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Identification of novel susceptibility genes in childhood-onset systemic lupus erythematosus using a uniquely designed candidate gene pathway platform. Arthritis Rheum 2007 Dec;56(12):4164-73

Date

12/01/2007

Pubmed ID

18050247

DOI

10.1002/art.23060

Scopus ID

2-s2.0-37149034017   68 Citations

Abstract

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.

CONCLUSION: 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.

Author List

Jacob CO, Reiff A, Armstrong DL, Myones BL, Silverman E, Klein-Gitelman M, McCurdy D, Wagner-Weiner L, Nocton JJ, Solomon A, Zidovetzki R

Author

James J. Nocton MD Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Bayes Theorem
Computational Biology
Female
Genetic Predisposition to Disease
Genotype
Humans
Interleukin-1 Receptor-Associated Kinases
Linkage Disequilibrium
Lupus Erythematosus, Systemic
Male
Microchip Analytical Procedures
Oligonucleotide Array Sequence Analysis
Polymorphism, Single Nucleotide
Selenoprotein P