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

Vanessa Y. Tan, Kalina M. Biernacka, Tom Dudding, Carolina Bonilla, Rebecca Gilbert, Robert C. Kaplan, Qibin Qi, Alexander Teumer, Richard M. Martin, Claire M. Perks, Nicholas J. Timpson, Jeff M.P. Holly

Research output: Contribution to journalArticle

Abstract

Background: Circulating insulin-like growth factor binding protein 3 (IGFBP-3) has been associated with prostate cancer. Preclinical studies found that vitamin D regulates IGFBP-3 expression, although evidence from epidemiologic studies is conflicting. Methods: Mendelian randomization analyses (MR) were conducted to reassess associations between IGFBP-3 and prostate cancer risk and advanced prostate cancer using summary statistics from the PRACTICAL consortium (44,825 cases; 27,904 controls). 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 (1,366 cases;1,071 controls) and summary statistics from the CHARGE consortium (n = 18,995). Results: The OR for prostate cancer per SD unit increase in circulating IGFBP-3 was 1.14 [95% confidence interval (CI), 1.02–1.28]. The OR for advanced prostate cancer 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 prostate cancer 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 prostate cancer risk factor but 25(OH)D are unlikely to be causally related to IGFBP-3 in the circulation.

Original languageEnglish (US)
Pages (from-to)1462-1471
Number of pages10
JournalCancer Epidemiology Biomarkers and Prevention
Volume27
Issue number12
DOIs
StatePublished - Dec 1 2018

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Insulin-Like Growth Factor Binding Protein 3
Random Allocation
Vitamin D
Mendelian Randomization Analysis
Prostatic Neoplasms
Confidence Intervals

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

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Reassessing the association between circulating Vitamin D and IGFBP-3 : Observational and Mendelian randomization estimates from independent sources. / Tan, Vanessa Y.; Biernacka, Kalina M.; Dudding, Tom; Bonilla, Carolina; Gilbert, Rebecca; Kaplan, Robert C.; Qi, Qibin; Teumer, Alexander; Martin, Richard M.; Perks, Claire M.; Timpson, Nicholas J.; Holly, Jeff M.P.

In: Cancer Epidemiology Biomarkers and Prevention, Vol. 27, No. 12, 01.12.2018, p. 1462-1471.

Research output: Contribution to journalArticle

Tan, Vanessa Y. ; Biernacka, Kalina M. ; Dudding, Tom ; Bonilla, Carolina ; Gilbert, Rebecca ; Kaplan, Robert C. ; Qi, Qibin ; Teumer, Alexander ; Martin, Richard M. ; Perks, Claire M. ; Timpson, Nicholas J. ; Holly, Jeff M.P. / Reassessing the association between circulating Vitamin D and IGFBP-3 : Observational and Mendelian randomization estimates from independent sources. In: Cancer Epidemiology Biomarkers and Prevention. 2018 ; Vol. 27, No. 12. pp. 1462-1471.
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abstract = "Background: Circulating insulin-like growth factor binding protein 3 (IGFBP-3) has been associated with prostate cancer. Preclinical studies found that vitamin D regulates IGFBP-3 expression, although evidence from epidemiologic studies is conflicting. Methods: Mendelian randomization analyses (MR) were conducted to reassess associations between IGFBP-3 and prostate cancer risk and advanced prostate cancer using summary statistics from the PRACTICAL consortium (44,825 cases; 27,904 controls). 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 (1,366 cases;1,071 controls) and summary statistics from the CHARGE consortium (n = 18,995). Results: The OR for prostate cancer per SD unit increase in circulating IGFBP-3 was 1.14 [95{\%} confidence interval (CI), 1.02–1.28]. The OR for advanced prostate cancer 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 prostate cancer 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 prostate cancer risk factor but 25(OH)D are unlikely to be causally related to IGFBP-3 in the circulation.",
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T2 - Observational and Mendelian randomization estimates from independent sources

AU - Tan, Vanessa Y.

AU - Biernacka, Kalina M.

AU - Dudding, Tom

AU - Bonilla, Carolina

AU - Gilbert, Rebecca

AU - Kaplan, Robert C.

AU - Qi, Qibin

AU - Teumer, Alexander

AU - Martin, Richard M.

AU - Perks, Claire M.

AU - Timpson, Nicholas J.

AU - Holly, Jeff M.P.

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N2 - Background: Circulating insulin-like growth factor binding protein 3 (IGFBP-3) has been associated with prostate cancer. Preclinical studies found that vitamin D regulates IGFBP-3 expression, although evidence from epidemiologic studies is conflicting. Methods: Mendelian randomization analyses (MR) were conducted to reassess associations between IGFBP-3 and prostate cancer risk and advanced prostate cancer using summary statistics from the PRACTICAL consortium (44,825 cases; 27,904 controls). 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 (1,366 cases;1,071 controls) and summary statistics from the CHARGE consortium (n = 18,995). Results: The OR for prostate cancer per SD unit increase in circulating IGFBP-3 was 1.14 [95% confidence interval (CI), 1.02–1.28]. The OR for advanced prostate cancer 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 prostate cancer 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 prostate cancer risk factor but 25(OH)D are unlikely to be causally related to IGFBP-3 in the circulation.

AB - Background: Circulating insulin-like growth factor binding protein 3 (IGFBP-3) has been associated with prostate cancer. Preclinical studies found that vitamin D regulates IGFBP-3 expression, although evidence from epidemiologic studies is conflicting. Methods: Mendelian randomization analyses (MR) were conducted to reassess associations between IGFBP-3 and prostate cancer risk and advanced prostate cancer using summary statistics from the PRACTICAL consortium (44,825 cases; 27,904 controls). 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 (1,366 cases;1,071 controls) and summary statistics from the CHARGE consortium (n = 18,995). Results: The OR for prostate cancer per SD unit increase in circulating IGFBP-3 was 1.14 [95% confidence interval (CI), 1.02–1.28]. The OR for advanced prostate cancer 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 prostate cancer 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 prostate cancer risk factor but 25(OH)D are unlikely to be causally related to IGFBP-3 in the circulation.

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