A Genome Scan for Familial Combined Hyperlipidemia Reveals Evidence of Linkage with a Locus on Chromosome 11

Aouizerat, Bradley E.; Allayee, Hooman; Cantor, Rita M.; Davis, Richard C.; Lanning, Christopher D.; Wen, Ping; Dallinga‐Thie, Geesje M.; Bruin, T.W.A. de; Rotter, Jerome I.; Lusis, Aldons J.

doi:10.1086/302490

Cited by 109 publications

(109 citation statements)

References 48 publications

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“…Thus, individuals harboring these mutations may have an increased risk of developing atherosclerosis. Interestingly, familial combined hyperlipidemia, a polygenic lipid disorder associated with the early onset of coronary artery disease, was recently found to have genetic linkage with a region of chromosome 11 that contains the LXR␣ gene (39). It remains to be determined whether mutations in either the LXR␣ gene or its regulatory regions contribute to this disease.…”

Section: Figmentioning

confidence: 99%

Liver X Receptor (LXR) Regulation of the LXRα Gene in Human Macrophages

Whitney

Watson

Goodwin

et al. 2001

Journal of Biological Chemistry

146

100

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The nuclear oxysterol receptors LXR␣ (NR1H3) and LXR␤ (NR1H2) coordinately regulate the expression of genes involved in the transport and catabolism of cholesterol. In macrophages, LXR stimulates the transcription of genes encoding transporters involved in cholesterol efflux, which may limit the transformation of these cells into foam cells in response to lipid loading. Here, we report that natural and synthetic LXR ligands induce the expression of the LXR␣ gene in primary human macrophages and differentiated THP-1 macrophages. This regulation was not observed in primary human adipocytes or hepatocytes, a human intestinal cell line, or in any mouse tissue or cell line examined. The human LXR␣ gene was isolated, and the transcription initiation site delineated. Analysis of the LXR␣ promoter revealed a functional LXR/RXR binding site ϳ2.9 kb upstream of the transcription initiation site. We conclude that LXR␣ regulates its own expression in human macrophages and that this response is likely to amplify the effects of oxysterols on reverse cholesterol transport. These findings underscore the importance of LXR as a potential therapeutic target for the treatment of atherosclerosis.

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Section: Figmentioning

confidence: 99%

Liver X Receptor (LXR) Regulation of the LXRα Gene in Human Macrophages

Whitney

Watson

Goodwin

et al. 2001

Journal of Biological Chemistry

146

100

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“…11 Recently, very promising findings were generated by analyzing the FCHL diagnosis or a related binary trait derived from increases over age/sex-specific cutoff values. These include linkage to 1q in large Finnish pedigrees, followed by successful association analyses of a positional candidate gene, upstream transcription factor 1, 16 replication of a linked region on 11p, 11,12 and a combined analysis of Finnish and Dutch families, which showed linkage to 16q. 17 Although some analyses of the quantitative lipid traits associated with FCHL have been included in these gene finding investigations, they have rarely been the main focus of the studies.…”

mentioning

confidence: 99%

Quantitative Trait Loci for Apolipoprotein B, Cholesterol, and Triglycerides in Familial Combined Hyperlipidemia Pedigrees

Cantor

Bruin²,

Kono³

et al. 2004

ATVB

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Objective-Familial combined hyperlipidemia (FCHL) is a genetically complex lipid disorder that is diagnosed in families by combinations of increased cholesterol, triglycerides, and/or apolipoprotein B (apoB) levels in patients and their first-degree relatives. Identifying the predisposing genes promises to reveal the primary risk factors and susceptibility pathways and suggest methods of prevention and treatment. As with most genetically complex disorders, a clinical definition of disease may not be the most useful phenotype for finding the complement of predisposing genes, and the quantitative traits used to define the disorder can provide important information. This is a report of a quantitative trait loci (QTL) analysis of FCHL. Methods and Results-A full genome scan of 377 multi-allelic markers genotyped at Ϸ10 centimorgan (cM) intervals was conducted in 150 sibling pairs from 22 nuclear families in FCHL pedigrees. These data were analyzed by 2 multipoint QTL linkage methods using the nonparametric and Haseman-Elston procedures of the Genehunter software. Using a criterion of PϽ0.001 by the nonparametric analysis, we found evidence of 2 apoB QTL at 1p21-31 (PϽ0.000009) and 17p11-q21 (PϽ0.000009), a total serum cholesterol QTL at 12p13 (PϽ0.0001), and a serum triglycerides QTL at 4p15-16 (PϽ0.0002). Using the criterion of PϽ0.03 for at least 2 traits at the same locus, additional evidence for cholesterol (PϽ0.01) and a triglycerides PϽ0.02) was observed at 17p11-21, as well as suggestive evidence for apoB (PϽ0.02) and triglycerides (PϽ0.01) at 4q34-35, and cholesterol (PϽ0.01) and triglycerides (PϽ0.02) and a binary FCHL trait (lodϭ1.5) at 16p12-13. Conclusions-QTL analyses of the traits that define FCHL are effective for localizing disease-predisposing genes.

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“…These studies focused on families with extreme HDL cholesterol levels (Shoulders, Jones, and Naoumova 2004;Aouizerat et al 1999). Our study as did some others, examined families with members having serum HDL cholesterol within the normal range (Mahaney et al 2003;Pajukanta et al 2003;Arya et al 2002).…”

Section: Resultsmentioning

confidence: 99%

Genome-wide Linkage Study for Plasma HDL Cholesterol Level in an Isolated Population of Mongolia

Park¹,

Kim²,

Cho³

et al. 2008

Genomics & Informatics

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High-density lipoprotein (HDL) whose primary role is to transport cholesterol from peripheral tissues to the liver, is associated with the incidence of coronary heart disease. We analyzed HDL cholesterol levels in a genetically isolated population of extended Mongolian families. A total of 1002 individuals (54.5% women) from 95 families were enrolled. After genotyping by use of 1000 microsatellite markers, we performed a genome-wide linkage search with variance component analysis. The estimated heritability of HDL cholesterol was 0.45, revealing that HDL cholesterol was under significant genetic influence. We found peak evidence of linkage (LOD score=1.88) for HDL cholesterol level on chromosome 6 (nearest marker D6S1660) and potential evidences for linkage on chromosomes 1, 12 and 19 with the LOD scores of 1.32, 1.44 and 1.14, respectively. These results should pave the way for the discovery of the relevant genes by fine mapping and association analysis.

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A Genome Scan for Familial Combined Hyperlipidemia Reveals Evidence of Linkage with a Locus on Chromosome 11

Cited by 109 publications

References 48 publications

Liver X Receptor (LXR) Regulation of the LXRα Gene in Human Macrophages

Liver X Receptor (LXR) Regulation of the LXRα Gene in Human Macrophages

Quantitative Trait Loci for Apolipoprotein B, Cholesterol, and Triglycerides in Familial Combined Hyperlipidemia Pedigrees

Genome-wide Linkage Study for Plasma HDL Cholesterol Level in an Isolated Population of Mongolia

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