This Article Abstract Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Björn Lundahl Articles by Karpe, F. Search for Related Content PubMed PubMed Citation Articles by Björn Lundahl, Articles by Karpe, F. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Genetics Home Reference Related Collections Clinical genetics Lipids Other arteriosclerosis Genetics of cardiovascular disease

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:1784.)
© 2000 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

A Functional Polymorphism in the Promoter Region of the Microsomal Triglyceride Transfer Protein (MTP -493G/T) Influences Lipoprotein Phenotype in Familial Hypercholesterolemia

Björn Lundahl; Trond P. Leren; Leiv Ose; Anders Hamsten; Fredrik Karpe

From the Atherosclerosis Research Unit (B.L., A.H., F.K.), King Gustaf V Research Institute, Karolinska Hospital, Stockholm, Sweden; the Medical Genetics Laboratory (T.P.L.), Medinnova/MSD Cardiovascular Research Center, Rikshospitalet, Oslo, Norway; and the Lipid Clinic (L.O.), Medical Department A, Rikshospitalet, Oslo, Norway.

Correspondence to Björn Lundahl, Atherosclerosis Research Unit, King Gustaf V Research Institute, Karolinska Hospital, S-17176 Stockholm, Sweden. E-mail bjorn.lundahl{at}bigfoot.com

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Abstract—The microsomal triglyceride transfer protein (MTP) has a key function in intracellular apolipoprotein (apo) B lipidation and secretion of very low density lipoprotein (VLDL). A recently discovered functional polymorphism in the promoter of the MTP gene (-493G/T) affects the plasma concentration of low density lipoprotein (LDL) cholesterol and the VLDL distribution between large and small particle species in healthy men. This phenotype is likely to be explained by an effect on VLDL synthesis. Against this background, we studied the effect of the MTP-493G/T polymorphism in a large cohort (217 men and 211 women) with heterozygous familial hypercholesterolemia (FH). A 40% to 50% lower serum triglyceride level was observed in homozygous carriers of the MTP-493 T allele (T/T, 0.93±0.34; G/T, 1.54±1.40; and G/G, 1.56±1.24 mmol/L; T/T vs G/T P=0.04, T/T vs G/G P=0.02). In contrast to the situation in healthy subjects, the MTP promoter polymorphism did not have a significant effect on the LDL cholesterol levels in FH subjects, although the same trend was observed (T/T, 7.31±1.87; G/T, 7.80±2.12; and G/G, 7.91±2.31 mmol/L, NS). Adjustment for the apo E gene polymorphism by inclusion of subjects homozygous for the apo E3 allele only revealed a reciprocal high density lipoprotein cholesterol–elevating effect (T/T, 1.41±0.73; G/T, 1.18±0.27; and G/G, 1.16±0.29 mmol/L; T/T vs G/T P=0.06, T/T vs G/G P=0.04). This effect seemed to be sex-specific because it was accounted for by the female patients. In conclusion, the LDL cholesterol–lowering effect of the rare MTP gene promoter variant (MTP-493T) present in healthy subjects is shifted to a triglyceride-lowering effect in FH. These data suggest that the MTP gene has a role in modulating the clinical phenotype of FH.

Key Words: polymorphisms • lipoproteins • promoter regions • microsomes • familial hypercholesterolemia

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
The microsomal triglyceride transfer protein (MTP) is a heterodimeric lipid transfer protein that is composed of a unique 97-kDa subunit and the multifunctional enzyme, protein disulfide isomerase.¹ MTP is present at high concentrations on the luminal side of the endoplasmic reticulum in tissues secreting apo B–containing lipoproteins, ie, the liver, intestine, and, as recently discovered, the heart.² In vitro studies have shown that MTP is capable of transferring a variety of lipids, although it has a preference for triglycerides and cholesteryl esters.^{3 4} Absence of a functional MTP causes abetalipoproteinemia,^{5 6} which is a rare, autosomal, recessive disease causing a deficiency in the assembly process and secretion of VLDL and chylomicrons into the plasma. A number of structural mutations leading to abetalipoproteinemia have now been characterized,⁷ and in addition, the MTP gene seems polymorphic as such.⁷

Owing to the central role of MTP in VLDL secretion, we recently hypothesized that more subtle changes in the MTP gene structure might influence the plasma lipoprotein phenotype in humans. A common, single-nucleotide polymorphism (a G-to-T substitution at position -493 of the MTP promoter) that affects the promoter activity of the MTP gene was recently discovered in humans.⁸ The rarer T variant (allele frequency of 0.2) was associated with elevated transcriptional activity (in vitro in HepG2 cells), and subjects homozygous for the T allele express a phenotype comprising triglyceride-enriched, large VLDL particles; normal whole-plasma triglycerides; and decreased LDL cholesterol concentration.

Familial hypercholesterolemia (FH) is a common, autosomal, dominant disorder with an estimated prevalence of 1/500 (the heterozygous form) in the general population. In the majority of patients with FH, the disorder is caused by a mutation in the coding region of the gene for the LDL receptor, resulting in excessive elevations of LDL in plasma. Although LDL receptor function is severely affected in FH, the clinical phenotype is highly variable, and this has been attributed to both genetic and environmental factors.^{9 10} A vicious gene-environment interaction has recently been reported by Gaudet et al.¹¹ The presence of abdominal obesity together with hyperinsulinemia was found to have increased the risk of coronary artery disease by 13 times in FH patients.¹¹ Among common variants in the genes coding for proteins involved in lipoprotein metabolism, variations in the lipoprotein(a) [Lp(a)], lipoprotein lipase, and apo E genes have been investigated on an FH background.^{12 13 14 15 16 17 18 19 20 21 22 23} Lp(a) levels are strongly determined by Lp(a) genotype, and Lp(a) levels are significantly higher in individuals with FH. The well-known LDL cholesterol–modulating effect of apo E in a normal population has generally been difficult to reproduce in FH subjects. The normal LDL cholesterol–elevating effect of apo E4 has not been observed at all, whereas a minor lowering effect has been attributed to apo E2 in a few studies. The lipoprotein lipase N291S variant, on the other hand, normally gives rise to elevations of serum triglycerides and lowering of HDL cholesterol levels, and this effect seems to be augmented on an FH background.¹⁴ Of note, the odds ratio for cardiovascular disease was elevated almost 4-fold in carriers of the dysfunctional lipoprotein lipase allele.

Against this background, we hypothesized that the MTP-493G/T polymorphism could influence the lipoprotein phenotype in subjects with FH. Furthermore, because the normal effect of the MTP-493 T allele is to lower LDL levels, we wanted to investigate whether this effect was maintained under conditions of failing LDL removal from the plasma.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Subjects
A total of 428 subjects with FH (217 males and 211 females) were included in this study. They were all unrelated. Seventy-nine percent (339 subjects) had a known mutation in the LDL receptor gene,²⁴ and the remaining 79 subjects were diagnosed on a clinical basis according to the method of Goldstein and Brown.²⁵ The age range was 4 to 87 years (median age, 34 years). All were white of Norwegian descent. None of the subjects possessed the apo B-3500 mutation as determined by the assay of Hansen et al.²⁶

Genotyping for the MTP-493G/T Polymorphism
Genotyping for the MTP-493G/T polymorphism was performed on a nested polymerase chain reaction (PCR) product. Primers for the first PCR were as follows: 5'-CCCTCTTAATCTCTTCCTAGAA (forward) and 5'-AAGAATCATATTGACCAGCAATC (reverse). This PCR was done with an MgCl₂ concentration of 2.0 mmol/L. The PCR protocol used for amplification was as follows: 94°C for 3 minutes followed by 35 cycles at 94°C for 0.5 minute, 55°C for 1 minute, 72°C for 5 minutes, and 72°C for 5 minutes. Primers for the second PCR were as follows: 5'-AGTTTCACACATAAGGACAATCATCTA (forward) and 5'-GGATTTAAATTTAAACTGTTAATTCATATCAC (reverse). One microliter of the product from the first reaction was used for the second. The MgCl₂ concentration was elevated to 5.0 mmol/L, and conditions were 94°C for 3 minutes followed by 35 cycles at 94°C for 0.5 minute, 57°C for 1.0 minute, 72°C for 2.0 minutes, and 72° for 5 minutes. The product of the second PCR was a fragment of 109 bp. This fragment was then incubated overnight with the restriction enzyme HphI, whereby the following genotype-specific fragments were obtained: homozygotes for the T variant, 1 fragment of 109 bp; G/T heterozygotes, 3 fragments of 109, 89, and 20 bp; and homozygotes for the G variant, 2 fragments of 89 and 20 bp. Because of the high risk of contamination when performing a nested PCR, 1 DNA-free control sample was included for every eighth sample containing FH DNA.

Genotyping for the Apo E Polymorphism
The method described by Hixson and Vernier²⁷ was used with minor modifications. PCR amplification was made with primers originally designed by van den Maagdenberg et al²⁸ (5'AGGCCGCGCTCGGCGCCCT) and (5'-TCCCCACTGTGCGACACCCT).

Lipid and Lipoprotein Determinations
Serum cholesterol, HDL cholesterol, and serum triglyceride concentrations were determined by standard enzymatic methods on fasting samples that were drawn before therapy with lipid-lowering drugs was started. The LDL cholesterol concentration was calculated by using the Friedewald formula.²⁹

Statistical Methods
Conventional methods were used for calculation of means and SDs. Coefficients of skewness and kurtosis were calculated to test deviations from a normal distribution. Logarithmic transformation was performed on the individual values of skewed variables, and a normal distribution of transformed values was confirmed before statistical computations and significance testing. Comparisons of clinical and biochemical traits between genotype groups were made by ANOVA with the Scheffe post hoc test and ANCOVA. StatView 5.0 software for Windows 95 was used for statistical analysis.

	Results

Top Abstract Introduction Methods Results Discussion References

 
The frequency of the MTP-493T allele was 25.5%, which is similar to that in a healthy Scandinavian population.⁸ Serum concentrations of lipids and major lipoproteins in FH subjects grouped according to MTP-493G/T genotype are shown in Table 1. Subjects homozygous for the rare MTP-493 T variant had a 40% lower serum triglyceride concentration compared with subjects carrying 1 or 2 copies of the common G allele (T/T, 0.93±0.34; G/T, 1.54±1.40; and G/G, 1.56±1.24 mmol/L; T/T versus G/T P=0.04, T/T versus G/G P=0.02). Whole-serum cholesterol concentrations were unaffected by the MTP promoter polymorphism. LDL cholesterol was not significantly affected, although levels were slightly lower in homozygotes for the T allele (T/T, 7.31±1.87; G/T, 7.80±2.12; and G/G, 7.91±2.31 mmol/L, NS). There was a tendency to higher HDL cholesterol levels among homozygotes for the T variant (P=0.08), and this effect was statistically significant in women but not in men (in women T/T, 1.49±0.70; G/T, 1.31±0.30; and G/G, 1.25±0.35 mmol/L; in men T/T, 1.16±0.27; G/T, 1.12±0.26; and G/G, 1.11±0.29 mmol/L).

View this table: [in this window] [in a new window]   Table 1. Serum Concentrations of Lipids and Major Lipoproteins in FH Subjects Grouped According to the MTP-493G/T Genotype

The age distribution did not differ between FH patients grouped according to MTP-493G/T genotype (T/T, 33.3±8.8; G/T, 35.1±15.4; and G/G, 34.4±1.2 years, NS). ANCOVA with age as a covariate increased the genotype-specific differences in LDL cholesterol concentration (interaction of MTP genotypexage, P=0.015), whereas the serum levels of other lipids and lipoproteins, including triglycerides, were unaffected.

The frequencies of the apo E genotypes are shown in Table 2. The overall allele frequencies of E2, E3, and E4 were 0.044, 0.618, and 0.344, respectively. Subjects were divided into 3 main apo E genotype groups to investigate the effect on serum lipid and lipoprotein levels of the apo E gene: E2+ (n=27, consisting of apo E2/3 carriers), E3/3 (n=265, consisting of apo E3/3 carriers), and E4+ (n=117, consisting of apo E3/4 plus apo E4/4 carriers). Carriers with the apo E2/4 genotype (n=11) were not included in this analysis. There were no significant effects of apo E genotype alone on serum lipid or lipoprotein levels (Table 3). Although apo E genotype did not significantly influence serum concentrations of lipids and major lipoproteins in the present FH cohort, we wanted to study the effect of the MTP-493G/T genotypic variation on a homogeneous apo E background. The lipid and lipoprotein phenotype was therefore studied in the E3/3 group. The triglyceride-lowering effect of the MTP-493 T allele remained significant, and in addition, a significant reciprocal elevation of HDL cholesterol emerged (T/T, 1.41±0.73; G/T, 1.18±0.27; and G/G, 1.16±0.29 mmol/L; T/T versus G/T P=0.06, T/T versus G/G P=0.04). ANCOVA with age as a covariate did not affect any of the lipid and lipoprotein results in regard to the apo E polymorphism.

View this table: [in this window] [in a new window]   Table 2. Frequencies of Apo E Genotypes in the FH Subjects

View this table: [in this window] [in a new window]   Table 3. Serum Concentrations of Lipids and Major Lipoproteins in FH Subjects Grouped According to Apo E Genotype

The present FH group is unique because 35% of the patients (n=151) are carriers of the same mutation at position +1 (GA) of intron 3 (Elverum).³⁰ This feature enabled the study of MTP-493G/T and apo E genotypic variations on a homogeneous FH background. The magnitude of serum triglyceride change depending on the MTP-493 T allele was essentially maintained with the homogeneous FH-Elverum background but was no longer statistically significant (Table 4). The apo E genotype showed a borderline statistically significant effect on HDL on the Elverum background (E2+, 1.35±0.30; E3/3, 1.14±0.28; and E4+, 1.15±0.29 mmol/L; E2+ versus E3/3 P=0.04, E2+ versus E4+ P=0.07; Table 5).

View this table: [in this window] [in a new window]   Table 4. Serum Concentrations of Lipids and Major Lipoproteins in FH-Elverum Subjects Grouped According to the MTP-493G/T Genotype

View this table: [in this window] [in a new window]   Table 5. Serum Concentrations of Lipids and Major Lipoproteins in FH-Elverum Subjects Grouped According Major Apo E Genotype

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The present study shows that a common, single-nucleotide polymorphism in the MTP gene promoter (-493G/T) affects the lipoprotein phenotype in subjects with FH. FH subjects homozygous for the rare MTP-493 T variant exhibited a significantly lower serum triglyceride level, whereas the effect on LDL levels seen in healthy individuals was not as clear in the FH population. The mechanism behind this alteration in lipoprotein phenotype expression is unknown and cannot be determined from an association study like this, but it is likely to be related to the regulation of VLDL secretion, which is particular for the FH situation. It is known from previous studies that the total apo B secretion rate is decreased in patients with FH compared with normal individuals and particularly so in comparison with hypertriglyceridemic subjects.³¹ Under normal circumstances, the major proportion of apo B is secreted as large, triglyceride-rich VLDL particles, whereas in FH, almost 40% of apo B is secreted as smaller and denser IDL and LDL particles. It is therefore perhaps not very surprising that an elevated MTP activity (presumed to be present in MTP-493 T carriers) might result in a different phenotype in FH compared with the normal situation. In addition, because it is well established that the elevated LDL levels in FH are a direct consequence of defective LDL removal from the plasma, it is less likely that the production rate of apo B–containing particles is a major determinant of the plasma LDL level in the FH situation. Furthermore, removal of VLDL from the plasma is subject to much more complex regulation than is removal of LDL, because lipolysis has to occur, and after that step, a large number of receptors might be involved.^{32 33 34 35} It cannot be ruled out that alternative removal pathways for VLDL are upregulated in the FH situation and that certain subpopulations of VLDL are more affected than others by these processes.³⁶

Previous studies of common genetic variants of enzymes or proteins involved in lipoprotein metabolism, likely to modify the clinical presentation of FH, are limited to the apo E and lipoprotein lipase genes and to Lp(a).^{12 13 14 15 16 17 18 19 20 21 22 23} The apo E polymorphism seems to modulate LDL concentrations less in FH than in normal subjects, which is in line with the present findings. On the other hand, the effect of a heterozygous deficiency of lipoprotein lipase, which should be an LDL receptor–independent mechanism, seems to produce an augmented hypertriglyceridemic effect on an FH background compared with the normal situation. An elevated Lp(a) level is a risk factor for coronary heart disease in patients with FH.¹² The Lp(a) level is strongly determined by the Lp(a) genotype, and the concentrations of Lp(a) are increased in FH.¹³

Modulation of the lipoprotein phenotype in FH by the MTP-493G/T polymorphism is of potential clinical relevance because combined hyperlipidemia confers a considerable increase in risk of coronary artery disease compared with isolated hypercholesterolemia.³⁷ A tendency to hypertriglyceridemia has also been specifically linked to atherosclerotic lesion progression in FH.³⁸

When interpreting the present data, it should be emphasized that a type I error cannot be excluded owing to the number of variables examined and the multiple comparisons performed on a fairly limited patient group. However, these restrictions notwithstanding, our findings are in line with our previous observations,⁸ they are internally consistent, and underlying metabolic mechanisms can be envisaged, as discussed above.

In summary, we have found that a common, functional variant of the MTP gene promoter, which normally has a marked LDL cholesterol–lowering effect, presents with reduced serum triglycerides in FH. This new genetic variant is therefore a modulator of the lipoprotein phenotype in FH and might also reduce the cardiovascular risk of subjects with FH.

	Acknowledgments

 
This study was supported by grants from the Swedish Medical Research Council (12659), the Swedish Heart-Lung Foundation, the Marianne and Marcus Wallenberg Foundation, and the Petrus and Augusta Hedlund Foundation.

Received June 3, 1999; accepted January 26, 2000.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Wetterau JR, Lin MC, Jamil H. Microsomal triglyceride transfer protein. Biochim Biophys Acta. 1997;1345:136–150.[Medline] [Order article via Infotrieve]

2. Borén J, Véniant MM, Young SG. Apo B100-containing lipoproteins are secreted by the heart. J Clin Invest. 1998;101:1197–1202.[Medline] [Order article via Infotrieve]

3. Atzel A, Wetterau JR. Identification of two classes of lipid molecule binding sites on the microsomal triglyceride transfer protein. Biochemistry. 1994;33:15382–15388.[Medline] [Order article via Infotrieve]

4. Atzel A, Wetterau JR. Mechanism of microsomal triglyceride transfer protein catalyzed lipid transport. Biochemistry. 1993;32:10444–10450.[Medline] [Order article via Infotrieve]

5. Wetterau JR, Aggerbeck LP, Bouma ME, Eisenberg C, Munck A, Hermier M, Schmitz J, Gay G, Rader DJ, Gregg RE. Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia. Science. 1992;258:999–1001.[Abstract/Free Full Text]

6. Shoulders CC, Brett DJ, Bayliss JD, Narcisi TM, Jarmuz A, Grantham TT, Leoni PR, Bhattacharya S, Pease RJ, Cullen PM, Levi S, Byfield PG, Purkiss P, Scott J. Abetalipoproteinemia is caused by defects of the gene encoding the 97 kDa subunit of a microsomal triglyceride transfer protein. Hum Mol Genet. 1993;2:2109–2116.[Abstract/Free Full Text]

7. Narcisi TM, Shoulders CC, Chester SA, Read J, Brett DJ, Harrison GB, Grantham TT, Fox MF, Povey S, de Bruin TW, Erkelens DW, Muller DP, Lloyd JK, Scott J. Mutations of the microsomal triglyceride-transfer-protein gene in abetalipoproteinemia. Am J Hum Genet. 1995;57:1298–1310.[Medline] [Order article via Infotrieve]

8. Karpe F, Lundahl B, Ehrenborg E, Eriksson P, Hamsten A. A common functional polymorphism in the promoter region of the microsomal triglyceride transfer protein gene influences plasma LDL levels. Arterioscler Thromb Vasc Biol. 1998;18:756–761.[Abstract/Free Full Text]

9. Soutar AK. Update on low density lipoprotein receptor mutations. Curr Opin Lipidol. 1998;9:141–147.

10. Nicholls P, Young IS, Graham CA. Genotype/phenotype correlations in familial hypercholesterolaemia. Curr Opin Lipidol. 1998;9:313–317.[Medline] [Order article via Infotrieve]

11. Gaudet D, Vohl MC, Perron P, Tremblay G, Gagne C, Lesiege D, Bergeron J, Moorjani S, Despres JP. Relationships of abdominal obesity and hyperinsulinemia to angiographically assessed coronary artery disease in men with known mutations in the LDL receptor gene. Circulation. 1998;97:871–877.[Abstract/Free Full Text]

12. Seed M, Hoppichler F, Reaveley D, McCarthy S, Thompson GR, Boerwinkle E, Utermann G. Relation of serum lipoprotein(a) concentration and apolipoprotein(a) phenotype to coronary heart disease in patients with familial hypercholesterolemia. N Engl J Med. 1990;322:1494–1499.[Abstract]

13. Lingenhel A, Kraft HG, Kotze M, Peeters AV, Kronenberg F, Kruse R, Utermann G. Concentrations of the atherogenic Lp(a) are elevated in FH. Eur J Hum Genet. 1998;6:50–60.[Medline] [Order article via Infotrieve]

14. Wittekoek ME, Pimstone SN, Reymer PW, Feuth L, Botma GJ, Defesche JC, Prins M, Hayden MR, Kastelein JJ. A common mutation in the lipoprotein lipase gene (N291S) alters the lipoprotein phenotype and risk for cardiovascular disease in patients with familial hypercholesterolemia. Circulation. 1998;97:729–735.[Abstract/Free Full Text]

15. Gylling H, Kuusi T, Vanhanen H, Miettinen TA. Apolipoprotein E phenotype and cholesterol metabolism in familial hypercholesterolemia. Atherosclerosis. 1989;80:27–32.[Medline] [Order article via Infotrieve]

16. De Knijff P, Stalenhoef AF, Mol MJ, Gevers Leuven JA, Smit J, Erkelens DW, Schouten J, Frants RR, Havekes LM. Influence of apo E polymorphism on the response to simvastatin treatment in patients with heterozygous familial hypercholesterolemia. Atherosclerosis. 1990;83:89–97.[Medline] [Order article via Infotrieve]

17. O’Malley J, Illingworth DR. The influence of apolipoprotein E phenotype on the response to lovastatin therapy in patients with heterozygous familial hypercholesterolemia. Metabolism. 1990;39:150–154.[Medline] [Order article via Infotrieve]

18. Hill JS, Hayden MR, Frohlich J, Pritchard PH. Genetic and environmental factors affecting the incidence of coronary artery disease in heterozygous familial hypercholesterolemia. Arterioscler Thromb. 1991;11:290–297.[Abstract/Free Full Text]

19. Dallongeville J, Roy M, Leboeuf N, Xhignesse M, Davignon J, Lussier-Cacan S. Apolipoprotein E polymorphism association with lipoprotein profile in endogenous hypertriglyceridemia and familial hypercholesterolemia. Arterioscler Thromb. 1991;11:272–278.[Abstract/Free Full Text]

20. Berglund L, Wiklund O, Eggertsen G, Olofsson SO, Eriksson M, Linden T, Bondjers G, Angelin B. Apolipoprotein E phenotypes in familial hypercholesterolaemia: importance for expression of disease and response to therapy. J Intern Med. 1993;233:173–178.[Medline] [Order article via Infotrieve]

21. Lindahl G, Mailly F, Humphries S, Seed M. Apolipoprotein E phenotype and lipoprotein(a) in familial hypercholesterolaemia: implication for lipoprotein(a) metabolism. Clin Investig. 1994;72:631–638.[Medline] [Order article via Infotrieve]

22. Ferrieres J, Sing CF, Roy M, Davignon J, Lussier-Cacan S. Apolipoprotein E polymorphism and heterozygous familial hypercholesterolemia: sex-specific effects. Arterioscler Thromb. 1994;14:1553–1560.[Abstract/Free Full Text]

23. Friedlander Y, Leitersdorf E. Influence of apolipoprotein E genotypes on plasma lipid and lipoprotein concentrations: results from a segregation analysis in pedigrees with molecularly defined familial hypercholesterolemia. Genet Epidemiol. 1996;96:169–177.

24. Leren TP, Tonstad S, Gundersen KE, Bakken KS, Rodningen OK, Sundvold H, Ose L, Berg K. Molecular genetics of familial hypercholesterolaemia in Norway. J Intern Med. 1997;241:185–194.

25. Goldstein JL, Brown MS. Familial hypercholesterolemia. In: Scriver CR, Bauudet AL, Sly WS, et al, eds. The Metabolic Basis of Inherited Disease. New York, NY: McGraw-Hill; 1989:1215–1250.

26. Hansen PS, Rudiger N, Tybjaerg-Hansen A, Faergeman O, Gregersen N. Detection of the apoB-3500 mutation (glutamine for arginine) by gene amplification and cleavage with MspI. J Lipid Res. 1991;32:1229–1233.[Abstract]

27. Hixson JE, Vernier DT. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res. 1990;31:545–548.[Abstract]

28. van den Maagdenberg AM, de Knijff P, Stalenhoef AF, Gevers Leuven JA, Havekes LM, Frants RR. Apolipoprotein E*3-Leiden allele results from a partial gene duplication in exon 4. Biochem Biophys Res Commun. 1989;165:851–857.[Medline] [Order article via Infotrieve]

29. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499–502.[Abstract]

30. Leren TP, Solberg K, Rødningen OK, Tonstad S, Ose L. Two founder mutations in the LDL receptor gene in Norwegian familial hypercholesterolemia subjects. Atherosclerosis. 1994;111:175–182.[Medline] [Order article via Infotrieve]

31. Fisher WR, Zech LA, Stacpoole PW. ApoB metabolism in familial hypercholesterolemia: inconsistencies with the LDL receptor paradigm. Arterioscler Thromb. 1994;14:501–510.

32. Beisiegel U, Weber W, Ihrke G, Herz J, Stanley KK. The LDL-receptor-related protein, LRP, is an apolipoprotein E-binding protein. Nature. 1989;341:162–164.[Medline] [Order article via Infotrieve]

33. Gianturco SH, Ramprasad MP, Song R, Li R, Brown ML, Bradley WA. Apolipoprotein B-48 or its apolipoprotein B-100 equivalent mediates the binding of triglyceride-rich lipoproteins to their unique human monocyte-macrophage receptor. Arterioscler Thromb Vasc Biol. 1998;18:968–976.[Abstract/Free Full Text]

34. Bihain BE, Yen FT. The lipolysis stimulated receptor: a gene at last. Curr Opin Lipidol. 1998;9:221–224.[Medline] [Order article via Infotrieve]

35. Patel DD, Forder RA, Soutar AK, Knight BL. Synthesis and properties of the very-low-density-lipoprotein receptor and a comparison with the low-density-lipoprotein receptor. Biochem J. 1997;324:371–377.

36. Hiltunen TP, Luoma JS, Nikkari T, Yla-Herttuala S. Expression of LDL receptor, VLDL receptor, LDL receptor-related protein, and scavenger receptor in rabbit atherosclerotic lesions: marked induction of scavenger receptor and VLDL receptor expression during lesion development. Circulation. 1998;97:1079–1086.[Abstract/Free Full Text]

37. Assmann G, Schulte H. Role of triglycerides in coronary artery disease: lessons from the Prospective Cardiovascular Munster Study. Am J Cardiol. 1992;70:10H–13H.[Medline] [Order article via Infotrieve]

38. Sidhu PS, Naoumova RP, Maher VM, MacSweeney JE, Neuwirth CK, Hollyer JS, Thompson GR. The extracranial carotid artery in familial hypercholesterolaemia: relationship of intimal-medial thickness and plaque morphology with plasma lipids and coronary heart disease. J Cardiovasc Risk. 1996;3:61–67.[Medline] [Order article via Infotrieve]

This article has been cited by other articles:

				M. J. Neville, R. Clarke, J. G. Evans, D. C. Rubinsztein, and F. Karpe Absence of Relationship Between MTTP Haplotypes and Longevity J. Gerontol. A Biol. Sci. Med. Sci., February 1, 2007; 62(2): 202 - 205. [Abstract] [Full Text] [PDF]

				M. Beekman, G. J. Blauw, J. J. Houwing-Duistermaat, B. W. Brandt, R. G. J. Westendorp, and P. E. Slagboom Chromosome 4q25, microsomal transfer protein gene, and human longevity: novel data and a meta-analysis of association studies. J. Gerontol. A Biol. Sci. Med. Sci., April 1, 2006; 61(4): 355 - 362. [Abstract] [Full Text] [PDF]

				B. Lundahl, C. Skoglund-Andersson, M. Caslake, D. Bedford, P. Stewart, A. Hamsten, C. J. Packard, and F. Karpe Microsomal triglyceride transfer protein -493T variant reduces IDL plus LDL apoB production and the plasma concentration of large LDL particles Am J Physiol Endocrinol Metab, April 1, 2006; 290(4): E739 - E745. [Abstract] [Full Text] [PDF]

				A Cenarro, M Artieda, S Castillo, P Mozas, G Reyes, D Tejedor, R Alonso, P Mata, M Pocovi, and F Civeira A common variant in the ABCA1 gene is associated with a lower risk for premature coronary heart disease in familial hypercholesterolaemia J. Med. Genet., March 1, 2003; 40(3): 163 - 168. [Abstract] [Full Text] [PDF]

				M. C. Lin, E.-J. Wang, C. Lee, K.T. Chin, D. Liu, J.-F. Chiu, and H.-f. Kung Garlic Inhibits Microsomal Triglyceride Transfer Protein Gene Expression in Human Liver and Intestinal Cell Lines and in Rat Intestine J. Nutr., June 1, 2002; 132(6): 1165 - 1168. [Abstract] [Full Text] [PDF]

				H. Ledmyr, F. Karpe, B. Lundahl, M. McKinnon, C. Skoglund-Andersson, and E. Ehrenborg Variants of the microsomal triglyceride transfer protein gene are associated with plasma cholesterol levels and body mass index J. Lipid Res., January 1, 2002; 43(1): 51 - 58. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Björn Lundahl Articles by Karpe, F. Search for Related Content PubMed PubMed Citation Articles by Björn Lundahl, Articles by Karpe, F. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Genetics Home Reference Related Collections Clinical genetics Lipids Other arteriosclerosis Genetics of cardiovascular disease