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Aldons J Lusis - One of the best experts on this subject based on the ideXlab platform.
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Association of the apolipoprotein A1/C3/A4/A5 gene cluster with triglyceride levelsandLDLparticlesize in familial Combined Hyperlipidemia
2016Co-Authors: Rebecca Mar, Ronald M. Krauss, Rita M. Cantor, Hooman Allayee, Tjerk W.a. De Bruin, Päivi Pajukanta, M Groenendijk, Janet S Sinsheimer, Geesje Dallinga-thie, Aldons J LusisAbstract:Abstract—The APOLIPOPROTEIN (APO)A1/C3/A4/A5 gene cluster on chromosome 11 has been hypothesized to be a modifier of plasma triglycerides in FCH. In the present study, we extended previous association analyses of the gene cluster to include APOA5, a newly discovered member of the cluster. Eight SNPs across the APOA1/C3/A4/A5 gene region were analyzed in 78 FCH probands and their normolipidemic spouses as well as in 27 Dutch FCH families. Of the individual SNPs tested in the case-control panel, the strongest evidence of association was obtained with SNPs in APOA1 (P0.001) and APOA5 (P0.001). A single haplotype defined by a missense mutation in APOA5 was enriched 3-fold in FCH probands when compared with the normolipidemic spouses (P0.001) and a second haplotype was significantly enriched in the spouses (P0.001). Family-based tests also indicated significant association of triglyceride levels and LDL particle size with the investigated SNPs of APOC3 and APOA5. These findings suggest that genetic variation in the APOA1/C3/A4/A5 gene cluster acts as a modifier of plasma triglyceride levels and LDL particle size within FCH families and furthermore indicate that a number of haplotypes may contribute to FCH. (Circ Res. 2004;94: 993-999.) Key Words: genetics coronary artery disease apolipoproteins Familial Combined Hyperlipidemia (FCH; see MendelianInheritance in Man [MIM-144250], which can be ac-cessed online [OMIM] a
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Xiang-dong Bu,
2016Co-Authors: Clin J. Invest, Jerome I. Rotter, Rita M. Cantor, Aldons J Lusis, Geesje M. Dallinga-thie, Margreet Van Linde-sibenius Trip, Tjerk W.a. De BruinAbstract:Familial Combined Hyperlipidemia (FCH) is a common ge-netic lipid disorder in Western societies. In a recent repor
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association of the apolipoprotein a1 c3 a4 a5 gene cluster with triglyceride levels and ldl particle size in familial Combined Hyperlipidemia
Circulation Research, 2004Co-Authors: Rebecca Mar, Ronald M. Krauss, Rita M. Cantor, Hooman Allayee, Tjerk W.a. De Bruin, Päivi Pajukanta, M Groenendijk, Geesje M Dallingathie, Janet S Sinsheimer, Aldons J LusisAbstract:The APOLIPOPROTEIN (APO)A1/C3/A4/A5 gene cluster on chromosome 11 has been hypothesized to be a modifier of plasma triglycerides in FCH. In the present study, we extended previous association analyses of the gene cluster to include APOA5, a newly discovered member of the cluster. Eight SNPs across the APOA1/C3/A4/A5 gene region were analyzed in 78 FCH probands and their normolipidemic spouses as well as in 27 Dutch FCH families. Of the individual SNPs tested in the case-control panel, the strongest evidence of association was obtained with SNPs in APOA1 (P=0.001) and APOA5 (P=0.001). A single haplotype defined by a missense mutation in APOA5 was enriched 3-fold in FCH probands when compared with the normolipidemic spouses (P=0.001) and a second haplotype was significantly enriched in the spouses (P=0.001). Family-based tests also indicated significant association of triglyceride levels and LDL particle size with the investigated SNPs of APOC3 and APOA5. These findings suggest that genetic variation in the APOA1/C3/A4/A5 gene cluster acts as a modifier of plasma triglyceride levels and LDL particle size within FCH families and furthermore indicate that a number of haplotypes may contribute to FCH.
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familial Combined Hyperlipidemia is associated with upstream transcription factor 1 usf1
Nature Genetics, 2004Co-Authors: Päivi Pajukanta, Rita M. Cantor, Janet S Sinsheimer, Aldons J Lusis, Heidi E Lilja, Massimiliano Gentile, Xiaoqun Joyce Duan, Aino Soropaavonen, Jussi Naukkarinen, Janna SaarelaAbstract:Familial Combined Hyperlipidemia (FCHL), characterized by elevated levels of serum total cholesterol, triglycerides or both1,2, is observed in about 20% of individuals with premature coronary heart disease1. We previously identified a locus linked to FCHL on 1q21–q23 in Finnish families with the disease3. This region has also been linked to FCHL in families from other populations4,5,6 as well as to type 2 diabetes mellitus7,8,9,10,11,12. These clinical entities have several overlapping phenotypic features, raising the possibility that the same gene may underlie the obtained linkage results. Here, we show that the human gene encoding thioredoxin interacting protein (TXNIP) on 1q, which underlies Combined Hyperlipidemia in mice13, is not associated with FCHL. We show that FCHL is linked and associated with the gene encoding upstream transcription factor 1 (USF1) in 60 extended families with FCHL, including 721 genotyped individuals (P = 0.00002), especially in males with high triglycerides (P = 0.0000009). Expression profiles in fat biopsy samples from individuals with FCHL seemed to differ depending on their carrier status for the associated USF1 haplotype. USF1 encodes a transcription factor known to regulate several genes of glucose and lipid metabolism14,15,16,17.
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contribution of the hepatic lipase gene to the atherogenic lipoprotein phenotype in familial Combined Hyperlipidemia
Journal of Lipid Research, 2000Co-Authors: Hooman Allayee, Ronald M. Krauss, Rita M. Cantor, Bradley E. Aouizerat, Tjerk W.a. De Bruin, K M Dominguez, J L Rotter, Aldons J LusisAbstract:Familial Combined Hyperlipidemia (FCH) is a common genetic lipid disorder with a frequency of 1-2% in the population. In addition to the hypercholesterolemia and/or hypertriglyceridemia that affected individuals exhibit, small, dense LDL particles and decreased HDL-cholesterol levels are traits frequently associated with FCH. Recently, we reported that families with FCH and families enriched for coronary artery disease (CAD) share genetic determinants for the atherogenic lipoprotein phenotype (ALP), a profile presenting with small, dense LDL particles, decreased HDL-cholesterol levels, and increased triglyceride levels. Other studies in normolipidemic populations have shown that the hepatic lipase (HL) gene is linked to HDL-cholesterol levels and that a polymorphism within the HL promoter (-514C-->T) is associated with increased HDL-cholesterol levels as well as larger, more buoyant LDL particles. In the present study, we tested whether the HL gene locus also contributes to ALP in a series of Dutch FCH families using nonparametric sibpair linkage analysis and association analysis. Evidence for linkage of LDL particle size (P T promoter polymorphism was significantly associated (P < 0.0001) with higher HDL-cholesterol levels in the unrelated males of this population, but not in unrelated females. No association was observed between the polymorphism and LDL particle size or triglyceride levels. Our results provide support that ALP is a multigenic trait and suggest that the relationship between small, dense LDL particles, HDL-cholesterol, and triglyceride levels in FCH families is due, in part, to common genetic factors.
Tjerk W.a. De Bruin - One of the best experts on this subject based on the ideXlab platform.
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Galanin Preproprotein Is Associated With Elevated Plasma Triglycerides
2016Co-Authors: Christopher L. Plaisier, Bradley E. Aouizerat, Tjerk W.a. De Bruin, Janet S Sinsheimer, Adriana Huertas-vazquez, Daphna Weissglas-volkov, Laura Riba, Clive R. Pullinger, Mary J. Malloy, John P. KaneAbstract:Objective—There is increasing physiological evidence in rodents connecting the neuropeptide galanin to triglyceride (TG) levels. We hypothesized that variation in the galanin preproprotein (GAL) gene may contribute to hypertriglyceridemia (HTG) in humans. Methods and Results—We investigated GAL as a TG candidate gene by genotyping 4 tagSNPs in Dutch, Finnish, and Mexican familial Combined Hyperlipidemia (FCHL) families as well as in white Combined Hyperlipidemia cases/controls (n2471). The common allele of rs2187331, residing in the promoter region of GAL, was significantly associated with HTG (probability value0.00038). In an unascertained population sample of 4463 Finnish males, the rare allele of rs2187331 was associated with higher TGs (probability value0.0028 to 0.00016). We also observed an allele specific difference with rs2187331 in reporter gene expression and nuclear factor binding in vitro. Furthermore, we detected differential expression of many key lipid genes in adipose tissue based on rs2187331 genotypes. Conclusions—The SNP rs2187331 is associated with HTG in FCHL and white Combined Hyperlipidemia cases/controls and influences TG levels in the population. Further studies are warranted to elucidate the allelic difference observed between FCHL and the general population. Functional evidence shows that rs2187331 has an allele specific cis-regulatory function and influences the expression of lipid related genes in adipose. (Arterioscler Thromb Vasc Biol. 2009;29:147-152.
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Pressure in Familial Combined Hyperlipidemia
2016Co-Authors: Systolic Blood, Jan M.w. Geurts, Rob G J H Janssen, Esther Beeks, Abraham A. Kroon, Eric T. P. Keulen, Peter W. De Leeuw, Tjerk W.a. De BruinAbstract:Background: In a genome scan for familial Combined Hyperlipidemia (FCHL), a locus contributing to systolic blood pressure (SBP) has been identified on chromosome 4, containing the -adducin gene (ADD1). In previous studies, an association has been found between the -ad-ducin Gly460Trp polymorphism and salt-sensitive hyper-tension. In this study, we investigated the association between the -adducin Gly460Trp polymorphism and blood pressure in FCHL patients. Methods: A total of 79 unrelated patients with FCHL and 121 unrelated controls (spouses) were recruited for the study. Blood pressure was measured in a standardized fashion, with the subject in sitting position after 10 min of rest. The -adducin Gly460Trp polymorphism was detected by mutagenically separated polymerase chain reaction. Results: The genotype frequencies of both FCHL pa-tients and controls were in Hardy-Weinberg equilibrium. The -adducin Gly460Trp polymorphism showed a sig-nificant association with FCHL, the number of subjects carrying a 460Trp allele was significantly higher in pa-tients compared with controls (53 % v 33%, 2 8.0, P .018). In FCHL patients carrying at least one 460Trp allele, SBP was significantly higher compared with pa-tients homozygous for the 460Gly allele (140 mm Hg and 130 mm Hg respectively, P .015). Conclusions: This study shows that the 460Trp allele is associated with FCHL. Furthermore, SBP is increased in patients carrying the 460Trp allele. Am J Hyperten
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Association of the apolipoprotein A1/C3/A4/A5 gene cluster with triglyceride levelsandLDLparticlesize in familial Combined Hyperlipidemia
2016Co-Authors: Rebecca Mar, Ronald M. Krauss, Rita M. Cantor, Hooman Allayee, Tjerk W.a. De Bruin, Päivi Pajukanta, M Groenendijk, Janet S Sinsheimer, Geesje Dallinga-thie, Aldons J LusisAbstract:Abstract—The APOLIPOPROTEIN (APO)A1/C3/A4/A5 gene cluster on chromosome 11 has been hypothesized to be a modifier of plasma triglycerides in FCH. In the present study, we extended previous association analyses of the gene cluster to include APOA5, a newly discovered member of the cluster. Eight SNPs across the APOA1/C3/A4/A5 gene region were analyzed in 78 FCH probands and their normolipidemic spouses as well as in 27 Dutch FCH families. Of the individual SNPs tested in the case-control panel, the strongest evidence of association was obtained with SNPs in APOA1 (P0.001) and APOA5 (P0.001). A single haplotype defined by a missense mutation in APOA5 was enriched 3-fold in FCH probands when compared with the normolipidemic spouses (P0.001) and a second haplotype was significantly enriched in the spouses (P0.001). Family-based tests also indicated significant association of triglyceride levels and LDL particle size with the investigated SNPs of APOC3 and APOA5. These findings suggest that genetic variation in the APOA1/C3/A4/A5 gene cluster acts as a modifier of plasma triglyceride levels and LDL particle size within FCH families and furthermore indicate that a number of haplotypes may contribute to FCH. (Circ Res. 2004;94: 993-999.) Key Words: genetics coronary artery disease apolipoproteins Familial Combined Hyperlipidemia (FCH; see MendelianInheritance in Man [MIM-144250], which can be ac-cessed online [OMIM] a
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Xiang-dong Bu,
2016Co-Authors: Clin J. Invest, Jerome I. Rotter, Rita M. Cantor, Aldons J Lusis, Geesje M. Dallinga-thie, Margreet Van Linde-sibenius Trip, Tjerk W.a. De BruinAbstract:Familial Combined Hyperlipidemia (FCH) is a common ge-netic lipid disorder in Western societies. In a recent repor
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plasma pai 1 levels are independently related to fatty liver and hypertriglyceridemia in familial Combined Hyperlipidemia involvement of apolipoprotein e
Thrombosis Research, 2008Co-Authors: Martijn C G J Brouwers, Marleen M.j. Van Greevenbroek, Carla J. H. Van Der Kallen, Jose W P Goversriemslag, Casper G Schalkwijk, Otto Bekers, Marja P Van Dieijenvisser, Jaap Ten Oever, Monique A L Bilderbeekbeckers, Tjerk W.a. De BruinAbstract:Abstract Background Familial Combined Hyperlipidemia (FCHL) is a genetic form of dyslipidemia, which is characterized by an increased cardiovascular risk. The current study was conducted to investigate the relation of endothelial, inflammatory and fibrinolysis markers with the presence of hypertriglyceridemia and fatty liver in FCHL, in order to advance insight in their contribution to the cardiovascular risk profile. Materials and methods Key plasma markers of low-grade inflammation, endothelial dysfunction and fibrinolysis were measured in 38 hypertriglyceridemic FCHL patients and 38 age and sex-matched spouses. The presence of fatty liver was determined with ultrasound. Results hsCRP, vWF, PAI-1, tPA and tPA/PAI-1 complex levels were significantly higher in hypertriglyceridemic FCHL patients compared to spouses ( p n = 25). Only PAI-1 and tPA levels were also elevated in the hypertriglyceridemic FCHL patients without fatty liver ( n = 13). Of interest, 11 hypertriglyceridemic non-FCHL patients with the E2/E2 genotype displayed significantly lower PAI-1 levels when compared to the overall FCHL population ( p = 0.001), implicating a role for apolipoprotein E in the relation of PAI-1 with plasma triglycerides. Conclusion Markers of fibrinolysis were increased in all hypertriglyceridemic FCHL patients, whereas an increased state of endothelial dysfunction and inflammation was particularly observed in those hypertriglyceridemic FCHL patients who also have fatty liver. These results demonstrate the complex genesis of the unfavourable cardiovascular risk profile that is present in FCHL, and illustrate the potential risk of fatty liver above, and beyond hypertriglyceridemia per se.
Päivi Pajukanta - One of the best experts on this subject based on the ideXlab platform.
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Association of the apolipoprotein A1/C3/A4/A5 gene cluster with triglyceride levelsandLDLparticlesize in familial Combined Hyperlipidemia
2016Co-Authors: Rebecca Mar, Ronald M. Krauss, Rita M. Cantor, Hooman Allayee, Tjerk W.a. De Bruin, Päivi Pajukanta, M Groenendijk, Janet S Sinsheimer, Geesje Dallinga-thie, Aldons J LusisAbstract:Abstract—The APOLIPOPROTEIN (APO)A1/C3/A4/A5 gene cluster on chromosome 11 has been hypothesized to be a modifier of plasma triglycerides in FCH. In the present study, we extended previous association analyses of the gene cluster to include APOA5, a newly discovered member of the cluster. Eight SNPs across the APOA1/C3/A4/A5 gene region were analyzed in 78 FCH probands and their normolipidemic spouses as well as in 27 Dutch FCH families. Of the individual SNPs tested in the case-control panel, the strongest evidence of association was obtained with SNPs in APOA1 (P0.001) and APOA5 (P0.001). A single haplotype defined by a missense mutation in APOA5 was enriched 3-fold in FCH probands when compared with the normolipidemic spouses (P0.001) and a second haplotype was significantly enriched in the spouses (P0.001). Family-based tests also indicated significant association of triglyceride levels and LDL particle size with the investigated SNPs of APOC3 and APOA5. These findings suggest that genetic variation in the APOA1/C3/A4/A5 gene cluster acts as a modifier of plasma triglyceride levels and LDL particle size within FCH families and furthermore indicate that a number of haplotypes may contribute to FCH. (Circ Res. 2004;94: 993-999.) Key Words: genetics coronary artery disease apolipoproteins Familial Combined Hyperlipidemia (FCH; see MendelianInheritance in Man [MIM-144250], which can be ac-cessed online [OMIM] a
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a systems genetics approach implicates usf1 fads3 and other causal candidate genes for familial Combined Hyperlipidemia
PLOS Genetics, 2009Co-Authors: Christopher L. Plaisier, Steve Horvath, Adriana Huertasvazquez, Ivette Cruzbautista, Miguel F Herrera, Teresa Tusieluna, Carlos A Aguilarsalinas, Päivi PajukantaAbstract:We hypothesized that a common SNP in the 3' untranslated region of the upstream transcription factor 1 (USF1), rs3737787, may affect lipid traits by influencing gene expression levels, and we investigated this possibility utilizing the Mexican population, which has a high predisposition to dyslipidemia. We first associated rs3737787 genotypes in Mexican Familial Combined Hyperlipidemia (FCHL) case/control fat biopsies, with global expression patterns. To identify sets of co-expressed genes co-regulated by similar factors such as transcription factors, genetic variants, or environmental effects, we utilized weighted gene co-expression network analysis (WGCNA). Through WGCNA in the Mexican FCHL fat biopsies we identified two significant Triglyceride (TG)-associated co-expression modules. One of these modules was also associated with FCHL, the other FCHL component traits, and rs3737787 genotypes. This USF1-regulated FCHL-associated (URFA) module was enriched for genes involved in lipid metabolic processes. Using systems genetics procedures we identified 18 causal candidate genes in the URFA module. The FCHL causal candidate gene fatty acid desaturase 3 (FADS3) was associated with TGs in a recent Caucasian genome-wide significant association study and we replicated this association in Mexican FCHL families. Based on a USF1-regulated FCHL-associated co-expression module and SNP rs3737787, we identify a set of causal candidate genes for FCHL-related traits. We then provide evidence from two independent datasets supporting FADS3 as a causal gene for FCHL and elevated TGs in Mexicans.
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association of the apolipoprotein a1 c3 a4 a5 gene cluster with triglyceride levels and ldl particle size in familial Combined Hyperlipidemia
Circulation Research, 2004Co-Authors: Rebecca Mar, Ronald M. Krauss, Rita M. Cantor, Hooman Allayee, Tjerk W.a. De Bruin, Päivi Pajukanta, M Groenendijk, Geesje M Dallingathie, Janet S Sinsheimer, Aldons J LusisAbstract:The APOLIPOPROTEIN (APO)A1/C3/A4/A5 gene cluster on chromosome 11 has been hypothesized to be a modifier of plasma triglycerides in FCH. In the present study, we extended previous association analyses of the gene cluster to include APOA5, a newly discovered member of the cluster. Eight SNPs across the APOA1/C3/A4/A5 gene region were analyzed in 78 FCH probands and their normolipidemic spouses as well as in 27 Dutch FCH families. Of the individual SNPs tested in the case-control panel, the strongest evidence of association was obtained with SNPs in APOA1 (P=0.001) and APOA5 (P=0.001). A single haplotype defined by a missense mutation in APOA5 was enriched 3-fold in FCH probands when compared with the normolipidemic spouses (P=0.001) and a second haplotype was significantly enriched in the spouses (P=0.001). Family-based tests also indicated significant association of triglyceride levels and LDL particle size with the investigated SNPs of APOC3 and APOA5. These findings suggest that genetic variation in the APOA1/C3/A4/A5 gene cluster acts as a modifier of plasma triglyceride levels and LDL particle size within FCH families and furthermore indicate that a number of haplotypes may contribute to FCH.
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familial Combined Hyperlipidemia is associated with upstream transcription factor 1 usf1
Nature Genetics, 2004Co-Authors: Päivi Pajukanta, Rita M. Cantor, Janet S Sinsheimer, Aldons J Lusis, Heidi E Lilja, Massimiliano Gentile, Xiaoqun Joyce Duan, Aino Soropaavonen, Jussi Naukkarinen, Janna SaarelaAbstract:Familial Combined Hyperlipidemia (FCHL), characterized by elevated levels of serum total cholesterol, triglycerides or both1,2, is observed in about 20% of individuals with premature coronary heart disease1. We previously identified a locus linked to FCHL on 1q21–q23 in Finnish families with the disease3. This region has also been linked to FCHL in families from other populations4,5,6 as well as to type 2 diabetes mellitus7,8,9,10,11,12. These clinical entities have several overlapping phenotypic features, raising the possibility that the same gene may underlie the obtained linkage results. Here, we show that the human gene encoding thioredoxin interacting protein (TXNIP) on 1q, which underlies Combined Hyperlipidemia in mice13, is not associated with FCHL. We show that FCHL is linked and associated with the gene encoding upstream transcription factor 1 (USF1) in 60 extended families with FCHL, including 721 genotyped individuals (P = 0.00002), especially in males with high triglycerides (P = 0.0000009). Expression profiles in fat biopsy samples from individuals with FCHL seemed to differ depending on their carrier status for the associated USF1 haplotype. USF1 encodes a transcription factor known to regulate several genes of glucose and lipid metabolism14,15,16,17.
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serum c3 but not plasma acylation stimulating protein is elevated in finnish patients with familial Combined Hyperlipidemia
Arteriosclerosis Thrombosis and Vascular Biology, 2001Co-Authors: Kati Ylitalo, Rita M. Cantor, Päivi Pajukanta, Seppo Meri, Juha Vakkilainen, Ilpo Nuotio, Niina Meromatikainen, Marja-riitta TaskinenAbstract:A trapping defect of fatty acids due to impaired function of acylation-stimulating protein (ASP) has been suggested as one mechanism underlying the metabolic abnormalities in familial Combined Hyperlipidemia (FCHL). The study aimed at defining the role of ASP and complement C3 in 35 Finnish FCHL families. There was no difference in plasma ASP levels between the 66 hypertriglyceridemic FCHL patients and their 84 normotriglyceridemic relatives. No response in plasma ASP could be observed after a fatty meal in 10 FCHL patients or in 10 control subjects. In familial correlation analyses, C3 exhibited a significant sibling-sibling correlation. The FCHL patients had higher serum C3 levels than their unaffected relatives (P<0.001). Furthermore, serum C3 levels correlated significantly with several lipid parameters. The correlations between ASP and lipid variables were weaker than those of C3. These analyses suggest that common genes might contribute to the regulation of serum C3, triglycerides, HDL-C, free fatty acids, and insulin. The present data do not support the hypothesis that defects of the ASP pathway are reflected in plasma lipoproteins or in impaired plasma lipid clearance postprandially.
Rita M. Cantor - One of the best experts on this subject based on the ideXlab platform.
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Association of the apolipoprotein A1/C3/A4/A5 gene cluster with triglyceride levelsandLDLparticlesize in familial Combined Hyperlipidemia
2016Co-Authors: Rebecca Mar, Ronald M. Krauss, Rita M. Cantor, Hooman Allayee, Tjerk W.a. De Bruin, Päivi Pajukanta, M Groenendijk, Janet S Sinsheimer, Geesje Dallinga-thie, Aldons J LusisAbstract:Abstract—The APOLIPOPROTEIN (APO)A1/C3/A4/A5 gene cluster on chromosome 11 has been hypothesized to be a modifier of plasma triglycerides in FCH. In the present study, we extended previous association analyses of the gene cluster to include APOA5, a newly discovered member of the cluster. Eight SNPs across the APOA1/C3/A4/A5 gene region were analyzed in 78 FCH probands and their normolipidemic spouses as well as in 27 Dutch FCH families. Of the individual SNPs tested in the case-control panel, the strongest evidence of association was obtained with SNPs in APOA1 (P0.001) and APOA5 (P0.001). A single haplotype defined by a missense mutation in APOA5 was enriched 3-fold in FCH probands when compared with the normolipidemic spouses (P0.001) and a second haplotype was significantly enriched in the spouses (P0.001). Family-based tests also indicated significant association of triglyceride levels and LDL particle size with the investigated SNPs of APOC3 and APOA5. These findings suggest that genetic variation in the APOA1/C3/A4/A5 gene cluster acts as a modifier of plasma triglyceride levels and LDL particle size within FCH families and furthermore indicate that a number of haplotypes may contribute to FCH. (Circ Res. 2004;94: 993-999.) Key Words: genetics coronary artery disease apolipoproteins Familial Combined Hyperlipidemia (FCH; see MendelianInheritance in Man [MIM-144250], which can be ac-cessed online [OMIM] a
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Xiang-dong Bu,
2016Co-Authors: Clin J. Invest, Jerome I. Rotter, Rita M. Cantor, Aldons J Lusis, Geesje M. Dallinga-thie, Margreet Van Linde-sibenius Trip, Tjerk W.a. De BruinAbstract:Familial Combined Hyperlipidemia (FCH) is a common ge-netic lipid disorder in Western societies. In a recent repor
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association of the apolipoprotein a1 c3 a4 a5 gene cluster with triglyceride levels and ldl particle size in familial Combined Hyperlipidemia
Circulation Research, 2004Co-Authors: Rebecca Mar, Ronald M. Krauss, Rita M. Cantor, Hooman Allayee, Tjerk W.a. De Bruin, Päivi Pajukanta, M Groenendijk, Geesje M Dallingathie, Janet S Sinsheimer, Aldons J LusisAbstract:The APOLIPOPROTEIN (APO)A1/C3/A4/A5 gene cluster on chromosome 11 has been hypothesized to be a modifier of plasma triglycerides in FCH. In the present study, we extended previous association analyses of the gene cluster to include APOA5, a newly discovered member of the cluster. Eight SNPs across the APOA1/C3/A4/A5 gene region were analyzed in 78 FCH probands and their normolipidemic spouses as well as in 27 Dutch FCH families. Of the individual SNPs tested in the case-control panel, the strongest evidence of association was obtained with SNPs in APOA1 (P=0.001) and APOA5 (P=0.001). A single haplotype defined by a missense mutation in APOA5 was enriched 3-fold in FCH probands when compared with the normolipidemic spouses (P=0.001) and a second haplotype was significantly enriched in the spouses (P=0.001). Family-based tests also indicated significant association of triglyceride levels and LDL particle size with the investigated SNPs of APOC3 and APOA5. These findings suggest that genetic variation in the APOA1/C3/A4/A5 gene cluster acts as a modifier of plasma triglyceride levels and LDL particle size within FCH families and furthermore indicate that a number of haplotypes may contribute to FCH.
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familial Combined Hyperlipidemia is associated with upstream transcription factor 1 usf1
Nature Genetics, 2004Co-Authors: Päivi Pajukanta, Rita M. Cantor, Janet S Sinsheimer, Aldons J Lusis, Heidi E Lilja, Massimiliano Gentile, Xiaoqun Joyce Duan, Aino Soropaavonen, Jussi Naukkarinen, Janna SaarelaAbstract:Familial Combined Hyperlipidemia (FCHL), characterized by elevated levels of serum total cholesterol, triglycerides or both1,2, is observed in about 20% of individuals with premature coronary heart disease1. We previously identified a locus linked to FCHL on 1q21–q23 in Finnish families with the disease3. This region has also been linked to FCHL in families from other populations4,5,6 as well as to type 2 diabetes mellitus7,8,9,10,11,12. These clinical entities have several overlapping phenotypic features, raising the possibility that the same gene may underlie the obtained linkage results. Here, we show that the human gene encoding thioredoxin interacting protein (TXNIP) on 1q, which underlies Combined Hyperlipidemia in mice13, is not associated with FCHL. We show that FCHL is linked and associated with the gene encoding upstream transcription factor 1 (USF1) in 60 extended families with FCHL, including 721 genotyped individuals (P = 0.00002), especially in males with high triglycerides (P = 0.0000009). Expression profiles in fat biopsy samples from individuals with FCHL seemed to differ depending on their carrier status for the associated USF1 haplotype. USF1 encodes a transcription factor known to regulate several genes of glucose and lipid metabolism14,15,16,17.
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serum c3 but not plasma acylation stimulating protein is elevated in finnish patients with familial Combined Hyperlipidemia
Arteriosclerosis Thrombosis and Vascular Biology, 2001Co-Authors: Kati Ylitalo, Rita M. Cantor, Päivi Pajukanta, Seppo Meri, Juha Vakkilainen, Ilpo Nuotio, Niina Meromatikainen, Marja-riitta TaskinenAbstract:A trapping defect of fatty acids due to impaired function of acylation-stimulating protein (ASP) has been suggested as one mechanism underlying the metabolic abnormalities in familial Combined Hyperlipidemia (FCHL). The study aimed at defining the role of ASP and complement C3 in 35 Finnish FCHL families. There was no difference in plasma ASP levels between the 66 hypertriglyceridemic FCHL patients and their 84 normotriglyceridemic relatives. No response in plasma ASP could be observed after a fatty meal in 10 FCHL patients or in 10 control subjects. In familial correlation analyses, C3 exhibited a significant sibling-sibling correlation. The FCHL patients had higher serum C3 levels than their unaffected relatives (P<0.001). Furthermore, serum C3 levels correlated significantly with several lipid parameters. The correlations between ASP and lipid variables were weaker than those of C3. These analyses suggest that common genes might contribute to the regulation of serum C3, triglycerides, HDL-C, free fatty acids, and insulin. The present data do not support the hypothesis that defects of the ASP pathway are reflected in plasma lipoproteins or in impaired plasma lipid clearance postprandially.
Hooman Allayee - One of the best experts on this subject based on the ideXlab platform.
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Association of the apolipoprotein A1/C3/A4/A5 gene cluster with triglyceride levelsandLDLparticlesize in familial Combined Hyperlipidemia
2016Co-Authors: Rebecca Mar, Ronald M. Krauss, Rita M. Cantor, Hooman Allayee, Tjerk W.a. De Bruin, Päivi Pajukanta, M Groenendijk, Janet S Sinsheimer, Geesje Dallinga-thie, Aldons J LusisAbstract:Abstract—The APOLIPOPROTEIN (APO)A1/C3/A4/A5 gene cluster on chromosome 11 has been hypothesized to be a modifier of plasma triglycerides in FCH. In the present study, we extended previous association analyses of the gene cluster to include APOA5, a newly discovered member of the cluster. Eight SNPs across the APOA1/C3/A4/A5 gene region were analyzed in 78 FCH probands and their normolipidemic spouses as well as in 27 Dutch FCH families. Of the individual SNPs tested in the case-control panel, the strongest evidence of association was obtained with SNPs in APOA1 (P0.001) and APOA5 (P0.001). A single haplotype defined by a missense mutation in APOA5 was enriched 3-fold in FCH probands when compared with the normolipidemic spouses (P0.001) and a second haplotype was significantly enriched in the spouses (P0.001). Family-based tests also indicated significant association of triglyceride levels and LDL particle size with the investigated SNPs of APOC3 and APOA5. These findings suggest that genetic variation in the APOA1/C3/A4/A5 gene cluster acts as a modifier of plasma triglyceride levels and LDL particle size within FCH families and furthermore indicate that a number of haplotypes may contribute to FCH. (Circ Res. 2004;94: 993-999.) Key Words: genetics coronary artery disease apolipoproteins Familial Combined Hyperlipidemia (FCH; see MendelianInheritance in Man [MIM-144250], which can be ac-cessed online [OMIM] a
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association of the apolipoprotein a1 c3 a4 a5 gene cluster with triglyceride levels and ldl particle size in familial Combined Hyperlipidemia
Circulation Research, 2004Co-Authors: Rebecca Mar, Ronald M. Krauss, Rita M. Cantor, Hooman Allayee, Tjerk W.a. De Bruin, Päivi Pajukanta, M Groenendijk, Geesje M Dallingathie, Janet S Sinsheimer, Aldons J LusisAbstract:The APOLIPOPROTEIN (APO)A1/C3/A4/A5 gene cluster on chromosome 11 has been hypothesized to be a modifier of plasma triglycerides in FCH. In the present study, we extended previous association analyses of the gene cluster to include APOA5, a newly discovered member of the cluster. Eight SNPs across the APOA1/C3/A4/A5 gene region were analyzed in 78 FCH probands and their normolipidemic spouses as well as in 27 Dutch FCH families. Of the individual SNPs tested in the case-control panel, the strongest evidence of association was obtained with SNPs in APOA1 (P=0.001) and APOA5 (P=0.001). A single haplotype defined by a missense mutation in APOA5 was enriched 3-fold in FCH probands when compared with the normolipidemic spouses (P=0.001) and a second haplotype was significantly enriched in the spouses (P=0.001). Family-based tests also indicated significant association of triglyceride levels and LDL particle size with the investigated SNPs of APOC3 and APOA5. These findings suggest that genetic variation in the APOA1/C3/A4/A5 gene cluster acts as a modifier of plasma triglyceride levels and LDL particle size within FCH families and furthermore indicate that a number of haplotypes may contribute to FCH.
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Identification of TNFRSF1B as a novel modifier gene in familial Combined Hyperlipidemia
Human molecular genetics, 2000Co-Authors: Jan M.w. Geurts, Jerome I. Rotter, Rob G J H Janssen, Marleen M.j. Van Greevenbroek, Carla J. H. Van Der Kallen, Rita M. Cantor, Bradley E. Aouizerat, Hooman Allayee, Tjerk W.a. De BruinAbstract:Familial Combined Hyperlipidemia (FCHL) is the most commonly inherited Hyperlipidemia in man, with a frequency of ±1% in the general population and ∼10% in myocardial infarction survivors. A genomic scan in 18 Dutch FCHL families resulted in the identification of several loci with evidence for linkage. One of these regions, 1p36.2, contains TNFRSF1B which encodes one of the tumor necrosis factor receptors. An intron 4 polymorphic CA-repeat was used to confirm linkage to FCHL. Linear regression analysis using 79 independent sib pairs showed linkage with a quantitative FCHL discriminant function (P = 0.032), and, borderline, with apolipoprotein B levels (P = 0.064). Furthermore, in a case–control study, association was demonstrated since the overall CA-repeat genotype distribution was significantly different among 40 unrelated FCHL patients and 48 unrelated healthy spouse controls (P = 0.029). This difference was due to a significant increase in allele CA271 homozygotes in the FCHL patients (P = 0.019). Mutation analysis of exon 6 in 73 FCHL family members demonstrated the presence of a single nucleotide polymorphism with two alleles, coding for methionine (196M) and arginine (196R). Complete linkage disequilibrium between CA267, CA271 and CA273 and this polymorphism was detected. In 85 hyperlipidemic FCHL subjects, an association was demonstrated between soluble TNFRSF1B plasma concentrations and the CA271-196M haplotype. In conclusion, TNFRSF1B was found to be associated with susceptibility to FCHL. Our data suggest that an as yet unknown disease-associated mutation, linked to alleles 196M and CA271, plays a role in the pathophysiology of FCHL.
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contribution of the hepatic lipase gene to the atherogenic lipoprotein phenotype in familial Combined Hyperlipidemia
Journal of Lipid Research, 2000Co-Authors: Hooman Allayee, Ronald M. Krauss, Rita M. Cantor, Bradley E. Aouizerat, Tjerk W.a. De Bruin, K M Dominguez, J L Rotter, Aldons J LusisAbstract:Familial Combined Hyperlipidemia (FCH) is a common genetic lipid disorder with a frequency of 1-2% in the population. In addition to the hypercholesterolemia and/or hypertriglyceridemia that affected individuals exhibit, small, dense LDL particles and decreased HDL-cholesterol levels are traits frequently associated with FCH. Recently, we reported that families with FCH and families enriched for coronary artery disease (CAD) share genetic determinants for the atherogenic lipoprotein phenotype (ALP), a profile presenting with small, dense LDL particles, decreased HDL-cholesterol levels, and increased triglyceride levels. Other studies in normolipidemic populations have shown that the hepatic lipase (HL) gene is linked to HDL-cholesterol levels and that a polymorphism within the HL promoter (-514C-->T) is associated with increased HDL-cholesterol levels as well as larger, more buoyant LDL particles. In the present study, we tested whether the HL gene locus also contributes to ALP in a series of Dutch FCH families using nonparametric sibpair linkage analysis and association analysis. Evidence for linkage of LDL particle size (P T promoter polymorphism was significantly associated (P < 0.0001) with higher HDL-cholesterol levels in the unrelated males of this population, but not in unrelated females. No association was observed between the polymorphism and LDL particle size or triglyceride levels. Our results provide support that ALP is a multigenic trait and suggest that the relationship between small, dense LDL particles, HDL-cholesterol, and triglyceride levels in FCH families is due, in part, to common genetic factors.
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a genome scan for familial Combined Hyperlipidemia reveals evidence of linkage with a locus on chromosome 11
American Journal of Human Genetics, 1999Co-Authors: Bradley E. Aouizerat, Jerome I. Rotter, Rita M. Cantor, Hooman Allayee, Tjerk W.a. De Bruin, Geesje M Dallingathie, Richard C Davis, Christopher D Lanning, Ping Zi Wen, Aldons J LusisAbstract:Familial Combined Hyperlipidemia (FCHL) is a common familial lipid disorder characterized by a variable pattern of elevated levels of plasma cholesterol and/or triglycerides. It is present in 10%-20% of patients with premature coronary heart disease. The genetic etiology of the disease, including the number of genes involved and the magnitude of their effects, is unknown. Using a subset of 35 Dutch families ascertained for FCHL, we screened the genome, with a panel of 399 genetic markers, for chromosomal regions linked to genes contributing to FCHL. The results were analyzed by use of parametric-linkage methods in a two-stage study design. Four loci, on chromosomes 2p, 11p, 16q, and 19q, exhibited suggestive evidence for linkage with FCHL (LOD scores of 1.3-2.6). Markers within each of these regions were then examined in the original sample and in additional Dutch families with FCHL. The locus on chromosome 2 failed to show evidence for linkage, and the loci on chromosome 16q and 19q yielded only equivocal or suggestive evidence for linkage. However, one locus, near marker D11S1324 on the short arm of human chromosome 11, continued to show evidence for linkage with FCHL, in the second stage of this design. This region does not contain any strong candidate genes. These results provide evidence for a candidate chromosomal region for FCHL and support the concept that FCHL is complex and heterogeneous.