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Front Neurosci. 2016 Aug 18;10:376. doi: 10.3389/fnins.2016.00376. eCollection 2016.

A Hypothesis for Using Pathway Genetic Load Analysis for Understanding Complex Outcomes in Bilirubin Encephalopathy.

Author information

1
Division of Child Neurology, Department of Pediatrics, Children's Mercy HospitalKansas City, MO, USA; Department of Neurology, University of Kansas Medical CenterKansas City, KS, USA.
2
Ward Family Heart Center, Children's Mercy HospitalKansas City, MO, USA; Department of Pediatrics, University of Missouri-Kansas City School of MedicineKansas City, MO, USA.
3
Division of Child Neurology, Department of Pediatrics, Children's Mercy HospitalKansas City, MO, USA; Department of Neurology, University of Kansas Medical CenterKansas City, KS, USA; Department of Pediatrics, University of Missouri-Kansas City School of MedicineKansas City, MO, USA; Department of Pediatrics, University of Kansas Medical CenterKansas City, KS, USA.
4
Italian Liver Foundation, Centro Studi Fegato (CSF) Trieste, Italy.
5
Italian Liver Foundation, Centro Studi Fegato (CSF)Trieste, Italy; Department of Medical Sciences, University of TriesteTrieste, Italy.
6
Division of Newborn Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine Pittsburgh, PA, USA.
7
Department of Pediatrics, University of Washington Seattle, WA, USA.

Abstract

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 (PGL) that affects the response to a specific insult has been previously reported as a 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.

KEYWORDS:

GWAS; bilirubin; bilirubin encephalopathy; kernicterus; pathway genetic load score

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