Dataset Information

Associations between Genetically Predicted Blood Protein Biomarkers and Pancreatic Cancer Risk.

ABSTRACT:

Background

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with few known risk factors and biomarkers. Several blood protein biomarkers have been linked to PDAC in previous studies, but these studies have assessed only a limited number of biomarkers, usually in small samples. In this study, we evaluated associations of circulating protein levels and PDAC risk using genetic instruments.

Methods

To identify novel circulating protein biomarkers of PDAC, we studied 8,280 cases and 6,728 controls of European descent from the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case-Control Consortium, using genetic instruments of protein quantitative trait loci.

Results

We observed associations between predicted concentrations of 38 proteins and PDAC risk at an FDR of < 0.05, including 23 of those proteins that showed an association even after Bonferroni correction. These include the protein encoded by ABO, which has been implicated as a potential target gene of PDAC risk variant. Eight of the identified proteins (LMA2L, TM11D, IP-10, ADH1B, STOM, TENC1, DOCK9, and CRBB2) were associated with PDAC risk after adjusting for previously reported PDAC risk variants (OR ranged from 0.79 to 1.52). Pathway enrichment analysis showed that the encoding genes for implicated proteins were significantly enriched in cancer-related pathways, such as STAT3 and IL15 production.

Conclusions

We identified 38 candidates of protein biomarkers for PDAC risk.

Impact

This study identifies novel protein biomarker candidates for PDAC, which if validated by additional studies, may contribute to the etiologic understanding of PDAC development.

SUBMITTER: Zhu J

PROVIDER: S-EPMC7334065 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Publications

Associations between Genetically Predicted Blood Protein Biomarkers and Pancreatic Cancer Risk.

Zhu Jingjing J Shu Xiang X Guo Xingyi X Liu Duo D Bao Jiandong J Milne Roger L RL Giles Graham G GG Wu Chong C Du Mengmeng M White Emily E Risch Harvey A HA Malats Nuria N Duell Eric J EJ Goodman Phyllis J PJ Li Donghui D Bracci Paige P Katzke Verena V Neale Rachel E RE Gallinger Steven S Van Den Eeden Stephen K SK Arslan Alan A AA Canzian Federico F Kooperberg Charles C Beane Freeman Laura E LE Scelo Ghislaine G Visvanathan Kala K Haiman Christopher A CA Le Marchand Loïc L Yu Herbert H Petersen Gloria M GM Stolzenberg-Solomon Rachael R Klein Alison P AP Cai Qiuyin Q Long Jirong J Shu Xiao-Ou XO Zheng Wei W Wu Lang L

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20200521 7

<h4>Background</h4>Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with few known risk factors and biomarkers. Several blood protein biomarkers have been linked to PDAC in previous studies, but these studies have assessed only a limited number of biomarkers, usually in small samples. In this study, we evaluated associations of circulating protein levels and PDAC risk using genetic instruments.<h4>Methods</h4>To identify novel circulating protein biomarkers of PDAC ...[more]

PMID: 32439797

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Project description:BackgroundInterleukin 6 (IL-6) signaling is being investigated as a therapeutic target for atherosclerotic cardiovascular disease (CVD). While changes in circulating high-sensitivity C-reactive protein (hsCRP) are used as a marker of IL-6 signaling, it is not known whether there is effect heterogeneity in relation to baseline hsCRP levels or other cardiovascular risk factors. The aim of this study was to explore the association of genetically predicted IL-6 signaling with CVD risk across populations stratified by baseline hsCRP levels and cardiovascular risk factors.MethodsAmong 397,060 White British UK Biobank participants without known CVD at baseline, we calculated a genetic risk score for IL-6 receptor (IL-6R)-mediated signaling, composed of 26 variants at the IL6R gene locus. We then applied linear and non-linear Mendelian randomization analyses exploring associations with a combined endpoint of incident coronary artery disease, ischemic stroke, peripheral artery disease, aortic aneurysm, and cardiovascular death stratifying by baseline hsCRP levels and cardiovascular risk factors.ResultsThe study participants (median age 59 years, 53.9% females) were followed-up for a median of 8.8 years, over which time a total of 46,033 incident cardiovascular events occurred. Genetically predicted IL-6R-mediated signaling activity was associated with higher CVD risk (hazard ratio per 1-mg/dL increment in absolute hsCRP levels: 1.11, 95% CI: 1.06-1.17). The increase in CVD risk was linearly related to baseline absolute hsCRP levels. There was no evidence of heterogeneity in the association of genetically predicted IL-6R-mediated signaling with CVD risk when stratifying the population by sex, age, body mass index, estimated glomerular filtration rate, or systolic blood pressure, but there was evidence of greater associations in individuals with low-density lipoprotein cholesterol ≥ 160 mg/dL.ConclusionsAny benefit of inhibiting IL-6 signaling for CVD risk reduction is likely to be proportional to absolute reductions in hsCRP levels. Therapeutic inhibition of IL-6 signaling for CVD risk reduction should therefore prioritize those individuals with the highest baseline levels of hsCRP.

Dataset Information

Associations between Genetically Predicted Blood Protein Biomarkers and Pancreatic Cancer Risk.

Background

Methods

Results

Conclusions

Impact

Publications

Associations between Genetically Predicted Blood Protein Biomarkers and Pancreatic Cancer Risk.

Similar Datasets

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