A hypothesis for using pathway genetic load analysis for understanding complex outcomes in bilirubin encephalopathy
Genetic-based susceptibility to bilirubin neurotoxicity and chronic bilirubin encephalopathy (kernicterus) is still poorly understood. Neonatal jaundice affects 60-80% of newborns, and considerable effort goes into preventing this relatively benign condition from escalating into the development of k...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2016-08-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fnins.2016.00376/full |
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| author | Sean M. Riordan Sean M. Riordan Douglas C. Bittel Jean-Baptiste LePichon Jean-Baptiste LePichon Jean-Baptiste LePichon Jean-Baptiste LePichon Silvia Gazzin Claudio Tiribelli Jon F Watchko Richard P. Wennberg Steven M. Shapiro Steven M. Shapiro Steven M. Shapiro Steven M. Shapiro |
| author_facet | Sean M. Riordan Sean M. Riordan Douglas C. Bittel Jean-Baptiste LePichon Jean-Baptiste LePichon Jean-Baptiste LePichon Jean-Baptiste LePichon Silvia Gazzin Claudio Tiribelli Jon F Watchko Richard P. Wennberg Steven M. Shapiro Steven M. Shapiro Steven M. Shapiro Steven M. Shapiro |
| author_sort | Sean M. Riordan |
| collection | DOAJ |
| description | Genetic-based susceptibility to bilirubin neurotoxicity and chronic bilirubin encephalopathy (kernicterus) is still poorly understood. Neonatal jaundice affects 60-80% of newborns, and considerable effort goes into preventing this relatively benign condition from escalating into the development of kernicterus making the incidence of this potentially devastating condition very rare in more developed countries. The current understanding of the genetic background of kernicterus is largely comprised of mutations related to alterations of bilirubin production, elimination, or both. Less is known about mutations that may predispose or protect against CNS bilirubin neurotoxicity. The lack of a monogenetic source for this risk of bilirubin neurotoxicity suggests that disease progression is dependent upon an overall decrease in the functionality of one or more essential genetically controlled metabolic pathways. In other words, a load is placed on key pathways in the form of multiple genetic variants that combine to create a vulnerable phenotype. The idea of epistatic interactions creating a pathway genetic load that affects the response to a specific insult has been previously reported as a pathway genetic load (PGL) score. We hypothesize that the PGL score can be used to investigate whether increased susceptibility to bilirubin-induced CNS damage in neonates is due to a mutational load being placed on key genetic pathways important to the central nervous system’s response to bilirubin neurotoxicity. We propose a modification of the PGL score method that replaces the use of a canonical pathway with custom gene lists organized into three tiers with descending levels of evidence combined with the utilization of single nucleotide polymorphism (SNP) causality prediction methods. The PGL score has the potential to explain the genetic background of complex bilirubin-induced neurological disorders (BIND) such as kernicterus and could be the key to understanding ranges of outcome severity in complex diseases. We anticipate that this method could be useful for improving the care of jaundiced newborns through its use as an at-risk screen. Importantly, this method would also be useful in uncovering basic knowledge about this and other polygenetic diseases whose genetic source is difficult to discern through traditional means such as a genome-wide association study. |
| first_indexed | 2024-12-12T21:36:14Z |
| format | Article |
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| language | English |
| last_indexed | 2024-12-12T21:36:14Z |
| publishDate | 2016-08-01 |
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| spelling | doaj.art-fa6cc01a58e74f8dada576288150868f2022-12-22T00:11:11ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2016-08-011010.3389/fnins.2016.00376213454A hypothesis for using pathway genetic load analysis for understanding complex outcomes in bilirubin encephalopathySean M. Riordan0Sean M. Riordan1Douglas C. Bittel2Jean-Baptiste LePichon3Jean-Baptiste LePichon4Jean-Baptiste LePichon5Jean-Baptiste LePichon6Silvia Gazzin7Claudio Tiribelli8Jon F Watchko9Richard P. Wennberg10Steven M. Shapiro11Steven M. Shapiro12Steven M. Shapiro13Steven M. Shapiro14Children's Mercy HospitalUniversity of Kansas Medical CenterChildren's Mercy HospitalChildren's Mercy HospitalUniversity of Kansas Medical CenterUniversity of Kansas Medical CenterUniversity of Missouri-Kansas City School of MedicineItalian Liver FoundationUniversity of TriesteUniversity of Pittsburgh School of MedicineUniversity of WashingtonChildren's Mercy HospitalUniversity of Kansas Medical CenterUniversity of Kansas Medical CenterUniversity of Missouri-Kansas City School of MedicineGenetic-based susceptibility to bilirubin neurotoxicity and chronic bilirubin encephalopathy (kernicterus) is still poorly understood. Neonatal jaundice affects 60-80% of newborns, and considerable effort goes into preventing this relatively benign condition from escalating into the development of kernicterus making the incidence of this potentially devastating condition very rare in more developed countries. The current understanding of the genetic background of kernicterus is largely comprised of mutations related to alterations of bilirubin production, elimination, or both. Less is known about mutations that may predispose or protect against CNS bilirubin neurotoxicity. The lack of a monogenetic source for this risk of bilirubin neurotoxicity suggests that disease progression is dependent upon an overall decrease in the functionality of one or more essential genetically controlled metabolic pathways. In other words, a load is placed on key pathways in the form of multiple genetic variants that combine to create a vulnerable phenotype. The idea of epistatic interactions creating a pathway genetic load that affects the response to a specific insult has been previously reported as a pathway genetic load (PGL) score. We hypothesize that the PGL score can be used to investigate whether increased susceptibility to bilirubin-induced CNS damage in neonates is due to a mutational load being placed on key genetic pathways important to the central nervous system’s response to bilirubin neurotoxicity. We propose a modification of the PGL score method that replaces the use of a canonical pathway with custom gene lists organized into three tiers with descending levels of evidence combined with the utilization of single nucleotide polymorphism (SNP) causality prediction methods. The PGL score has the potential to explain the genetic background of complex bilirubin-induced neurological disorders (BIND) such as kernicterus and could be the key to understanding ranges of outcome severity in complex diseases. We anticipate that this method could be useful for improving the care of jaundiced newborns through its use as an at-risk screen. Importantly, this method would also be useful in uncovering basic knowledge about this and other polygenetic diseases whose genetic source is difficult to discern through traditional means such as a genome-wide association study.http://journal.frontiersin.org/Journal/10.3389/fnins.2016.00376/fullBilirubinKernicterusGWASBilirubin encephalopathypathway genetic load score |
| spellingShingle | Sean M. Riordan Sean M. Riordan Douglas C. Bittel Jean-Baptiste LePichon Jean-Baptiste LePichon Jean-Baptiste LePichon Jean-Baptiste LePichon Silvia Gazzin Claudio Tiribelli Jon F Watchko Richard P. Wennberg Steven M. Shapiro Steven M. Shapiro Steven M. Shapiro Steven M. Shapiro A hypothesis for using pathway genetic load analysis for understanding complex outcomes in bilirubin encephalopathy Frontiers in Neuroscience Bilirubin Kernicterus GWAS Bilirubin encephalopathy pathway genetic load score |
| title | A hypothesis for using pathway genetic load analysis for understanding complex outcomes in bilirubin encephalopathy |
| title_full | A hypothesis for using pathway genetic load analysis for understanding complex outcomes in bilirubin encephalopathy |
| title_fullStr | A hypothesis for using pathway genetic load analysis for understanding complex outcomes in bilirubin encephalopathy |
| title_full_unstemmed | A hypothesis for using pathway genetic load analysis for understanding complex outcomes in bilirubin encephalopathy |
| title_short | A hypothesis for using pathway genetic load analysis for understanding complex outcomes in bilirubin encephalopathy |
| title_sort | hypothesis for using pathway genetic load analysis for understanding complex outcomes in bilirubin encephalopathy |
| topic | Bilirubin Kernicterus GWAS Bilirubin encephalopathy pathway genetic load score |
| url | http://journal.frontiersin.org/Journal/10.3389/fnins.2016.00376/full |
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