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Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:2054-2060

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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:2054-2060.)
© 1997 American Heart Association, Inc.

Articles

Heritability Analysis of Lipids and Three Gene Loci in Twins Link the Macrophage Scavenger Receptor to HDL Cholesterol Concentrations

Hans Knoblauch; Andreas Busjahn; Sylvia Münter; Zsuzsanna Nagy; Hans-Dieter Faulhaber; Herbert Schuster; ; Friedrich C. Luft

From the Franz Volhard Clinic and Max Delbrück Center for Molecular Medicine, Virchow Klinikum, Humboldt University of Berlin, Berlin, Germany.

Correspondence to Friedrich C. Luft, MD, Franz Volhard Clinic, Wiltbergstrasse 50, 13122 Berlin, Germany. E-mail fcluft{at}mdc-berlin.de


*    Abstract
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 *Abstract
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Abstract We studied 100 healthy monozygotic and 72 dizygotic twin pairs (mean age, 34±14 years) to test for genetic influences on blood lipids and to examine relevant gene loci. Total cholesterol (TC), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), and triglyceride (TG) levels were determined after a 12-hour fast. Zygosity was determined with the use of microsatellite markers. Heritability estimates were conducted by using the lisrel 8 program; a sib-pair analysis was conducted by using the sibpal program. Linear regression analyses were carried out between identical-by-descent status and squared within-pair differences of TC, LDL-C, HDL-C, and TG values. Heritability estimates of the lipid serum concentrations ranged from.58 to.66. A significant linkage relationship was found for HDL-C (P=.008) and TGs (P=.05) with D8S261 on chromosome 8p. However, no linkage was found between any of the lipid variables and the lipoprotein lipase gene locus (LPL GZ14/15 and D8S282). Because D8S261 is located approximately halfway between the LPL and macrophage scavenger receptor genes, we examined the nearby markers D8S549 and D8S1731. Linkage was found for HDL-C and D8S549 (P=.001) and for HDL-C and D8S1731 (P=.04). On the other hand, we found no linkage between the LDL receptor gene locus and LDL-C serum concentrations nor between the LPL gene locus and the various other lipid fractions. Our data suggest a significant influence of the macrophage scavenger receptor gene locus on HDL-C and weak influence on TG levels. We suggest that inherited variability in the macrophage scavenger receptor gene has an influence on serum lipid concentrations.


Key Words: genetics • HDL cholesterol • lipoprotein lipase • LDL cholesterol • macrophage scavenger receptor


*    Introduction
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 *Introduction
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Coronary heart disease, particularly at a young age, is largely influenced by genetic variance.1 2 Because serum TC, LDL-C, and TG levels are directly correlated with cardiovascular risk and HDL-C is inversely correlated with cardiovascular risk,3 4 the influence of genetic variance on these serum lipids is of great interest. However, the heritability data are not entirely clear and are in part conflicting.5 MZ and DZ twins provide a classic model with which to determine estimates of the influence of heredity and environment on various traits, including the risk for CHD and detrimental serum lipid levels.6 7 8 Twin studies also provide an opportunity to examine possible linkage between genetic loci and phenotypic traits in terms of a modified sibling-pair analysis.9 Although LDLR gene mutations have dramatic effects on circulating LDL-C levels in persons with familial hypercholesterolemia,10 the influence of the LDLR gene on LDL-C concentrations in the general population is less clear.11 12 13 Furthermore, data on the influence of the LPL gene locus on lipoprotein and TG levels do not uniformly agree.14 15 16 17 18 This state of affairs may be related to the use of neutral polymorphisms in some studies14 15 compared with functional polymorphisms in others.19 20 21 We studied 100 MZ and 72 DZ pairs of healthy twins to determine the influence of heredity and environment on TC, LDL-C, HDL-C, and TG levels. We first tested the loci for the LDLR and LPL genes. We chose the LPL gene because of the aforementioned association studies. When we found no linkage at either locus, we directed our attention to the nearby macrophage scavenger receptor gene locus for influences on lipoprotein concentrations.


*    Methods
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General Procedures
We recruited 172 pairs of twins (100 MZ) and (72 DZ) by advertisement to participate in studies involving blood pressure regulation and cardiovascular phenotypes.22 23 The subjects were all healthy, normotensive whites of German ancestry from various parts of Germany. The protocol was approved by the University's committee on the protection of human subjects, and written, informed consent was obtained from all participants. Women who were using oral contraceptives or estrogen preparations, women >50 years old, and individuals of both sexes who were ingesting lipid-influencing medications were excluded from this analysis. Persons with histories of familial lipid disorders were also excluded. Blood was obtained from all twins after a 12-hour fast. TC, HDL-C, and TG levels were determined by automated methods.24 LDL-C concentrations were calculated by the Friedewald equation.25 Blood was also obtained for determination of zygosity and other molecular genetic studies.

Molecular Genetic Methods
Zygosity was verified by the use of five PCR-amplified microsatellite markers as described in detail elsewhere.26 In brief, we used five highly polymorphic short-tandem-repeat loci that were coamplified by PCR with the use of fluorescence-labeled primers. Four markers were multiplexed simultaneously, while the fifth was run separately. Thirty-six samples were electrophoresed and detected simultaneously by laser. The PCR products were sized by automated fragment analysis. We modified our reaction slightly to include six additional markers, namely, D8S261 and D8S549, D8S1731 and LPL GZ 14/15, and D8S282 and D19S394, which are in close proximity to the macrophage scavenger receptor, LPL, and LDLR genes, respectively.27 The PCR reactions were performed in a final volume of 15 µL containing dNTPs (200 mmol/L), primers (5 pmol), PCR reaction buffer (supplied by the manufacturer), MgCl2 (1.5 mmol/L), and AmpliTaq gold (0.65 U). The annealing temperatures were 58°C for 56°C for D19S394 and D8S261, 52°C for D8S549, 44°C for D8S1731, 56°C for D8S282, and 56°C for LPL GZ 14/15.

Twin Analysis Methods
Linkage analyses were carried out using the sibpal program of the Statistical Analysis for Genetic Epidemiology (SAGE) package.28 The underlying basis for the sib-pair linkage approach is to compare the quantitative variation in a trait between siblings as a function of the number of marker alleles that they share IBD. Because parental genotypes were not available, we estimated the number of IBD alleles on the basis of allele frequencies from each twin in each pair separately. Estimates were calculated by the sibpal program. The underlying trait can follow either mendelian or nonmendelian modes of inheritance. We assessed linkage for continuous traits, such as LDL-C, HDL-C and TGs, against candidate gene loci as described elsewhere.29 Because we used a candidate gene approach, we accepted P<.05 to test for significance.

To test whether or not our observations were the result of chance alone, we performed a simulation analysis in which we examined pair differences with randomly allocated IBD 100 times. Our simulation analysis confirmed that the probability of a false-positive result was estimated correctly from the regression analysis. The average probability of false-positive results at the.05 level was.046. The probability of a false-positive result below the obtained probability value was <.001.

Statistical analysis was conducted with the spss program. To test for differences in mean levels for any given variable, t tests for independent groups were used. Parameters of the quantitative genetic models were estimated by path analysis techniques using the lisrel 8 program developed by Jöreskog and Sörbom.30 Analogous to that obtained by regression analysis, the variability of any given phenotype (P) within a population can be partitioned into genetic influences (A), environmental influences shared by twins within the same family (C), and random environmental influences (E): P=aA+cC+eE, with the coefficients a, c, and e as the estimated relative influence. For MZ and DZ twins, the covariance of their phenotype is given by rMZ=a2+c2+e2 and rDZ=0.5a2+c2+e2, respectively. Path analysis in twin studies can estimate additive and nonadditive (dominance) components of genetic variability (estimated as h2 and d2, respectively) as well as two environmental influences, shared (c2) and unshared (e2).31 These values estimate the relative amount of the variable's influence on interindividual differences to a sum of 1. Genetic as well as environmental effects were estimated by a best-fit model selected by the {chi}2 test. The lisrel 8 output also provides estimates of the goodness-of-fit index, the adjusted goodness-of-fit index, and the Akaike information criterion. Because these estimates concurred with those derived by {chi}2 analysis, we have elected to not present them here.

The hypothesis that different genes influence lipid fractions can be examined by a bivariate path analysis.32 The basic structure of the model, which assumes only additive genetic effects, is displayed in Fig 1Down. This model includes two sets of genes, one set that influences both phenotypes (eg, TGs and HDL-C; Aa), and the second set that influences the second phenotype only (Ab), two sets of shared (Ca and Cb), and unshared (Ea and Eb) environmental factors. For the first phenotype the total genetic influence is estimated; for the second phenotype the genetic variance is divided into common and specific factors.



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  		Figure 1. Bivariate path analysis model. Aa is a set of genes influencing both HDL-C and TGs; Ab is a set of genes specific for TG level; C and E are environmental influences within and between families.


*    Results
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Table 1Down shows the demographic and lipid-related variables for the 100 pairs of MZ twins and the 72 pairs of DZ twins. The number of females represented was twice as great as the number of males. The subjects were generally young adults of normal height, weight, and body mass index. TC, HDL-C, LDL-C, and TG values were all within normal limits.


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  		Table 1. Clinical Data and Serum Lipid Values

Table 2Down shows the results of the heritability analysis. A major genetic effect was demonstrated for all lipid parameters, although strong environmental effects were also demonstrated. A slight albeit significant shared environmental effect was also observed for HDL-C. Fig 2Down shows the genetic and environmental effects shared by two phenotypes, namely, HDL-C with TGs, LDL-C with \E TGs, and HDL-C with LDL-C in a combined analysis. The y axis shows the total genetic and environmental influences on the given lipid variable pairs as a percentage. HDL-C and TGs shared common family environmental and common genetic effects, which comprised {approx}20% of the total variance. LDL-C and TGs shared only a small amount (10%) of common genetic effects. HDL-C and LDL-C shared neither genetic nor environmental influences.


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  		Table 2. Genetic and Environmental Effects on Serum Lipid Values



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  		Figure 2. Effect of genetic and environmental effects shared by two phenotypes. The y axis shows the total genetic and environmental influence on the given lipid variable pairs. HDL-C and TGs shared common family environmental effects and, to a lesser degree, common genetic effects. LDL-C and TGs shared only a small amount of genetic effects. HDL-C and LDL-C shared neither genetic nor environmental influences.

Table 3Down shows the probability values for the regression analysis performed to examine the relationship between IBD versus within-pair difference at the three loci in question. A significant linkage relationship was found for HDL-C (P=.008) and TGs (P=.05) with D8S261. Similarly, linkage was found for HDL-C and D8S549 (P=.001) and D8S1731 (P=.04). On the other hand, no linkage was found between any of the lipid variables and the LPL gene loci (LPL GZ14/15 and D8S282) or the LDLR gene locus (D19S394). Fig 3Down is a map of the area in question on chromosome 8p. The macrophage scavenger receptor gene locus and the LPL gene locus are {approx}9 cM apart from each another. The marker locations that we tested are also shown on the figure.27


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  		Table 3. Linkage Between a Given Variable and Markers at the Macrophage Scavenger Receptor (MSR), LPL, and LDLR Gene Loci



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  		Figure 3. Chromosome map of markers in the vicinity of the LPL gene and the macrophage scavenger receptor (MSR) gene on chromosome 8p.27 Those markers in which linkage to HDL and/or TGs was found are indicated by an asterisk.


*    Discussion
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 *Discussion
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The important findings in this study are that TC, HDL-C, LDL-C, and TGs are all equally influenced by both genetic and environmental influences. A similar shared-environmental effect was observed between HDL-C and TG values. Lesser concordance of genetic effects was observed when HDL-C versus TG values and LDL-C versus TG values were compared. Environmental and genetic effects between HDL-C and LDL-C appeared to be entirely separate. When we examined the three marker gene loci, the LDLR gene locus was not linked to any of them. On the other hand, the marker D8S261 was linked to TG concentrations. An effect of this locus on HDL-C concentrations was also observed. D8S261 lies on chromosome 8p in proximity to loci for the LPL gene and the macrophage scavenger receptor gene. The chromosome map indicates that the genes are {approx}9 cM apart. We next examined a microsatellite marker within the LPL gene (LPL GZ14/15) as well as another marker (D8S282) very nearby. Evaluation of these markers suggested no linkage between serum lipid concentrations and the LPL gene locus. However, when we examined markers closer to the macrophage scavenger receptor, linkage was found for HDL-C and D8S549 and HDL-C and D8S1731. To our knowledge, these results are the first demonstration of linkage between any serum lipid concentration and the macrophage scavenger receptor gene locus. Of course, we cannot be certain that the macrophage scavenger receptor gene alone is responsible for these findings, since another unknown locus influencing lipoprotein metabolism, distinct from the macrophage scavenger receptor gene but within 5 cM, could also be responsible.

Numerous studies have examined genetic and environmental influences on serum lipid levels in twins.5 6 33 34 35 36 37 38 The most comprehensive study in terms of defining the effects of genetics and environment was the Swedish Adoption/Twin Study of Aging (SATSA).6 This remarkable study involved 302 pairs of twins, of which 146 pairs had been reared apart. Furthermore, the age range of the twins was sufficient to allow insight into age-related effects. The heritability of lipid serum levels ranged from.28 to.78 in that study. The environment of rearing (shared) had a substantial impact on the levels of TC but not on those of HDL-C or TGs. The influence of heredity, particularly for TGs, decreased with age. Our estimates of heritability, as well as shared and unshared environmental effects, is in basic agreement with the SATSA results for young adult twins.6 We were unable to test age-related hypotheses because of the narrow age range of our subjects. However, our primary hypotheses were not related to heritability estimates, environmental effects, or age-related effects but rather to a possible linkage between serum lipid levels and two gene loci, namely, the LDLR gene and the LPL gene loci.

We were unable to find any linkage between the LDLR gene locus and LDL-C concentrations in the twins. Our approach may be criticized because we did not use flanking markers on either side of the LDLR gene locus, and recombinations admittedly may have occurred. However, we think that this possibility is unlikely because the microsatellite on chromosome 19 resides within 250 kb of the LDLR gene. Furthermore, Haddad et al39 used the same marker in a study of patients with familial hypercholesterolemia and found no recombinations. Earlier studies found associations between polymorphisms of the LDLR gene and LDL-C serum concentrations. Pedersen and Berg40 found that persons homozygous for the absence of the Pvu II restriction site at the LDLR gene locus had a higher chance of being in the uppermost quartile of TC levels. We were able to confirm this association in a normocholesterolemic German population.41 Humphries et al42 examined four restriction fragment length polymorphisms at the LDLR gene locus in an Italian population. They confirmed the Pvu II polymorphism association and also observed an association between the LDL-C–lowering P2 allele and increased survival for those >65 years. We studied the Pvu II polymorphism with a novel, anchored PCR in three populations (Iceland, Scotland, and England).43 When the two groups from the United Kingdom were combined, a significant association between the T/T genotype, compared with other genotypes, and lower TC and TG values was identified. Ahn et al44 studied the Ava II and the Nco I polymorphism in the LDLR genes of Hispanic and non-Hispanic Americans. Both polymorphisms revealed an effect on TC and LDL-C; however, the effects were confined to women only.

We believe that the number of twins in our study was sufficient to find linkage between the LDLR gene locus and LDL-C serum concentrations, had it been present. Indeed, we did find linkage between markers in proximity to the macrophage scavenger receptor gene locus and HDL-C and, though not as strong, to serum TGs. Greenberg45 has provided a careful discussion to explain the apparent "discrepancies" in such findings. He pointed out the difference between so-called susceptibility gene loci, which are neither necessary nor sufficient to cause disease, and those loci that are necessary but may not be sufficient for disease expression. Susceptibility gene loci increase risk and may involve the existence of multiple interacting genes (epistasis) or a disease locus in linkage disequilibrium with the marker locus. Greenberg then used a computer simulation model in which the hypothetical allele increased the risk of disease expression by a factor of 10. Nevertheless, even with 30 nuclear families, each with two affected members, the chances of finding linkage were extremely low. Greenberg then expanded his argument by indicating that linkage analysis on risk factor data may not yield additional information about linkage in the usual sense but may help distinguish between different hypotheses to explain the association.

The role of TG concentrations in the development of CHD and the value of its measurement in predicting disease risk remain controversial.46 TG is often not a significant predictor of CHD in multivariate statistical models because of the large variation in TG measurements and the strong inverse relation between HDL-C and TG levels.47 LPL plays a role in determining the plasma lipid profile, since it is the rate-limiting enzyme in the clearance of TG-rich lipoproteins from the circulation.48 This enzyme also influences apolipoprotein and phospholipid exchange between VLDL-C and HDL-C. LPL thereby affects inter-HDL-C conversions and LDL-C generation derived from VLDL clearance.49 Mutations in the LPL gene and their influence on lipid levels, particularly TGs and HDL-C, have generated major interest.14 15 16 17 18 19 20 21 Nevertheless, Heliö et al17 were unable to find evidence for linkage between familial hypertriglyceridemia and the LPL gene. We were also unable to link the LPL gene locus with serum TG concentrations in these healthy twin subjects. We used one marker that lies within the gene and another very close to it. These markers should have been sufficiently informative to demonstrate linkage; however, it is possible that our numbers were not sufficiently large for this purpose. The LPL gene resides on chromosome 8p, {approx}9 cM from the macrophage scavenger receptor gene.

We found much more impressive results when we examined markers closer to the macrophage scavenger receptor gene locus. Interestingly, the linkage results between HDL-C and these markers were much more robust than those with TGs. These results are consistent with studies that have found associations between polymorphisms in the LPL gene and TG levels, HDL-C levels, and CHD.14 15 16 17 18 19 20 21 For instance, persons heterozygous for LPL deficiency are known to have higher TG levels, lower HDL-C concentrations, and higher systolic blood pressures than LPL-normal individuals.50 51 The latter interaction is of interest because of recent observations by Pimstone et al,52 who presented evidence that mutations in the LPL gene may be a cause of low HDL-C levels in some individuals heterozygous for familial hypercholesterolemia. However, the aforementioned association studies could also be interpreted to indicate that polymorphisms in the LPL gene were in disequilibrium with a mutation in a nearby gene, namely, that for the macrophage scavenger receptor gene. We intend to apply multiplex sequencing techniques to both the LPL and the macrophage scavenger receptor genes in DZ twins to further examine these important issues.

Macrophage scavenger receptors are implicated in the pathological deposition of cholesterol (modified LDL-C) in macrophages during atherogenesis, resulting in foam cell formation.53 Macrophage scavenger receptors bind a wide range of ligands, including TG-rich lipoproteins and even bacterial pathogens.54 Targeted disruption of the macrophage scavenger receptor-A gene in mice resulted in reductions in the size of atherosclerotic lesions in animals deficient in apolipoprotein E.55 The macrophages from these mice showed a marked decrease in modified LDL-C uptake in vitro, but in vivo modified-LDL clearance was not affected. We cannot explain the linkage of the macrophage scavenger receptor gene locus in DZ twins. However, the interrelationships between the various lipid fractions and the apparent alternative mechanisms of elimination that have not yet been elucidated lead us to speculate that variations in the macrophage scavenger receptor gene have an influence on HDL-C concentrations and therefore on the risk for atherosclerosis. We realize that this hypothesis remains speculative until functionally significant mutations in the gene have been identified. Finally, we cannot exclude the possibility that another neighboring gene is responsible.

In summary, we examined healthy MZ and DZ twins to test for linkage between the LDLR gene locus, LPL gene locus, and the macrophage scavenger receptor gene locus and serum lipid concentrations. We found evidence for linkage between the macrophage scavenger receptor gene locus and serum HDL-C values, as well as a weaker one to TG concentrations, but could find no linkage between the LDLR gene locus and serum LDL-C concentrations or between the LPL gene locus and the various lipid fractions. The latter observation in no way detracts from the results of earlier association studies but may instead be explained by the difference in susceptibility gene loci and those loci necessary for disease expression. We suggest that the macrophage scavenger receptor gene locus should receive increased attention in terms of atherosclerotic risk.


*    Selected Abbreviations and Acronyms
 
CHD = coronary heart disease
DZ = dizygotic
IBD = identical by descent
LDLR = LDL receptor
LPL = lipoprotein lipase
MZ = monozygotic
PCR = polymerase chain reaction
TC = total cholesterol
TG = triglyceride


*    Acknowledgments
 
This study was supported by grants-in-aid from the Leopoldina Stiftung (to A.B.), the Deutsche Forschungsgemeinschaft (to H.S.), and the Bundesministerium für Bildung und Forschung (F.C.L.), and the Danone Corporation.

Received January 14, 1997; accepted May 15, 1997.


*    References
up arrowTop
 up arrowAbstract
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 up arrowResults
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 *References
 

  1. Goldstein JL, Schrott HG, Hazzard WR, Bierman EL, Motulsky AG. Hyperlipidemia in coronary heart disease, II: genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia. J Clin Invest. 1973;52:1544-1568.
  2. Marenberg ME, Risch N, Berkman LF, Floderus B, de Faire U. Genetic susceptibility to death from coronary heart disease in a study of twins. N Engl J Med. 1994;330:1041-1046.[Abstract/Free Full Text]
  3. Kannel WB, Castelli WP, Gordon T, McNamara PM. Serum cholesterol, lipoproteins, and the risk of coronary heart disease. Ann Intern Med. 1971;74:1-12.
  4. Assmann G, Schulte H. Relation of high density lipoprotein cholesterol and triglycerides to incidence of atherosclerotic coronary artery disease: the PROCAM experience. Am J Cardiol. 1992;70:733-737.[Medline] [Order article via Infotrieve]
  5. Breslow JL. Genetics of lipoprotein disorders. Circulation. 1993;87(suppl III):III-16-III-21.
  6. Heller DA, de Faire U, Pedersen NL, Dahlén G, McClearn GE. Genetic and environmental influences on serum lipid levels in twins. N Engl J Med. 1993;328:1150-1156.[Abstract/Free Full Text]
  7. Feinleib M, Garrison RJ, Fabsitz R, Christian JC, Itvubec Z, Bovhani NO, Uannel WB, Rosenman R, Swartz JT, Wagner JO. The NHLBI twin study of cardiovascular disease risk factors: methodology and summary of results. Am J Epidemiol. 1977;106:284-295.[Abstract/Free Full Text]
  8. Whitefield JB, Martin NG. Plasma lipids in twins: environmental and genetic influences. Atherosclerosis. 1983;48:265-277.[Medline] [Order article via Infotrieve]
  9. Morrison NA, Qi JC, Tokita A, Kelly PJ, Crofts L, Nguyen TV, Sambrook PN, Eisman JA. Prediction of bone density from vitamin D receptor alleles. Nature. 1994;367:284-287.[Medline] [Order article via Infotrieve]
  10. Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science. 1986;232:34-47.[Free Full Text]
  11. Maartmann-Moe K, Berg-Johnsen P. Genetics of the low density lipoprotein receptor, I: low density lipoprotein receptor activity in cultured fibroblasts from subjects with or without familial hypercholesterolemia. Clin Genet. 1981;20:90-103.[Medline] [Order article via Infotrieve]
  12. Magnus P, Maartmann-Moe K, Golden W, Nance WE, Berg K. Genetics of the low density lipoprotein receptor, II: genetic control of variation in cell membrane low density lipoprotein receptor activity in cultured fibroblasts. Clin Genet. 1981;20:104-112.[Medline] [Order article via Infotrieve]
  13. Maartmann-Moe K, Magnus P, Golden W, Berg K. Genetics of the low density lipoprotein receptor, III: evidence for multiple normal alleles at the low density lipoprotein receptor locus. Clin Genet. 1981;20:113-129.[Medline] [Order article via Infotrieve]
  14. Jemaa R, Fumeron F, Poirier O, Lecerf L, Evans A, Arveiler D, Luc G, Cambou J-P, Bard J-M, Fruchart J-C, Apfelbaum M, Cambien F, Tiret L. Lipoprotein lipase gene polymorphisms: associations with myocardial infarction and lipoprotein levels, the ECTIM study. J Lipid Res. 1995;36:2141-2146.[Abstract]
  15. Gerdes C, Gerdes LU, Hansen PS, Faergeman O. Polymorphisms in the lipoprotein lipase gene and their associations with plasma lipid concentrations in 40-year-old Danish men. Circulation. 1995;92:1765-1769.[Abstract/Free Full Text]
  16. Mattu RK, Needham EWA, Morgan R, Rees A, Hackshaw AK, Stocks J, Elwood PC, Galton DJ. DNA variants at the LPL gene locus associate with angiographically defined severity of atherosclerosis and serum lipoprotein levels in a Welsh population. Arterioscler Thromb Vasc Biol. 1994;14:1090-1097.[Abstract/Free Full Text]
  17. Heliö T, Palotie A, Sane T, Tikkanen MJ, Kontula K. No evidence for linkage between familial hypertriglyceridemia and apolipoprotein B, apolipoprotein C-III or lipoprotein lipase genes. Hum Genet. 1994;94:271-278.[Medline] [Order article via Infotrieve]
  18. Peacock RE, Hansten A, Nilsson-Ehle P, Humphries SE. Associations between lipoprotein lipase gene polymorphisms and plasma correlations of lipids, lipoproteins and lipase activities in young myocardial infarction survivors and age-matched healthy individuals from Sweden. Atherosclerosis. 1992;97:171-185.[Medline] [Order article via Infotrieve]
  19. Mailly F, Tugrul Y, Reymer PWA, Bruin T, Seed M, Groenemeyer BF, Asplund-Carlson A, Vallance D, Winder AF, Miller GJ, Kastelein JJP, Hamsten A, Olivecrona G, Humphries SE, Talmud PJ. A common variant in the gene for lipoprotein lipase (Asp9->Asn): functional implications and prevalence in normal and hyperlipidemic subjects. Arterioscler Thromb Vasc Biol. 1995:15:468-478.
  20. Reymer PWA, Gagne E, Groenemeyer BE, Zhang H, Forsyth I, Jansen H, Seidell JC, Kromhout D, Lie KE, Kastelein J, Hayden MR. A lipoprotein lipase mutation (Asn291Ser) is associated with reduced HDL cholesterol levels in premature atherosclerosis. Nat Genet. 1995;10:28-33.[Medline] [Order article via Infotrieve]
  21. Jukema JW, van Boven AJ, Groenemeijer B, Zwinderman AH, Reiber JHC, Bruschke AVG, Henneman JA, Molhoek GP, Bruin T, Jansen H, Gagne E, Hayden MR, Kastelein JJP, on behalf of the REGRESS study group. The Asp9 Asn mutation in the lipoprotein lipase gene is associated with increased progression of coronary atherosclerosis. Circulation. 1996;94:1913-1918.[Abstract/Free Full Text]
  22. Busjahn A, Faulhaber H-D, Viken RJ, Rose RJ, Luft FC. Genetic influences on blood pressure with the cold pressor test: a twin study. J Hypertens. 1996;14:1195-1199.[Medline] [Order article via Infotrieve]
  23. Busjahn A, Knoblauch J, Knoblauch M, Schuster H, Bohlender J, Faulhaber H-D, Luft FC. Angiotensin converting enzyme and angiotensinogen gene polymorphisms, plasma levels, and left ventricular size: a twin study. Hypertension. 1997;29:165–170.[Abstract/Free Full Text]
  24. Allain CC, Poon lS, Chan CSG, Richmond W, Fu PC. Enzymatic determination of total serum cholesterol. Clin Chem. 1974;20:470-475.[Abstract]
  25. Friedewald WT, Levy RI, Fredrickson DS. Estimation of plasma low-density lipoprotein cholesterol concentration, without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499-501.[Abstract]
  26. Becker A, Busjahn A, Faulhaber H-D, Bähring S, Schuster H, Luft FC. Automated zygosity determination with microsatellites. J Reprod Med. 1997;42:260–266.[Medline] [Order article via Infotrieve]
  27. Dib C, Faure S, Fizames C, Samson D, Drouot N, Vignal A, Millasseau P, Marc S, Hazan J, Seboun E, Lathrop M, Gyapay G, Morissette J, Weissenbach J. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature. 1996;380:152-154.[Medline] [Order article via Infotrieve]
  28. S.A.G.E.: Statistical Analysis for Genetic Epidemiology, release 2.2. Cleveland, Ohio: Department of Epidemiology and Biostatistics, Case-Western Reserve University; 1994.
  29. Wu D, Bu X, Warden CH, Shen DDC, Jeng C-Y, Sheu WHH, Fuh MMT, Katsuya T, Dzau VJ, Reaven GM, Lusis AJ, Rotter JI, Chen Y-D I. Quantitative trait locus mapping of human blood pressure to a genetic region at or near the lipoprotein lipase gene locus on chromosome 8p22. J Clin Invest. 1996;97:2111-2118.[Medline] [Order article via Infotrieve]
  30. Jöreskog KG, Sörbom D. lisrel 8. Chicago, Ill: Scientific Software International Inc; 1993.
  31. Neale MC, Cardon LR. Methodology for Genetic Studies of Twins and Families. Dordrecht, Netherlands: Kluwer Academic Publishers; 1992.
  32. Neale MC, Cardon LR. Methodology for Genetic Studies of Twins and Families. Dordrecht, Netherlands: Kluwer Academic Publishers; 1992:496.
  33. Stistonen P, Ehnholm C. On the heritability of serum high density lipoprotein in twins. Am J Hum Genet. 1980;32:1-7.[Medline] [Order article via Infotrieve]
  34. Hunt SC, Hassstedt SJ, Kuida H, Stults BM, Hopkins PN, Williams RR. Genetic heritability and common environmental components of resting and stressed blood pressures, lipids, and body mass index in Utah pedigrees and twins. Am J Epidemiol. 1989;129:625-638.[Abstract/Free Full Text]
  35. Duccini GM, Colletto D, Krieger H, Magalhäes JR. Estimates of the genetical and environmental determinants of serum lipid and lipoprotein concentrations in Brazilian twins. Hum Hered. 1981;31:232-237.[Medline] [Order article via Infotrieve]
  36. Boomsma DI, Kempen HJM, Gevers Leuven JA, Havekes L, de Knijff P, Frants RR. Genetic analysis of sex and generation differences in plasma lipid, lipoprotein and apolipoprotein levels in adolescent twins and their parents. Genet Epidemiol. 1996; 13:49-60.
  37. Lamon-Fava S, Jimenez D, Christian JC, Fabsitz RR, Reed T, Carmelli D, Castelli WP, Ordovas JM, Wilson PWF, Schaefer EJ. The NHLBI twin study: heritability of apolipoprotein A-I, B, and low density lipoprotein subclasses and concordance for lipoprotein(a). Atherosclerosis. 1991;91:97-106.[Medline] [Order article via Infotrieve]
  38. Selby JV, Newman B, Quiroga J, Christian JC, Austin MA, Fabsitz RR. Concordance for dyslipidemic hypertension in male twins. JAMA. 1991;265:2079-2084.[Abstract]
  39. Haddad L, OxDell SD, Day LB, Whittall RA, Humphries SE. Identification of a common low density lipoprotein receptor mutation (R329X) in the south of England: complete linkage disequilibrium with an allele of microsatellite D19S394. J Med Genet. 1997;34:111-116.[Abstract/Free Full Text]
  40. Berg K, Pedersen JC. Normal DNA polymorphism at the low density lipoprotein receptor (LDLR) locus associated with serum cholesterol level. Clin Genet. 1988;34:306-312.[Medline] [Order article via Infotrieve]
  41. Schuster H, Humphries S, Rauh G, Held C, Keller CH, Wolfram G, Zöllner N. Association of DNA-haplotypes in the human LDLR gene with normal serum cholesterol levels. Clin Genet. 1990;38:401-409.[Medline] [Order article via Infotrieve]
  42. Humphries S, Coviello DA, Masturzo P, Balestreri R, Orecchini G, Bertolini S. Variation in the low density lipoprotein receptor gene is associated with differences in plasma low density lipoprotein cholesterol levels in young and old normal individuals from Italy. Arterioscler Thromb. 1991;11:509-526.[Abstract/Free Full Text]
  43. Gudnason V, Zhou T, Thormar K, Baehring S, Cooper J, Miller G, Humphries SE, Schuster H. Detection of the low density lipoprotein receptor gene PvuII intron 15 polymorphism using the polymerase chain reaction: association with plasma lipid traits in healthy men and women. Clin Genet. In press.
  44. Ahn YI, Kamboh I, Aston CE, Ferrell RE, Hamman RF. Role of common genetic polymorphisms in the LDL receptor gene in affecting plasma cholesterol levels in the general population. Arterioscler Thromb. 1994;14:663-670.[Abstract/Free Full Text]
  45. Greenberg DA. Linkage analysis of "necessary" disease loci versus "susceptibility" loci. Am J Hum Genet. 1993;52:135-143.[Medline] [Order article via Infotrieve]
  46. Hulley SB, Rosenman RH, Bawol RD, Brand RJ. Epidemiology as a guide to clinical diagnosis: the association between triglyceride and coronary heart disease. N Engl J Med. 1980;302:1383-1389.[Abstract]
  47. Austin MA. Plasma triglyceride as a risk factor for coronary heart disease. Am J Epidemiol. 1989;129:249-259.[Free Full Text]
  48. Pykalisto OJ, Smith PH, Brunzell JD. Determinants of adipose tissue lipoprotein lipase. J Clin Invest. 1987;56:1108-1117.
  49. Garfinkel AS, Schotz MC. Lipoprotein lipase. In: Gotto AM Jr, ed. Plasma Lipoproteins. New York, NY: Elsevier Science Publishers; 1987:335-357.
  50. Bijvoet S, Gagne SE, Moorjani S, Gagne C, Henderson HE, Fruchart J-C, Dallongeville J, Alaupovic P, Prins M, Kastelein JJP, Hayden MR. Alterations in plasma lipoproteins and apolipoproteins before the age of 40 in heterozygotes for lipoprotein lipase deficiency. J Lipid Res. 1996;37:640-650.[Abstract]
  51. Sprecher DL, Harris BV, Stein EA, Bellet PS, Keilson LM, Simbartl LA. Higher triglycerides, lower high-density lipoprotein cholesterol, and higher systolic blood pressure in lipoprotein lipase-deficient heterozygotes: a preliminary report. Circulation. 1996;94:3239-3245.[Abstract/Free Full Text]
  52. Pimstone SN, Gagne E, Gagne C, Lupien PJ, Gaudet D, Williams RR, Kotze M, Reymer PWA, Defesche JC, Kastelein JJP, Moorjani S, Hayden MR. Mutations in the gene for lipoprotein lipase: a cause for low HDL cholesterol levels in individuals heterozygous for familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 1995;15:1704-1712.[Abstract/Free Full Text]
  53. Mazzone T, Lopez C, Bergstraesser L. Modification of very low density lipoproteins leads to macrophage scavenger receptor uptake and cholesteryl ester deposition. Arteriosclerosis. 1987;7:191-196.[Abstract/Free Full Text]
  54. Ramprasad MP, Li R, Bradley WA, Gianturco SH. Human THP-1 monocyte-macrophage membrane binding proteins: distinct receptor(s) for triglyceride-rich lipoproteins. Biochemistry. 1995;34:9126-9135.[Medline] [Order article via Infotrieve]
  55. Suzuki H, Kurihara Y, Takeya M, Kamada N, Kataoka M, Jishage K, Ueda O, Sakaguchi H, Higashi T, Suzuki T, Takashima Z, Kawabe Z, Cynshi O, Wada Z, Honda M, Kurihara H, Aburatani H, Doi T, Matsumoto A, Akzuma S, Noda T, Toyoda Y, Itakura H, Yazaki Y, Horiuchi S, Takahashi K, Kruijt JK, van Berkel TJC, Steinbrecher UP, Ishibashi S, Maeda N, Gordon S, Kodama T. A role for macrophage scavenger receptors in atherosclerosis and susceptibility to infection. Nature. 1997;386:292-296.[Medline] [Order article via Infotrieve]




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