Epistatic interactions associated with Stevens-Johnson syndrome
1Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan. mueta@koto.kpu-m.ac.jp
Cornea
|October 6, 2012
Summary
Gene interactions increase the risk of Stevens-Johnson syndrome (SJS) with ocular complications. Researchers identified specific gene pairs, including toll-like receptor 3 and prostaglandin E receptor 3, as key factors in SJS/TEN susceptibility.
Area of Science:
- Pharmacogenomics
- Immunogenetics
- Ophthalmology
Background:
- Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse reactions.
- Susceptibility genes for SJS/TEN are not fully understood, limiting risk prediction.
- Human leukocyte antigen (HLA) alleles are known risk factors, but other genetic interactions are unexplored.
Purpose of the Study:
- Investigate gene-gene interactions for Stevens-Johnson syndrome (SJS) susceptibility.
- Identify specific genetic loci contributing to SJS/TEN risk, particularly with ocular complications.
- Explore functional interactions between candidate genes using a murine model.
Main Methods:
- Employed iterative sure independence screening for high-dimensional variable selection in Japanese SJS/TEN patients.
- Analyzed linkage disequilibria around toll-like receptor (TLR)3 and prostaglandin E receptor (PTGER)3 genes.
- Utilized a murine experimental allergic conjunctivitis (EAC) model to assess functional gene interactions.
Main Results:
- Identified two significant gene-pair interactions associated with SJS/TEN susceptibility: TLR3-PTGER3 and HLA-A-IL1α.
- Demonstrated functional interaction between TLR3 and EP3 (PTGER3 protein) in the EAC model.
- These findings suggest an epistatic interaction contributing to SJS risk with ocular involvement.
Conclusions:
- Gene-gene interactions, specifically TLR3-PTGER3, play a crucial role in SJS/TEN pathogenesis with ocular complications.
- The study highlights the importance of investigating epistatic interactions for understanding complex drug reactions.
- Functional validation in an animal model supports the identified genetic associations.
Related Concept Videos
01:29Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu
Genetic variations significantly influence drug response through pharmacokinetics, receptor interactions, and biologic milieu modifications. Pharmacokinetic alterations impact drug metabolism and clearance, affecting efficacy and toxicity. Variants in drug-metabolizing enzymes, such as CYP2C9 and CYP2C19, alter drug activation and elimination. For example, CYP2C9 loss-of-function variants require lower warfarin doses to prevent excessive bleeding, while CYP2C19 variants reduce clopidogrel...
01:33Pleiotropy
Pleiotropy is the phenomenon in which a single gene impacts multiple, seemingly unrelated phenotypic traits. For example, defects in the SOX10 gene cause Waardenburg Syndrome Type 4, or WS4, which can cause defects in pigmentation, hearing impairments, and an absence of intestinal contractions necessary for elimination. This diversity of phenotypes results from the expression pattern of SOX10 in early embryonic and fetal development. SOX10 is found in neural crest cells that form melanocytes,...
01:30Drug Toxicity: Allergic Reactions
Drug-related allergies are immune-mediated responses triggered by the administration of pharmacological agents. These hypersensitivity reactions are classified based on the immune mechanisms involved. The four primary types—Type I, II, III, and IV—are mediated by different immunological pathways and exhibit distinct clinical manifestations.Type I Hypersensitivity/ IgE-Mediated Reactions: Immunoglobulin E (IgE) immediately mediates Type I hypersensitivity reactions. Upon initial exposure to a...
01:09Epistasis Analysis
Although Mendel chose seven unrelated traits in peas to study gene segregation, most traits involve multiple gene interactions that create a spectrum of phenotypes. When the interaction of various genes or alleles at different locations influences a phenotype, this is called epistasis. Epistasis often involves one gene masking or interfering with the expression of another (antagonistic epistasis). Epistasis often occurs when different genes are part of the same biochemical pathway. The...
01:16Drug toxicity: Idiosyncratic Reactions
Idiosyncratic drug reactions represent abnormal chemical responses that vary significantly among individuals, ranging from extreme sensitivity to low doses to insensitivity to high doses. These reactions often occur due to the drug's covalent binding with serum proteins, forming a foreign hapten that triggers an immunotoxicological response. The variability in drug reactions has a strong pharmacogenetic foundation, with genetic differences crucial in how individuals metabolize drugs. For...
01:39Epistasis
In addition to multiple alleles at the same locus influencing traits, numerous genes or alleles at different locations may interact and influence phenotypes in a phenomenon called epistasis. For example, rabbit fur can be black or brown depending on whether the animal is homozygous dominant or heterozygous at a TYRP1 locus. However, if the rabbit is also homozygous recessive at a locus on the tyrosinase gene (TYR), it will have an unshaded coat that appears white, regardless of its TYRP1...