Proteome-Wide Mendelian Randomization Identifies Causal Links Between Blood Proteins and Acute Pancreatitis

Bourgault, Jérôme; Abner, Erik; Manikpurage, Hasanga D.; Pujol-Gualdo, Natàlia; Laisk, Triin; Gobeil, Émilie; Gagnon, Éloi; Girard, Arnaud; Mitchell, Patricia L.; Thériault, Sébastien; Esko, Tõnu; Mathieu, Patrick; Arsenault, Benoît J.

doi:10.1053/j.gastro.2023.01.028

Cited by 33 publications

(15 citation statements)

References 53 publications

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“…In addition, we performed the analysis with cis-pQTLs as they are known for their resistance to horizontal pleiotropy 22 . Previously, a study has identified several potential drug targets for acute pancreatitis through MR analysis of cis-pQTLs for 4719 plasma proteins 23 . Here, we employed the same plasma protein screening approach as follows: Firstly, a rigorous association screening was performed on 4917 plasma protein pQTL ( p < 5e-8), which be advantageous for excluding weak instrumental variables.…”

Section: Methodsmentioning

confidence: 99%

“…The Bayesian colocalization method provides posterior probabilities of five hypotheses 35 . To assess the presence of shared causal variation in a specific genomic region between the two phenotypes, Bayesian colocalization analysis (pQTL-GWAS) was performed using SNPs located within 500 Mb from the lead SNP of all cis-pQTL with MAF > 0.01 23 . There are four hypotheses for co-localization analysis.…”

Section: Methodsmentioning

confidence: 99%

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Potential drug targets for tumors identified through Mendelian randomization analysis

Song,

Shi,

Cui

et al. 2024

Sci Rep

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According to the latest cancer research data, there are a significant number of new cancer cases and a substantial mortality rate each year. Although a substantial number of clinical patients are treated with existing cancer drugs each year, the efficacy is unsatisfactory. The incidence is still high and the effectiveness of most cancer drugs remains unsatisfactory. Therefore, we evaluated the human proteins for their causal relationship to for cancer risk and therefore also their potential as drug targets. We used summary tumors data from the FinnGen and cis protein quantitative trait loci (cis-pQTL) data from a genome-wide association study, and employed Mendelian randomization (MR) to explore the association between potential drug targets and nine tumors, including breast, colorectal, lung, liver, bladder, prostate, kidney, head and neck, pancreatic caners. Furthermore, we conducted MR analysis on external cohort. Moreover, Bidirectional MR, Steiger filtering, and colocalization were employed to validate the main results. The DrugBank database was used to discover potential drugs of tumors. Under the threshold of False discovery rate (FDR) < 0.05, results showed that S100A16 was protective protein and S100A14 was risk protein for human epidermal growth factor receptor 2-positive (HER-positive) breast cancer, phosphodiesterase 5A (PDE5A) was risk protein for colorectal cancer, and melanoma inhibitory activity (MIA) was protective protein for non-small cell lung carcinoma (NSCLC). And there was no reverse causal association between them. Colocalization analysis showed that S100A14 (PP.H4.abf = 0.920) and S100A16 (PP.H4.abf = 0.932) shared causal variation with HER-positive breast cancer, and PDE5A (PP.H4.abf = 0.857) shared causal variation with colorectal cancer (CRC). The MR results of all pQTL of PDE5A and MIA were consistent with main results. In addition, the MR results of MIA and external outcome cohort were consistent with main results. In this study, genetic predictions indicate that circulating S100 calcium binding protein A14 (S100A14) and S100 calcium binding protein A16 (S100A16) are associated with increase and decrease in the risk of HER-positive breast cancer, respectively. Circulating PDE5A is associated with increased risk of CRC, while circulating MIA is associated with decreased risk of NSCLC. These findings suggest that four proteins may serve as biomarkers for cancer prevention and as potential drug targets that could be expected for approval.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Potential drug targets for tumors identified through Mendelian randomization analysis

Song,

Shi,

Cui

et al. 2024

Sci Rep

View full text Add to dashboard Cite

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“…We employed a bidirectional two-sample MR approach to explore the mutual causal relationship between AP and sepsis, focusing on the mediating role of immune cells. The AP dataset, publicly available and primarily of European ancestry, included genetic associations for 10,630 cases and 844,679 controls ( 15 ). Similarly, the sepsis dataset, also publicly accessible and predominantly of European ancestry, comprised 1,573 cases and 454,775 controls ( 16 ).…”

Section: Methodsmentioning

confidence: 99%

Unraveling the immunological landscape in acute pancreatitis progression to sepsis: insights from a Mendelian randomization study on immune cell traits

Liu,

Wang,

Zhao

et al. 2024

Front. Immunol.

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BackgroundAcute pancreatitis (AP) is a severe digestive system disorder with a significant risk of progressing to sepsis, a major cause of mortality. Unraveling the immunological pathways in AP is essential for developing effective treatments, particularly understanding the role of specific immune cell traits in this progression.MethodsEmploying a bidirectional two-sample Mendelian Randomization (MR) approach, this study first examined the causal relationship between AP and 731 immune cell traits to identify those significantly associated with AP. Subsequently, we explored the causal associations between 731 immune cell traits and sepsis. The analysis utilized extensive genome-wide association studies (GWAS) summary datasets, with a focus on identifying common immune cell traits with statistically significant causal associations between AP and sepsis.ResultsOur investigation identified 44 immune cell traits unidirectionally associated with AP and 36 traits unidirectionally associated with sepsis. Among these, CD127 on CD28+ CD45RA- CD8+ T cells emerged as a common mediator, accounting for 5.296% of the increased risk of sepsis in AP patients. This finding highlights the significant role of specific memory CD8+ T cells in the pathophysiology of AP and its progression to sepsis.ConclusionThis study elucidates the critical role of specific immune cell traits, particularly CD127hi memory CD8+ T cells, in the progression of AP to sepsis. Our findings provide a foundation for future research into targeted immune-modulatory therapies, potentially improving patient outcomes in AP-related sepsis and offering new insights into the complex immunological dynamics of this condition.

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“…In this study, we utilized publicly available summary statistics for both either IgG N-glycosylation and pancreatitis, without involving any original data collection. The consortia that provided these statistics had previously obtained ethical approval and informed consent from all participants, as documented in their respective publications ( 30 , 31 ).…”

Section: Methodsmentioning

confidence: 99%

Genetic insights into across pancreatitis types: the causal influence of immunoglobulin G N-glycosylation variants on disease risk

Chen,

Li,

et al. 2024

Front. Immunol.

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BackgroundWhile a few case-control studies indicated a possible correlation of IgG N-glycosylation patterns with pancreatitis, their restricted sample sizes and methodologies prevented conclusive insights into causality or distinguishing traits across pancreatitis types.MethodWe conducted a two-sample Mendelian Randomization (MR) analysis to investigate the causal relationship between 77 IgG N-glycosylation traits and various types of pancreatitis, including acute pancreatitis (AP), chronic pancreatitis (CP), alcohol acute pancreatitis (AAP), and alcohol chronic pancreatitis (ACP). This analysis utilized summary-level data from genome-wide association studies (GWAS), employing methods such as IVW, MR-Egger, and weighted median. To ensure the robustness of our findings, several sensitivity analyses, including Cochran’s Q statistic, leave-one-out, MR-Egger intercept, and MR-PRESSO global test were conducted.ResultOur study uncovered the causal relationship between specific IgG N-glycosylation traits and various types of pancreatitis. Notably, an increase in genetically predicted IGP7 levels was associated with a decreased risk of developing AP. For CP, our data suggested a protective effect associated with higher levels of both IGP7 and IGP31, contrasting with increased levels of IGP27 and IGP65, which were linked to a heightened risk. Moreover, in the case of AAP, elevated IGP31 levels were causatively associated with a lower incidence, while higher IGP26 levels correlated with an increased risk for ACP.ConclusionThis study establishes causal relationship between specific IgG N-glycosylation patterns and varying risks of different pancreatitis forms, underscoring their potential as predictive biomarkers. These findings necessitate further exploration into the underlying mechanisms, promising to inform more personalized diagnostic and therapeutic strategies in pancreatitis management.

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Proteome-Wide Mendelian Randomization Identifies Causal Links Between Blood Proteins and Acute Pancreatitis

Cited by 33 publications

References 53 publications

Potential drug targets for tumors identified through Mendelian randomization analysis

Potential drug targets for tumors identified through Mendelian randomization analysis

Unraveling the immunological landscape in acute pancreatitis progression to sepsis: insights from a Mendelian randomization study on immune cell traits

Genetic insights into across pancreatitis types: the causal influence of immunoglobulin G N-glycosylation variants on disease risk

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