Case-only analysis of gene–gene interactions in inflammatory bowel disease

Aleknonytė‐Resch, Milda; Freitag‐Wolf, Sandra; Schreiber, Stefan; Krawczak, Michael; Dempfle, Astrid

doi:10.1080/00365521.2020.1790646

Cited by 4 publications

(3 citation statements)

References 32 publications

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“…Chu et al described that ATG16L1/NOD2 and microbiome cooperate to promote beneficial immune responses ( 41 ). Aleknonytė-Resch et al revealed a significant interaction between rs26528 in the IL27 gene and rs9297145 in the KPNA7 gene ( 42 ). At the gene level, we showed that the expression network status of susceptibility genes contributes to CD.…”

Section: Discussionmentioning

confidence: 99%

A broken network of susceptibility genes in the monocytes of Crohn’s disease patients

Liu,

Guan,

et al. 2024

Life Sci. Alliance

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Genome-wide association studies have identified over 200 genetic loci associated with inflammatory bowel disease; however, the mechanism of such a large amount of susceptibility genes remains uncertain. In this study, we integrated bioinformatics analysis and two independent single-cell transcriptome datasets to investigate the expression network of 232 susceptibility genes in Crohn’s disease (CD) patients and healthy controls. The study revealed that most of the susceptibility genes are specifically and strictly expressed in the monocytes of the human intestinal tract. The susceptibility genes established a network within the monocytes of health control. The robustness of a gene network may prevent disease onset that is influenced by the genetic and environmental alteration in the expression of susceptibility genes. In contrast, we showed a sparse network in pediatric/adult CD patients, suggesting the broken network contributed to the CD etiology. The network status of susceptibility genes at the single-cell level of monocytes provided novel insight into the etiology.

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Section: Discussionmentioning

confidence: 99%

A broken network of susceptibility genes in the monocytes of Crohn’s disease patients

Liu,

Guan,

et al. 2024

Life Sci. Alliance

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“…We used the case‐only design to analyse G×G interactions. This study design provides a considerable gain in power over classical case–control analyses and has been applied to identify G×G and G–environment interactions (Piegorsch et al, 1994; Freitag‐Wolf et al, 2019, 2021; Aleknonyte‐Resch et al, 2020). We calculated the statistical power to detect G × G with the case‐only design post hoc using Quanto software (Gauderman, 2002).…”

Section: Methodsmentioning

confidence: 99%

Case‐only design identifies interactions of genetic risk variants at SIGLEC5 and PLG with the lncRNA CTD‐2353F22.1 implying the importance of periodontal wound healing for disease aetiology

Müller

Freitag‐Wolf

Weiner

et al. 2022

J Clinic Periodontology

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Aim: The basis of phenotypic variation of periodontitis is genetic variability. Disease relevant effects of individual risk alleles are considered to result from genetic interactions. We investigated gene Â gene (GÂG) interactions of suggestive periodontitis susceptibility alleles.Materials and Methods: We used the case-only design and investigated singlenucleotide polymorphism (SNPs) that showed associations in our recent genomewide association study (GWAS) and GWAS meta-analysis with p < 5 Â 10 À6 . CRISPR-dCas9 gene activation followed by RNA-sequencing and gene-set enrichment analyses elucidated differentially expressed genes and gene networks. With the databases of SNPInspector and Transfac professional, luciferase reporter gene assays and antibody electrophoretic mobility shift experiments, we analysed allele-specific effects on transcription factor binding.Results: SNPs at the genes sialic acid binding Ig-like lectin 5 (SIGLEC5) and plasminogen (PLG) showed GÂG interactions with rs1122900 at the long non-coding RNA (lncRNA) CTD-2353F22. Associated chromatin cis-activated CTD-2353F22.1 6.5-fold (p = .003), indicating CTD-2353F22.1 as target gene of this interaction. CTD-2353F22.1 regulated GADD45A (p adj < 4.9 Â 10 À11 , log 2 fold change (FC) = À0.55), THBS1, SERPINE1 and Tissue Factor F3 (p adj < 5 Â 10 À7 , log 2 FC ≥ À0.35) and the gene set "angiogenesis" (area under the curve = 0.71, p adj = 8.2 Â 10 À5 ). rs1122900 effect C-allele decreased reporter gene activity (5.5-fold, p = .0003) and PRDM14 binding (76%).Ricarda Müller and Sandra Freitag-Wolf contributed equally.

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“…In a review about the application of the CO design, it has been shown to be very valuable for real data analyses (6) and important insights have already been gained, for instance, into the interplay between e.g. smoking or sex and genes as well as gene-gene (G×G) interactions (7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Validity and Power of the Case-Only Approach in Prospective Cohort and Case-Cohort Studies with Time-to-Event Endpoints

Freitag-Wolf,

Akinloye,

Dempfle

2024

Preprint

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For genetic epidemiological studies with binary outcomes, the case-only (CO) approach has been shown to be powerful for examining statistical interactions, in particular gene-environment interactions. For time-to-event outcomes, the CO approach has been extended in the context of randomized clinical trials (RCT), but has not yet been investigated in prospective observational data. We explore the CO approach for time-to-event outcomes in scenarios with main effects of different strength (small, moderate) and compare its results with classical Cox proportional hazard and logistic regression models. We use only the earliest observed events (as ‘cases’) in the CO approach and also consider censored events (as ‘controls’ in logistic regression) by a restricted follow-up scheme in a cohort design or a random subsample of these in a case-cohort design. In our simulation study, the CO approach was consistently valid in the cohort settings and had a similar power as the benchmark analyses. In contrast, in the case-cohort design, the CO approach was valid and more powerful only in the scenario with just one main effect. However, in the presence of two moderate main effects, estimators may be biased, with a moderately inflated type I error rate. In a real-world example of a cohort study, the CO design represents an efficient approach that can be applied at an early follow-up time. Under a variety of circumstances, the CO approach is as powerful as the standard models for time-to-event data in the cohort framework, but can be biased in the presence of two main effects in the case-cohort framework.

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Case-only analysis of gene–gene interactions in inflammatory bowel disease

Cited by 4 publications

References 32 publications

A broken network of susceptibility genes in the monocytes of Crohn’s disease patients

A broken network of susceptibility genes in the monocytes of Crohn’s disease patients

Case‐only design identifies interactions of genetic risk variants at SIGLEC5 and PLG with the lncRNA CTD‐2353F22.1 implying the importance of periodontal wound healing for disease aetiology

Validity and Power of the Case-Only Approach in Prospective Cohort and Case-Cohort Studies with Time-to-Event Endpoints

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