Role of Angiotensin-Converting Enzyme and Vitamin D Receptor Gene Polymorphisms in Cancer Anorexia-Cachexia Syndrome

Abstract

The ubiquitin-proteasome pathway is a crucial connection between aberrant immune system activation, systemic inflammation and Cancer Anorexia-Cachexia Syndrome (CACS), a syndrome that culminates in hyper-activation of the ubiquitin-proteasome pathway. Angiotensin directly up-regulates this pathway, while vitamin D down-regulates it indirectly through the insulin-like growth factor-1 pathway. We investigated the genetic predisposition towards CACS in a cancer population, examining Insertion/Deletion (I/D) polymorphism of angiotensin-converting enzyme gene and FokI and BsmI polymorphisms of vitamin D receptor gene. Sixty-two cancer patients were recruited and divided into three groups: primary cachectic (C1, n = 14; dysmetabolic body weight loss ≥5% in 6 months); secondary cachectic (C2, n = 34; similar weight loss, mechanic or iatrogenic origin); and non-cachectic (NC, n = 16). C2+NC were merged in the control group. The three groups showed significant differences in average prognostic inflammatory nutritional index (C1: 26.4±23.4; C2: 5.4±5.6; NC: 0.37±0.5), C-reactive protein serum levels (C1: 6.6±2.1; C2: 2.4±2.2; NC: 1.0±2.0 mg/dL), albumin serum levels (C1: 3.1±0.6; C2: 3.5±0.4; NC 3.7±0.6 g/dL), weight loss (C1: 22±8; C2: 15±6.7; NC 5±6%) and life expectancy (C1: 6.4±3.3; C2: 25±28; NC: 45±25 months). However, none of the chosen polymorphisms showed any statistically significant correlation with CACS. The complexity of the changes of the immune system in the chronic inflammation state associated with CACS is far greater than expected and further studies are required to identify genetic independent markers of progression toward CACS.