Evidence on the association between vitamin D status and pancreatic cancer risk is inconsistent. Introduction Vitamin D signaling is of interest in relation to cancer because of its hypothesized role in inducing immune cell differentiation and inhibiting tumor proliferation and angiogenesis [1]. In humans most vitamin D is synthesized endogenously via exposure of the skin to solar ultra-violet B radiation which converts 7-dehyrocholesterol in skin to vitamin D. Small amounts come also from dietary sources such as fish or fortified dairy products and in some populations dietary supplements ATF3 [2]. Some previous studies have suggested lower pancreatic cancer risk with proxy markers of higher vitamin D status. Ecologic studies which are based on population averages rather than individual level data have shown lower pancreatic cancer death rates in areas with more sun exposure in Spain [3] the United States [4 5 and Japan [6 7 A large prospective study that used a predicted estimate of vitamin D status based on five determinants of serum 25-hydroxyvitamin D (25(OH)D) (dietary and supplemental vitamin D skin pigmentation adiposity geographic residence MTEP hydrochloride and leisure activity) also found an inverse association with pancreatic cancer risk [8]. Serum 25(OH)D is the most widely used biomarker to assess vitamin D status in epidemiologic studies as it reflects both endogenous synthesis and dietary vitamin D intake [9]. However previous studies evaluating measured circulating 25(OH)D concentrations with risk of pancreatic cancer show conflicting results. A large pooled study of serum concentrations from eight cohorts as part of the Vitamin D Pooling Project (952 cases 1 333 controls) reported increased pancreatic cancer risk with higher circulating vitamin D concentrations (odds ratio (OR) = 2.12 95 confidence interval (CI)) comparing serum MTEP hydrochloride levels ≥100 nmol/L to the referent 50-75nmol/L [10]. In contrast a nested case-control study pooling five prospective cohorts (451 cases 1 167 controls) suggested an inverse association OR = 0.67 95 CI 0.46-0.97 comparing plasma 25(OH)D quintiles (>81.05 to <45.64 nmol/L) and no association when using the categories employed in the Vitamin D Pooling Project [11]. Pathway-based analysis of GWAS can detect associations that might be missed by focusing on single loci or even genes [12]. To our knowledge only one previous population based case-control study (628 cases 1 193 controls) evaluated associations between genetic variants related to vitamin D and pancreatic cancer and reported no single-nucleotide polymorphism (SNP) associations after adjustment for multiple comparisons [13]. In the present study we used data from 20 studies in PanScans I-III to examine 11 genes in the vitamin D metabolic pathway and 213 corresponding SNPs with risk of pancreatic cancer. In a subset of the cohorts we assessed effect measure modification by circulating vitamin D concentrations. Some of the samples used in this analysis overlap with those utilized in the Vitamin D Pooling Project [10]. We hypothesized that the contradictory evidence on circulating vitamin D and risk of pancreatic cancer might be explained by genetic variations in MTEP hydrochloride vitamin D-related genes and multiplicative interaction between circulating vitamin D and genetic variation. Materials and Methods Study Participants We obtained data from the MTEP hydrochloride 20 studies in the PanScan collaboration who agreed to participate in this pathway analysis. PanScan phases I-III have been previously described [14-16]. Our primary analysis included genotype data from 10 cohort studies and 10 case control studies in the PanScan collaboration. Participating cohorts included the Agricultural Health Study Alpha-Tocopherol Beta-Carotene Cancer Prevention Study (ATBC) Give us a Clue to Cancer and Heart Disease Study (CLUE II) Cancer Prevention Study II (CPS-II) Melbourne Collaborative Cohort Study (MCCS) Multiethnic Cohort (MEC) New York University Women’s Health Study (NYU-WHS) Prostate Lung Colorectal and Ovarian Cancer Screening Trial (PLCO) Selenium and Vitamin MTEP hydrochloride E Cancer Prevention Trial (SELECT) and the VITamins and Lifestyle cohort (VITAL). The included case-control studies were the Mayo Clinic Molecular Epidemiology of Pancreatic Cancer Study University of California San.