Gene–gene interaction of ATG5, ATG7, BLK and BANK1 in systemic lupus erythematosus

Aim: Autophagy-related gene 5 (ATG5), ATG7, B-lymphoid tyrosine kinase (BLK) and B-cell scaffold protein with ankyrin repeats 1 (BANK1) are involved in B-cell signaling; several genome-wide association studies detected these genes as candidates involved in systemic lupus erythematosus (SLE). We aimed to replicate the association of these genes with SLE in Chinese Han and to search for possible gene–gene interactions. Methods: TaqMan single-nucleotide polymorphism (SNP) genotyping was used to detect rs548234, rs665791 in ATG5, rs11706903 in ATG7, rs2736340 in BLK and rs10516487 in BANK1 in 382 SLE patients and 660 healthy controls. The epistasis effect was analyzed by logistic regression, multifactor dimensionality reduction (MDR) and linear regression analysis. Results: SLE was associated with frequency of rs548234 (P = 0.010; odds ratio [OR] = 1.298), rs2736340 (P = 2.47 × 10⁻⁵; OR = 1.574) and rs10516487 (P = 0.002; OR = 0.642). Although no epistasis effects were found among three autophagy-related gene loci or with rs2736340 and rs10516487, BLK and BANK1 had the closest interaction effect on logistic regression analysis (P = 0.013; OR = 1.205), MDR (P < 0.0001), and linear regression analysis (P = 0.0017; R² = 0.1806). The risk genotype TT of rs2736340 was associated with decreased messenger RNA level of BLK; BLK transcript level was lower in SLE patients than healthy controls. Conclusion: We confirmed the association of rs548234, rs2736340 and rs10516487 with SLE in Chinese Han and reinforced our hypothesis of their epistasis effect in regulating B-cell signaling in SLE.