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.

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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.

SummaryElevated levels of PAI-1 are found in coronary artery disease (CAD) and non-insulin-dependent diabetes (NIDDM). PAI-1 may be involved in the pathogenesis of CAD through suppression of fibrinolysis, alternatively the high levels may result from vascular damage. There is evidence that PAI-1 levels are related to genotype at a PAI-1 promoter polymorphism. Genotype at this 4G/5G polymorphism was determined in 160 NIDDM (90 males and 70 females) patients with (n = 38) or without (n = 122) clinical evidence of CAD. Levels of cholesterol were higher (6.5 vs 5.9 mM, p <0.01) and of PAI-1 tended to be higher (PAI-1 activity 23.0 vs 20.4 U/ml) with CAD. The frequency of the 4G/4G genotype was increased and the 5G/5G genotype decreased, in the group CAD compared to those without (p <0.05). These results suggest that possession of the 4G/4G PAI-1 promoter genotype is a risk factor for the development of CAD in subjects with NIDDM.

There is an increased risk of falls and fractures in early-diagnosed knee and hip osteoarthritis compared to those without osteoarthritis. International guidelines on the management of hip and knee osteoarthritis should consider the management of falls risk.