The 4G/5G polymorphism in the promoter region of SERPINE1 has been consistently reported to be a functional variant influencing PAI‐1 expression.27, 49 Knockout of Serpine1, a mouse ortholog, creates PAI‐1 deficiency.50 Therefore, when exploring whether metabolic risk factors and subclinical atherosclerosis are mediators of potential PAI‐1 effects on CHD, we only used the SERPINE1 locus SNPs as an IV. This evidence concerns the gene SERPINE1 and atherosclerosis.