Lower Plasma Creatinine and Urine Albumin in Individuals at Increased Risk of Type 2 Diabetes with Factor V Leiden Mutation

The factor V Leiden (FVL) mutation is the most frequent genetic cause of venous thrombosis in Caucasians. However, protective effects have been suggested to balance the disadvantages. We have recently observed protective effects of FVL mutation on experimental diabetic nephropathy in mice as well as an association with reduced albuminuria in two human cohorts of diabetic patients. In the present study we aimed to reevaluate these findings in an independent, larger cohort of 1905 Caucasians at risk of developing type 2 diabetes and extend possible associations to earlier disease stages of nephropathy. Carriers of FVL mutation had a significantly lower urine albumin excretion ( ) and tended to have lower plasma creatinine concentrations ( ). The difference in plasma creatinine concentrations was significant after adjustment for the influencing factors: age, gender, and lean body mass ( ). These observations at a very early “disease” stage are an important extension of previous findings and suggest that modification of glomerular dysfunction by FVL mutation is relevant during very early stages of diabetic nephropathy. This makes the underlying mechanism an interesting therapeutic target and raises the question whether FVL mutation may also exert protective effects in other glomerulopathies. 1. Introduction The factor V Leiden (FVL) mutation is the most frequent genetic cause of venous thrombosis in Caucasians. The high frequency of the FVL mutation implies associated positive effects which balance the negative sequels of the FVL mutation [1]. Indeed, several protective effects associated with the FVL mutation and potentially conveying a positive selection bias have been proposed [2]. Thus, the presence of the FVL mutation has been associated with lower peripartal blood loss and reduced mortality in sepsis [2, 3]. Obviously the amelioration of these acute and potentially deadly health threats mediates a positive selection pressure, maintaining the FVL mutation in the gene pool despite the potentially negative effects associated with venous thrombosis. We have recently proposed that the protective mechanism(s) selected in FVL carriers may not only be relevant in acute diseases, but also modulate the course of chronic diseases, which pose the prevailing health threats in modern times. Thus, low but sustained thrombin generation associated with the presence of the FVL mutation results in larger but more stable plaques in atherosclerosis prone mice, indicating a partial benefit [4]. Furthermore, in a second mouse model we observed a protective effect of the FVL