Functional promoter variant in zinc finger protein 202 predicts severe atherosclerosis and ischemic heart disease

R. Frikke-Schmidt; Børge Nordestgaard; Peer Grande; Anne Tybjærg-Hansen; Peter Schnohr

doi:10.1016/j.jacc.2008.03.059

Functional promoter variant in zinc finger protein 202 predicts severe atherosclerosis and ischemic heart disease

R. Frikke-Schmidt, Børge Nordestgaard, Peer Grande, Anne Tybjærg-Hansen, Peter Schnohr

12 Citations (Scopus)

Abstract

Objectives This study was designed to test the hypotheses that single nucleotide polymorphisms ( SNPs), in zinc finger protein 202 ( ZNF202), predict severe atherosclerosis and ischemic heart disease ( IHD). Background ZNF202 is a transcriptional repressor controlling promoter elements in genes involved in vascular maintenance and lipid metabolism. Methods We first determined genotype association for 9 ZNF202 SNPs with severe atherosclerosis ( ankle brachial index >0.7 vs. <= 0.7) in a cross-sectional study of 5,355 individuals from the Danish general population. We then determined genotype association with IHD in 10,431 individuals from the Danish general population, the CCHS ( Copenhagen City Heart Study), including 1,511 incident IHD events during 28 years of follow-up. Results were verified in 2 independent case-control studies including, respectively, 942 and 1,549 cases with IHD and 8,998 controls. Finally, we determined whether g. -660A>G altered transcriptional activity of the ZNF202 promoter in vitro. Results Cross-sectionally, ZNF202 g. -660 GG versus AA homozygosity predicted an odds ratio for severe atherosclerosis of 2.01 ( 95% confidence interval [CI]: 1.34 to 3.01). Prospectively, GG versus AA homozygosity predicted a hazard ratio for IHD of 1.21 ( 95% CI: 1.02 to 1.43). In the 2 case-control studies, the equivalent odds ratios for IHD were 1.29 ( 95% CI: 1.02 to 1.62) and 1.60 ( 95% CI: 1.34 to 1.92), confirming the results from the prospective study. Only 2 other SNPs, which were highly correlated with g. -660A>G, also predicted risk of severe atherosclerosis and IHD. Finally, ZNF202 g. -660G versus g. -660A was associated with a 60% reduction in transcriptional activity in vitro, whereas none of the 2 correlated SNPs were predicted to be functional. Conclusions Homozygosity for a common functional promoter variant in ZNF202 predicts severe atherosclerosis and an increased risk of IHD
Udgivelsesdato: 2008/7/29

Original language	English
Journal	Journal of the American College of Cardiology
Volume	52
Issue number	5
Pages (from-to)	369-377
Number of pages	8
ISSN	0735-1097
DOIs	https://doi.org/10.1016/j.jacc.2008.03.059
Publication status	Published - 2008

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10.1016/j.jacc.2008.03.059

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@article{e7222c80f74a11ddbf70000ea68e967b,

title = "Functional promoter variant in zinc finger protein 202 predicts severe atherosclerosis and ischemic heart disease",

abstract = "Objectives This study was designed to test the hypotheses that single nucleotide polymorphisms ( SNPs), in zinc finger protein 202 ( ZNF202), predict severe atherosclerosis and ischemic heart disease ( IHD). Background ZNF202 is a transcriptional repressor controlling promoter elements in genes involved in vascular maintenance and lipid metabolism. Methods We first determined genotype association for 9 ZNF202 SNPs with severe atherosclerosis ( ankle brachial index >0.7 vs. <= 0.7) in a cross-sectional study of 5,355 individuals from the Danish general population. We then determined genotype association with IHD in 10,431 individuals from the Danish general population, the CCHS ( Copenhagen City Heart Study), including 1,511 incident IHD events during 28 years of follow-up. Results were verified in 2 independent case-control studies including, respectively, 942 and 1,549 cases with IHD and 8,998 controls. Finally, we determined whether g. -660A>G altered transcriptional activity of the ZNF202 promoter in vitro. Results Cross-sectionally, ZNF202 g. -660 GG versus AA homozygosity predicted an odds ratio for severe atherosclerosis of 2.01 ( 95% confidence interval [CI]: 1.34 to 3.01). Prospectively, GG versus AA homozygosity predicted a hazard ratio for IHD of 1.21 ( 95% CI: 1.02 to 1.43). In the 2 case-control studies, the equivalent odds ratios for IHD were 1.29 ( 95% CI: 1.02 to 1.62) and 1.60 ( 95% CI: 1.34 to 1.92), confirming the results from the prospective study. Only 2 other SNPs, which were highly correlated with g. -660A>G, also predicted risk of severe atherosclerosis and IHD. Finally, ZNF202 g. -660G versus g. -660A was associated with a 60% reduction in transcriptional activity in vitro, whereas none of the 2 correlated SNPs were predicted to be functional. Conclusions Homozygosity for a common functional promoter variant in ZNF202 predicts severe atherosclerosis and an increased risk of IHD Udgivelsesdato: 2008/7/29",

author = "R. Frikke-Schmidt and B{\o}rge Nordestgaard and Peer Grande and Anne Tybj{\ae}rg-Hansen and Peter Schnohr",

note = "Times Cited: 1ArticleEnglishTybjaerg-Hansen, AUniv Copenhagen Hosp, Rigshosp, Dept Clin Biochem KB3011, Mol Genet Sect, Blegdamsvej 9, DK-2100 Copenhagen, DenmarkCited References Count: 29329CPELSEVIER SCIENCE INC360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USANEW YORK",

year = "2008",

doi = "10.1016/j.jacc.2008.03.059",

language = "English",

volume = "52",

pages = "369--377",

journal = "Journal of the American College of Cardiology",

issn = "0735-1097",

publisher = "Elsevier",

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TY - JOUR

T1 - Functional promoter variant in zinc finger protein 202 predicts severe atherosclerosis and ischemic heart disease

AU - Frikke-Schmidt, R.

AU - Nordestgaard, Børge

AU - Grande, Peer

AU - Tybjærg-Hansen, Anne

AU - Schnohr, Peter

N1 - Times Cited: 1ArticleEnglishTybjaerg-Hansen, AUniv Copenhagen Hosp, Rigshosp, Dept Clin Biochem KB3011, Mol Genet Sect, Blegdamsvej 9, DK-2100 Copenhagen, DenmarkCited References Count: 29329CPELSEVIER SCIENCE INC360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USANEW YORK

PY - 2008

Y1 - 2008

N2 - Objectives This study was designed to test the hypotheses that single nucleotide polymorphisms ( SNPs), in zinc finger protein 202 ( ZNF202), predict severe atherosclerosis and ischemic heart disease ( IHD). Background ZNF202 is a transcriptional repressor controlling promoter elements in genes involved in vascular maintenance and lipid metabolism. Methods We first determined genotype association for 9 ZNF202 SNPs with severe atherosclerosis ( ankle brachial index >0.7 vs. <= 0.7) in a cross-sectional study of 5,355 individuals from the Danish general population. We then determined genotype association with IHD in 10,431 individuals from the Danish general population, the CCHS ( Copenhagen City Heart Study), including 1,511 incident IHD events during 28 years of follow-up. Results were verified in 2 independent case-control studies including, respectively, 942 and 1,549 cases with IHD and 8,998 controls. Finally, we determined whether g. -660A>G altered transcriptional activity of the ZNF202 promoter in vitro. Results Cross-sectionally, ZNF202 g. -660 GG versus AA homozygosity predicted an odds ratio for severe atherosclerosis of 2.01 ( 95% confidence interval [CI]: 1.34 to 3.01). Prospectively, GG versus AA homozygosity predicted a hazard ratio for IHD of 1.21 ( 95% CI: 1.02 to 1.43). In the 2 case-control studies, the equivalent odds ratios for IHD were 1.29 ( 95% CI: 1.02 to 1.62) and 1.60 ( 95% CI: 1.34 to 1.92), confirming the results from the prospective study. Only 2 other SNPs, which were highly correlated with g. -660A>G, also predicted risk of severe atherosclerosis and IHD. Finally, ZNF202 g. -660G versus g. -660A was associated with a 60% reduction in transcriptional activity in vitro, whereas none of the 2 correlated SNPs were predicted to be functional. Conclusions Homozygosity for a common functional promoter variant in ZNF202 predicts severe atherosclerosis and an increased risk of IHD Udgivelsesdato: 2008/7/29

AB - Objectives This study was designed to test the hypotheses that single nucleotide polymorphisms ( SNPs), in zinc finger protein 202 ( ZNF202), predict severe atherosclerosis and ischemic heart disease ( IHD). Background ZNF202 is a transcriptional repressor controlling promoter elements in genes involved in vascular maintenance and lipid metabolism. Methods We first determined genotype association for 9 ZNF202 SNPs with severe atherosclerosis ( ankle brachial index >0.7 vs. <= 0.7) in a cross-sectional study of 5,355 individuals from the Danish general population. We then determined genotype association with IHD in 10,431 individuals from the Danish general population, the CCHS ( Copenhagen City Heart Study), including 1,511 incident IHD events during 28 years of follow-up. Results were verified in 2 independent case-control studies including, respectively, 942 and 1,549 cases with IHD and 8,998 controls. Finally, we determined whether g. -660A>G altered transcriptional activity of the ZNF202 promoter in vitro. Results Cross-sectionally, ZNF202 g. -660 GG versus AA homozygosity predicted an odds ratio for severe atherosclerosis of 2.01 ( 95% confidence interval [CI]: 1.34 to 3.01). Prospectively, GG versus AA homozygosity predicted a hazard ratio for IHD of 1.21 ( 95% CI: 1.02 to 1.43). In the 2 case-control studies, the equivalent odds ratios for IHD were 1.29 ( 95% CI: 1.02 to 1.62) and 1.60 ( 95% CI: 1.34 to 1.92), confirming the results from the prospective study. Only 2 other SNPs, which were highly correlated with g. -660A>G, also predicted risk of severe atherosclerosis and IHD. Finally, ZNF202 g. -660G versus g. -660A was associated with a 60% reduction in transcriptional activity in vitro, whereas none of the 2 correlated SNPs were predicted to be functional. Conclusions Homozygosity for a common functional promoter variant in ZNF202 predicts severe atherosclerosis and an increased risk of IHD Udgivelsesdato: 2008/7/29

U2 - 10.1016/j.jacc.2008.03.059

DO - 10.1016/j.jacc.2008.03.059

M3 - Journal article

C2 - 18652945

SN - 0735-1097

VL - 52

SP - 369

EP - 377

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

IS - 5

ER -