14-OR

Abstract

Aim The HLA class II gene BCL2-associated athanogene 6 (BAG6, previously BAT3) is induced by heat shock. Its product is a ligand for NKp30 receptor of NK cells, and is also involved in apoptotic pathways through interactions with caspase and P53. Its SNP rs3117582 is associated with lung cancer risk. Our previous work showed that it is exclusively present on the conserved extended haplotype (CEH) 8.1 (B8DR3). We aimed to clarify whether this SNP is the primary association or a proxy for a CEH8.1 association by bioinformatics and experimental approaches. Methods We examined the rs3117582 association in a case-control study using BioServe Lung Cancer SNPlates (180 cases and 180 controls). For bioinformatics analysis, we used tools available online. For functional replication, we assessed the correlation of this SNP with BAG6 expression using TaqMan analysis on 15 HLA homozygous IHWG cell lines. We used HSPA1B expression to control the experimental approach and for comparison. Results Bioinformatic analysis predicts alteration of heat shock factor binding site by this SNP (FS score = 0.242). The case-control study replicated the previously reported association with lung cancer risk (OR (recessive model) = 5.2, 95% CI = 1.1 to 23.5, P = 0.02) compounded by violation of Hardy-Weinberg equilibrium in cases ( P = 0.001), but not in controls ( P = 0.63). The cell line COX carrying CEH8.1 was homozygous for BAG6 rs3117582 allele C. It showed the expected heat shock response in HSPA1B expression comparable to all other cell lines. The BAG3 expression was increased up to four-fold with heat shock, but COX did not respond that well and ranked 10 among 15 cell lines. Conclusions We replicated the BAG6 rs3117582 association in lung cancer, and also performed functional replication by experimentally confirming bioinformatically predicted function. Given the evidence that this SNP is also involved in breast cancer susceptibility, BAG3 may be a general cancer susceptibility gene located in the central HLA complex.