doi: 10.1161/01.RES.0000151332.39871.13
© 2005 American Heart Association, Inc.
Reviews |
Genetics of Variation in HDL Cholesterol in Humans and Mice
From the Jackson Laboratory, Bar Harbor, Me.
Correspondence to Xiaosong Wang, MD, the Jackson Laboratory, 600 Main St, Bar Harbor, ME 04609. E-mail xw{at}jax.org
This Review is part of a thematic series on New Pathways in HDL Metabolism, which includes the following articles:
Antiinflammatory Properties of HDL
Genetics of Variation in HDl Cholesterol in Humans and Mice
New Insights Into the Regulation of HDL Metabolism and Reverse Cholesterol Transport
Endothelial and Antithrombotic Effects of HDL
Daniel Rader Guest Editor
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Abstract |
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 Top Abstract IntroductionCandidate Genes Regulating HDL...Searching for New Genes...SummaryReferences |
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Plasma high-density lipoprotein cholesterol (HDL-C) concentrations are genetically determined to a great extent, and quantitative trait locus (QTL) analysis has been used to identify chromosomal regions containing genes regulating HDL-C levels. We discuss new genes found to participate in HDL metabolism. We also summarize 37 mouse and 30 human QTLs for plasma HDL-C levels, finding that all but three of the mouse QTLs have been confirmed by a second cross or a homologous human QTL, that the mouse QTL map is almost saturated because 92% of recently reported QTLs are repeats of those already found, and that 28 of the 30 human QTLs are located in regions homologous to mouse QTLs. This high degree of concordance between mouse and human QTLs suggests that the underlying genes may be the same. Strategies to more rapidly identify genes underlying mouse and human QTLs for HDL-C include focusing on the mouse and using mouse–human homologies, combining crosses, and haplotyping to narrow the region. Sequence analysis and expression studies can distinguish candidate genes consistent across multiple mouse crosses, and testing the candidate genes in human association studies can provide additional evidence for the candidacy of a gene. Together these strategies can accelerate the pace of finding genes that regulate HDL.
Key Words: high-density lipoprotein • genetics • quantitative trait locus • mouse • human
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Introduction |
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TopAbstractIntroductionCandidate Genes Regulating HDL...Searching for New Genes...SummaryReferences |
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Atherosclerosis is the pathological basis for ischemic cardiovascular disease (CVD), the leading cause of morbidity and mortality in the United States and other industrialized nations. Major risk factors for atherosclerosis include high plasma levels of low-density lipoprotein cholesterol (LDL-C), lipoprotein(a), and low levels of plasma high-density lipoprotein cholesterol (HDL-C) levels.1 However, high levels of plasma HDL-C are protective against CVD, as shown by two lines of evidence. First, epidemiological studies have shown an inverse relationship between HDL-C levels and the incidence of CVD. Men and women with HDL-C 6 to 7 mg/dL higher than average have a 20% to 27% decrease in the risk of CVD, and increasing HDL-C level by 1 mg/dL may reduce the risk of CVD by 2% to 3%, independent of plasma LDL-C levels.1 Second, raising plasma HDL-C levels protects against atherosclerosis in mice, rabbits, and humans.2
HDL may reduce atherosclerosis through several different mechanisms,3 including increasing reverse cholesterol transport, inhibiting physical and chemical modifications of LDL and thus reducing foam cell formation, protecting against endothelial dysfunction, inhibiting chronic inflammation by suppressing adhesion molecules and macrophage chemotactic proteins, and reducing arterial lipoprotein retention. Because plasma HDL is largely genetically determined (heritability estimates of HDL-C ranged from 24% to 83%, depending on different twin or family studies, with most studies in the 40% to 60% range4), its regulating genes have been extensively studied in the past few decades. Finding HDL-regulating genes is important in at least two aspects in terms of regulating plasma HDL-C concentrations. First, it has led to studies of new therapies that raise plasma HDL-C levels and/or increase HDL-mediated reverse cholesterol transport. Finding CETP as the causal gene for increased HDL levels in some patients has led to using CETP inhibitors to increase plasma HDL concentrations.2 The discovery of ABCA1 as a key player in cholesterol and phospholipid efflux has led to experiments on targeting this transporter (through specific LXR and PPAR agonists) for increasing HDL-mediated reverse cholesterol transport and reducing atherosclerosis.5 Apolipoprotein A-I (apoA-I) is the major structural protein of HDL and accounts for most of the protective effect of HDL against atherosclerosis. Infusion of phospholipids and apoA-IMilano (a cysteine is substituted for an arginine at position 173 of apoA-I) significantly reduced atheroma volume in coronary arteries of patients with acute coronary syndromes.6 Second, finding HDL-regulating genes has helped understand previously unknown mechanisms of some HDL-regulating drugs. For example, fibrates have been used to decrease plasma LDL and increase plasma HDL levels for a long time, and later it was found that they are agonists for PPAR
, a nuclear receptor that regulates genes encoding apoA-I, apoA-II, SR-BI, LPL, apoC-III, and ABCA1 (indirectly through stimulation of LXR).1 Several major HDL-raising drugs currently in clinical use (such as niacin, fibrates, statins) do so in part by decreasing apoA-I catabolism and/or increase apoA-I synthesis.6
In this review, we discuss two approaches that have been used to find HDL-regulating genes: a candidate gene approach and a genome-wide search for new genes by quantitative trait locus (QTL) analysis.
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Candidate Genes Regulating HDL Metabolism and Functions |
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TopAbstractIntroductionCandidate Genes Regulating HDL...Searching for New Genes...SummaryReferences |
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With the identification of some HDL metabolic pathways, the genes involved in the processes have been identified and cloned. In addition, some genes are identified from naturally occurring rare mutations. The genes that are known to regulate HDL metabolisms can be separated into five groups: (1) HDL-associated apolipoproteins; (2) HDL-associated enzymes and transfer proteins; (3) plasma and cell-associated enzymes; (4) cellular receptors, their adaptors, and transporters; and (5) transcription factors (Table 1). Some of the genes regulate HDL-C levels and atherosclerosis. We have summarized many of these genes in our previous review,7 and recent publications have extensively discussed some of them, such as Apoa1, Abca1, SR-BI (Scarb1), cholesterol ester transfer protein (Cetp), endothelial lipase (Lipg), and hepatic lipase; therefore, we limit our discussion to new genes found since the last review, which all belong to the last three groups.
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Plasma and Cell-Associated Enzymes
Recent studies suggest that the following four cell-associated enzymes may be candidate genes for HDL metabolism and functions: Dgat1, Pemt, Pcyt1a, and Lipe. Diacylglycerol O-acyltransferase 1 (DGAT1; also called acyl coenzyme A:diacylglycerol acyltransferase) catalyzes the final step in mammalian triglyceride synthesis. The C79T SNP in the 5' noncoding region of DGAT1 is associated with plasma HDL-C levels in females in the Turkish Heart Study population.8 In addition, the 79T construct has 20% to 33% less promoter activity than the 79C construct,8 suggesting that the C79T SNP is functional. Phosphatidylethanolamine N-methyltransferase (PEMT) catalyzes the conversion of phosphatidylethanolamine to phosphatidylcholine in liver. Compared with wild-type controls, Pemt-targeted mutant mice have lower plasma HDL-C levels in females fed chow and in both females and males fed high-fat diet,9 suggesting that PEMT is involved in regulating plasma HDL-C levels. Similarly, liver-specific targeted disruption of phosphate cytidylyltransferase 1 alpha isoform (Pcyt1a), the gene encoding another phosphatidylcholine-synthesizing enzyme, CTP:phosphocholine cytidylyltransferase, leads to decreased plasma HDL-C in mice fed chow, suggesting that PCYT1A regulates plasma HDL-C levels.10 Hormone-sensitive lipase (LIPE) hydrolyzes triacylglycerols, diglycerides, cholesterol esters, and retinyl esters. Lipe-targeted mutant mice have higher plasma HDL-C concentrations than do wild-type controls, possibly as a result of increased lipoprotein lipase activity in cardiac and skeletal muscle.11
Cellular Receptors, Their Adaptors, and Transporters
PDZK1, a PDZ (PSD-95, Drosophila discs-large protein, Zonula occludens protein 1) domain-containing protein, was recently found to regulate plasma HDL-C concentrations. It binds and interacts with the last three carboxyl-terminal amino acids (Arg-Lys-Leu) of SR-BI, and is essential for cell surface expression of SR-BI in mouse liver.12,13 In Pdzk1-targeted mutant mice, SR-BI protein expression is reduced by 95% in the liver and 50% in the proximal intestine, but is unaffected in steroidogenic organs (adrenal, ovary and testis).14 In addition, total and HDL cholesterol are elevated and HDL particle size is increased,14 phenotypes similar to those observed in Scarb1-targeted mutant mice,15 suggesting that loss of hepatic SR-BI is likely the underlying cause. PDZK1, which regulates hepatic SR-BI expression, is in turn regulated by a small PDZK1-associated protein called MAP17 (membrane-associated protein 17).16 Hepatic overexpression of MAP17 in mice results in liver deficiency of PDZK1 and SR-BI and markedly increased plasma HDL-C levels. Metabolic labeling experiments suggest that MAP17 may regulate PDZK1 turnover endogenously.16
Both ABCG1 and ABCG4 have been found to mediate cholesterol efflux to HDL2 and HDL3.17 Another two ABCG family members, ABCG5 and ABCG8, are two neighboring and oppositely oriented genes. The mutation of either causes sitosterolemia, a rare autosomal-recessive disorder characterized by accumulation of plant and animal sterols in blood and tissues.18 ABCG5 and ABCG8 may form a functional complex to decrease the absorption of plant sterols by secreting sterols from gut epithelial cells into the lumen and increasing secretion of hepatic sterols into bile, thereby attenuating dietary sterol accumulation.19,20 Mice overexpressing both human ABCG5 and ABCG8 have a moderate decrease in plasma HDL-C levels on chow,20 consistent with the role of these two genes to decrease dietary cholesterol absorption and increase biliary cholesterol secretion. However, mice with targeted mutation of both Abcg5 and Abcg8 also had a decrease in plasma total cholesterol (mostly HDL-C) levels, reflecting either dietary or genetic differences between mouse and human.19 ABCA7 may also mediate the release of cellular cholesterol and phospholipids to generate HDL. Human ABCA7 mediates the efflux of both cellular cholesterol and phospholipids to apoA-I,21 whereas mouse ABCA7 mediates only phospholipids but not cholesterol efflux to apoA-I.22
Transcription Factors
Transcription factor 1 (Tcf1; also called hepatocyte nuclear factor-1, or Hnf1a) is important in glucose, amino acid, and cholesterol homeostasis. Mutations in TCF1 cause maturity-onset diabetes of the young, type 3 (MODY3). The following evidence suggests that TCF1 is an important regulator of plasma cholesterol (including HDL-C) concentrations. TCF1 represses apoA-I and apoC-III gene expression in HepG2 cells.23 Compared with wild-type mice, Tcf1-targeted mutant mice have hypercholesteremia and increased HDL-C levels.24 HDL particles are abnormally large in the mutant mice, probably reflecting increased HDL cholesterol esterification by LCAT, which has an increased expression in the mutant mice, and a decreased HDL phospholipids hydrolysis by hepatic lipase, whose expression is decreased in the mutant mice.24 In addition, both the G319S25 and I27L26 polymorphisms in TCF1 are significantly associated with plasma HDL-C concentrations in humans.
Hepatic nuclear factor 4 (Hnf4; also called hepatocyte nuclear factor 4 alpha, or nuclear receptor 2A1) activates TCF1-mediated gene activation, while TCF1 suppresses HFN4-dependent transcription.23 Mutations in HNF4 cause MODY1. HNF4 regulates hepatic expression of a number of genes associated with lipoprotein metabolism,27 including genes encoding apoA-I, A-II, A-IV, B, C-II, C-III, E, microsomal triglyceride transfer protein (MTP), cholesterol 7-hydroxylase (CYP7A), SR-BI, and PPAR. Mice with targeted mutation of Hnf4 have a dramatic decrease in LDL and HDL cholesterol levels, and HDL particles in these mice are small and lipid-poor.27
Mammalian NF
B (nuclear factor B) is composed of homo- and hetero-dimers of five structurally related and evolutionary conserved proteins: NFB1/p50, NFB2/p52, RelA/p65, RelB and c-Rel. NFB is involved in a variety of diseases including atherosclerosis. Mice with targeted mutation of Nfkb1 (encoding NFB1/p50) have significantly increased plasma concentrations of HDL-C and apoA-I through activation of PPAR in the absence of NFB activity: PPAR binds to peroxisome proliferators response element (PPRE) in apoA-I enhancer and activates apoA-I transcription.28
Among the 54 candidate genes for regulating HDL metabolism and functions (Table 1), eight have been confirmed to be able to regulate plasma HDL levels in both mice and humans (genes encoding apoA-I, CETP, LCAT, LIPC, LIPG, LPL, ABCA1, ABCG5/8), and 17 others play a role in regulating HDL levels in mouse models but have not been confirmed in humans (genes encoding apoA-II, apoA-IV, apoA-V, apoC-III, apoE, PLTP, LIPE, PCYT1A, PEMT, MAP17, PDZK1, SR-BI, HNF4, NFB1, FXR, PPAR and TCF1).
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Searching for New Genes Regulating Plasma HDL Cholesterol Levels: QTL Analysis in Mice and Humans |
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TopAbstractIntroductionCandidate Genes Regulating HDL...Searching for New Genes...SummaryReferences |
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QTLs for HDL-C Concentrations in Mice and Humans
QTL analysis has been used to identify chromosome segments that are responsible for variation of plasma HDL-C levels in both mice and humans. A total of 22 mouse crosses, involving 20 inbred mouse strains, have been used to map HDL-C QTLs: (1) C57BL/6x129; (2) C57BL/6xBALB; (3) C57BL/6xC3H; (4) C57BL/6xCASA; (5) C57BL/6xCAST; (6) C57BL/6xDBA/2; (7) C57BL/6xFVB; (8) C57BL/6xKK; (9) C57BL/6xNZB; (10) C57BL/6xSPRET; (11) CAST x129; (12) DBA/2xCAST; (13) KKxBALB; (14) KKxRR; (15) MRL/MpJxBALB; (16) NZBxSM; (17) PERAxDBA/2; (18) PERA/EixI; (19) RIII x129; (20) SJLxNZO; (21) SJLx129; and (22) SMxA (Table 2). According to the International Committee on Standardized Genetic Nomenclature for Mice (http://www.informatics.jax.org/mgihome/nomen/), QTLs at different chromosome locations, or at the same chromosome location but from different crosses, should be assigned different names. According to this definition, there are 99 HDL-C QTLs, scattered on every somatic chromosome (Table 2; Figure 1). However, if different crosses detect multiple QTLs at the same chromosome location, these QTLs probably have the same underlying gene; therefore, we regard them as the same QTL unless we have evidence that they are not. A total of 37 HDL-C QTLs have been identified according to this latter definition, which we use throughout this review. The 37 unique QTLs are an estimation because the confidence intervals of some are overlapping (for example, those on Chr 5 and Chr 6). Most of the QTLs have been confirmed because they are repeated in multiple crosses; a few have not (for example, Chr 13 and proximal Chr 18) (Table 2).
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In humans, 21 publications have reported 45 HDL-C QTLs in genome-wide scans in 15 different human populations (Table 3). Some of the HDL-C QTLs are at similar chromosome locations, so they are probably the same QTLs with the same underlying genes. We estimate that 30 unique HDL-C QTLs in humans have been reported in humans. They scatter on all the somatic chromosomes except Chrs 14, 17, 18, 19, and 21 (Figure 2).
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Mouse and Human HDL-C QTLs Are Concordant
To gain further insight into the relevance of the mouse HDL-C QTL to human studies, we compared HDL-C QTLs found in mice and those found in humans. Of the 37 mouse HDL-C QTLs, mouse homologous regions of human HDL-C QTLs fall within 27 of them (Table 2; Figure 1). However, for 28 of the 30 (93%) human HDL-C QTLs (except for one on distal Chr 2 and one on proximal Chr 5), at least part of their mouse homologous segments are within HDL-C QTLs detected in mouse crosses (Table 3; Figure 2). Because a total of 667 cM (42%) of mouse genome is covered by mouse HDL-C QTLs, by chance mouse homologous regions of 13 (30x42%) human QTLs will fall within mouse QTLs, just by chance. However, this number is significantly different from the actual number of 28 (P<0.0001, Fisher exact test). The result of this comparison implies that many of the QTL for HDL-C levels found in humans have homologous counterparts in mice. Because more mouse HDL-C QTLs have been found, possibly as a result of more extensive studies in mice than in humans, additional human chromosome segments that affect HDL-C concentrations may be predicted by the comparative genomics strategy.
Identifying the Genes Underlying QTLs for Plasma HDL-C Concentrations
Because >90% of human HDL-C QTLs have homologous QTLs in mice, and because finding genes in mice is much more cost-effective in mouse models than in humans, the priority of identifying genes underlying HDL-C QTLs should be in mice. After the genes are identified in mice, their homologous genes can be tested in association studies in human populations.
Since the first two reports on genome-wide scan in mouse crosses to map HDL-C QTLs in 1993,7 22 mouse crosses have been used in mapping HDL-C QTLs, revealing 99 raw QTLs (those detected at the same chromosome location but from different crosses are defined as different QTLs) and 37 unique ones (those detected at the same chromosome location from different crosses are regarded as the same QTL) (Figure 3). It is noteworthy that although nine new mouse crosses have been reported between March 2003 and August 2004 and 31 raw QTLs were detected, only four of them (one on distal Chr 4, two on Chr 10, and one on Chr 13) were unique new QTLs, suggesting that the mouse HDL-C QTL map is close to being saturated, and that our effort should be shifted from making more mapping crosses to identifying the underlying genes for the QTLs we have already had.
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Identifying QTL genes has been a challenging and labor-intensive task. Traditionally, QTLs are fine-mapped with a genetic approach using various mouse cross strategies,29 such as overlapping congenic lines, advanced intercross lines, recombinant inbred segregation test, interval specific congenic strains, outbred strains, heterogeneous stocks, recombinant progeny testing, recombinant inbred intercross strains, and selective phenotyping. New genomic and bioinformatics resources, most importantly human and mouse genome sequences and single nucleotide polymorphisms (SNPs) databases, should greatly facilitate this process. The following strategies can be used to narrow HDL-C QTL, and some can even be used to test and prove the underlying genes.
Narrow a QTL by Mouse and Human QTL Comparison
Homologous regions of many human HDL-C QTLs fall within mouse HDL-C QTLs, and vice versa. These homologous QTLs may have the same underlying gene; therefore, overlapping an HDL-C QTL from one species with the homologous regions of the QTL from another species may result in a shortened list of candidate genes in a reduced QTL interval.
SNP and Haplotype Analysis to Narrow a QTL and Test Its Candidate Genes
Recent SNP maps indicate that the genome of common inbred mouse strains is defined by 1- to 2-Mb haplotype blocks, although in some regions the haplotype patterns may be much more complex.30 The haplotype blocks can be used to narrow a QTL because its underlying gene should be in subregions where the parental strains have different haplotypes. When multiple mouse crosses detect HDL-C QTLs at the same or very close chromosomal location, it is probable that these crosses have detected the same QTL with the same underlying gene. Therefore, a QTL interval can be narrowed by comparing the haplotype blocks of all the strains in the crosses that detect the QTL.31 A gene that lies in a region identical by decent in the parental strains that detected the QTL is unlikely to be the causal gene; the true QTL gene should have different SNPs/haplotypes between the parental strains. This approach becomes more powerfully as the number of cross detecting the QTL increases.31
Narrow a QTL by Combining Crosses
Gary Churchill and his colleague Renhua Li at the Jackson Laboratory have developed a statistical method that combines crosses that have identified the same QTL (Li et al, submitted, 2004). In this method, the alleles from multiple crosses are designated according to their direction of effect—either high or low, instead of their strain names. Data from separate crosses can then be combined for re-analysis on the QTL location. Such combining increases the resolution power because both the number of animals and recombinations are increased. This method has been successfully used to narrow the 95% confidence interval of a blood pressure QTL from 42 cM to 18 cM.32
Sequence Analysis to Test the Candidate Genes
A QTL gene should be different between the two parental strains, either in the coding sequences, which change the amino acid sequences and the protein’s functions, or in the regulatory elements, which change the gene expression (at either transcriptional or translational level), or both. It is noteworthy that although sequence differences can detect promising candidates for further functional tests, one cannot eliminate genes solely based on negative findings of sequence variation.
Gene Expression Assay to Reduce the Candidate List
Gene expression studies can help in two ways. First, the genes underlying HDL-C QTLs should be expressed in organs or tissues relevant to HDL metabolism, such as liver, intestine, adipose, and endothelium. Second, if the protein sequence of a QTL gene is the same between the two parental strains, the gene should be expressed differently in the relevant tissues from the two parental strains.
Testing the Candidate Genes by Association Studies in Humans
Once a candidate gene has been identified in the mouse, it is useful to go directly to human association studies for testing SNPs in that candidate and the adjoining genes. This testing of mouse candidate genes in human studies has been useful in identifying genes for obesity,33 diabetes, Graves disease,34 autism,35 atherosclerosis (Wang et al, submitted), and hypertension (DiPetrillo et al, submitted).
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Summary |
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TopAbstractIntroductionCandidate Genes Regulating HDL...Searching for New Genes...SummaryReferences |
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Because the mouse map appears to be almost saturated for HDL-C QTLs, we can assume that the regions accounting for most of the variation have been found. To search for the genes, it is most efficient to start with those QTLs that have a human homolog, because it is the human genes we eventually want to identify, and to choose preferentially those that have been found in multiple crosses. By combining crosses and using haplotype analysis, the QTL regions can be narrowed rapidly with in silico techniques. Genes in the narrowed region can be prioritized by using all the parental strains to find those with a sequence difference in the coding region or an expression difference in a relevant tissue that is consistent with the allele effect of the QTL. These candidate genes can then be tested in human populations characterized for HDL-C for an association with the trait. Any gene that is associated with HDL-C in humans can then be tested in the mouse to prove the gene by transgenic or knockout technologies and to study the function of the alternate alleles.
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Acknowledgments |
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This work was supported by the Program for Genomic Applications of the Heart, Lung, and Blood Institute, NIH (HL66611), NIH RO1 (HL074986 to X.W.), and the Scientist Development Grant of the American Heart Association (AHA 0430381N to X.W.). We thank Henning Wittenburg and Naoki Ishimori for sharing their unpublished data, and Ray Lambert and Jennifer L. Torrance for helping to prepare the manuscript.
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Footnotes |
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Original received September 7, 2004; revision received November 2, 2004; accepted November 9, 2004.
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References |
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TopAbstractIntroductionCandidate Genes Regulating HDL...Searching for New Genes...SummaryReferences |
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1. Gotto AM, Jr, Brinton EA. Assessing low levels of high-density lipoprotein cholesterol as a risk factor in coronary heart disease: a working group report and update. J Am Coll Cardiol. 2004; 43: 717–724.
2. Brewer HB, Jr. High-density lipoproteins: a new potential therapeutic target for the prevention of cardiovascular disease. Arterioscler Thromb Vasc Biol. 2004; 24: 387–391.
3. Assmann G, Nofer JR. Atheroprotective effects of high-density lipoproteins. Annu Rev Med. 2003; 54: 321–341.[CrossRef][Medline] [Order article via Infotrieve]
4. Peacock JM, Arnett DK, Atwood LD, Myers RH, Coon H, Rich SS, Province MA, Heiss G. Genome Scan for Quantitative Trait Loci Linked to High-Density Lipoprotein Cholesterol: The NHLBI Family Heart Study. Arterioscler Thromb Vasc Biol. 2001; 21: 1823–1828.
5. Lorkowski S, Cullen P. High-density lipoprotein cholesterol levels and cholesterol efflux: a missing link? Curr Opin Lipidol. 2004; 15: 81–84.[CrossRef][Medline] [Order article via Infotrieve]
6. Brewer HB, Remaley AT, Neufeld EB, Basso F, Joyce C. Regulation of plasma high-density lipoprotein levels by the ABCA1 transporter and the emerging role of high-density lipoprotein in the treatment of cardiovascular disease. Arterioscler Thromb Vasc Biol. 2004; 24: 1–6.
7. Wang X, Paigen B. Quantitative trait loci and candidate genes regulating HDL cholesterol: a murine chromosome map. Arterioscler Thromb Vasc Biol. 2002; 22: 1390–1401.
8. Ludwig EH, Mahley RW, Palaoglu E, Ozbayrakci S, Balestra ME, Borecki IB, Innerarity TL, Farese RV, Jr. DGAT1 promoter polymorphism associated with alterations in body mass index, high density lipoprotein levels and blood pressure in Turkish women. Clin Genet. 2002; 62: 68–73.[CrossRef][Medline] [Order article via Infotrieve]
9. Noga AA, Vance DE. A gender-specific role for phosphatidylethanolamine N-methyltransferase-derived phosphatidylcholine in the regulation of plasma high density and very low density lipoproteins in mice. J Biol Chem. 2003; 278: 21851–21859.
10. Jacobs RL, Devlin C, Tabas I, Vance DE. Targeted deletion of hepatic CTP:phosphocholine cytidylyltransferase a in mice decreases plasma high density and very low density lipoproteins. J Biol Chem. 2004; 279: 47402–47410.
11. Haemmerle G, Zimmermann R, Strauss JG, Kratky D, Riederer M, Knipping G, Zechner R. Hormone-sensitive lipase deficiency in mice changes the plasma lipid profile by affecting the tissue-specific expression pattern of lipoprotein lipase in adipose tissue and muscle. J Biol Chem. 2002; 277: 12946–12952.
12. Ikemoto M, Arai H, Feng D, Tanaka K, Aoki J, Dohmae N, Takio K, Adachi H, Tsujimoto M, Inoue K. Identification of a PDZ-domain-containing protein that interacts with the scavenger receptor class B type I. Proc Natl Acad Sci U S A. 2000; 97: 6538–6543.
13. Silver DL. A carboxyl-terminal PDZ-interacting domain of scavenger receptor B, type I is essential for cell surface expression in liver. J Biol Chem. 2002; 277: 34042–34047.
14. Kocher O, Yesilaltay A, Cirovic C, Pal R, Rigotti A, Krieger M. Targeted disruption of the PDZK1 gene in mice causes tissue-specific depletion of the high density lipoprotein receptor scavenger receptor class B type I and altered lipoprotein metabolism. J Biol Chem. 2003; 278: 52820–52825.
15. Rigotti A, Trigatti BL, Penman M, Rayburn H, Herz J, Krieger M. A targeted mutation in the murine gene encoding the high density lipoprotein (HDL) receptor scavenger receptor class B type I reveals its key role in HDL metabolism. Proc Natl Acad Sci U S A. 1997; 94: 12610–12615.
16. Silver DL, Wang N, Vogel S. Identification of small PDZK1-associated protein, DD96/MAP17, as a regulator of PDZK1 and plasma high density lipoprotein levels. J Biol Chem. 2003; 278: 28528–28532.
17. Wang N, Lan D, Chen W, Matsuura F, Tall AR. ATP-binding cassette transporters G1 and G4 mediate cellular cholesterol efflux to high-density lipoproteins. Proc Natl Acad Sci U S A. 2004; 101: 9774–9779.
18. Berge KE, Tian H, Graf GA, Yu L, Grishin NV, Schultz J, Kwiterovich P, Shan B, Barnes R, Hobbs HH. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science. 2000; 290: 1771–1775.
19. Yu L, Hammer RE, Li-Hawkins J, Von Bergmann K, Lutjohann D, Cohen JC, Hobbs HH. Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion. Proc Natl Acad Sci U S A. 2002; 99: 16237–16242.
20. Yu L, Li-Hawkins J, Hammer RE, Berge KE, Horton JD, Cohen JC, Hobbs HH. Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol. J Clin Invest. 2002; 110: 671–680.[CrossRef][Medline] [Order article via Infotrieve]
21. Abe-Dohmae S, Ikeda Y, Matsuo M, Hayashi M, Okuhira K, Ueda K, Yokoyama S. Human ABCA7 supports apolipoprotein-mediated release of cellular cholesterol and phospholipid to generate high density lipoprotein. J Biol Chem. 2004; 279: 604–611.
22. Wang N, Lan D, Gerbod-Giannone M, Linsel-Nitschke P, Jehle AW, Chen W, Martinez LO, Tall AR. ATP-binding cassette transporter A7 (ABCA7) binds apolipoprotein A-I and mediates cellular phospholipid but not cholesterol efflux. J Biol Chem. 2003; 278: 42906–42912.
23. Kritis AA, Ktistaki E, Barda D, Zannis VI, Talianidis I. An indirect negative autoregulatory mechanism involved in hepatocyte nuclear factor-1 gene expression. Nucleic Acids Res. 1993; 21: 5882–5889.
24. Shih DQ, Bussen M, Sehayek E, Ananthanarayanan M, Shneider BL, Suchy FJ, Shefer S, Bollileni JS, Gonzalez FJ, Breslow JL, Stoffel M. Hepatocyte nuclear factor-1alpha is an essential regulator of bile acid and plasma cholesterol metabolism. Nat Genet. 2001; 27: 375–382.[CrossRef][Medline] [Order article via Infotrieve]
25. Hegele RA, Cao H, Harris SB, Hanley AJ, Zinman B, Connelly PW. The private hepatocyte nuclear factor-1alpha G319S variant is associated with plasma lipoprotein variation in Canadian Oji-Cree. Arterioscler Thromb Vasc Biol. 2000; 20: 217–222.
26. Babaya N, Ikegami H, Fujisawa T, Nojima K, Itoi-Babaya M, Inoue K, Nakura J, Abe M, Yamamoto M, Jin JJ, Wu Z, Miki T, Fukuda M, Ogihara T. Association of I27L polymorphism of hepatocyte nuclear factor-1 alpha gene with high-density lipoprotein cholesterol level. J Clin Endocrinol Metab. 2003; 88: 2548–2551.
27. Hayhurst GP, Lee YH, Lambert G, Ward JM, Gonzalez FJ. Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol Cell Biol. 2001; 21: 1393–1403.
28. Morishima A, Ohkubo N, Maeda N, Miki T, Mitsuda N. NFkappaB regulates plasma apolipoprotein A-I and high density lipoprotein cholesterol through inhibition of peroxisome proliferator-activated receptor alpha. J Biol Chem. 2003; 278: 38188–38193.
29. Wang X, Le Roy I, Nicodeme E, Li R, Wagner R, Petros C, Churchill GA, Harris S, Darvasi A, Kirilovsky J, Roubertoux PL, Paigen B. Using advanced intercross lines for high-resolution mapping of HDL cholesterol quantitative trait loci. Genome Res. 2003; 13: 1654–1664.
30. Yalcin B, Fullerton J, Miller S, Keays DA, Brady S, Bhomra A, Jefferson A, Volpi E, Copley RR, Flint J, Mott R. Unexpected complexity in the haplotypes of commonly used inbred strains of laboratory mice. Proc Natl Acad Sci U S A. 2004; 101: 9734–9739.
31. Wang X, Korstanje R, Higgins D, Paigen B. Haplotype analysis in multiple crosses to identify a QTL gene. Genome Res. 2004; 14: 1767–1772.
32. DiPetrillo K, Tsaih SW, Sheehan S, Johns C, Kelmenson P, Gavras H, Churchill GA, Paigen B. Genetic analysis of blood pressure in C3H/HeJ and SWR/J mice. Physiol Genomics. 2004; 17: 215–220.
33. Krude H, Biebermann H, Luck W, Horn R, Brabant G, Gruters A. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet. 1998; 19: 155–157.[CrossRef][Medline] [Order article via Infotrieve]
34. Ueda H, Howson JM, Esposito L, Heward J, Snook H, Chamberlain G, Rainbow DB, Hunter KM, Smith AN, Di Genova G, Herr MH, Dahlman I, Payne F, Smyth D, Lowe C, Twells RC, Howlett S, Healy B, Nutland S, Rance HE, Everett V, Smink LJ, Lam AC, Cordell HJ, Walker NM, Bordin C, Hulme J, Motzo C, Cucca F, Hess JF, Metzker ML, Rogers J, Gregory S, Allahabadia A, Nithiyananthan R, Tuomilehto-Wolf E, Tuomilehto J, Bingley P, Gillespie KM, Undlien DE, Ronningen KS, Guja C, Ionescu-Tirgoviste C, Savage DA, Maxwell AP, Carson DJ, Patterson CC, Franklyn JA, Clayton DG, Peterson LB, Wicker LS, Todd JA, Gough SC. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature. 2003; 423: 506–511.[CrossRef][Medline] [Order article via Infotrieve]
35. Gharani N, Benayed R, Mancuso V, Brzustowicz LM, Millonig JH. Association of the homeobox transcription factor, ENGRAILED 2, 3, with autism spectrum disorder. Mol Psychiatry. 2004; 9: 474–484.[CrossRef][Medline] [Order article via Infotrieve]
36. Williamson R, Lee D, Hagaman J, Maeda N. Marked reduction of high density lipoprotein cholesterol in mice genetically modified to lack apolipoprotein A-I. Proc Natl Acad Sci U S A. 1992; 89: 7134–7138.
37. Rubin EM, Krauss RM, Spangler EA, Verstuyft JG, Clift SM. Inhibition of early atherogenesis in transgenic mice by human apolipoprotein AI. Nature. 1991; 353: 265–267.[CrossRef][Medline] [Order article via Infotrieve]
38. Breslow JL. Familial disorders of high density lipoprotein metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic Basis of Inherited Disease. New York: McGraw-Hill, Inc; 1989: 1251–1266.
39. Blanco-Vaca F, Escola-Gil JC, Martin-Campos JM, Julve J. Role of apoA-II in lipid metabolism and atherosclerosis: advances in the study of an enigmatic protein. J Lipid Res. 2001; 42: 1727–1739.
40. Weinstock PH, Bisgaier CL, Hayek T, Aalto-Setala K, Sehayek E, Wu L, Sheiffele P, Merkel M, Essenburg AD, Breslow JL. Decreased HDL cholesterol levels but normal lipid absorption, growth, and feeding behavior in apolipoprotein A-IV knockout mice. J Lipid Res. 1997; 38: 1782–1794.[Abstract]
41. Aalto-Setala K, Bisgaier CL, Ho A, Kieft KA, Traber MG, Kayden HJ, Ramakrishnan R, Walsh A, Essenburg AD, Breslow JL. Intestinal expression of human apolipoprotein A-IV in transgenic mice fails to influence dietary lipid absorption or feeding behavior. J Clin Invest. 1994; 93: 1776–1786.[Medline] [Order article via Infotrieve]
42. Cohen RD, Castellani LW, Qiao JH, Van Lenten BJ, Lusis AJ, Reue K. Reduced aortic lesions and elevated high density lipoprotein levels in transgenic mice overexpressing mouse apolipoprotein A-IV. J Clin Invest. 1997; 99: 1906–1916.[Medline] [Order article via Infotrieve]
43. van der Vliet HN, Schaap FG, Levels JH, Ottenhoff R, Looije N, Wesseling JG, Groen AK, Chamuleau RA. Adenoviral overexpression of apolipoprotein A-V reduces serum levels of triglycerides and cholesterol in mice. Biochem Biophys Res Commun. 2002; 295: 1156–1159.[CrossRef][Medline] [Order article via Infotrieve]
44. Aalto-Setala K, Fisher EA, Chen X, Chajek-Shaul T, Hayek T, Zechner R, Walsh A, Ramakrishnan R, Ginsberg HN, Breslow JL. Mechanism of hypertriglyceridemia in human apolipoprotein (apo) CIII transgenic mice. Diminished very low density lipoprotein fractional catabolic rate associated with increased apo CIII and reduced apo E on the particles. J Clin Invest. 1992; 90: 1889–1900.[Medline] [Order article via Infotrieve]
45. Zhang SH, Reddick RL, Piedrahita JA, Maeda N. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science. 1992; 258: 468–471.
46. Plump AS, Smith JD, Hayek T, Aalto-Setala K, Walsh A, Verstuyft JG, Rubin EM, Breslow JL. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell. 1992; 71: 343–353.[CrossRef][Medline] [Order article via Infotrieve]
47. Santamarina-Fojo S, Lambert G, Hoeg JM, Brewer HB, Jr. Lecithin-cholesterol acyltransferase: role in lipoprotein metabolism, reverse cholesterol transport and atherosclerosis. Curr Opin Lipidol. 2000; 11: 267–275.[CrossRef][Medline] [Order article via Infotrieve]
48. Jiang XC, Bruce C, Mar J, Lin M, Ji Y, Francone OL, Tall AR. Targeted mutation of plasma phospholipid transfer protein gene markedly reduces high-density lipoprotein levels. J Clin Invest. 1999; 103: 907–914.[Medline] [Order article via Infotrieve]
49. Foger B, Santamarina-Fojo S, Shamburek RD, Parrot CL, Talley GD, Brewer HB, Jr. Plasma phospholipid transfer protein. Adenovirus-mediated overexpression in mice leads to decreased plasma high density lipoprotein (HDL) and enhanced hepatic uptake of phospholipids and cholesteryl esters from HDL. J Biol Chem. 1997; 272: 27393–27400.
50. Jiang X, Francone OL, Bruce C, Milne R, Mar J, Walsh A, Breslow JL, Tall AR. Increased prebeta-high density lipoprotein, apolipoprotein AI, and phospholipid in mice expressing the human phospholipid transfer protein and human apolipoprotein AI transgenes. J Clin Invest. 1996; 98: 2373–2380.[Medline] [Order article via Infotrieve]
51. Homanics GE, de Silva HV, Osada J, Zhang SH, Wong H, Borensztajn J, Maeda N. Mild dyslipidemia in mice following targeted inactivation of the hepatic lipase gene. J Biol Chem. 1995; 270: 2974–2980.
52. Busch SJ, Barnhart RL, Martin GA, Fitzgerald MC, Yates MT, Mao SJ, Thomas CE, Jackson RL. Human hepatic triglyceride lipase expression reduces high density lipoprotein and aortic cholesterol in cholesterol-fed transgenic mice. J Biol Chem. 1994; 269: 16376–16382.
53. Applebaum-Bowden D, Kobayashi J, Kashyap VS, Brown DR, Berard A, Meyn S, Parrott C, Maeda N, Shamburek R, Brewer HB, Jr, Santamarina-Fojo S. Hepatic lipase gene therapy in hepatic lipase-deficient mice. Adenovirus-mediated replacement of a lipolytic enzyme to the vascular endothelium. J Clin Invest. 1996; 97: 799–805.[Medline] [Order article via Infotrieve]
54. Ruel IL, Couture P, Cohn JS, Bensadoun A, Marcil M, Lamarche B. Evidence that hepatic lipase deficiency in humans is not associated with proatherogenic changes in HDL composition and metabolism. J Lipid Res. 2004; 45: 1528–1537.
55. Zambon A, Deeb SS, Pauletto P, Crepaldi G, Brunzell JD. Hepatic lipase: a marker for cardiovascular disease risk and response to therapy. Curr Opin Lipidol. 2003; 14: 179–189.[CrossRef][Medline] [Order article via Infotrieve]
56. Jaye M, Krawiec J. Endothelial lipase and HDL metabolism. Curr Opin Lipidol. 2004; 15: 183–189.[CrossRef][Medline] [Order article via Infotrieve]
57. Levak-Frank S, Weinstock PH, Hayek T, Verdery R, Hofmann W, Ramakrishnan R, Sattler W, Breslow JL, Zechner R. Induced mutant mice expressing lipoprotein lipase exclusively in muscle have subnormal triglycerides yet reduced high density lipoprotein cholesterol levels in plasma. J Biol Chem. 1997; 272: 17182–17190.
58. Merkel M, Eckel RH, Goldberg IJ. Lipoprotein lipase: genetics, lipid uptake, and regulation. J Lipid Res. 2002; 43: 1997–2006.
59. McNeish J, Aiello RJ, Guyot D, Turi T, Gabel C, Aldinger C, Hoppe KL, Roach ML, Royer LJ, de Wet J, Broccardo C, Chimini G, Francone OL. High density lipoprotein deficiency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1. Proc Natl Acad Sci U S A. 2000; 97: 4245–4250.
60. Christiansen-Weber TA, Voland JR, Wu Y, Ngo K, Roland BL, Nguyen S, Peterson PA, Fung-Leung WP. Functional loss of ABCA1 in mice causes severe placental malformation, aberrant lipid distribution, and kidney glomerulonephritis as well as high-density lipoprotein cholesterol deficiency. Am J Pathol. 2000; 157: 1017–1029.
61. Vaisman BL, Lambert G, Amar M, Joyce C, Ito T, Shamburek RD, Cain WJ, Fruchart-Najib J, Neufeld ED, Remaley AT, Brewer HB, Jr., Santamarina-Fojo S. ABCA1 overexpression leads to hyperalphalipoproteinemia and increased biliary cholesterol excretion in transgenic mice. J Clin Invest. 2001; 108: 303–309.[CrossRef][Medline] [Order article via Infotrieve]
62. Bodzioch M, Orso E, Klucken J, Langmann T, Bottcher A, Diederich W, Drobnik W, Barlage S, Buchler C, Porsch-Ozcurumez M, Kaminski WE, Hahmann HW, Oette K, Rothe G, Aslanidis C, Lackner KJ, Schmitz G. The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Genet. 1999; 22: 347–351.[CrossRef][Medline] [Order article via Infotrieve]
63. Brooks-Wilson A, Marcil M, Clee SM, Zhang LH, Roomp K, van Dam M, Yu L, Brewer C, Collins JA, Molhuizen HO, Loubser O, Ouelette BF, Fichter K, Ashbourne-Excoffon KJ, Sensen CW, Scherer S, Mott S, Denis M, Martindale D, Frohlich J, Morgan K, Koop B, Pimstone S, Kastelein JJ, Hayden MR, et al. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet. 1999; 22: 336–345.[CrossRef][Medline] [Order article via Infotrieve]
64. Rust S, Rosier M, Funke H, Real J, Amoura Z, Piette JC, Deleuze JF, Brewer HB, Duverger N, Denefle P, Assmann G. Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nat Genet. 1999; 22: 352–355.[CrossRef][Medline] [Order article via Infotrieve]
65. Lee MH, Lu K, Hazard S, Yu H, Shulenin S, Hidaka H, Kojima H, Allikmets R, Sakuma N, Pegoraro R, Srivastava AK, Salen G, Dean M, Patel SB. Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption. Nat Genet. 2001; 27: 79–83.[Medline] [Order article via Infotrieve]
66. Trigatti BL, Krieger M, Rigotti A. Influence of the HDL receptor SR-BI on lipoprotein metabolism and atherosclerosis. Arterioscler Thromb Vasc Biol. 2003; 23: 1732–1738.
67. Lambert G, Amar MJ, Guo G, Brewer HB, Jr., Gonzalez FJ, Sinal CJ. The farnesoid X-receptor is an essential regulator of cholesterol homeostasis. J Biol Chem. 2003; 278: 2563–2570.
68. Peters JM, Hennuyer N, Staels B, Fruchart JC, Fievet C, Gonzalez FJ, Auwerx J. Alterations in lipoprotein metabolism in peroxisome proliferator-activated receptor alpha-deficient mice. J Biol Chem. 1997; 272: 27307–27312.
69. Meiner VL, Cases S, Myers HM, Sande ER, Bellosta S, Schambelan M, Pitas RE, McGuire J, Herz J, Farese RV, Jr. Disruption of the acyl-CoA:cholesterol acyltransferase gene in mice: evidence suggesting multiple cholesterol esterification enzymes in mammals. Proc Natl Acad Sci U S A. 1996; 93: 14041–14046.
70. Anunciado RV, Nishimura M, Mori M, Ishikawa A, Tanaka S, Horio F, Ohno T, Namikawa T. Quantitative trait locus analysis of serum insulin, triglyceride, total cholesterol and phospholipid levels in the (SM/J x A/J)F2 mice. Exp Anim. 2003; 52: 37–42.[CrossRef][Medline] [Order article via Infotrieve]
71. Lyons MA, Wittenburg H, Li R, Walsh KA, Korstanje R, Churchill GA, Carey MC, Paigen B. Quantitative trait loci that determine lipoprotein cholesterol levels in an intercross of 129S1/SvImJ and CAST/Ei inbred mice. Physiol Genomics. 2004; 17: 60–68.
72. Dansky HM, Shu P, Donavan M, Montagno J, Nagle DL, Smutko JS, Roy N, Whiteing S, Barrios J, McBride TJ, Smith JD, Duyk G, Breslow JL, Moore KJ. A phenotype-sensitizing Apoe-deficient genetic background reveals novel atherosclerosis predisposition loci in the mouse. Genetics. 2002; 160: 1599–1608.
73. Lyons MA, Korstanje R, Li R, Walsh KA, Churchill GA, Carey MC, Paigen B. Genetic contributors to lipoprotein cholesterol levels in an intercross of 129S1/SvImJ and RIIIS/J inbred mice. Physiol Genomics. 2004; 17: 114–121.
74. Korstanje R, Li R, Howard T, Kelmenson P, Marshall J, Paigen B, Churchill G. Influence of sex and diet on quantitative trait loci for HDL cholesterol levels in an SM/J by NZB/BlNJ intercross population. J Lipid Res. 2004; 45: 881–888.
75. Schwarz M, Davis DL, Vick BR, Russell DW. Genetic analysis of cholesterol accumulation in inbred mice. J Lipid Res. 2001; 42: 1812–1819.
76. Ishimori N, Li R, Kelmenson PM, Korstanje R, Walsh KA, Churchill GA, Forsman-Semb K, Paigen B. Quantitative trait loci analysis for plasma HDL-cholesterol concentrations and atherosclerosis susceptibility between inbred mouse strains C57BL/6J and 129S1/SvImJ. Arterioscler Thromb Vasc Biol. 2004; 24: 161–166.
77. Lyons MA, Wittenburg H, Li R, Walsh KA, Churchill GA, Carey MC, Paigen B. Quantitative trait loci that determine lipoprotein cholesterol levels in DBA/2J and CAST/Ei inbred mice. J Lipid Res. 2003; 44: 953–967.
78. Colinayo VV, Qiao JH, Wang X, Krass KL, Schadt E, Lusis AJ, Drake TA. Genetic loci for diet-induced atherosclerosis lesions and plasma lipids in mice. Mamm Genome. 2003; 14: 464–471.
79. Shike T, Hirose S, Kobayashi M, Funabiki K, Shirai T, Tomino Y. Susceptibility and negative epistatic loci contributing to type 2 diabetes and related phenotypes in a KK/Ta mouse model. Diabetes. 2001; 50: 1943–1948.
80. Giesen K, Plum L, Kluge R, Ortlepp J, Joost HG. Diet-dependent obesity and hypercholesterolemia in the New Zealand obese mouse: identification of a quantitative trait locus for elevated serum cholesterol on the distal mouse chromosome 5. Biochem Biophys Res Commun. 2003; 304: 812–817.[CrossRef][Medline] [Order article via Infotrieve]
81. Welch CL, Bretschger S, Wen PZ, Mehrabian M, Latib N, Fruchart-Najib J, Fruchart JC, Myrick C, Lusis AJ. Novel QTLs for HDL levels identified in mice by controlling for Apoa2 allelic effects: confirmation of a chromosome 6 locus in a congenic strain. Physiol Genomics. 2004; 17: 48–59.
82. Sehayek E, Duncan EM, Yu HJ, Petukhova L, Breslow JL. Loci controlling plasma non-HDL and HDL cholesterol levels in a C57BL /6J x CASA /Rk intercross. J Lipid Res. 2003; 44: 1744–1750.
83. Suto J, Sekikawa K. Quantitative trait locus analysis of plasma cholesterol and triglyceride levels in KK x RR F2 mice. Biochem Genet. 2003; 41: 325–341.[CrossRef][Medline] [Order article via Infotrieve]
84. Pajukanta P, Allayee H, Krass KL, Kuraishy A, Soro A, Lilja HE, Mar R, Taskinen MR, Nuotio I, Laakso M, Rotter JI, de Bruin TW, Cantor RM, Lusis AJ, Peltonen L. Combined analysis of genome scans of dutch and finnish families reveals a susceptibility locus for high-density lipoprotein cholesterol on chromosome 16q. Am J Hum Genet. 2003; 72: 903–917.[CrossRef][Medline] [Order article via Infotrieve]
85. Sonnenberg GE, Krakower GR, Martin LJ, Olivier M, Kwitek AE, Comuzzie AG, Blangero J, Kissebah AH. Genetic determinants of obesity-related lipid traits. J Lipid Res. 2004; 45: 610–615.
86. Soro A, Pajukanta P, Lilja HE, Ylitalo K, Hiekkalinna T, Perola M, Cantor RM, Viikari JS, Taskinen MR, Peltonen L. Genome scans provide evidence for low-HDL-C loci on chromosomes 8q23, 16q24.1–24.2, and 20q13.11 in Finnish families. Am J Hum Genet. 2002; 70: 1333–1340.[CrossRef][Medline] [Order article via Infotrieve]
87. North KE, Martin LJ, Dyer T, Comuzzie AG, Williams JT. HDL cholesterol in females in the Framingham Heart Study is linked to a region of chromosome 2q. BMC Genet. 2003; 4 (Suppl 1): S98.[CrossRef][Medline] [Order article via Infotrieve]
88. Lin JP. Genome-wide scan on plasma triglyceride and high density lipoprotein cholesterol levels, accounting for the effects of correlated quantitative phenotypes. BMC Genet. 2003; 4 (Suppl 1): S47.[CrossRef][Medline] [Order article via Infotrieve]
89. Arya R, Lehman D, Hunt KJ, Schneider J, Almasy L, Blangero J, Stern MP, Duggirala R. Evidence for bivariate linkage of obesity and HDL-C levels in the Framingham Heart Study. BMC Genet. 2003; 4 (Suppl 1): S52.[CrossRef][Medline] [Order article via Infotrieve]
90. Lilja HE, Suviolahti E, Soro-Paavonen A, Hiekkalinna T, Day A, Lange K, Sobel E, Taskinen MR, Peltonen L, Perola M, Pajukanta P. Locus for quantitative HDL-cholesterol on chromosome 10q in Finnish families with dyslipidemia. J Lipid Res. 2004; 45: 1876–1884.
91. Arya R, Duggirala R, Almasy L, Rainwater DL, Mahaney MC, Cole S, Dyer TD, Williams K, Leach RJ, Hixson JE, MacCluer JW, O’Connell P, Stern MP, Blangero J. Linkage of high-density lipoprotein-cholesterol concentrations to a locus on chromosome 9p in Mexican Americans. Nat Genet. 2002; 30: 102–105.[CrossRef][Medline] [Order article via Infotrieve]
92. Canizales-Quinteros S, Aguilar-Salinas CA, Reyes-Rodriguez E, Riba L, Rodriguez-Torres M, Ramirez-Jimenez S, Huertas-Vazquez A, Fragoso-Ontiveros V, Zentella-Dehesa A, Ventura-Gallegos JL, Vega-Hernandez G, Lopez-Estrada A, Auron-Gomez M, Gomez-Perez F, Rull J, Cox NJ, Bell GI, Tusie-Luna MT. Locus on chromosome 6p linked to elevated HDL cholesterol serum levels and to protection against premature atherosclerosis in a kindred with familial hypercholesterolemia. Circ Res. 2003; 92: 569–576.
93. Duggirala R, Blangero J, Almasy L, Dyer TD, Williams KL, Leach RJ, O’Connell P, Stern MP. A major susceptibility locus influencing plasma triglyceride concentrations is located on chromosome 15q in Mexican Americans. Am J Hum Genet. 2000; 66: 1237–1245.[CrossRef][Medline] [Order article via Infotrieve]
94. Bosse Y, Chagnon YC, Despres JP, Rice T, Rao DC, Bouchard C, Perusse L, Vohl MC. Genome-wide linkage scan reveals multiple susceptibility loci influencing lipid and lipoprotein levels in the Quebec Family Study. J Lipid Res. 2004; 45: 419–426.
95. Mahaney MC, Almasy L, Rainwater DL, VandeBerg JL, Cole SA, Hixson JE, Blangero J, MacCluer JW. A quantitative trait locus on chromosome 16q influences variation in plasma HDL-C levels in Mexican Americans. Arterioscler Thromb Vasc Biol. 2003; 23: 339–345.
96. Pollin TI, Hsueh WC, Steinle NI, Snitker S, Shuldiner AR, Mitchell BD. A genome-wide scan of serum lipid levels in the Old Order Amish. Atherosclerosis. 2004; 173: 89–96.[CrossRef][Medline] [Order article via Infotrieve]
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