Accumulation of gene polymorphisms related to plaque disruption and thrombosis is associated with cerebral infarction in subjects with type 2 diabetes

doi:10.2337/dc09-1518

Accumulation of gene polymorphisms related to plaque disruption and thrombosis is associated with cerebral infarction in subjects with type 2 diabetes

Naoto Katakami, MD, PhD (katakami{at}medone.med.osaka-u.ac.jp)¹,
Mitsuyoshi Takahara, MD, PhD¹,
Hideaki Kaneto, MD, PhD¹,
Ikki Shimizu, MD, PhD²,
Keizo Ohno, MD, PhD³,
Fukashi Ishibashi, MD, PhD⁴,
Takeshi Osonoi, MD, PhD⁵,
Atsunori Kashiwagi, MD, PhD⁶,
Ryuzo Kawamori, MD, PhD⁷,
Iichiro Shimomura, MD, PhD¹,
Munehide Matsuhisa, MD, PhD¹ and
Yoshimitsu Yamasaki, MD, PhD⁸

1 Department of Metabolic Medicine, Osaka University Graduate School of Medicine
2 Ehime Prefectural Central Hospital
3 Ehime Prefectural Imabari Hospital
4 Ishibashi Clinic
5 Naka Kinen Clinic
6 Department of Medicine, Shiga University of Medical Science
7 Department of Medicine, Metabolism and Endocrinology,; Juntendo University School of Medicine
8 Center for Advanced Science and Innovation, Osaka University

Abstract

Objective: It is believed that disruption of vulnerable atherosclerotic plaque and subsequent thrombus formation play critical roles in the pathogenesis of cerebral infarction. We simultaneously determined 4 relatively common genetic variants related to plaque rupture or subsequent local thrombus formation, and evaluated the combined effect on cerebral infarction.

Research Design and Methods: We enrolled 3094 Japanese type 2 diabetic subjects (males 62.7%; 61.5±8.4 years old) and determined their genotypes regarding matrix metalloproteinase 9 (MMP9) C-1562T, Coagulation factor XII (FXII) C46T, von Willebrand factor (VWF) G-1051A, and plasminogen activator inhibitor (PAI-1) -675 4G/5G polymorphisms. The diagnosis of cerebral infarction was performed based on history, physical examination, and neuroimaging.

Results: The single association analysis revealed that there were no statistically significant associations between each polymorphism and the prevalence of cerebral infarction. Interestingly, the prevalence of cerebral infarction was higher with the increase of the total number of 4 concomitant unfavorable “pro-atherothrombotic alleles” in each subject (p value for linear trend=0.004). Furthermore, a multiple logistic regression analysis showed that the number of pro-atherothrombotic alleles was a risk factor for cerebral infarction independently of conventional risk factors (Odds ratio for 1-point increase in the number of pro-atherothrombotic allele=1.15 with 95%CI 1.05-1.26, p=0.004).

Conclusions: Accumulation of gene polymorphisms related to plaque rupture and thrombus formation is likely associated with the prevalence of cerebral infarction in type 2 diabetic patients, suggesting that the combined information about these variants is useful to assess the risk of cerebral infarction.