Background. Transforming growth factor-β1 (TGF-β1) is involved in cell growth and differentiation and it plays an important role in the genesis of fibrosis through the stimulation of neointima proliferation and accumulation of components of the extracellular matrix and it has been suggested that polymorphisms (polym) in its gene contribute to determining the patency of the vascular access (VA) in patients (pts) on hemodialysis (HD) by contributing to both atherogenesis and VA thrombosis. On the other hand it has been demonstrated that polym in the gene encoding the plasminogen activator inhibitor type-1 (PAI-1) are a risk factor for ischemic heart disease and possibly stroke although their role in other vascular territories is unknown. It is also known that TGF-β1 is an important up-regulator of the PAI-1 gene.

Methods. We conducted a case-control study to determine the relationship between TGF-β1 polym of the signal sequence (869 T>C; 915 G>C) and VA thrombosis in 416 HD pts. (107 with VA thrombosis, 309 controls had no thrombosis). We also explored for possible interactions with the 4G/5G polym of the PAI-1 gene. TGF-β1 and PAI-1 polym were amplified using PCR and genotyped using an ABI PRISM 3100 Genetic Analyzer. TGF-β1 producing haplotypes (haplo) were defined as low, intermediate or high as previously reported. All pts were also tested for thrombophilia. Statistical analysis was done using univariate and multivariate logistic regression adjusted for thrombophilia, age, access type, etc.

Results. Frequencies for low, intermediate and high TGF-β1 producing haplo were 9.3, 26.2 and 64.5% in cases and 2.6, 22.3 and 75.1% in controls.

Odds of thrombosis for TGF-β1 haplotypes

HaplotypeCrude OR (95% CI)pAdjusted OR (95% CI)p
High producing haplotype is reference category 
Low 5.11 (1.93, 13.5) 0.001 7.31 (2.15, 24.88) 0.001 
Intermediate 1.30 (0.74, 2.29) 0.36 1.39 (0.70, 2.75) 0.35 
HaplotypeCrude OR (95% CI)pAdjusted OR (95% CI)p
High producing haplotype is reference category 
Low 5.11 (1.93, 13.5) 0.001 7.31 (2.15, 24.88) 0.001 
Intermediate 1.30 (0.74, 2.29) 0.36 1.39 (0.70, 2.75) 0.35 
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Frequencies for 5G/5G, 4G/5G and 4G/4G PAI-1 polym. were 21.5, 56.1 and 22.4% in cases and 25.6, 50.2 and 24.3% in controls respectively. When we explored the interaction between both gene polym we found a highly significant result for the interaction between the low TGF-β1 producers and the 4G/4G PAI-1 polym (adjusted OR 19.3; 95% CI 2.82, 132.40; p=0.003).

Conclusions. Our results show that intermediate and high producing TGF-β1 haplo have a protective effect against VA thrombosis in HD patients that is not modified by PAI-1 polym and also suggest that the interaction between low TGF-β1 producing haplo and the 4G/4G PAI-1 polym might be an important contributor to thrombosis of the VA in HD pts. Further studies are ongoing to determine the relationship between TGF-β1 haplo, TGF-β1 level, and PAI-1 polym with thrombosis in this and other populations as well as to clarify the mechanisms underlying this apparently paradoxical effect.

Topics:
genes, hemodialysis, plasminogen activator, polymorphism, thrombosis, plasminogen activator inhibitor 1, brachial plexus neuritis, thrombophilia, atherogenesis, cerebrovascular accident

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2005, The American Society of Hematology
2005
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