Sex-specific associations between adiponectin signaling and pancreatic cancer survival

Background: Low circulating levels of adiponectin and high levels of leptin have been associated with increased risk of pancreatic cancer. However, the relationship between long-term exposure to these adipokines in the prediagnostic period with survival following pancreatic cancer diagnosis has not been investigated.

Methods: We evaluated the association between circulating adiponectin and leptin levels in prospectively collected samples and mortality among 472 pancreatic cancer patients from five U.S. prospective cohorts. Due to sex-specific differences in adipokine levels, associations were evaluated separately for men and women. We used multivariate Cox proportional hazards regression to estimate hazard ratios for death. In a subset of 415 patients, we also evaluated the association between 23 tagging single nucleotide polymorphisms (SNPs) in adiponectin receptor genes (ADIPOR1, ADIPOR2) and 30 tagging SNPs in the leptin receptor gene (LEPR) with pancreatic cancer survival.

Results: Higher adiponectin levels were associated with shorter survival in women (HR=1.47, 95% CI: 1.03-2.11, comparing top to bottom quartile) but not in men (HR=0.93, 95% CI: 0.54-1.59). In women, rs1418445, previously associated with higher ADIPOR1 expression, was associated with increased mortality (per minor allele HR=1.40, 95% CI: 1.15-1.71, multiple hypotheses corrected P-value=0.04). Conversely, rs10753929, associated with lower ADIPOR1 expression, was associated with decreased mortality (HR=0.67, 95% CI: 0.51-0.88, P=0.03). There was no association between leptin levels or LEPR polymorphisms and survival in men or women.

Conclusions: High levels of adiponectin in the prediagnostic period and germline polymorphisms affecting ADIPOR1 expression were associated with shorter survival among women, but not among men with pancreatic cancer.”