Tissue inhibitor of metalloproteinases (TIMP-1), genetic markers of insulin resistance and cardiomyopathy in patients with kidney failure.

Abstract Background. Left ventricular hypertrophy (LVH) is a major cardiovascular (CV) complication in patients with kidney failure, and an association between polymorphisms in the ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene, a genetic marker of insulin resistance, and LVH and Left ventricular (LV) concentric remodelling has been recently documented in these patients. Aims. Since myocardial fibrosis is a prominent feature in LVH induced by insulin resistance, we tested the hypothesis that the interaction between ENPP1 rs1974201 and rs9402349 polymorphisms and the tissue inhibitor of metalloproteinases (TIMP-1)--a pro-fibrotic protein which inhibits extracellular matrix degradation--is implicated in concentric LVH and diastolic dysfunction in a cohort of 223 dialysis patients. Results. Both ENPP1 polymorphisms rs1974201 and rs9402349 were in Hardy-Weinberg equilibrium in dialysis patients. In an analysis stratified by ENPP1, rs1974201 polymorphism, circulating levels of TIMP-1 in GG patients were coherently associated with two markers of concentric remodelling [relative wall thickness (RWT) and LV massto- volume ratio] as well as with a marker of diastolic dysfunction (E/A ratio) (P ranging from 0.005 to 0.02), whereas no such associations existed in CC or CG patients. These observations suggest that the rs1974201 modifies the relationship between TIMP-1 and LV geometry and diastolic dysfunction. Accordingly, in a multiple regression model, an identical increase of TIMP-1 (100 ng/mL) was associated with an increase of 22% in RWT, 14% in LV mass-to-volume ratio and 29% in E/A ratio in GG patients but with almost no change (from 0.22 to -3.78%) in these echocardiographic indices in the remaining patients (P for the effect modification 0.024). The rs9402349 did not modify the relationship between TIMP-1 and LV geometry and function. Conclusions. In dialysis patients, the ENPP1 rs1974201 polymorphism modifies the association between TIMP-1 and LV geometry and diastolic function. These results are consistent with the hypothesis that insulin resistance is involved not only in LVH but also in myocardial fibrosis, an alteration of primary importance in the high risk of this population.