Gene–gene interaction and association of Wnt/Β-catenin signalling pathway gene polymorphisms with ankylosing spondylitis susceptibility in the Chinese Han population

<b>Objectives:</b> To explore the genetic interaction between Wnt/β-catenin signalling pathway genes and ankylosing spondylitis (AS) in the Chinese population. <b>Methods:</b> Six single-nucleotide polymorphisms (SNPs) in DKK1, LRP5, LRP6, and SOST genes were genotyped in 673 AS patients and 687 healthy controls by using SNPs can Technic. Single marker genetic association analysis was performed. Haplotypes were constructed after linkage disequilibrium analysis; additive, multiplicative, and higher-order interactions were analysed. <b>Results:</b> The DKK1 gene rs1569198 polymorphism was significantly associated with AS susceptibility in females (<i>χ</i>² = 4.55, <i>p</i> = .03), but the association disappeared after Bonferroni correction. Moreover, a haplotype (T-G) in the DKK1 gene showed a protective role in AS susceptibility in females (<i>p</i> = .04). Significant additive interactions were observed between DKK1: rs1896368 and LRP5: rs3736228, relative excess risk due to interaction (RERI) = 0.40, 95% CI = 0.08 – 0.71; attributable proportion due to interaction (AP) = 51%, 95% CI = 0.07 – 0.94, DKK1: rs1569198 and LRP5: rs3736228 (RERI = 0.49, 95% CI = 0.12 – 0.86; AP = 49%, 95% CI = 0.17 – 0.82), LRP5: rs3736228 and SOST: rs4792909 (RERI = 0.33, 95% CI = 0.002 – 0.65; AP = 41%, 95% CI = 0.01 – 0.81) in the dominant model. <b>Conclusions:</b> Our research implies a potential gene–gene interaction, thus revealing the importance of the Wnt/β-catenin signalling pathway for understanding the genetic architecture of AS.

**研究目的**：旨在探究中国人群中Wnt/β-连环蛋白（Wnt/β-catenin）信号通路基因与强直性脊柱炎（ankylosing spondylitis, AS）之间的遗传交互作用。
**研究方法**：本研究对DKK1、LRP5、LRP6与SOST基因上的6个单核苷酸多态性（single-nucleotide polymorphisms, SNPs）位点，采用SNPscan技术对673例强直性脊柱炎患者及687例健康对照者进行基因分型。随后开展单标记遗传关联分析；经连锁不平衡分析后构建单体型，并分析加性、相乘模型及高阶遗传交互作用。
**研究结果**：DKK1基因rs1569198多态性与女性强直性脊柱炎易感性显著相关（χ²=4.55，*P*=0.03），但经Bonferroni校正后该关联不再显著。此外，DKK1基因上的(T-G)单体型可对女性强直性脊柱炎易感性起到保护作用（*P*=0.04）。在显性模型中，本研究观察到多组显著的加性交互作用：DKK1:rs1896368与LRP5:rs3736228之间（交互作用相对超额危险度（relative excess risk due to interaction, RERI）=0.40，95%置信区间（confidence interval, CI）=0.08~0.71；交互作用归因比例（attributable proportion due to interaction, AP）=51%，95%CI=0.07~0.94）、DKK1:rs1569198与LRP5:rs3736228之间（RERI=0.49，95%CI=0.12~0.86；AP=49%，95%CI=0.17~0.82），以及LRP5:rs3736228与SOST:rs4792909之间（RERI=0.33，95%CI=0.002~0.65；AP=41%，95%CI=0.01~0.81）。
**研究结论**：本研究结果提示存在潜在的基因-基因交互作用，从而揭示了Wnt/β-连环蛋白信号通路在解析强直性脊柱炎遗传架构中的重要意义。