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CLINICAL RESEARCH: GENETICS/GENOMICS

Functional Promoter Variant in Zinc Finger Protein 202 Predicts Severe Atherosclerosis and Ischemic Heart Disease

Maria C.A. Stene, MSc, PhD^_*, Ruth Frikke-Schmidt, MD, PhD^_*, Børge G. Nordestgaard, MD, DMSc^,, Peer Grande, MD, DMSc, Peter Schnohr, MD and Anne Tybjærg-Hansen, MD, DMSc^_*,,_*

^_* Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
Department of Clinical Biochemistry, Herlev University Hospital, Copenhagen, Denmark
Copenhagen City Heart Study, Bispebjerg University Hospital; all Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.

Manuscript received October 2, 2007; revised manuscript received February 8, 2008, accepted March 25, 2008.

^_* Reprint request and correspondence: Dr. Anne Tybjærg-Hansen, Chief Physician, Associate Professor, Department of Clinical Biochemistry KB3011, Section for Molecular Genetics, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. (Email: at-h{at}rh.regionh.dk).

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.

Key Words: atherosclerosis • cardiovascular diseases • epidemiology • genetics • risk factors

Abbreviations and Acronyms   ABI = ankle brachial index   HDL = high-density lipoprotein   IHD = ischemic heart disease   MI = myocardial infarction   SNP = single nucleotide polymorphism

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