A prospective study of plasma adiponectin and pancreatic cancer risk in five US cohorts

Abstract

Background: The adipocyte-secreted hormone adiponectin has insulin-sensitizing and anti-inflammatory properties. Although development of pancreatic cancer is associated with states of insulin resistance and chronic inflammation, the mechanistic basis of the associations is poorly understood.

Methods: To determine whether prediagnostic plasma levels of adiponectin are associated with risk of pancreatic cancer, we conducted a nested case-control study of 468 pancreatic cancer case subjects and 1080 matched control subjects from five prospective US cohorts: Health Professionals Follow-up Study, Nurses' Health Study, Physicians' Health Study, Women's Health Initiative, and Women's Health Study. Control subjects were matched to case subjects by prospective cohort, year of birth, smoking status, fasting status, and month of blood draw. All samples for plasma adiponectin were handled identically in a single batch. Odds ratios were calculated with conditional logistic regression, and linearity of the association between adiponectin and pancreatic cancer was modeled with restricted cubic spline regression. All statistical tests were two-sided.

Results: Median plasma adiponectin was lower in case subjects versus control subjects (6.2 vs 6.8 µg/mL, P = .009). Plasma adiponectin was inversely associated with pancreatic cancer risk, which was consistent across the five prospective cohorts (P (heterogeneity) = .49) and independent of other markers of insulin resistance (eg, diabetes, body mass index, physical activity, plasma C-peptide). Compared with the lowest quintile of adiponectin, individuals in quintiles 2 to 5 had multivariable odds ratios ([ORs] 95% confidence intervals [CIs]) of OR = 0.61 (95% CI = 0.43 to 0.86), OR = 0.58 (95% CI = 0.41 to 0.84), OR = 0.59 (95% CI = 0.40 to 0.87), and OR = 0.66 (95% CI = 0.44 to 0.97), respectively (P (trend) = .04). Restricted cubic spline regression confirmed a nonlinear association (P (nonlinearity) < .01). The association was not modified by sex, smoking, body mass index, physical activity, or C-peptide (all P (interaction) > .10).

Conclusions: In this pooled analysis, low prediagnostic levels of circulating adiponectin were associated with an elevated risk of pancreatic cancer.

Figure 1.

Nonparametric regression curve for the association between plasma adiponectin and risk of pancreatic cancer. A) Full population. B) Men. C) Women. Multivariable odds ratios were calculated by restricted cubic spline conditional logistic model. Odds ratios were conditioned on the matching factors including year of birth, prospective cohort (Health Professionals Follow-up Study, Nurses’ Health Study, Physicians’ Health Study, Women’s Health Initiative, Women’s Health Study), smoking status (never, past, current), fasting status (fasting, nonfasting), and month of blood draw, and adjusted for covariates in the multivariable model 3, including race (white, black, other), history of diabetes mellitus (yes, no), current multivitamin use (yes, no), plasma 25-hydroxyvitamin D levels (quartiles), body mass index (<18.5, 18.5–24.9, 25–29.9, ≥30kg/m²), physical activity (quartiles), and plasma C-peptide levels (quartiles). Solid curve represents point estimates and dashed curves represent 95% confidence intervals.

Figure 2.

Cohort-specific and meta-analysis pooled odds ratios (ORs) of pancreatic cancer according to dichotomized plasma adiponectin levels (<4.4 vs ≥4.4 µg/mL). Cohort-specific multivariable odds ratios are conditioned on the matching factors including year of birth, prospective cohort (Health Professionals Follow-up Study, Nurses’ Health Study, Physicians’ Health Study, Women’s Health Initiative, Women’s Health Study), smoking status (never, past, current), fasting status (fasting, nonfasting), and month of blood draw, and adjusted for covariates in the multivariable model 3, including race (white, black, other), history of diabetes mellitus (yes, no), current multivitamin use (yes, no), plasma 25-hydroxyvitamin D levels (quartiles), body mass index (<18.5, 18.5–24.9, 25–29.9, ≥30kg/m²), physical activity (quartiles), and plasma C-peptide levels (quartiles). The pooled odds ratio is calculated by the DerSimonian and Laird random-effects model. The solid squares and horizontal lines correspond to the cohort-specific multivariable odds ratios and 95% confidence intervals (CIs), respectively. The area of the solid square reflects the cohort-specific weight (inverse of the variance). The open diamond represents the pooled multivariable odds ratio and 95% confidence interval. The dashed vertical line indicates the pooled odds ratio. The solid vertical line indicates an odds ratio of 1.0.