P‐selectin genotype is associated with the development of cancer cachexia

• Published in: EMBO molecular medicine 2012-06, Vol.4 (6), p.462-471
• Main Authors: Tan, Benjamin H. L., Fladvad, Torill, Braun, Theodore P., Vigano, Antonio, Strasser, Florian, Deans, D. A. Christopher, Skipworth, Richard J. E., Solheim, Tora S., Damaraju, Sambasivarao, Ross, James A., Kaasa, Stein, Marks, Daniel L., Baracos, Vickie E., Skorpen, Frank, Fearon, Kenneth C. H.
• Format: Article
• Language: English
• Subjects: Adult; Age; Aged; Aged, 80 and over; Alleles; Animal models; Animals; Atrophy; Body mass index; C-Reactive Protein - analysis; Cachexia; Cachexia - genetics; Cancer; Chromosomes; Cohort Studies; Disease Models, Animal; Female; Gene expression; Gene Frequency; Genetic Association Studies; Genotype; Genotype & phenotype; Humans; inflammation; Laboratory animals; Lipopolysaccharides; Male; Mice; Middle Aged; Musculoskeletal system; Neoplasms - complications; P-Selectin - genetics; Patients; Peritoneum; Polymorphism; Polymorphism, Single Nucleotide; polymorphisms; P‐selectin; Quality control; Rats; Research Article; Risk factors; Sepsis; Single-nucleotide polymorphism; Tumors; Weight Loss - genetics
• ISSN: 1757-4676; 1757-4684
• DOI: 10.1002/emmm.201200231

The variable predisposition to cachexia may, in part, be due to the interaction of host genotype. We analyzed 129 single nucleotide polymorphisms (SNPs) in 80 genes for association with cachexia based on degree of weight loss (>5, >10, >15%) as well as weight loss in the presence of systemic inflammation (C‐reactive protein, >10 mg/l). 775 cancer patients were studied with a validation association study performed on an independently recruited cohort ( n  = 101) of cancer patients. The C allele (minor allele frequency 10.7%) of the rs6136 ( SELP ) SNP was found to be associated with weight loss >10% both in the discovery study (odds ratio (OR) 0.52; 95% confidence intervals (CI), 0.29–0.93; p  = 0.026) and the validation study (OR 0.09, 95% CI 0.01–0.98, p  = 0.035). In separate studies, induction of muscle atrophy gene expression was investigated using qPCR following either tumour‐induced cachexia in rats or intra‐peritoneal injection of lipopolysaccharide in mice. P‐selectin was found to be significantly upregulated in muscle in both models. Identification of P‐selectin as relevant in both animal models and in cachectic cancer patients supports this as a risk factor/potential mediator in cachexia. See accompanying article http://dx.doi.org/10.1002/emmm.201200232