The receptor for advanced glycation end products (RAGE)

SummaryFactor XIII when activated by thrombin, crosslinks fibrin, however its role in thrombotic disorders is unknown. A common point mutation (G T) in exon 2 of the A-subunit gene which codes for an amino acid change three amino acids from the thrombin activation site (Factor XIIIVal34Leu) is a candidate for a role in the pathogenesis of acute myocardial infarction. Factor XIII genotype frequencies were determined in a case-control study of 398 caucasian patients and 196 healthy controls. Patients had undergone angiography for investigation of coronary artery disease and were evaluated for a history of myocardial infarction. The prevalence of the mutation was lower in patients with myocardial infarction than without (32% vs. 50%), p = 0.0009 and than in controls (32% vs. 48%), p = 0.005. Patients possessing the mutation with a history of myocardial infarction had higher PAI-1 concentrations (mean, 27.9 vs. 16.7 ng/ml, p = 0.004) and the PAI-1 4G/4G genotype was commoner (43% vs. 26%, p = 0.03). There was no difference in PAI-1 4G/4G genotype (33% vs. 32%) and PAI-1 levels (mean, 21.0 vs. 20.9 ng/ml) in patients possessing wild type with MI compared to those without MI. These results indicate that the G T mutation coding for factor XIIIVal34Leu is protective against myocardial infarction and suggest a mechanism whereby elevated levels of PAI-1 may contribute to vascular risk.

Interactions between advanced glycation end products (AGEs) and the receptor for AGE (RAGE) are implicated in the vascular complications in diabetes. We have identified eight novel polymorphisms, of which the ؊1420 (GGT)n, ؊1393 G/T, ؊1390 G/T, and ؊1202 G/A were in the overlapping PBX2 3 untranslated region (UTR), and the ؊429 T/C (66.5% TT, 33.5% TC/CC), ؊407 to -345 deletion (99% I, 1% I/D, 0% D), ؊374 T/A (66.4% TT, 33.6% TA/AA), and ؉20 T/A were in the RAGE promoter. To evaluate the effects on transcriptional activity, we measured chloramphenicol acetyl transferase (CAT) reporter gene expression, driven by variants of the -738 to ؉49 RAGE gene fragment containing the four polymorphisms identified close to the transcriptional start site. The -429 C, ؊374 A, and 63-bp deletion alleles resulted in a mean increase of CAT expression of twofold (P < 0.0001), threefold (P < 0.001), and fourfold (P < 0.05), respectively, with the -374 T and A alleles yielding highly differential binding of nuclear protein extract from both monocyte-and hepatocyte-derived cell lines. The prevalence of the functional polymorphisms were investigated in subjects with type 2 diabetes (106 with and 109 without retinopathy), with the -429 C allele showing an increase in the retinopathy group (P < 0.05). These data suggest that the polymorphisms involved in differences in RAGE gene regulation may influence the pathogenesis of diabetic vascular complications. Diabetes 50:1505-1511, 2001

SummaryTo investigate the interaction of metabolic and genetic factors in relation to PAI-1, genotype was determined at a 4G/5G polymorphism in the PAI-1 gene promoter and at a Hind III RFLP of the PAI-1 gene in 189 Caucasian NIDDM patients. PAI-1 levels were equivalent in each genotype group and PAI-1 activity correlated with fasting insulin (r = 0.45), triglyceride (r = 0.39) body mass index (r = 0.44), cholesterol (r = 0.17) and glucose (r = 0.15). The regression slope (B) of PAI-1 activity on triglycerides was steeper in the 4G/4G group than the other two groups: 4G/4G B = 0.91, r = 0.62; 4G/5G B = 0.36, r = 0.27; 5G/5G B = 0.31, r = 0.29 (difference between slopes p = 0.02) and the association between PAI-1 activity and glucose remained only in the 4G/4G group (r = 0.35). These results confirm the association of PAI-1 levels with the features of insulin resistance and indicate that the association between PAI-1 levels and both triglyceride and glucose is influenced by genotype in the region of the PAI-1 gene promoter.

To investigate the relationship between an insertion/deletion (4G/5G) polymorphism in the promoter region of the plasminogen activator inhibitor-1 (PAI-1) gene and the phenotypes of PAI-1 levels, coronary atheroma, and a past history of coronary thrombosis, we studied 453 patients (320 men and 133 women) characterized by coronary angiography. Patients were classified as having normal vessels (n = 125) or single-vessel (n = 92) or multivessel (n = 232) coronary disease on the basis of > or = 50% stenosis. PAI-1 antigen levels were highest in patients with the 4G/4G genotype (22.5 ng/mL), with a stepwise decrease in levels as the number of 4G alleles decreased (21.5 ng/mL for 4G/5G and 15.8 ng/mL for 5G/5G, P = .02) after adjusting for age, sex, triglyceride levels, and body mass index (BMI). The association between triglyceride level and PAI-1 was genotype specific, with a steeper slope in subjects with the 4G/4G genotype (P = .004). A gene-environment interaction between BMI, PAI-1, and genotype was observed, with a steeper association in patients with the 5G/5G genotype (P = .02). The 4G/4G genotype was significantly associated with a history of myocardial infarction (P < .03; odds ratio, 2.0; 95% CI, 1.1 to 3.7). This relationship was stronger in subjects with diseased vessels (P = .006). There was no relationship between either PAI-1 genotype or levels and the presence of atheroma. Our data suggest that PAI-1 promoter polymorphism influences the development of myocardial infarction through its effect on thrombus formation in patients with preexisting coronary atheroma.

No abstract

Low ACE activity at sroke presentation and possession of the D allele may be associated with increased risk of early death from acute cerebral infarction.

We have shown an association between a common mutation in the factor XIII a-subunit gene, coding for an amino acid change, 3 amino acids from the thrombin activation site (factor XIII Val34Leu) that may protect against myocardial infarction and predisposes to intracranial hemorrhage. To investigate the possible role of factor XIII Val34Leu in the pathogenesis of venous thromboembolism (VTE) and potential interactions with factor V Leiden (FV:Q506) and prothrombin G → A 20210, we studied 221 patients with a history of VTE and 254 healthy controls. Patients with VTE showed an increased frequency of the FXIII Val/Val genotype (63% v 49%) and a lower frequency of the Val/Leu genotype (31% v 42%) than controls (P = .007). FV:Q506 heterozygotes were more frequent in VTE patients (11%) than controls (5%; P = .04). The prothrombin G → A 20210 mutation was present in only 3 patients and no controls (P = .10). In a logistic regression model for a history of VTE, the odds ratio (95% confidence interval) for FXIII Val/Leu or Leu/Leu genotype was 0.63 (0.38 to 0.82) and for possession of FV:Q506 2.40 (1.17 to 4.90). There was no evidence for an interaction between factor XIII Val34Leu genotype and FV:Q506, prothrombin G → A 20210, sex, or age. It is concluded that possession of the Leu allele at factor XIII Val34Leu is protective against deep venous thrombosis.