Presentation: BAK1 Polymorphism Influences the Risk of Developing Autoimmune Rheumatic Diseases (2007)

842 BAK1 Polymorphism Influences the Risk of Developing Autoimmune Rheumatic Diseases

PURPOSE: Bak is a proapoptotic member of the Bcl-2 family encoded by BAK1 gene, at 6p21.3, ~380 kb centromeric to the class II HLA region. Previous studies have incriminated Bak in autoimmune diseases. Thus, we investigated the influence of BAK1 polymorphism on the risk of developing autoimmune rheumatic diseases (AIRD) in a well established population.
METHODS: This was an association study in which genomic DNA from patients with systemic lupus erythematosus (SLE, N=209), primary Sjogren’s syndrome (pSS, N=99), rheumatoid arthritis (RA, N=159), and ethnic-, gender-, age- and socioeconomic-matched controls (n=252) was genotyped for BAK1. Coding exons were analyzed by PCR-SSCP, and DNA samples showing abnormal mobility patterns were sequenced. From the linkage disequilibrium (LD) and haplotype structure of BAK1 in HapMap-CEU population, four tag single nucleotide polymorphisms (SNPs) were selected to capture the diversity of the 12 principal BAK1 SNPs with a mean r2=0.989 and MAF>0.05. Genotyping was done by real-time PCR. HLA typing was done by reverse dot-blot hybridization of the PCR products (Inno-LiPA assay). Haplotype frequencies were estimated by EM algorithm. Comparisons were done by likelihood ratio test and logistic regression analysis.
RESULTS: After quality assessment of genotype data, 3 SNPs were tested for association (rs513349, rs561276 and rs5745582). No deviations from Hardy Weinberg equilibrium were observed, and there was no population stratification (Fst=0.01). Strong association between all AIRD with both rs513349 and rs5745582 was observed and confirmed by the Armitage’s test. The odds to develop AIRD taken together increased by a factor of 1.84 and 1.52 for each risk allele G and T carried at rs513349 and rs5745582, respectively. These SNPs were in strong LD (D’=0.88). Three common haplotypes, accounting for nearly all (97%), were observed. The estimated haplotype frequency showed increase of r513349G-rs561276C-rs5745582T (GCT) and decrease of r513349A-rs561276C-rs5745582C (ACC) haplotype in each patient cohort as compared to controls. The OR assigned to the risk-haplotype (GCT) was 2.04 (95%CI: 1.34-3.09), p=0.008, for pSS; 1.8 (95%CI: 1.30-2.49), p=0.003, for SLE; 2.10 (95%CI: 1.49-2.96), p=0.0001, for RA; and 1.95 (95%CI: 1.50-2.54) p<0.0001 for all AIRD taken together, with an statistical power of 97%, 86%, and 94% for SLE, pSS and RA, respectively. These associations were independent of HLA-DRB1 and -DQB1 status.
CONCLUSION: Our results indicate that BAK1 gene influences the development of AIRD, and give additional evidence to support that the increased rate of the target autoimmunity cell apoptosis might result from the imbalance between the down-regulated apoptosis-inhibitor Bcl-2 and the up-regulated apoptosis-inducers Bax and Bak.

 A.M. Delgado-Vega, None; J. Castiblanco, None; A. Rojas-Villaraga, None; J. Anaya, None.