Identification of novel susceptibility genes in childhood‐onset systemic lupus erythematosus using a uniquely designed candidate gene pathway platform

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 ؋ 10 ؊6 ) and a C203S polymorphism in the interleukin-1 receptor-associated kinase 1 gene (IRAK1) (P ‫؍‬ 9.58 ؋ 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.

Identification ofIRAK1as a risk gene with critical role in the pathogenesis of systemic lupus erythematosus

“…1. The classical Bonferroni correction and similar procedures for controlling the family-wise error rate for multiple testing are both too strict and inappropriate in studies such as the present one because they assume that each test is independent, whereas in actuality a complex and unknown mutual dependence exists among SNPs on the same gene (3,7). Therefore, for multiple test correction we calculated estimates of the false discovery rate (FDR) q values by using the BenjaminiHochberg procedure (8) considering the total number of SNPs tested and the 4 different ethnic groups (Table 1).…”

“…We have previously used this bioinformatics-driven design for a custom-made platform incorporating Ϸ10,000 SNPs derived from Ϸ1,000 selected genes to genotype a sample of 753 subjects composed of 251 childhood-onset SLE trios (SLE patient and both parents) (3). Family-based transmission disequilibrium test (TDT) and multitest correction analyses showed a significant association between the IRAK1 gene on chromosome Xq28 and childhoodonset SLE (3).…”

Transition of Care and Health‐Related Outcomes in Pediatric‐Onset Systemic Lupus Erythematosus

“…Patients diagnosed with pediatric-onset SLE and treated at Children's Hospital Los Angeles between 1992 and 2007 who had since been discharged from pediatric care were identified as eligible for inclusion if they had been part of a previously studied cohort (26) and had consented to be contacted for future research. All patients fulfilled at least 4 of the American College of Rheumatology criteria for SLE at diagnosis (27).…”

Variation in the upstream region of P-Selectin (SELP) is a risk factor for SLE

“…Although our study is the first to report an association for P-Selectin arising from the upstream region of the gene, there has been one earlier report of an association in SELP with lupus from an SNP in the coding region. 31 The variant in question, is SNP 38 (rs3917815) a Ser/Asn non-synonymous polymorphism located in E12. We genotyped SNP 38 as part of our current study, but the variant proved to be monomorphic, and therefore was excluded from our analyses.…”