Sex-Specific Associations between Adiponectin and Leptin Signaling and Pancreatic Cancer Survival

Background: Circulating adiponectin and leptin have been associated with risk of pancreatic cancer. However, the relationship between long-term exposure to these adipokines in the prediagnostic period with patient survival has not been investigated. Methods: Adipokine levels were measured in prospectively collected samples from 472 patients with pancreatic cancer. Because of sex-specific differences in adipokine levels, associations were evaluated separately for men and women. In a subset of 415 patients, we genotyped 23 SNPs in adiponectin receptor genes (ADIPOR1 and ADIPOR2) and 30 SNPs in the leptin receptor gene (LEPR). Results: Adiponectin levels were inversely associated with survival in women [HR, 1.71; 95% confidence interval (CI), 1.15–2.54]; comparing top with bottom quartile but not in men (HR, 0.89; 95% CI, 0.46–1.70). The SNPs rs10753929 and rs1418445 in ADIPOR1 were associated with survival in the combined population (per minor allele HR, 0.66; 95% CI, 0.51–0.84, and HR, 1.33; 95% CI, 1.12–1.58, respectively). Among SNPs in LEPR, rs12025906, rs3790431, and rs17127601 were associated with survival in the combined population [HRs, 1.54 (95% CI, 1.25–1.90), 0.72 (95% CI, 0.59–0.88), and 0.70 (95% CI, 0.56–0.89), respectively], whereas rs11585329 was associated with survival in men only (HR, 0.39; 95% CI, 0.23–0.66; P_interaction = 0.0002). Conclusions: High levels of adiponectin in the prediagnostic period were associated with shorter survival among women, but not among men with pancreatic cancer. Several polymorphisms in ADIPOR1 and LEPR are associated with patient survival. Impact: Our findings reveal the association between adipokine signaling and pancreatic cancer survival and demonstrate the importance of examining obesity-associated pathways in relation to pancreatic cancer in a sex-specific manner.