Rare Modifier Variants Alter the Severity of Cardiovascular Disease in Pseudoxanthoma Elasticum: Identification of Novel Candidate Modifier Genes and Disease Pathways Through Mixture of Effects Analysis
Introduction: Pseudoxanthoma elasticum (PXE), an ectopic mineralization disorder caused by pathogenic ABCC6 variants, is characterized by skin, ocular and cardiovascular (CV) symptoms. Due to striking phenotypic variability without genotype-phenotype correlations, modifier genes are thought to play...
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Frontiers Media S.A.
2021-06-01
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doaj-0a7d47e021de4c4bbb2ae7637c12ffa92021-06-08T14:24:18ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-06-01910.3389/fcell.2021.612581612581Rare Modifier Variants Alter the Severity of Cardiovascular Disease in Pseudoxanthoma Elasticum: Identification of Novel Candidate Modifier Genes and Disease Pathways Through Mixture of Effects AnalysisEva Y. G. De Vilder0Eva Y. G. De Vilder1Eva Y. G. De Vilder2Ludovic Martin3Georges Lefthériotis4Paul Coucke5Paul Coucke6Filip Van Nieuwerburgh7Olivier M. Vanakker8Olivier M. Vanakker9Center for Medical Genetics, Ghent University Hospital, Ghent, BelgiumThe Research Foundation – Flanders, Ghent, BelgiumDepartment of Ophthalmology, Ghent University Hospital, Ghent, BelgiumDepartment of Dermatology, Angers University Hospital, Angers, FranceDepartment of Vascular Physiology and Sports Medicine, Angers University, Angers, FranceCenter for Medical Genetics, Ghent University Hospital, Ghent, BelgiumDepartment of Biomolecular Medicine, Ghent University, Ghent, BelgiumDepartment of Pharmaceutics, Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, BelgiumCenter for Medical Genetics, Ghent University Hospital, Ghent, BelgiumDepartment of Biomolecular Medicine, Ghent University, Ghent, BelgiumIntroduction: Pseudoxanthoma elasticum (PXE), an ectopic mineralization disorder caused by pathogenic ABCC6 variants, is characterized by skin, ocular and cardiovascular (CV) symptoms. Due to striking phenotypic variability without genotype-phenotype correlations, modifier genes are thought to play a role in disease variability. In this study, we evaluated the collective modifying effect of rare variants on the cardiovascular phenotype of PXE.Materials and Methods: Mixed effects of rare variants were assessed by Whole Exome Sequencing in 11 PXE patients with an extreme CV phenotype (mild/severe). Statistical analysis (SKAT-O and C-alpha testing) was performed to identify new modifier genes for the CV PXE phenotype and enrichment analysis for genes significantly associated with the severe cohort was used to evaluate pathway and gene ontology features.Results Respectively 16 (SKAT-O) and 74 (C-alpha) genes were significantly associated to the severe cohort. Top significant genes could be stratified in 3 groups–calcium homeostasis, association with vascular disease and induction of apoptosis. Comparative analysis of both analyses led to prioritization of four genes (NLRP1, SELE, TRPV1, and CSF1R), all signaling through IL-1B.Conclusion This study explored for the first time the cumulative effect of rare variants on the severity of cardiovascular disease in PXE, leading to a panel of novel candidate modifier genes and disease pathways. Though further validation is essential, this panel may aid in risk stratification and genetic counseling of PXE patients and will help to gain new insights in the PXE pathophysiology.https://www.frontiersin.org/articles/10.3389/fcell.2021.612581/fullpseudoxanthoma elasticumABCC6candidate modifier genecardiovascular diseasemixture of effects analysisC-alpha test |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Eva Y. G. De Vilder Eva Y. G. De Vilder Eva Y. G. De Vilder Ludovic Martin Georges Lefthériotis Paul Coucke Paul Coucke Filip Van Nieuwerburgh Olivier M. Vanakker Olivier M. Vanakker |
| spellingShingle |
Eva Y. G. De Vilder Eva Y. G. De Vilder Eva Y. G. De Vilder Ludovic Martin Georges Lefthériotis Paul Coucke Paul Coucke Filip Van Nieuwerburgh Olivier M. Vanakker Olivier M. Vanakker Rare Modifier Variants Alter the Severity of Cardiovascular Disease in Pseudoxanthoma Elasticum: Identification of Novel Candidate Modifier Genes and Disease Pathways Through Mixture of Effects Analysis Frontiers in Cell and Developmental Biology pseudoxanthoma elasticum ABCC6 candidate modifier gene cardiovascular disease mixture of effects analysis C-alpha test |
| author_facet |
Eva Y. G. De Vilder Eva Y. G. De Vilder Eva Y. G. De Vilder Ludovic Martin Georges Lefthériotis Paul Coucke Paul Coucke Filip Van Nieuwerburgh Olivier M. Vanakker Olivier M. Vanakker |
| author_sort |
Eva Y. G. De Vilder |
| title |
Rare Modifier Variants Alter the Severity of Cardiovascular Disease in Pseudoxanthoma Elasticum: Identification of Novel Candidate Modifier Genes and Disease Pathways Through Mixture of Effects Analysis |
| title_short |
Rare Modifier Variants Alter the Severity of Cardiovascular Disease in Pseudoxanthoma Elasticum: Identification of Novel Candidate Modifier Genes and Disease Pathways Through Mixture of Effects Analysis |
| title_full |
Rare Modifier Variants Alter the Severity of Cardiovascular Disease in Pseudoxanthoma Elasticum: Identification of Novel Candidate Modifier Genes and Disease Pathways Through Mixture of Effects Analysis |
| title_fullStr |
Rare Modifier Variants Alter the Severity of Cardiovascular Disease in Pseudoxanthoma Elasticum: Identification of Novel Candidate Modifier Genes and Disease Pathways Through Mixture of Effects Analysis |
| title_full_unstemmed |
Rare Modifier Variants Alter the Severity of Cardiovascular Disease in Pseudoxanthoma Elasticum: Identification of Novel Candidate Modifier Genes and Disease Pathways Through Mixture of Effects Analysis |
| title_sort |
rare modifier variants alter the severity of cardiovascular disease in pseudoxanthoma elasticum: identification of novel candidate modifier genes and disease pathways through mixture of effects analysis |
| publisher |
Frontiers Media S.A. |
| series |
Frontiers in Cell and Developmental Biology |
| issn |
2296-634X |
| publishDate |
2021-06-01 |
| description |
Introduction: Pseudoxanthoma elasticum (PXE), an ectopic mineralization disorder caused by pathogenic ABCC6 variants, is characterized by skin, ocular and cardiovascular (CV) symptoms. Due to striking phenotypic variability without genotype-phenotype correlations, modifier genes are thought to play a role in disease variability. In this study, we evaluated the collective modifying effect of rare variants on the cardiovascular phenotype of PXE.Materials and Methods: Mixed effects of rare variants were assessed by Whole Exome Sequencing in 11 PXE patients with an extreme CV phenotype (mild/severe). Statistical analysis (SKAT-O and C-alpha testing) was performed to identify new modifier genes for the CV PXE phenotype and enrichment analysis for genes significantly associated with the severe cohort was used to evaluate pathway and gene ontology features.Results Respectively 16 (SKAT-O) and 74 (C-alpha) genes were significantly associated to the severe cohort. Top significant genes could be stratified in 3 groups–calcium homeostasis, association with vascular disease and induction of apoptosis. Comparative analysis of both analyses led to prioritization of four genes (NLRP1, SELE, TRPV1, and CSF1R), all signaling through IL-1B.Conclusion This study explored for the first time the cumulative effect of rare variants on the severity of cardiovascular disease in PXE, leading to a panel of novel candidate modifier genes and disease pathways. Though further validation is essential, this panel may aid in risk stratification and genetic counseling of PXE patients and will help to gain new insights in the PXE pathophysiology. |
| topic |
pseudoxanthoma elasticum ABCC6 candidate modifier gene cardiovascular disease mixture of effects analysis C-alpha test |
| url |
https://www.frontiersin.org/articles/10.3389/fcell.2021.612581/full |
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