Abstract 19411: Circulating Protein Z Levels, Variants in the Protein Z Gene and Unexplained Cerebral Infarction in Young and Middle-Aged Adults (The Thrombophilia in Cryptogenic stroke [THICK] Study)
Background: Protein Z (PZ) is a vitamin K-dependent plasma protein that exhibits both pro- and anticoagulant properties. Both low and high PZ levels have been linked to ischemic stroke in different studies. PZ-lowering gene variants have in turn been found to be less common in ischemic stroke, suggesting that PZ deficiency may be protective, but the relationship remains unclear.
Methods: We investigated PZ levels and PROZ gene variants in a prospective case-control study of prothrombotic risk factors for unexplained stroke in subjects ages 18 to 64. Cases consisted of patients referred to Weill Cornell Medical Center (2002 - 2012) for the first cerebral infarction whose etiology proved indeterminate (TOAST criteria). Controls included stroke-free volunteers from the area. Plasma PZ was measured in cases (≥2 months post-stroke) and controls. PZ polymorphisms G79A (rs3024735) and A13G (rs2273971) were genotyped. A combined genetic score (0-4) was created assuming additive effects.
Results: A total of 679 subjects (mean age 43; 50% women; 64% white, 12% black, 17% Hispanic) were included. PZ was available in 239 cases and 351 controls. Participants were similar in age, sex, and ethnicity, but cases more often had hypertension (23 vs 13%) and migraine with aura (21 vs 8%). Analyses revealed evidence of a non-linear association, with a threshold at PZ of 2.6 μg/ml (90th %ile). After adjustment for demographic and clinical covariates (age, sex, race, hypertension, diabetes, smoking, family history of premature cardiovascular disease, and migraine with aura), levels above the 90th %ile were significantly associated with cryptogenic stroke (OR 2.35 [95% CI 1.31, 4.22], P=0.004) as compared to those below. The combined genetic score was associated with progressively lower levels of PZ, with a suggestion of an inverse association with cryptogenic stroke for a score of 4 vs 0 (adjusted OR 0.36 [95% CI 0.11, 1.19]).
Conclusions: In this study of young and middle-aged adults, there was evidence of a non-linear positive association between PZ levels and unexplained stroke, with a suggestive, directionally consistent association for genetic variants related to PZ levels. These findings support PZ excess, rather than deficiency, as a risk factor for cryptogenic stroke.
Author Disclosures: L. Zhang: None. A.Z. Segal: None. R.L. Silverstein: None. L.M. Gerber: None. M.L. Lesser: None. R.B. Devereux: None. J.R. Kizer: Expert Witness; Significant; Expert Witness work for Pfizer regarding the relationship of PremPro with stroke.
- © 2014 by American Heart Association, Inc.