Abstract 3192: Genetic Variation in Zinc Finger Protein 202 Promoter Contributes to Lipid Phenotype and Predicts Risk of Ischemic Heart Disease and Myocardial Infarction
Zinc Finger Protein 202 (ZNF202) is a transcriptional repressor of genes affecting the vascular endothelium as well as lipid metabolism. A phenotype associated with genetic variation in ZNF202 is presently unknown. We tested the following hypotheses:
genetic variation in the ZNF202 promoter contributes to lipid phenotype;
ZNF202 promoter genotype predicts risk of ischemic heart disease (IHD) and myocardial infarction (MI) in the general population. We resequenced 700 bp of the ZNF202 promoter upstream of exon1 in approximately 200 individuals, and identified 4 SNPs (rare allele frequency>1%) and 3 mutations, 4 of which were new. All 7 genetic variants were genotyped in more than 9,000 individuals from the general population, and the effect on lipid phenotype and on risk of disease was determined in a large prospective study. g. − 685G>A (frequency 0.04), located in a silencer sequence, was associated with an increase in total cholesterol in both genders (P=0.006 and 0.05 in women and men, respectively), with an increase in LDL cholesterol and apoB in women (P=0.001 and 0.002, respectively) and with similar trends in men. g. − 447T>C (0.004), in a putative Yin Yang 1 binding site, was associated with an increase in HDL cholesterol and apoAI in women only (P=0.002 and 0.007, respectively). In a prospective study of more than 9,000 individuals with 25 years follow-up, g. − 660G>A (frequency 0.30), located in a silencer sequence, predicted both risk of IHD and MI in women (CI: 1.5 (1.1–1.9) and 1.6 (1.1–2.4), respectively). We show that genetic variation in the ZNF202 promoter contributes to a heterogeneous lipid phenotype and predicts risk of IHD and MI in the general population.