Familial combined hyperlipidemia: upstream transcription factor 1 and beyond

Lee, Jenny C.; Lusis, Aldons J.; Pajukanta, Päivi

doi:10.1097/01.mol.0000217890.54875.13

Cited by 39 publications

(33 citation statements)

References 78 publications

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“…7 In many of these studies, there is evidence of sex specificity, with the common allele of rs3737787 showing strongest evidence for association with high TGs in males. 2,3,7 Interestingly, in females, the minor allele seems to be associated with elevated lipids, as well as cardiovascular disease and mortality. 7 The underlying functional mechanisms explaining this replicated sex specificity are currently unknown.…”

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confidence: 99%

“…1 Importantly, FCHL is observed in up to 20% of premature coronary artery disease (CAD) patients. 2 In addition to high serum total cholesterol (TC) and triglycerides (TGs), low plasma levels of high-density lipoprotein cholesterol (HDL-C), small dense low-density lipoprotein particles, and elevated apolipoprotein B (apoB) are also often observed in FCHL. 1,2 Association between FCHL and variants of the upstream transcription factor 1 (USF1) located in the FCHL-linked chromosome 1q21 region was originally identified by Pajukanta et al in Finnish FCHL families.…”

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confidence: 99%

“…2 In addition to high serum total cholesterol (TC) and triglycerides (TGs), low plasma levels of high-density lipoprotein cholesterol (HDL-C), small dense low-density lipoprotein particles, and elevated apolipoprotein B (apoB) are also often observed in FCHL. 1,2 Association between FCHL and variants of the upstream transcription factor 1 (USF1) located in the FCHL-linked chromosome 1q21 region was originally identified by Pajukanta et al in Finnish FCHL families. 3 Several independent studies have investigated the USF1 variants in samples ascertained for FCHL or risk factors for premature CAD.…”

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confidence: 99%

“…2 The USF1 gene has been sequenced in 2 independent FCHL cohorts and no missense or nonsense variants have been identified, 3,4 implying that the causative variant is likely to be within an element affecting the transcription level or splicing of USF1.…”

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USF1 Contributes to High Serum Lipid Levels in Dutch FCHL Families and U.S. Whites With Coronary Artery Disease

Lee

Weissglas‐Volkov

Kyttälä

et al. 2007

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Objective-Familial combined hyperlipidemia (FCHL) characterized by high serum total cholesterol and/or triglycerides (TGs) is a common dyslipidemia predisposing to coronary artery disease (CAD). Recently, the upstream transcription factor 1 (USF1) was linked and associated with FCHL and TGs in Finnish FCHL families. Here we examined the previously associated rs3737787 SNP in extended Dutch FCHL families (nϭ532) and in a cohort of US subjects who underwent diagnostic coronary angiography (nϭ1533). Methods and Results-In males of the Dutch FCHL families, we observed significant sex-dependent associations between the common allele of rs3737787 and FCHL, TGs, and related metabolic traits (Pϭ0.02 to 0.006). In the U.S. Whites, sex-dependent associations with TGs and related metabolic traits were observed for the common allele of rs3737787 in males (Pϭ0.04 to 0.02) and rare allele in females (Pϭ0.05 to 0.002). This intriguing relationship was further supported by the highly significant genotype x sex interactions observed for TGs in the Dutch and TGs and body mass index (BMI) in U.S. White subjects with CAD (Pϭ0.0005 to 0.00004). Key Words: upstream transcription factor 1 Ⅲ familial combined hyperlipidemia Ⅲ coronary artery disease Ⅲ association Ⅲ lipids F amilial combined hyperlipidemia (FCHL) is a common familial dyslipidemia with a population prevalence of 1% to 2%. 1 Importantly, FCHL is observed in up to 20% of premature coronary artery disease (CAD) patients. 2 In addition to high serum total cholesterol (TC) and triglycerides (TGs), low plasma levels of high-density lipoprotein cholesterol (HDL-C), small dense low-density lipoprotein particles, and elevated apolipoprotein B (apoB) are also often observed in FCHL. 1,2 Association between FCHL and variants of the upstream transcription factor 1 (USF1) located in the FCHL-linked chromosome 1q21 region was originally identified by Pajukanta et al in Finnish FCHL families. 3 Several independent studies have investigated the USF1 variants in samples ascertained for FCHL or risk factors for premature CAD. 2,4 -6 The common allele of rs3737787 or SNPs in linkage disequilibrium (LD) with this SNP were associated with FCHL or one of its component traits in each of these studies. Komulainen et al investigated USF1 variants in a population-based prospective Finnish cohort and observed an association of USF1 with cardiovascular disease and mortality among females, demonstrating a consequence of USF1 at the population level in Finns. 7 In many of these studies, there is evidence of sex specificity, with the common allele of rs3737787 showing strongest evidence for association with high TGs in males. 2,3,7 Interestingly, in females, the minor allele seems to be associated with elevated lipids, as well as cardiovascular disease and mortality. 7 The underlying functional mechanisms explaining this replicated sex specificity are currently unknown. Conclusion-These

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USF1 Contributes to High Serum Lipid Levels in Dutch FCHL Families and U.S. Whites With Coronary Artery Disease

Lee

Weissglas‐Volkov

Kyttälä

et al. 2007

ATVB

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“…3 Our clusters show an average correlation coefficient of 0.85, comfortably over the limit. In the transcription factor dataset which they based these conclusions off of, 22 they found that only 37% of the genes actually showed significant experimental binding to transcription factors. So while with a .85 correlation in the signal suggests only a 50% commonality between two genes, we believe that biologically the percentage in mammalian systems is quite higher due to the relatively sparse nature of the isolated yeast transcription factors.…”

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Context Specific Transcription Factor Prediction

et al. 2007

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Abstract-One of the goals of systems biology is the identification of regulatory mechanisms that govern an organism's response to external stimuli. Transcription factors have been hypothesized as a major contributor to an organism's response to various outside stimuli, and a great deal of work has been done to predict the set of transcription factors which regulate a given gene. Most of the current methods seek to identify possible binding sites from genomic sequence. Initial attempts at predicting transcription factors from genomic sequences suffered from the problem of false positives. Making the problem more difficult, it has also been shown that while predicted binding sites might be false positives, they can be shown to bind to their corresponding sequences in vitro. One method for rectifying this is through the use of phylogenetic analysis in which only regions which show high evolutionary conservation are analyzed. However such an approach may be too stringent because of the level of degeneracy shown in transcription factor binding site position weight matrices. Due to the degeneracy, there may be only a few bases that need to be conserved across species. Therefore, while a sequence may not show a high level of evolutionary conservation, these sequences may still show high affinity for the same transcription factor. In predicting transcription factor binding we explore the notion that ''Coexpression implies co-regulation'' [Allocco et al. BMC Bioinformatics 5:18, 2004]. With multiple genes requiring similar transcription factors binding sites, there exists a basis for eliminating false positives. This method allows for the selection of transcription factors binding sites that are active under a given experimental paradigm, thereby allowing us to indirectly incorporate the effects of chromosome and recognition site presentation upon transcription factor binding prediction. Rather than having to rationalize that a few transcription factors binding sites are over-represented in a cluster of genes, one can show that a few transcription factors are active in the cluster of genes that have been grouped together. Although the method focuses on predicting experiment-specific transcription factor binding sites, it is possible that if such a methodology were used in an iterative process where different experiments were analyzed, one could obtain a comprehensive set of transcription factors binding sites which regulate the various dynamic responses shown by biological systems under a variety of conditions hence building a more comprehensive model of transcriptional regulation.

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