Reassessing the association between circulating Vitamin D and IGFBP-3: observational and Mendelian randomization estimates from independent sources

Background:
Circulating insulin-like growth factor binding protein 3 (IGFBP-3) has been associated with PCa. Preclinical studies found that vitamin D regulates IGFBP-3 expression, although evidence from epidemiological studies are conflicting.

Methods:
Mendelian Randomisation analyses (MR) were conducted to reassess associations between IGFBP-3 and Prostate cancer (PCa) risk and advanced PCa using summary statistics from the PRACTICAL consortium (44,825cases;27,904controls). Observational and MR analyses were conducted to assess the relationship between inactive vitamin D (25(OH)D) and IGFBP-3 using data from the ProtecT study (1,366cases;1,071controls) and summary statistics from the CHARGE consortium (n=18,995).

Results:
The odds ratio (OR) for PCa per standard deviation (SD) unit increase in circulating IGFBP-3 was 1.14(95%CI:1.02-1.28). The OR for advanced PCa per SD unit increase in IGFBP-3 was 1.22(95%CI:1.07-1.40). Observationally, a SD increase in 25(OH)D was associated with a 0.1SD(95%CI:0.05, 0.14) increase in IGFBP-3. MR analyses found little evidence for a causal relationship between circulating 25(OH)D and IGFBP-3 in the circulation.

Conclusions:
This study provided confirmatory evidence that IGFBP-3 is a risk factor for PCa risk and progression. Observationally, there was evidence that 25(OH)D is associated with IGFBP-3, but MR analyses suggested that these findings were unlikely to be causal. Findings may be limited by the nature of instrumentation of 25(OH)D and IGFBP-3 and the utility of circulating measures. 25(OH)D appears unlikely to be causally related to IGFBP-3 in the circulation, however, our findings do not preclude causal associations at the tissue level.

Impact:
IGFBP-3 is a PCa risk factor but 25(OH)D are unlikely to be causally related to IGFBP-3 in the circulation.