Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement
The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.
Genetic Interactions Reveal a Novel B-Cell Pathway in Systemic Lupus Erythematosus
Castillejo-Lopez1, Casimiro, Delgado-Vega1, Angelica M., Wojcik2, Jerome, Kozyrev1, Sergey, Egido1, Juan R. Lopez, Sanchez3, Elena, Pollmann1, David
Uppsala University, Uppsala, Sweden,
Merck Serono International, Geneva, Switzerland,
Instituto de Biomedicina y Parasitología López-Neyra, Granada, Spain,
Oklahoma Medical Research Foundation, Oklahoma City, OK,
Medical University of South Carolina, Charleston, SC,
Sanatorio Parque, Rosario, Argentina,
University of Eastern Piedmont, Novara, Italy,
Hannover Medical School, Hannover, Germany,
Hospital Clinico San Cecilio, Granada, Spain
Purpose:
Epistasis, or genetic interactions, might explain larger genetic effects than single-gene associations on the susceptibility to diseases, and help to define functional pathways with potential therapeutic targets. We aim to identify genes that modify the susceptibility to SLE through their interaction with the B-cell scaffold protein with ankyrin repeats gene (BANK1).
Method:
We searched for genetic interactions in an Affymetrix 100k genome-wide scan performed in 256 cases and 515 controls from Sweden. A subsequent replication study included two independent multi-center cohorts of European-Americans (n=676 cases and 850 controls) and Europeans (n=1265 SLE cases and 1506 controls). We developed a genotype interaction test based on contingency tables for all possible genotype combinations between pairs of SNPs with r2 <.80 and calculated a Pearson S score of interaction association and its C2P value. Each interacting combination was tested against the hypothesis of independence to derive an epistasis score (Se) and a P value (Pe) was obtained through permutation.
Results:
BANK1 showed genetic interactions with 29 genes, including the B-cell tyrosine kinase (BLK) and the inositol 1,4,5-triphosphate receptor 2 (ITPR2). One fifth of SLE patients (21%) vs. 8% of controls were homozygous for the risk alleles of polymorphisms in these three genes with a significant epistatic effect (Pe < 0.0002). The interactions BANK1xITPR2 and BANK1xBLK were replicated in two independent European-American (P= 2.1 × 10-6) and European sets (P= 4.11 × 10-9). The data was verified using multifactor dimensionality reduction (MDR) and logistic regression analysis. Moreover, BLK co-immunoprecipitated and co-localized with BANK1 in co-transfected HEK-293T. Exogenous expression of BANK1 in human Daudi B cells curbed BLK from reaching the plasma membrane with the subsequent accumulation in cytoplasmic compartments. Expression of BANK1 and BLK but not ITPR2 was modulated by IFNa
Conclusion:
BANK1, BLK and ITPR2 are genetically and functionally interacting partners and through their protein-protein interactions might results in a novel B-cell signaling pathway regulated by type I interferon a. This pathway may affect B-cell responses to self-antigens in human lupus.
To cite this abstract, please use the following information:
Castillejo-Lopez, Casimiro, Delgado-Vega, Angelica M., Wojcik, Jerome, Kozyrev, Sergey, Egido, Juan R. Lopez, Sanchez, Elena, et al; Genetic Interactions Reveal a Novel B-Cell Pathway in Systemic Lupus Erythematosus [abstract]. Arthritis Rheum 2009;60 Suppl 10 :1226
DOI: 10.1002/art.26300
