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Cancer cachexia is associated with the IL10 –1082 gene promoter polymorphism in patients with gastroesophageal malignancy

¹ From the Department of Clinical and Surgical Sciences, Medical School, University of Edinburgh, Edinburgh, United Kingdom (DACD, BHLT, JAR, SJW, and KCHF); the Divisions of Human Genetics and Infection, Inflammation, and Repair (MR-Z), and the Institute of Human Nutrition (RG), School of Medicine, University of Southampton, Southampton, United Kingdom; and the Department of Histocompatibility and Immunogenetics, NHS Blood & Transplant, Newcastle-upon-Tyne, United Kingdom (WMH).

² DACD was supported by a fellowship from the Royal College of Surgeons of England. KCHF was supported by EU grant 037777 (Improved treatment of pain, depression, and cachexia through translational research) and an NCRI Supportive and Palliative Care Capacity Building Grant (SuPaC CBG10).

³ Reprints not available. Address correspondence to KCH Fearon, University Department of Surgery, Royal Infirmary, 51 Little France Crescent, Edinburgh EH16 4SA, United Kingdom. E-mail: k.fearon{at}ed.ac.uk.

Background: The genetic predisposition of the host to local or systemic inflammation may contribute to the effect of cancer cachexia.

Objective: We investigated the relation between cytokine polymorphisms (IL1B –511, IL6 –174, IL10 –1082, TNFA –308, and LTA +252) and markers of nutritional status among patients with gastroesophageal cancer to determine whether any such association was reflected by cytokine concentrations in the tumor or plasma compartments.

Design: Patients (n = 203) with a diagnosis of gastroesophageal cancer underwent nutritional assessment (body mass index, anthropometric measures, dysphagia scoring, and estimation of dietary intake). Single nucleotide polymorphism genotyping was performed by TaqMan allelic discrimination genotyping. Serum cytokine and C-reactive protein concentrations were determined by enzyme-linked immunosorbent assay. Tumor tissue cytokine protein concentrations (n = 56) were determined by using the Cytometric Bead Array System.

Results: IL10 GG and IL6 CC polymorphisms were associated with elevated serum C-reactive protein concentrations, and the IL6 CC genotype was also associated with elevated tumor tissue cytokine concentrations. At diagnosis, the IL10 GG, but not the IL6, genotype was linked with increased total weight loss: 4.9% for AA, 7.1% for AG, and 12.0% for GG (P = 0.007). Serum C-reactive protein concentrations correlated with increased weight loss (r = 0.24, P < 0.001). Compared with other genotypes, the IL10 GG genotype retained an independent association in determining the extent of weight loss on multivariate analysis (95% CI: 0.52, 3.43; P = 0.008). Possession of the GG allele was associated with a 2.3 times increased risk of developing cachexia (95% CI: 1.2, 4.3; P = 0.014).

Conclusion: These data suggest that the IL10 genotype of the host can influence the development of cachexia among patients with gastroesophageal malignancy.