We previously have shown a positive association between estimated risk of non-Hodgkin lymphoma (NHL), increasing body mass index (BMI) and single nucleotide polymorphisms (SNPs) in the leptin and leptin receptor genes that are involved in body weight regulation (Skibola CF et al. Cancer Epi Biomarkers Prev 2004, 13(5):779-86). Leptin is produced by adipose tissue and controls the release of neuropeptide Y (NPY), a potent appetite stimulator. NPY also acts as a mediator of immune function via its expression in primary and secondary lymphoid organs, and its levels are upregulated upon activation of B cells, monocytes, and macrophages. We hypothesized that leptin’s association with lymphoma may be mediated through NPY and that SNPs in the NPY gene would confer increased risk estimates for NHL. Four polymorphisms in the NPY gene were examined using DNA from 458 cases and 812 controls from a population-based case-control study of NHL conducted in the San Francisco Bay Area between 1988 and 1995. NPY -485T>C, 1258G>A, and 5671C>T, were in total linkage disequilibrium (D’=0.99) and were associated with significantly increased risk estimates for all NHL (-485T>C: OR=1.7, 95% CI=1.1-2.5; 1258G>A: OR=1.7; 95% CI=1.1-2.5; and 5671C>T: OR=1.9; 95% CI=1.3-2.8). When stratified by NHL subtype, NPY -485T>C, 1258G>A, and 5671C>T were positively associated with follicular lymphoma (-485T>C: OR=2.4; 95% CI=1.3-4.4; 1258G>A: OR=2.0; 95% CI=1.1-3.5; and 5671C>T: OR=1.8; 95% CI=1.1-3.0). Increased ORs for follicular lymphoma also were observed for carriers of the variant allele for NPY 1128T>C (OR=2.3; 95% CI=1.1-4.9), a non synonymous SNP (Leu>Pro) associated with increased NPY secretion, elevated cholesterol levels, enhanced angiogenesis, and lymphocyte proliferation. These results suggest that SNPs in NPY that are associated with enhanced NPY levels, and SNPs in leptin and other energy regulating genes may be susceptibility loci for NHL, and that imbalanced energy homeostasis could play a role in the etiology of NHL. This work was supported in part by NIH grants RO1CA104862, RO1CA87014, RO3CA89745 and RO1CA45614.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]