) a novel 24 bp deletion in exon 8/intron 8 junction inherited from the hypercholesterolemic (LDL-C 6.1 mmol/L) father. The deletion allele encodes an messenger RNA with a partial deletion of exon 8, whose translation product has an in-frame deletion of 17 amino acids [p.(Glu380_Gly396del)]. Family screening revealed that the 2 siblings of the twin sisters were also compound heterozygotes but had much lower LDL-C levels (8.2 and 7.1 mmol/L). The sequence of potential modifying genes showed that the 2 siblings and the mother of the twin sisters were heterozygous for a rare missense variant of apoB [p.(S2429T)], which might have an LDL-lowering effect. Conclusions We report a rare event of 4 siblings found to be compound heterozygotes for 2 LDLR gene mutations but showing a different phenotype severity. The less severely affected siblings were carriers of a rare apoB missense variant.

Diarrhoea is a common clinical problem for treating clinicians in developing countries. Mostly, it is attributed to malnutrition and infection. We, as clinicians, tend to miss some of cases who have inherited enteropathies because of lack of suspicion and non availability of diagnostic facilities. Here, we report a case of homozygous hypobetalipoproteinaemia in a nine-month-old female patient presenting with chronic diarrhoea and failure to thrive. Simple parental screening of lipid parameters led to correct diagnosis and early intervention in present case.

Monogenic hypercholesterolemia is a group of lipid disorders, most of which have autosomal dominant transmission. Familial defective apoB (FDB) resulting from mutations in the APOB gene is a well-recognized cause of autosomal dominant monogenic hypercholesterolemia (ADMH). However, the frequency of FDB among patients with ADMH is not well established. The aim of our research was to screen for mutations responsible for FDB in subjects with a clinical diagnosis of familial hypercholesterolemia. We studied 408 patients from the Spanish Register of Familial Hypercholesterolemia, proportionally distributed among all Spanish regions. Abnormal SSCP patterns of the APOB gene were checked by DNA sequencing and restriction analysis. Three out of the 408 patients were carriers of the R3500Q mutation, and 2 subjects were carriers of the silent T3552T mutation; in both of these patients functional mutations in the LDL receptor gene were found. We conclude that FDB is not a common cause of ADMH in Spain; the R3500Q mutation is the only mutation in APOB causing FDB, and the LDL receptor binding domain of APOB is highly conserved in the studied sample.

Familial hypobetalipoproteinemia (FHBL), an autosomal co-dominant disorder, is associated with reduced plasma concentrations (5th percentile for age and sex) of apolipoprotein (apo) B and beta-migrating lipoproteins. To date, only mutations in APOB encoding prematurely truncated apoB have been found in FHBL. We discovered a novel APOB gene mutation, namely R463W, in an extended Christian Lebanese FHBL kindred. Heterozygotes for R463W had the typical FHBL phenotype, whereas homozygotes had barely detectable apoB-100. The effect of the R463W mutation on apoB secretion was examined using transfected McA-RH7777 cells that expressed one of two recombinant human apoBs, namely B48 and B17. In both cases, the mutant proteins (B48RW and B17RW) were retained within the endoplasmic reticulum and were secreted poorly compared with their wild-type counterparts. Pulse-chase analysis showed that secretion efficiencies of B48RW and B17RW were, respectively, 45 and 40% lower than those of the wild-types. Substitution of Arg(463) with Ala in apoB-17 (B17RA) decreased secretion efficiency by approximately 50%, but substitution with Lys (B17RK) had no effect on secretion, indicating that the positive charge was important. Molecular modeling of apoB predicted that Arg(463) was in close proximity to Glu(756) and Asp(456). Substitution of Glu(756) with Gln (B17EQ) had no effect on secretion, but substitution of Asp(456) with Asn (B17DN) decreased secretion to the same extent as B17RW. In co-transfection experiments, the mutant B17RW showed increased binding to microsomal triglyceride transfer protein as compared with wild-type B17. Thus, the naturally occurring R463W mutant reveals a key local domain governing assembly and secretion of apoB-containing lipoproteins.

The present paper informs about allele frequency distributions for the two VNTR loci (ApoB, D1S80) in Slovak Romanies from Jarovnice and Richnava settlements. The results are compared with the data of non-Romany Slovak population. Thirteen segregating alleles were detected in a total sample of 267 Romany individuals on the locus ApoB. The most frequent alleles were 37 and 35 on the locus for ApoB gene. Genotype 37/37 occurs as the most frequent in Slovak Romany population. 13 alleles were detected in a total sample of 198 Romany individuals on the locus D1S80. Alleles 24 and 18 and genotype 24/24 were the most frequent in Romany individuals.

Familial hypobetalipoproteinemia (FHBL) is commonly caused by mutations in the apolipoprotein B gene ( APOB ). The APOB gene encodes 2 proteins, apolipoprotein (apo) B-48 and apo B-100. Apo B-48 is formed in the intestine and is essential for the formation and recognition of dietary derived chylomicrons, and apo B-100 is found in VLDLs and LDLs of hepatic origin and is involved in the endogenous transport of triglycerides, cholesterol, and fat-soluble vitamins. A number of abnormally truncated apo B proteins have been described, and by convention are referred to by a centile system reflecting their apparent M r in relation to apo B-100 (1). Truncations shorter than apo B-27 are not expressed in lipoproteins, and those shorter than apo B-75 are underrepresented in LDL (2)(3)(4). Consequently homozygous mutations in the N-terminal third of APOB result in the virtual absence of both apo B-48 and apo B-100 and their corresponding lipoproteins, and thus very low concentrations of plasma triglycerides, cholesterol, and the fat-soluble vitamins. This condition …

La hipobetalipoproteinemia familiar (HBF) es un trastorno infrecuente, con un patrón de herencia heterogéneo, que da origen a valores anormalmente disminuidos de apoproteína (apo) B, colesterol total o lipoproteínas de baja densidad (c-LDL). Los pacientes portadores de mutaciones en el gen APOB (2p24) en heterozigosis suelen ser asintomáticos, pero aquellos que las portan en homozigosis pueden presentar diferentes alteraciones clínicas, debidas a la malabsorción de grasas y deficiencia de vitaminas liposolubles.Se presenta un varón asintomático de 8 años y 7 meses de edad con disminución de los niveles de colesterol total, triglicéridos, c-LDL, lipoproteínas de muy baja densidad (c-VLDL) y apo-B, así como deficiencia de vitamina E. Un total de 3 familiares también asintomáticos presentaron niveles disminuidos de colesterol total, c-LDL y apo-B. La secuenciación del gen APOB demostró, tanto en el paciente como en los 3 familiares afectados, una mutación en heterozigosis en el exón número 26 (G → T). El estudio genético familiar en la HBF puede ser útil para la detección de los portadores homozigotos y la instauración de tratamiento precoz. : Familial hypobetalipoproteinemia (FHB) is a rare genetically heterogeneous disorder provoking abnormally low serum levels of apoprotein (apo) B, total cholesterol, and low-density lipoprotein (LDL-C). Patients carrying heterozygous mutations in the APOB (2p24) gene are usually asymptomatic, but homozygous mutations cause clinical disturbances as a result of intestinal fat malabsorption and fat-soluble vitamin deficiency.We present an asymptomatic boy, aged 8 years and 7 months, with low serum levels of apo-B, total cholesterol, triglyceride, LDL-C and very low-density lipoprotein (VLDL-C), as well as vitamin E deficiency. Three asymptomatic relatives also exhibited low apo-B, total cholesterol and LDL-C levels. The APOB (2p24) gene was fully sequenced, demonstrating a heterozygous mutation in exon 26 (G → T) in all four members of this family. Familial genetic studies in FHB could be useful in the early detection and treatment of homozygous carriers.

We have analyzed allele frequency distribution at the hypervariable locus 3 to the apolipoprotein B gene in a healthy population sample (241 women and 246 men) from the Belgrade area. The bimodal distribution of sixteen different hypervariable region (HVR) alleles and the heterozygosity index (average 0.76) in both samples are similar to ones reported for other Caucasian populations. However, we found the hypervariable element containing 34 repeats-HVE34 allele to be the most common one in both female and male samples, and that there was a lower frequency of the HVE GT 36 alleles. For further analysis of 3HVR allele frequency and its possible association with serum lipid levels, all HVR alleles were grouped into five main types (HVE LT 32, HVE32, HVE34, HVE36, and HVE GT 36), and the samples were divided into lipid quartiles. We found that (1) apo B gene 3HVR polymorphism is associated with variation of normal lipid levels in males, (2) HVE32 alleles are associated with decreased serum levels of total cholesterol, LDL cholesterol, and triglycerides, and (3) HVR genotypes containing HVE34 and HVE36 alleles are associated with elevated serum levels of total cholesterol, low density lipoprotein (LDL) cholesterol, and triglycerides. (C) 1998 Wiley-Liss, Inc.

Familial hypobetalipoproteinemia (FHBL) exists in three forms: a) FHBL genetically linked to truncated forms of apolipoprotein B (apoB); b) FHBL linked to the apoB gene but with no apoB truncations; and c) FHBL not linked to the apoB gene. Mean production rate (PR) of apoB-100 in FHBL subjects heterozygous for apoB truncations is approximately 30% of normal. In a 49-member D-kindred (FHBL phenotype defined as apoB < 40 mg/dl), no apoB truncations were detectable either by immunoblotting of plasma or by sequencing of relevant stretches of the apoB gene. Herein we report on the kinetic parameters of apoB-100-containing lipoproteins in four affected members of the D-kindred, and compare their kinetic values to 14 normal subjects, and 8 previously reported FHBL subjects heterozygous for various truncated forms of apoB. After an 8-h primed intravenous infusion of [13C]-leucine, enrichments of apoB-100 were assessed by gas chromatography-mass spectrometry and kinetic parameters were calculated by multicompartmental modeling. The affected members of the D-kindred had similar very low, intermediate, and low density lipoprotein (VLDL, IDL, and LDL) PRs as normal controls, but their fractional catabolic rates (FCR) for VLDL and LDL were approximately 2 and 3 times higher, respectively, than those of normals. By contrast in apoB truncation subjects, apoB-100 PRs were uniformly reduced, while apoB-100 FCRs were similar to normals. Thus, diverse physiologic mechanisms are responsible for the low apoB levels in these two different, genetically determined forms of FHBL.

ObjectiveTo study correlation between the Xba I polymorphism of apoB gene and plasma lipid profiles in Li ethnic group.MethodsTotal 151 cases of healthy Li people were recruited randomly by cluster sampling and 200 Han people were recruited as control; blood was drawn to analyze Xba I polymorphism distribution of apoB gene and serum lipid levels.ResultsThere were lower serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) levels in serum of Li people; while, high density lipoprotein cholesterol (HDL-C), X−/X+ genotype and X+ allele frequencies exhibited higher levels than Han people. Interestingly, HDL-C level was reduced, while LDL-C level was enhanced in subjects carrying heterozygous (X−/X+) genotype compared to homozygous (X−/X−) genotype. Additionally, there were no difference in serum level of triglyceride, TC, apoprotein A (apo A) and apoprotein B (apo B) between Li and Han people, the same results were showed between X−/X+ and X−/X− genotype carriers.ConclusionsXba I polymorphism of apoB gene is correlated to the profiles of serum lipid level, X−/X+ genotype carriers are phenotyped with higher LDL-C level and lower level of HDL-C in Li ethnic group.

Familial defective apolipoprotein B (FDB) is an autosomal dominant genetic disorder causing hypercholesterolemia in affected patients. It is occurring due to mutation of apoB gene leading to a decreased low density lipoprotein (LDL) particles clearance. The R3527Q mutation is one of the disease’s causative mutations. Data support mutation’s origin 6000-7000 years ago in Central Europe and its prevalence is decreasing in relation to the distance from where initially occurred. Until now, the presence of R3527Q mutation had not been confirmed in Greece. This is the first report of FDB due to R3527Q mutation in a family in Northwest Greece.

BACKGROUND: In the Netherlands, a screening programme was set up in 1994 in order to identify all patients with familial hypercholesterolaemia (FH). After 15 years of screening, we evaluated the geographical distribution, possible founder effects and clinical phenotype of the 12 most prevalent FH gene mutations. METHODS: Patients who carried one of the 12 most prevalent mutations, index cases and those identified between 1994 and 2009 through the screening programme and whose postal code was known were included in the study. Low-density lipoprotein cholesterol (LDL-C) levels at the time of screening were retrieved. The prevalence of identified FH patients in each postal code area was calculated and visualised in different maps. RESULTS: A total of 10,889 patients were included in the study. Mean untreated LDL-C levels ranged from 4.4 to 6.4 mmol/l. For almost all mutations, a region of high prevalence could be observed. In total, 51 homozygous patients were identified in the Netherlands, of which 13 true homozygous for one of the 12 most prevalent mutations. The majority of them were living in high-prevalence areas for that specific mutation. CONCLUSIONS: Phenotypes with regard to LDL-C levels varied between the 12 most prevalent FH mutations. For most of these mutations, a founder effect was observed. Our observations can have implications with regard to the efficiency of molecular screening and physician's perception of FH and to the understanding of the prevalence and distribution of homozygous patients in the Netherlands.