Activated protein C (APC) and its receptor, the endothelial protein C receptor (EPCR), represent the most important anticoagulant system in regulation of inflammation (1,2) and a major physiological control system of the vascular wall permeability during sepsis (3). The EPCR is a type 1 transmembrane glycoprotein highly expressed on the endothelium of large vessels, especially in arteries (4,5), which enhances the protein C activation by thrombin/thrombomodulin complex (4,6). Because of the important role of EPCR in the protein C anticoagulant pathway, it is possible to hypothesize that any functional mutation will lead to increased risk of thrombosis and hyperinflammatory response (7). It has been demonstrated that a 23 bp insertion in the exon 3 of the EPCR gene, which is located in 20q11.2 chromosome region, predicts a truncated protein that lacks part of the extracellular domain, and can neither bind APC nor be expressed on cell surface (8,9). This abnormality of the EPCR gene has been found in adult subjects with deep vein thrombosis (1.5%) and myocardial infarction (2%) (9), and in pediatric thrombotic cases (2.36%) (10). An homozygous 23 bp insertion of the EPCR gene may be associated with a tendency to sepsis and poor outcome in children(11). High levels of C-reactive protein (CRP), the main acute phase protein, have been demonstrated to be strong predictors of future cardiovascular events in subjects both with and without overt cardiovascular disease. Increased CRP serum levels have also been significantly correlated with weight excess, and overweight and obesity represent a strong risk factor for premature cardiovascular diseases as well as for recurrent venous thromboembolism (12,13,14). High levels of CRP have been also demonstrated in subjects with Prader-Willi syndrome (PWS) (15), a rare genetic obesity syndrome which has distinct physical, endocrine, and metabolic characteristics that are not common to severe obesity itself. Total fat mass is increased but unlike in obesity, visceral fat deposits are reduced (16) and insulin sensitivity is higher than in the obese (17). Regardless of their metabolic advantages, however, PWS patients are at risk of premature death (18,19). Complications conventionally related to obesity, including cardiovascular disease and respiratory insufficiency, are recognized as the main risk factors for sudden death during the life-span of patients with PWS (20,21). Nevertheless, it is not clear which components related to obesity may contribute to the increased risk of cardiovascular disease. In this context, evidence of microcirculatory dysfunctions as well as a trend toward increased mean intima—media thickness have been reported in young PWS adults (22). Moreover, several cardiovascular risk factors, such as abnormal levels of low-density lipoprotein cholesterol (LDL-C), apolipoprotein B, high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and lipoprotein (a), are already present in prepubertal children with PWS (23). All these findings are potentially associated with coronary artery disease and thus early sudden death. To date, however, only few cases of coronary artery and atherosclerotic heart diseases have been reported in PWS subjects (24,25,26), but this circumstance may be simply related to the early mortality of PWS, since ischemic heart disease is generally observed after the middle age. In addition, both superficial and deep venous thrombosis are frequently observed in PWS, particularly in patients who have stopped to walk for any reason (27).
The aim of this study was to analyze the 23 bp insertion in the exon 3 of the EPCR gene in a cohort of PWS adults and children with PWS, as well as in a control group of obese and overweight children, to evaluate the frequency of this alteration in these two types of obesity. In addition, we investigated the predisposition to develop thrombotic events in association with biochemical and inflammatory profile of PWS children in comparison to those obtained in the control group. Finally, measurement of the metabolic and inflammatory markers was performed in the group of PWS adults, to evaluate the development of these risk factors in different ages.