P‐selectin genotype is associated with the develop

Authors: Benjamin H L Tan Torill Fladvad Theodore P Braun Antonio Vigano Florian Strasser D A Christopher Deans Richard J E Skipworth Tora S Solheim Sambasivarao Damaraju James A Ross Stein Kaasa Daniel L Marks Vickie E Baracos Frank Skorpen Kenneth C H Fearon European Palliative Care Research Collaborative

Publish Date: 2012/06/04

Volume: 4, Issue: 6, Pages: 462-471

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Abstract

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 107 of the rs6136 SELP SNP was found to be associated with weight loss 10 both in the discovery study odds ratio OR 052 95 confidence intervals CI 029–093 p = 0026 and the validation study OR 009 95 CI 001–098 p = 0035 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 cachexiaMore than half of cancer patients suffer from cachexia and it is responsible for death in up to 20 of cases Cachexia is also a significant cause of morbidity in cancer patients Based on our current knowledge of demographic and clinical factors we are unable to predict for any given cohort of patients who will develop cancer cachexia and who will not Such variation may in part be due to the patients genotype Knowledge of genotypic variation associated with cachexia would contribute to early identification of patients at risk and allow institution of prophylactic measuresIn a large scale genetic association study the C allele of the rs6136 P‐selectin SNP was found to be associated with weight loss 10 both in the discovery study and the validation study To further corroborate the P‐selectin SNP to cancer cachexia in the gene association study we tested the same gene for participation in the induction of the skeletal muscle atrophy gene program in animal models of cachexia P‐selectin was found to be significantly upregulated in muscle following both tumour‐induced cachexia in rats and intra‐peritoneal injection of LPS in miceThe C‐allele of the rs6136 polymorphism is associated with reduced risk of developing cachexia 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

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