Results
The characteristics of cases and controls in each cohort and combined are shown in Table 1. The interval between serum collection and diagnosis was up to 22.8 years for ATBC, up to 14.5 years for PLCO, and up to 7.4 years for CPS-II. The median time between serum collection and diagnosis was 8.3 years overall (11.4 years for ATBC, 7.7 years for PLCO, and 2.9 years for CPS-II). The median age at pancreatic cancer diagnosis was 71 years. The range of leptin concentrations varied across cohorts with participants in the ATBC cohort having slightly lower concentrations compared with male participants in the PLCO and CPS-II cohorts. As expected, leptin concentrations were about 3-fold higher among women than among men in the CPS-II and PLCO cohorts. The characteristics of cases and controls did not differ greatly, except for the higher proportion of current smokers among cases than among controls.
Table 2 shows the means and proportions of selected baseline characteristics among the controls according to quintile of leptin concentrations, adjusted for cohort. Increasing leptin concentrations were directly related to male sex, former smoker status, higher body mass index, history of diabetes, less alcohol use, higher fat intake, higher C-peptide and transforming growth factor β1 concentrations, and lower total adiponectin concentrations.
In analyses including the entire follow-up period, leptin was not associated with risk of pancreatic cancer (Table 3). However, the association between leptin concentrations and risk of pancreatic cancer differed by follow-up time, with suggestion of an inverse association during the first 5 years of follow-up (continuous odds ratio (OR) = 0.79, 95% confidence interval (CI): 0.61, 1.03), no apparent association during follow-up between 5 and 10 years (continuous OR = 1.12, 95% CI: 0.88, 1.41), and a positive association during follow-up occurring more than 10 years after baseline (continuous OR = 1.44, 95% CI: 1.11, 1.88). The P value for difference in association by follow-up time was 0.003 (calculated on the basis of continuous terms for both follow-up time and leptin concentration).
Because the overall associations between leptin and pancreatic cancer risk were limited to follow-up after 10 years, we conducted further sensitivity and interaction analyses focused on this time period. Adjustment for body mass index strengthened the association; that is, for models without body mass index (quintile 4 and quintile 5 vs. quintile 1: OR = 2.09, 95% CI: 1.20, 3.62 and OR = 1.84, 95% CI: 1.06, 3.20; Ptrend = 0.03) and for continuous body mass index (OR = 1.24, 95% CI: 1.02, 1.50). Additional adjustment for C-peptide slightly increased the significance of the association (quintile 5 vs. quintile 1: OR = 3.25, 95% CI: 1.50, 7.05; Ptrend = 0.001) and for continuous C-peptide (OR = 1.57, 95% CI: 1.18, 2.09), while adjustment for total adiponectin or transforming growth factor β1 did not change the association (data not shown).
There were no significant interactions by study, sex, age, smoking status, body mass index, or history of diabetes. Positive associations were strongest during follow-up 5–10 years for the CPS-II/PLCO participants (continuous OR = 1.36, 95% CI: 1.03, 1.81) and during follow-up more than 10 years for the ATBC participants (continuous OR = 1.67, 95% CI: 1.19, 2.35) (Table 4), men (continuous OR = 1.53, 95% CI: 1.15, 2.04), and current smokers (continuous OR = 1.25, 95% CI: 0.98, 1.60) (Web Table 1 available at http://aje.oxfordjournals.org/). Among cases that occurred more than 10 years after baseline, associations were stronger among participants with a body mass index of less than 25 (continuous OR = 2.96, 95% CI: 1.35, 6.50) than among those with a body mass index of ≥25 (continuous OR = 1.13, 95% CI: 0.91, 1.41; Pheterogeneity = 0.03).