A general framework for functionally informed set-based analysis: Application to a large-scale colorectal cancer study

Dong, Xue; Su, Yu Ru; Barfield, Richard; Bien, Stephanie A.; He, Qianchuan; Harrison, Tabitha A.; Huyghe, Jeroen R.; Keku, Temitope O.; Lindor, Noralane M.; Schafmayer, Clemens; Chan, Andrew T.; Gruber, Stephen B.; Jenkins, Mark A.; Kooperberg, Charles; Peters, Ulrike; Hsu, Li

doi:10.1371/journal.pgen.1008947

Cited by 6 publications

(3 citation statements)

References 34 publications

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“…Differences in gene expression have been reported in CRC and adenoma tissue relative to normal colorectal tissue [ 9 – 12 ], with genes involved in metabolism, transcription, and translation and cellular processes commonly altered [ 13 ]. Recent transcriptome wide association studies confirm the importance of gene expression in carcinogenesis [ 14 , 15 ]. Vitamin D broadly influences gene expression through activation of the ligand-activated transcription factor VDR , which has been shown to influence cancer cell growth in vitro [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Oral vitamin D supplementation induces transcriptomic changes in rectal mucosa that are linked to anti-tumour effects

Vaughan-Shaw

Grimes

Blackmur

et al. 2021

BMC Med

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Background The risk for several common cancers is influenced by the transcriptomic landscape of the respective tissue-of-origin. Vitamin D influences in vitro gene expression and cancer cell growth. We sought to determine whether oral vitamin D induces beneficial gene expression effects in human rectal epithelium and identify biomarkers of response. Methods Blood and rectal mucosa was sampled from 191 human subjects and mucosa gene expression (HT12) correlated with plasma vitamin D (25-OHD) to identify differentially expressed genes. Fifty subjects were then administered 3200IU/day oral vitamin D3 and matched blood/mucosa resampled after 12 weeks. Transcriptomic changes (HT12/RNAseq) after supplementation were tested against the prioritised genes for gene-set and GO-process enrichment. To identify blood biomarkers of mucosal response, we derived receiver-operator curves and C-statistic (AUC) and tested biomarker reproducibility in an independent Supplementation Trial (BEST-D). Results Six hundred twenty-nine genes were associated with 25-OHD level (P < 0.01), highlighting 453 GO-term processes (FDR<0.05). In the whole intervention cohort, vitamin D supplementation enriched the prioritised mucosal gene-set (upregulated gene-set P < 1.0E−07; downregulated gene-set P < 2.6E−05) and corresponding GO terms (P = 2.90E−02), highlighting gene expression patterns consistent with anti-tumour effects. However, only 9 individual participants (18%) showed a significant response (NM gene-set enrichment P < 0.001) to supplementation. Expression changes in HIPK2 and PPP1CC expression served as blood biomarkers of mucosal transcriptomic response (AUC=0.84 [95%CI 0.66–1.00]) and replicated in BEST-D trial subjects (HIPK2 AUC=0.83 [95%CI 0.77–0.89]; PPP1CC AUC=0.91 [95%CI 0.86–0.95]). Conclusions Higher plasma 25-OHD correlates with rectal mucosa gene expression patterns consistent with anti-tumour effects, and this beneficial signature is induced by short-term vitamin D supplementation. Heterogenous gene expression responses to vitamin D may limit the ability of randomised trials to identify beneficial effects of supplementation on CRC risk. However, in the current study blood expression changes in HIPK2 and PPP1CC identify those participants with significant anti-tumour transcriptomic responses to supplementation in the rectum. These data provide compelling rationale for a trial of vitamin D and CRC prevention using easily assayed blood gene expression signatures as intermediate biomarkers of response.

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Section: Introductionmentioning

confidence: 99%

Oral vitamin D supplementation induces transcriptomic changes in rectal mucosa that are linked to anti-tumour effects

Vaughan-Shaw

Grimes

Blackmur

et al. 2021

BMC Med

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“…Recently, many methods have been developed based on individual variants GWAS summary statistics such as marginal association effect size estimates and standard errors for developing genome‐wide risk prediction models (Mak et al, 2017; Thomas et al, 2020; Vilhjálmsson et al, 2015), understanding the molecular mechanism underlying diseases using integrative genomics such as gene expression, methylation, and proteomics (Dong et al, 2020; Gamazon et al, 2015), estimating the causal effects of lifestyle and environmental risk factors such as body mass index and smoking by using genetic variants as instruments in Mendelian Randomization (Emdin et al, 2017), among others. These methods use the summary statistics of many genetic variants simultaneously and have greatly expanded the data analyses to address important questions such as risk prediction and the causal relationship of risk factors or intermediate (molecular) phenotypes with complex traits.…”

Section: Introductionmentioning

confidence: 99%

An empirical Bayes approach to improving population‐specific genetic association estimation by leveraging cross‐population data

Hsu

Kooperberg

Reiner

et al. 2022

Genetic Epidemiology

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Populations of non-European ancestry are substantially underrepresented in genome-wide association studies (GWAS). As genetic effects can differ between ancestries due to possibly different causal variants or linkage disequilibrium patterns, a meta-analysis that includes GWAS of all populations yields biased estimation in each of the populations and the bias disproportionately impacts non-European ancestry populations. This is because meta-analysis combines study-specific estimates with inverse variance as the weights, which causes biases towards studies with the largest sample size, typical of the European ancestry population. In this paper, we propose two empirical Bayes (EB) estimators to borrow the strength of information across populations although accounting for between-population heterogeneity.Extensive simulation studies show that the proposed EB estimators are largely unbiased and improve efficiency compared to the population-specific estimator. In contrast, even though the meta-analysis estimator has a much smaller variance, it yields significant bias when the genetic effect is heterogeneous across populations. We apply the proposed EB estimators to a large-scale trans-ancestry GWAS of stroke and demonstrate that the EB estimators reduce the variance of the population-specific estimator substantially, with the effect estimates close to the population-specific estimates.

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“…Differences in gene expression have been reported in CRC and adenoma tissue relative to normal colorectal tissue [9-12], with genes involved in metabolism, transcription and translation and cellular processes commonly altered [13]. Recent transcriptome wide association studies confirm importance of gene expression in carcinogenesis [14, 15]. Vitamin D broadly influences gene expression through activation of the ligand-activated transcription factor VDR , which has been shown to influence cancer cell growth in vitro [16].…”

Section: Introductionmentioning

confidence: 99%

Oral Vitamin D supplementation induces transcriptomic changes in rectal mucosa that are consistent with anti-tumour effects

Vaughan-Shaw

Grimes

Blackmur

et al. 2021

Preprint

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Background Risk for several common cancers is influenced by the transcriptomic landscape of the respective tissue-of-origin. Vitamin D influences in-vitro gene expression and cancer cell growth. We sought to determine whether oral vitamin D induces beneficial gene expression effects in human rectal epithelium and identify biomarkers of response. Methods Blood and rectal mucosa was sampled from 191 human subjects and mucosa gene expression (HT12) correlated with plasma vitamin D (25-OHD) to identify differentially expressed genes. Fifty subjects were then administered 3200IU/day oral vitamin D3 and matched blood/mucosa resampled after 12 weeks. Transcriptomic changes (HT12/RNAseq) after supplementation were tested against the prioritised genes for gene-set and GO-process enrichment. To identify blood biomarkers of mucosal response, we derived receiver-operator curves and C-statistic (AUC) and tested biomarker reproducibility in an independent Supplementation Trial (BEST-D). Results 629 genes were associated with 25-OHD level (P<0.01), highlighting 453 GO-term processes (FDR<0.05). In the whole intervention cohort, vitamin D supplementation enriched the prioritised mucosal gene-set (upregulated gene-set P<1.0E-07; downregulated gene-set P<2.6E-05) and corresponding GO terms (P=2.90E-02), highlighting gene expression patterns consistent with anti-tumour effects. However, only 9 individual participants (18%) showed a significant response (NM gene-set enrichment P<0.001) to supplementation. Expression changes in HIPK2 and PPP1CC expression served as blood biomarkers of mucosal transcriptomic response (AUC=0.84 [95%CI:0.66-1.00]), and replicated in BEST-D trial subjects (HIPK2 AUC=0.83 [95%CI:0.77-0.89]; PPP1CC AUC=0.91 [95%CI:0.86-0.95]). Conclusions Higher plasma 25-OHD correlates with rectal mucosa gene expression patterns consistent with anti-tumour effects and this beneficial signature is induced by short-term vitamin D supplementation. Heterogenous gene expression responses to vitamin D may limit the ability of randomised trials to identify beneficial effects of supplementation on CRC risk. However, in the current study blood expression changes in HIPK2 and PPP1CC identify those participants with significant anti-tumor transcriptomic responses to supplementation in the rectum. These data provide compelling rationale for a trial of vitamin D and CRC prevention using easily assayed blood gene expression signatures as intermediate biomarkers of response.

show abstract

A general framework for functionally informed set-based analysis: Application to a large-scale colorectal cancer study

Cited by 6 publications

References 34 publications

Oral vitamin D supplementation induces transcriptomic changes in rectal mucosa that are linked to anti-tumour effects

Oral vitamin D supplementation induces transcriptomic changes in rectal mucosa that are linked to anti-tumour effects

An empirical Bayes approach to improving population‐specific genetic association estimation by leveraging cross‐population data

Oral Vitamin D supplementation induces transcriptomic changes in rectal mucosa that are consistent with anti-tumour effects

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