Rare genotypes of protein Z gene are a risk factor for premature myocardial infarction but not protein Z plasma level

Abstract

Protein Z (PZ) is the cofactor of PZ dependent inhibitor (ZPI) that inhibits activated coagulation factor X. PZ was expected to play a role in coronary artery disease (CAD) but with inconsistent clinical findings. We therefore evaluated whether PZ plasma level and/or three genetic variants encoding for low PZ plasma level were associated with premature CAD in stable young post-myocardial infarction (MI) patients. PZ plasma level and three polymorphisms A-13G, G-103A and G79A were determined in 176 young stable post-MI patients and in 176 sex- and age-matched controls (FITE-NAT population). Moreover the genotypes, resulting from the combination of the three polymorphisms (A-13G/G-103A/G79A), were studied. PZ plasma level and the number of patients disclosing a PZ deficiency did not differ between post-MI patients and controls. The presence of the mutated allele for each polymorphism was associated with a significantly reduced level of PZ. The A-13G polymorphism was associated with premature CAD only in univariate analysis. Whereas, the presence of rare genotypes of PZ gene was an independent risk factor for premature CAD. In conclusion, PZ plasma level is not a key player in the pathophysiology of premature coronary artery disease. But, rare genotypes of PZ gene were found to be associated with premature CAD.

A meta-analysis of potential risks of low levels of protein Z for diseases related to vascular thrombosis

“…Most were conducted in European countries. The vast majority of the studies investigated low protein Z levels in association with an increased risk of thrombosis (5, 7, 8, 10–12, 14–23, 25–32), whereas four studies evaluated the opposite hypothesis, i.e. whether high protein Z levels were associated with an increased risk of thrombotic events (6, 9, 13, 24).…”

“…An association between protein Z deficiency and thrombosis has been demonstrated in animal models (33, 34), but human studies have produced conflicting results (5–32). Indeed, in four of these studies high circulating levels of protein Z were found to be associated with an increased risk of disease (6, 9, 13, 24).…”

“…The potential role of alterations of protein Z levels in the pathogenesis of thrombotic diseases has been evaluated in several studies that have produced conflicting findings (4–32). On one side, many of the clinical studies reported low protein Z levels to be associated with the occurrence and progression of several types of ischaemic vascular diseases, such as ischaemic stroke, coronary heart disease, venous thromboembolic diseases and fetal loss (5, 7, 8, 10–12, 14, 17, 19, 21, 23, 25–29, 31), whereas, on the other side, some studies either did not observe an association or reported an association between high, instead of low, levels of protein Z and thrombotic disease (6, 9, 13, 15, 16, 18, 20, 22, 24, 30, 32).…”