Pathogenic variants screening in seventeen candidate genes on 2p15 for association with ankylosing spondylitis in a Han Chinese population

Objectives
Previous studies have found the association between rs10865331 in 2p15 area and ankylosing spondylitis (AS). This study aimed to identify additional functional genetic variants in 2p15 region associated with AS susceptibility.
Methods
We used next generation sequencing (NGS) in 100 AS cases and 100 healthy controls to screen AS susceptible genetic variants, and validated these variants in 620 cases and 620 controls by using imLDRTM technique for single nucleotide polymorphism (SNP) genotyping.
Results
Totally, we identified 12 SNPs that might confer susceptibility to AS. Of those SNPs, three (rs14170, rs2123111 and rs1729674) were nominally associated (P<0.05) with AS, but were no longer statistically significant after Bonferroni correction. After stratified by gender, another two SNPs (rs11428092 and rs10208769 in USP34) were associated with AS in males but not females, though this was not statistically significant after Bonferroni correction. In addition, rs1729674, rs14170, rs2123111 and rs10208769 were in strong linkage disequilibrium (LD) and were further enrolled in haplotype analysis. A novel haplotype TAGA was found to be associated with a decreased risk of AS (odds ratio (OR) (95% confidence interval (CI)) = 0.832 (0.705–0.982)). Beyond that, we also demonstrated a strong relationship between rs10865331 and AS susceptibility (OR (95% CI) = 1.303(1.111–1.526)).
Conclusions
rs14170 and rs2123111 inUSP34 and rs1729674 in C2orf74 may be associated with AS susceptibility in Han Chinese population. USP34 and C2orf74 in 2p15 region may be AS novel susceptibility genes.

研究目的
既往研究已发现2p15区域rs10865331与强直性脊柱炎（ankylosing spondylitis, AS）存在关联。本研究旨在筛选2p15区域内与强直性脊柱炎易感性相关的其他功能性遗传变异。

研究方法
本研究纳入100例强直性脊柱炎患者与100例健康对照，采用下一代测序（next generation sequencing, NGS）技术筛选强直性脊柱炎易感遗传变异；随后在620例患者及620例健康对照中，采用imLDR™技术进行单核苷酸多态性（single nucleotide polymorphism, SNP）基因分型，以验证筛选出的变异位点。

研究结果
本研究共筛选出12个可能与强直性脊柱炎易感性相关的单核苷酸多态性位点。其中3个位点（rs14170、rs2123111及rs1729674）与强直性脊柱炎呈名义关联（P<0.05），但经邦费罗尼校正后，该关联不再具有统计学意义。按性别分层分析后，另2个位于USP34基因的位点（rs11428092与rs10208769）在男性群体中与强直性脊柱炎存在关联，而女性群体中未观察到该关联，不过经邦费罗尼校正后该关联亦无统计学显著性。此外，rs1729674、rs14170、rs2123111及rs10208769存在较强的连锁不平衡（linkage disequilibrium, LD），遂进一步纳入单体型分析。研究发现新型单体型TAGA与强直性脊柱炎发病风险降低相关（比值比（odds ratio, OR）（95%置信区间（confidence interval, CI））=0.832（0.705~0.982））。除此之外，本研究还证实rs10865331与强直性脊柱炎易感性存在显著关联（OR（95% CI）=1.303（1.111~1.526））。

研究结论
位于USP34基因的rs14170、rs2123111及位于C2orf74基因的rs1729674，可能与汉族人群强直性脊柱炎易感性相关。2p15区域的USP34与C2orf74基因可能为强直性脊柱炎新型易感基因。