Identification of novel genetic risk loci in Maltese dogs with necrotizing meningoencephalitis and evidence of a shared genetic risk across toy dog breeds.

Isabelle Schrauwen,Matthew J Huentelman,Christopher L Mariani,Rebekah I Keesler,Thomas Flegel,Ashley L Siniard,Renee M Barber,Gayle C Johnson,Karen M Vernau,Brian F Porter,Teresa Southard,Kaspar Matiasek,Andrew D Miller,Jason J Corneveaux,Scott J Schatzberg

doi:10.1371/journal.pone.0112755

Abstract

Necrotizing meningoencephalitis (NME) affects toy and small breed dogs causing progressive, often fatal, inflammation and necrosis in the brain. Genetic risk loci for NME previously were identified in pug dogs, particularly associated with the dog leukocyte antigen (DLA) class II complex on chromosome 12, but have not been investigated in other susceptible breeds. We sought to evaluate Maltese and Chihuahua dogs, in addition to pug dogs, to identify novel or shared genetic risk factors for NME development. Genome-wide association testing of single nucleotide polymorphisms (SNPs) in Maltese dogs with NME identified 2 regions of genome-wide significance on chromosomes 4 (chr4:74522353T>A, p = 8.1×10−7) and 15 (chr15:53338796A>G, p = 1.5×10−7). Haplotype analysis and fine-mapping suggests that ILR7 and FBXW7, respectively, both important for regulation of immune system function, could be the underlying associated genes. Further evaluation of these regions and the previously identified DLA II locus across all three breeds, revealed an enrichment of nominal significant SNPs associated with chromosome 15 in pug dogs and DLA II in Maltese and Chihuahua dogs. Meta-analysis confirmed effect sizes the same direction in all three breeds for both the chromosome 15 and DLA II loci (p = 8.6×10–11 and p = 2.5×10−7, respectively). This suggests a shared genetic background exists between all breeds and confers susceptibility to NME, but effect sizes might be different among breeds. In conclusion, we identified the first genetic risk factors for NME development in the Maltese, chromosome 4 and chromosome 15, and provide evidence for a shared genetic risk between breeds associated with chromosome 15 and DLA II. Last, DLA II and IL7R both have been implicated in human inflammatory diseases of the central nervous system such as multiple sclerosis, suggesting that similar pharmacotherapeutic targets across species should be investigated.

Highlights

Necrotizing meningoencephalitis (NME) is a disease of young to middle aged dogs that results in a unique pattern of mononuclear inflammation and necrosis in the brain [1]
The second region on chromosome 15 spreads about 1.9 Mb between chr15:51,567,064-53,471,253 and using tBLASTn, 19 human proteins mapped to this region of the canine genome (Table S1 in file S1, Figure 2). All genes in these regions were prioritized based on ENDEAVOUR gene prioritization with a training set of human multiple sclerosis genes [20], which resulted in prioritization of IL7R on chromosome 4 and FBXW7 on chromosome 15 (Table S1 in file S1, Figure 2)
Genome wide association in Maltese dogs identified risk loci associated with NME on chromosome 4 and chromosome 15, both of which contain genes of interest that are critical for normal immune system function

Summary

Introduction

Necrotizing meningoencephalitis (NME) is a disease of young to middle aged dogs that results in a unique pattern of mononuclear inflammation and necrosis in the brain [1]. An infectious etiology was suspected [1] but thorough molecular investigations have ruled out infectious causes [8,9,10] and NME now is accepted to be an immune-mediated disease that occurs as a result of genetic susceptibility [11]; to date, no environmental triggers have been identified to contribute to disease onset [12]. Studies focused on elucidating the etiopathogenesis of NME are necessary to help improve diagnosis and treatment of this devastating disease

Methods

Results

Conclusion