Identification of novel susceptibility genes in childhood-onset systemic lupus erythematosus using a uniquely designed candidate gene pathway platform.
OBJECTIVE
Childhood-onset systemic lupus erythematosus (SLE) presents a unique subgroup of patients for genetic study. The present study was undertaken to identify susceptibility genes contributing to SLE, using a novel candidate gene pathway microarray platform to investigate gene expression in patients with childhood-onset SLE and both of their parents.


METHODS
Utilizing bioinformatic tools, a platform of 9,412 single-nucleotide polymorphisms (SNPs) from 1,204 genes was designed and validated. Molecular inversion probes and high-throughput SNP technologies were used for assay development. Seven hundred fifty three subjects, corresponding to 251 full trios of childhood-onset SLE families, were genotyped and analyzed using transmission disequilibrium testing (TDT) and multitest corrections.


RESULTS
Family-based TDT showed a significant association of SLE with a N673S polymorphism in the P-selectin gene (SELP) (P = 5.74 x 10(-6)) and a C203S polymorphism in the interleukin-1 receptor-associated kinase 1 gene (IRAK1) (P = 9.58 x 10(-6)). These 2 SNPs had a false discovery rate for multitest correction of <0.05, and therefore a >95% probability of being considered as proven. Furthermore, 7 additional SNPs showed q values of <0.5, suggesting association with SLE and providing a direction for followup studies. These additional genes notably included TNFRSF6 (Fas) and IRF5, supporting previous findings of their association with SLE pathogenesis.


CONCLUSIONS
SELP and IRAK1 were identified as novel SLE-associated genes with a high degree of significance, suggesting new directions in understanding the pathogenesis of SLE. The overall design and results of this study demonstrate that the candidate gene pathway microarray platform used provides a novel and powerful approach that is generally applicable in identifying genetic foundations of complex diseases.
Department of Medicine, University of Southern California School of Medicine, 2011 Zonal Avenue, Los Angeles, CA 90033, USA. Jacob@usc.edu
Chaim O
CO
Jacob
Andreas
A
Reiff
Don L
DL
Armstrong
Barry L
BL
Myones
Earl
E
Silverman
Marisa
M
Klein-Gitelman
Deborah
D
McCurdy
Linda
L
Wagner-Weiner
James J
JJ
Nocton
Aaron
A
Solomon
Raphael
R
Zidovetzki
D001499:Bayes Theorem; D019295:Computational Biology / Q000379:methods; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics*; D015810:Linkage Disequilibrium / Q000235:genetics; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008297:Male; D046208:Microchip Analytical Procedures; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D051149:Selenoprotein P / Q000235:genetics*
D051149:Selenoprotein P; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases