Bimonthly update: lipidology. Genetics and molecular biology.
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Animals↗
Biomedical subjects
P J Talmud
Publications and source records attributed to P J Talmud.
Contribution of apolipoprotein C-III gene variants to determination of triglyceride levels and interaction with smoking in middle-aged men.
Variation within and around the apolipoprotein C-III (APOC3) gene has been associated with elevated triglyceride (Tg) levels and cardiovascular disease. The associations of 4 polymorphic variants in the APOC3 gene (3238C>G in the 3' untranslated region [SST:I], 1100C>T in exon 3, -482C>T in the insulin-responsive element, and -2854T>G in the APOC3-A4 intergenic region) with plasma Tg and cholesterol levels and their interaction with smoking have been investigated in the Second Northwick Park Heart Study (NPHSII), a large cohort of healthy men (n=2745). Analyzing the variants separately showed that 3238G, 1100T, and -482T alleles were all associated with raised Tg levels. For the 3238C>G and -482C>T sites, the Tg-raising effect appeared to depend on smoking status (test for interaction, P:=0.042 and P:=0.009, respectively), but for the 1100C>T site, the effect was constant irrespective of smoking status (test for interaction, P:=0.27). The -2854T>G site was not associated with effects on Tg levels in this sample. Because all of the variants showed significant allelic association, regression modeling was used to quantify the relative size of each effect and to assess whether the effects of the separate variants were independent. The 1100C>T variant had an independent effect on Tg levels that was not influenced by smoking status (increase of 8.2% in Tg with each T1100 allele), whereas the -482C>T variant had a separate effect that was dependent on smoking (increase of 13.7% in Tg for each -482T allele in current smokers, 8.6% in exsmokers, and -7.4% in those who never smoked). The 3238C>G variant did not show a separate independent effect on Tg concentration. Thus, by use of the regression model, it was possible to estimate how mean Tg levels would vary in groups of individuals with respect to APOC3 genotype and smoking information. Analysis in this large group of healthy men has allowed the identification of a statistically robust APOC3 genotype-smoking interaction, which now warrants further molecular study.
Alleles↗
Genotypic associations of the hepatic secretion of VLDL apolipoprotein B-100 in obesity.
We examined the effect of genetic polymorphisms of proteins regulating intrahepatic processing of apolipoprotein B-100 (apoB) and the supply of neutral lipids to the liver on the hepatic secretion of very low density lipoprotein (VLDL) apoB in obesity. Hepatic secretion of very low density apolipoprotein B-100 (VLDL apoB) was measured using an infusion of [1-(13)C]leucine in 29 obese men. Isotopic enrichment and turnover of VLDL apoB was determined using gas chromatography-mass spectrometry and multi-compartmental modelling, respectively. Visceral fat was measured by magnetic resonance imaging. Genotypes for the apoB signal peptide (SP27/SP24 alleles), microsomal triglyceride transfer protein promoter (MTP, -493 G/T alleles), apoE (E2, E3, E4 alleles), hepatic lipase promoter (-514 C/T alleles), and cholesteryl ester transfer protein (CETP, Taq1B B1/B2 alleles) were determined using polymerase chain reaction. Statistically significant associations were found between hepatic secretion of apoB and allelic combinations of i) apoB SP with apoE (P = 0.02), hepatic lipase (P = 0.02), and CETP (P = 0. 006) genes, ii) MTP promoter with CETP genes (P = 0.03); the association with apoBSP/MTP promoter allelic combinations just failed to reach significance (P = 0.06), however. The CETP/apoBSP allelic combination was the most significant predictor of apoB secretion, and this was independent of visceral fat, plasma lathosterol and insulin levels, and dietary fat. SP24 carriers who were homozygous for CETP B1 had 60% lower apoB secretion than B2 heterozygotes who were non-carriers of SP24 (10.5 +/- 1.74 mg/kg fat free mass/day, n = 7 vs. 26.1 +/- 3.16, n = 22). The data suggest that variation in both the apoB and CETP genes may be a major genetic determinant of the hepatic secretion of apoB in men with visceral obesity.
Adult↗
Plasma levels of remnant particles are determined in part by variation in the APOC3 gene insulin response element and the APOCI-APOE cluster.
Remnant particles of triglyceride-rich lipoproteins (RLP) are known to be a strong predictor of atherogenicity. The serum concentrations of remnant-like particle triglyceride (RLPTG) and remnant-like particle cholesterol (RLPC) have been determined in a representative sample of the Czech MONICA study (n = 285). The relationship was investigated between remnant particle triglyceride/cholesterol concentrations and polymorphisms in the genes APOC3 (-482C-->T/3238C-->G), APOE (epsilon2/epsilon3/epsilon4), APOCI (-317-321ins), APOB (signal peptide), hepatic lipase (LIPE, -480C-->T), and lipoprotein lipase (LPL, S447X). Univariate analysis showed significant effects on RLPTG associated only with the APOE genotype (P = 0.009), the APOC3 -482C-->T genotype (P = 0.018), and the APOCI -317-321ins (P = 0.014) genotype and significant effects on RLPC with APOE (P = 0.01) and APOCI -317-321ins (P = 0.021). The raising effect of the APOE genotype for both remnant cholesterol and triglyceride was confined to the epsilon2/4 (n = 6) and varepsilon4/4 (n = 3) groups, and thus when the epsilon2/4 group was omitted in order to analyze by allele (epsilon2+/epsilon3+/epsilon4+), significance was lost (P = 0.6). There was strong linkage disequilibrium between the APOE and APOCI alleles (chi(2), P < 0.001) and a multivariate ANOVA of RLPTG with all three significantly associated variants as factors demonstrated that while the APOC3 -482C-->T effect was independent of the others (P = 0.003), the APOCI -317-321ins and APOE effects were not. This was also true for the APOCI -317-321ins and APOE effects on RLPC. To assess whether APOE-CI effects on RLPC were independent of their effects on total cholesterol and triglyceride levels, multiple linear regression was used. Using multiple linear regression, it appeared that the APOE-CI effects on RLPC were independent of their effects on plasma cholesterol, but the effects of APOC3 and APOE-CI on RLPTG could not be separated from their effects on plasma Tg levels. Further characterization of this remnant particle phenotype and its genetic determinants may lead to a better understanding of its metabolism and contribution to atherosclerosis.
Adult↗
Sib-pair linkage analysis of longitudinal changes in lipoprotein risk factors and lipase genes in women twins.
Based on longitudinal twin data in women, we have previously demonstrated a genetic influence on changes in lipoprotein risk factors, blood pressure measurements, and body mass index over a decade. The present study examined the linkage between changes in lipoprotein variables and candidate genes encoding the hormone-sensitive lipase (HSL), hepatic lipase (HL), and lipoprotein lipase (LPL). The sample consisted of 126 dizygotic (DZ) pairs of women twins who participated in the two examinations of the Kaiser Permanente Women Twins Study, performed a decade apart. Using quantitative sib-pair linkage analysis, a linkage was demonstrated between the locus for hormone-sensitive lipase and age-adjusted changes in plasma triglyceride (P = 0.015), which became more significant after adjustment for environmental factors and the exam-1 level (P = 0.005). There was also evidence suggesting linkage between the locus for hepatic lipase and changes in triglyceride (P = 0.023), but no linkage was detected for lipoprotein lipase and changes of lipid levels with time. These findings suggest that variation at these candidate gene loci may underlie a portion of the intraindividual variations in these coronary heart disease (CHD) risk factors, and that studies to identify the functional variants could provide new insights into genetic susceptibility to cardiovascular disease.
Adult↗
Characterization of the lipid-binding properties and lipoprotein lipase inhibition of a novel apolipoprotein C-III variant Ala23Thr.
We have identified a G-to-A transition in exon 3 of the APOC3 gene resulting in a novel Ala23Thr apolipoprotein (apo) C-III variant, associated with apoC-III deficiency in three unrelated Yucatan Indians. The Ala23Thr substitution modifies the hydrophobic/hydrophilic repartition of the helical N-terminal peptide and hence could disturb the lipid association. In vitro expression in Escherichia coli of wild-type and mutant apoC-III enabled the characterization of the variant. Compared with wild-type apoC-III-Ala23, the mutant apoC-III-Thr23 showed reduced affinity for dimyristoylphosphatidylcholine (DMPC) multilamellar vesicles with higher amounts of free apoC-III. Displacement of apoE from discoidal apoE:dipalmitoylphosphatidycholine (DPPC) complex by apoC-III-Thr23 was comparable to wild type but the less efficient binding of the apoC-III-Thr23 to the discoidal complex resulted in a higher apoE/apoC-III (mol/mol) ratio (34%) than with wild-type/apoE:DPPC mixtures. The inhibition of lipoprotein lipase (LPL) by apoC-III-Thr23 was comparable to that of wild type, and therefore effects on LPL activity could not explain the lower triglyceride (Tg) levels in Thr-23 carriers. Thus, these in vitro results suggest that in vivo the less efficient lipid binding of apoC-III-Thr23 might lead to a faster catabolism of free apoC-III, reflected in the reduced plasma apoC-III levels identified in Thr-23 carriers, and poorer competition with apoE, which might enhance clearance of Tg-rich lipoproteins and lower plasma Tg levels seen in Thr-23 carriers.
1,2-Dipalmitoylphosphatidylcholine↗
The T allele of the hepatic lipase promoter variant C-480T is associated with increased fasting lipids and HDL and increased preprandial and postprandial LpCIII:B : European Atherosclerosis Research Study (EARS) II.
The common C-480T transition in the hepatic lipase (HL) promoter has been shown to be associated with lower HL activity and increased high density lipoprotein (HDL) cholesterol. We examined the frequency and lipid associations of this HL polymorphism in 385 healthy, young (18- to 28-year-old) men whose fathers had had a premature myocardial infarction (designated cases) and 405 age-matched controls. These individuals were participants in the European Atherosclerosis Research Study II postprandial trial, who had been recruited from 11 European countries in 4 regions (the Baltic; United Kingdom; and central and southern Europe). Overall, the frequency of the T allele was 0.207 in controls and 0.244 in cases (P=0.08). The T allele was associated with higher fasting plasma total cholesterol (P<0.01), triglycerides (P<0.01), and HDL cholesterol (P<0.01). The strongest association was found with apolipoprotein (apo) A-I concentration, which was 10% higher in individuals homozygous for the T allele compared with those homozygous for the C allele (P<0.001). This polymorphism had no effect on the rise in plasma triglyceride levels after a fatty meal. However, before and after the fat load was ingested, levels of particles containing both apoC-III and apoB (LpC-III:B) were higher in carriers of the T allele, with homozygotes having 23% and 27% higher levels preprandially and postprandially, respectively, than those homozygous for the C allele (P<0.05). Thus, our results demonstrate that the C-480T polymorphism in the HL promoter is associated with alterations in plasma lipids and lipoproteins and the accumulation of atherogenic LpC-III:B particles.
Adolescent↗
Genetics and molecular biology.
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Animals↗
Identification of genetic variation in the human hormone-sensitive lipase gene and 5' sequences: homology of 5' sequences with mouse promoter and identification of potential regulatory elements.
Hormone-sensitive lipase (HSL) plays a crucial role in triglyceride hydrolysis in adipose tissue and exhibits cholesterol hydrolase activity in steroidogenic tissue and macrophages. Thus, common genetic variation in the HSL gene could affect both energy metabolism and atherogenesis. Using overlapping single-strand conformational polymorphism analysis (SSCP), a common single base change (T/C) in intron 4 [allele frequency 0.012 (95% CI 0.007-0. 018)] and a variable CA repeat in intron 6 with 9 alleles (heterozygosity index = 0.66) were identified. Sequence of 1.123 kb upstream from the reported 5'UTR (1) which includes intron B, exon B, and 159 bp of the promoter (2) was obtained and a single common nucleotide change, -60C/G [allele frequency 0.052 (95% CI 0.039-0. 064)], identified. Preliminary in vitro studies show that the -60G construct has 38.5% lower luciferase activity compared to the -60C construct (P = 0.035), suggesting a functional change affecting HSL gene expression. The 5' sequence shows 57-59% homology with the mouse promoter with higher homology at potential regulatory motifs. Thus, the 1.7 kb of 5' sequences is well conserved and may play a part in the regulation of HSL gene expression.
Adipocytes↗
Human gene for physical performance.
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Adult↗
The 5A/6A polymorphism in the promoter of the stromelysin-1 (MMP-3) gene predicts progression of angiographically determined coronary artery disease in men in the LOCAT gemfibrozil study. Lopid Coronary Angiography Trial.
The relationship between the 5A/6A stromelysin-1 promoter polymorphism and progression of angiographically determined coronary artery disease (CAD) has been examined in men treated for 32 months with gemfibrozil or placebo in the Lopid Coronary Angiography Trial (LOCAT). The frequency of the 5A allele was 0.40 (95%, CI, 0.36-0.43), and in the sample as a whole 12% of the men were homozygous for the 5A allele. In the placebo group, diffuse progression of disease was, on average, completely prevented in men with the genotype 5A/5A as measured by a 0.30% increase in mean average diameter of the coronary artery segments (ADS), compared with a mean 1.79% decrease in the combined group with the genotype 5A6A or 6A6A (mean +/- S.E.M., +0.007 +/- 0.020 mm vs. -0.043 +/- 0.0.08 mm, P = 0.03). A similar relationship with genotype was seen for disease progression determined by the mean minimal luminal diameter (MLD); with the 5A5A group decreasing by an average of 1.72% compared with 5.54% in the 5A/6A plus 6A/6A group (-0.029 +/- 0.034 mm vs. -0.102 +/- 0.013 mm, P = 0.06). In the gemfibrozil-treated group, the effect on disease progression associated with the 5A/6A alleles was of a similar pattern as in the placebo group, but the effect was less marked and was not statistically significant. This study confirms the previously reported beneficial effect on disease progression associated with the 5A allele and raises the possibility that patients with CAD who are homozygous for the 6A allele, and who represent 25-30% of the population, may be at particular risk of rapid progression of disease and may require particularly aggressive lipid lowering therapy to prevent disease progression.
Aged↗
Candidate-gene studies of the atherogenic lipoprotein phenotype: a sib-pair linkage analysis of DZ women twins.
There is a growing body of evidence supporting the roles of small, dense LDL and plasma triglyceride (TG), both features of the atherogenic lipoprotein phenotype, as risk factors for coronary heart disease. Although family studies and twin studies have demonstrated genetic influences on these risk factors, the specific genes involved remain to be determined definitively. The purpose of this study was to investigate genetic linkage between LDL size, TG, and related atherogenic lipoproteins and candidate genes known to be involved in lipid metabolism. The linkage analysis was based on a sample of 126 DZ women twin pairs, which avoids the potentially confounding effects of both age and gender, by use of a quantitative sib-pair linkage-analysis approach. Eight candidate genes were examined, including those for microsomal TG-transfer protein (MTP), hepatic lipase, hormone-sensitive lipase, apolipoprotein (apo) B, apo CIII, apo E, insulin receptor, and LDL receptor. The analysis suggested genetic linkage between markers for the apo B gene and LDL size, plasma levels of TG, of HDL cholesterol, and of apo B, all features of the atherogenic lipoprotein phenotype. Furthermore, evidence for linkage was maintained when the analysis was limited to women with a major LDL-subclass diameter >255 A, indicating that the apo B gene may influence LDL heterogeneity in the intermediate-to-large size range. In addition, linkage was found between the MTP gene and TG, among all the women. These findings add to the growing evidence for genetic influences on the atherogenic lipoprotein phenotype and its role in genetic susceptibility to atherosclerosis.
Apolipoproteins B↗
Lipoprotein lipase gene variation is associated with a paternal history of premature coronary artery disease and fasting and postprandial plasma triglycerides: the European Atherosclerosis Research Study (EARS).
The H-allele of the intron 8 HindIII polymorphism in the lipoprotein lipase (LPL) gene has been associated with a lower risk of myocardial infarction (MI) and plasma levels of triglycerides (TG). To test whether the HindIII site was in linkage disequilibrium with the functional variant LPL Serine447Stop (S447X), subjects from the European Atherosclerosis Research Study (EARS I) were genotyped for both polymorphic sites. This study included 515 offspring of fathers with a premature (<55 years old) MI, who were designated cases, and 930 age- and sex-matched control subjects from five different regions of Europe. Linkage disequilibrium between the two sites was very strong (>.99), with only three of the four possible haplotypes identified: H+S447, H-S447, and H-X447. The frequency of the H-X447 but not of the H-S447 haplotype was significantly lower in cases than in control subjects (.090 versus .117, P<.01) suggesting a protective effect for MI, with this difference being consistent in all five regions of Europe. Compared with individuals homozygous for the H+S447 haplotype, the odds ratio of having a paternal history of premature MI for H-X447 heterozygotes (approximately 20% of the population) was 0.71 (95% confidence interval, 0.55 to 0.92). In addition, there was an increase of the H-X447 haplotype frequency from north to south in control subjects (0.119 in Finland to 0.143 in the Mediterranean region, P<.01). Compared with the H+S447 haplotype, the H-X447 haplotype was associated with significantly lower concentrations of plasma TGs (5.4% lower, P=.01), with this effect being consistent over the regions of Europe. There was no significant evidence for a heterogeneity of effect between males and females or between cases and control subjects, although the effect on TG levels appeared to be the greatest in male cases (11% lower, P=.05). In a second study (EARS II), of 332 cases and 342 control subjects, postprandial clearance of TGs after a standard fat meal was examined. The H-X447 haplotype was associated with significantly lower postprandial triglyceride levels than was the H+S447 haplotype (9.4% smaller area under the curve, P<.05). Thus, the effects on MI risk and plasma lipids associated with the H allele appeared to be mainly mediated by the X447 mutation, and although the lowering effects associated with the H-X447 haplotype on fasting and postprandial TGs are not large, they are consistent with the lowering effect observed on MI risk throughout Europe.
Adolescent↗
Effect of angiotensin-converting enzyme (ACE) gene polymorphism on progression of renal disease and the influence of ACE inhibition in IDDM patients: findings from the EUCLID Randomized Controlled Trial. EURODIAB Controlled Trial of Lisinopril in IDDM.
We examined whether the ACE gene insertion/deletion (I/D) polymorphism modulates renal disease progression in IDDM and how ACE inhibitors influence this relationship. The EURODIAB Controlled Trial of Lisinopril in IDDM is a multicenter randomized placebo-controlled trial in 530 nonhypertensive, mainly normoalbuminuric IDDM patients aged 20-59 years. Albumin excretion rate (AER) was measured every 6 months for 2 years. Genotype distribution was 15% II, 58% ID, and 27% DD. Between genotypes, there were no differences in baseline characteristics or in changes in blood pressure and glycemic control throughout the trial. There was a significant interaction between the II and DD genotype groups and treatment on change in AER (P = 0.05). Patients with the II genotype showed the fastest rate of AER progression on placebo but had an enhanced response to lisinopril. AER at 2 years (adjusted for baseline AER) was 51.3% lower on lisinopril than placebo in the II genotype patients (95% CI, 15.7 to 71.8; P = 0.01), 14.8% in the ID group (-7.8 to 32.7; P = 0.2), and 7.7% in the DD group (-36.6 to 37.6; P = 0.7). Absolute differences in AER between placebo and lisinopril at 2 years were 8.1, 1.7, and 0.8 microg/min in the II, ID, and DD groups, respectively. The significant beneficial effect of lisinopril on AER in the II group persisted when adjusted for center, blood pressure, and glycemic control, and also for diastolic blood pressure at 1 month into the study. Progression from normoalbuminuria to microalbuminuria (lisinopril versus placebo) was 0.27 (0.03-2.26; P = 0.2) in the II group, and 1.30 (0.33-5.17; P = 0.7) in the DD group (P = 0.6 for interaction). Knowledge of ACE genotype may be of value in determining the likely impact of ACE inhibitor treatment.
Adult↗
LPL promoter -93T/G transition influences fasting and postprandial plasma triglycerides response in African-Americans and Hispanics.
The lipoprotein lipase (LPL) promoter -93T/G transition has previously been reported as having a triglyceride (Tg)-lowering effect, whereas the D9N variant has been shown to have a Tg-raising effect. These two variants were studied in 66 healthy subjects of Hispanic and 42 subjects of African-American origin, who had participated in a study of postprandial lipemia. While the allele frequency of the -93G was significantly different in the Hispanics and African Americans (0.09: 95% CI 0.04-0.13 and 0.28: 95% CI 0.19-0.38; P=0.0001, respectively), the N9 allele frequency was not different (0.06: 95% CI 0.02-0.1 and 0.05: 95% CI 0.002-0.093, respectively). Linkage disequilibrium between the -93T/G and D9N was highly significant in Hispanics (delta=0.67. P=0.0001), compared to delta=0.09 (NS) in African-Americans. In the combined group, compared to individuals with the common genotype (TT/DD; n=71) with fasting plasma Tg of 1.34 (+/-4.5% SEM) mmol/l, carriers of the G/D haplotype (TG/DD + GG/DD; n=25) had significantly lower plasma Tg levels of 1.08 (+/-10% SEM) mmol/l (P < 0.02). After the fat meal, compared to individuals with neither mutation, TT/DD, the effect of the G/D haplotype was to reduce significantly postprandial Tg (P < 0.036). Retinyl palmitate concentration at 5 hrs was significantly lower in G/D carriers than TT/DD individuals (P < 0.05). The lipid-raising effect of the N9 allele in carriers of the -93G (TG/DN + GG/DN) and effect on postprandial Tg clearance was not significant in this group. Thus carriers of the G/D haplotype have lower fasting plasma Tg and reduced alimentary lipemia. This allele may be associated with reduced risk of coronary artery disease.
Adult↗
Apolipoprotein B signal peptide and apolipoprotein E genotypes as determinants of the hepatic secretion of VLDL apoB in obese men.
We aimed to examine the effect of genetic polymorphisms of apolipoprotein B-100 (apoB) signal peptide and apolipoprotein E (apoE) on the hepatic secretion of very low density lipoprotein (VLDL) apoB in 29 men with visceral obesity. We studied apoB secretion using a primed (1 mg/kg), constant (1 mg/kg/h) intravenous infusion of [1-(13)C]leucine. The isotopic enrichment of VLDL apoB was determined using gas chromatography-mass spectrometry (GCMS). A multi-compartmental model was used to estimate the fractional turnover rate of VLDL apoB. Genotypes for the apoB signal peptide length polymorphism, 27 amino acid (SP27) and 24 amino acid (SP24), and apoE genotypes were determined using polymerase chain reaction. In subjects who were not apoE2 carriers and were homozygous for the SP27 of the apoB signal peptide, the hepatic secretion of VLDL apoB was significantly higher than in subjects who were not apoE2 carriers and were either heterozygous or homozygous for the SP24 allele (31.3 +/- 11.8 mg/kg fat-free mass/day, n = 8 vs. 16.9 +/- 12.2 mg/kg fat-free mass/day, n = 13, P = 0.01). In subjects who were not apoE4 carriers and were either heterozygous or homozygous for the apoB SP24 allele, the hepatic secretion of VLDL apoB was significantly lower than in subjects who were not apoE4 carriers and were homozygous for the SP27 allele (15.8 +/- 12.9 mg/kg fat-free mass/day, n = 13 vs. 27.4 +/- 11.5 mg/kg fat-free mass/day, n = 7, P = 0.03). The data suggest that in men with visceral obesity, the apoB signal peptide and apoE genotypes appear to be involved in the hepatic secretion of apoB.
Adult↗
Lipoprotein lipase variants D9N and N291S are associated with increased plasma triglyceride and lower high-density lipoprotein cholesterol concentrations: studies in the fasting and postprandial states: the European Atherosclerosis Research Studies.
BACKGROUND: Variations at the DNA level with moderate effects on biochemical variables may be important for the occurrence of disease at the population level, if they are common. Two mutations in the LPL gene, N9 and S291, are associated with variation in fasting plasma concentrations of HDL cholesterol (HDL-C) and triglycerides (TG). We investigated whether these mutants were more frequent in offspring of cases with premature coronary disease and analyzed the effects on fasting plasma lipids and postprandial TG. METHODS AND RESULTS: Students with and without paternal history of myocardial infarction (cases and control subjects [controls]) were studied in the European Atherosclerosis Research Studies I and II (EARS-I and -II). Allelic frequencies for the N9 and S291 mutations did not differ between cases and control subjects. The N9 mutation was identified in 4.2% of all subjects in EARS-I, and carriers had higher fasting TG levels (P<.001) than noncarriers. In an oral fat tolerance test, there were no differences in postprandial TG between carriers and noncarriers of the N9 allele. The S291 mutation was identified in 3.1% of all subjects in EARS-I, and carriers had lower fasting HDL-C levels (P<.005) than noncarriers. There was a significant interaction between S291 genotype and body mass index on fasting TG levels (P<.01). In the cases, carriers of the S291 allele had higher TG levels 6 hours postprandially (P<.04) than did noncarriers. CONCLUSIONS: The two LPL mutations are common and may predispose to elevated TG and decreased HDL-C concentrations, even in young subjects. In the case of the S291 mutation, this effect appears to be mediated via delayed postprandial TG clearance. Moreover, even moderate obesity potentiates the TG-raising and HDL-lowering effects associated with the S291 allele.
Adolescent↗
The use of a highly informative CA repeat polymorphism within the abetalipoproteinaemia locus (4q22-24).
Abetalipoproteinaemia is a rare autosomal-recessive disorder caused by a defect in the large subunit of the microsomal triglyceride transfer protein (MTP) which is required for the assembly and secretion of apolipoprotein B-containing lipoproteins. We report here the use of a polymorphic CA dinucleotide repeat in intron 10, MTPIVS10, of the large subunit of the human MTP protein in the analysis of a pregnancy in a consanguineous family, in which abetalipoproteinaemia was suspected, although prenatal diagnosis was subsequently refused. The mutation in the family has been identified as a novel four-nucleotide insertion/duplication of exon 17 between nucleotides 2349 and 2350 of the cDNA sequence of the MTP gene. However, the marker, MTPIVS10, can be used as an alternative to the time-consuming mutation detection techniques.
Abetalipoproteinemia↗