肿瘤坏死因子超家族成员15基因多态性与溃疡性结肠炎的关系

An association of ulcerative colitis with tumor necrosis factor superfamily member 15 gene polymorphisms in Chinese patients

目的 在浙江籍汉族人群中探讨肿瘤坏死因子超家族成员（TNFSF）15基因多态性及单倍型与溃疡性结肠炎（UC）易感性的关系。方法 收集408例UC患者和574名性别、年龄相匹配的健康对照者，采用＂改良多重高温连接酶检测反应技术（iMLDR）＂检测TNFSF15基因3个单核苷酸多态性（SNP）位点（rs3810936、rs4263839、rs4979462），并进行连锁不平衡和单倍型分析。结果 UC组中rs4263839的变异等位基因A和基因型（GA＋AA）频率均低于对照组（45.34%比50.17%，P=0.035；68.38%比76.66%，P=0.004）。依据UC严重程度和疾病部位进一步分层分析，经多重比较校正检验水准（α=0.012 5），结果发现重度结肠炎患者中rs4263839的变异等位基因A和基因型（GA＋AA）频率低于对照组（37.69%比50.17%，P=0.007；60.00%比76.66%，P=0.004）；广泛性结肠炎患者中rs4263839的变异等位基因A和基因型（GA＋AA）频率亦低于对照组（42.22%比50.17%，P=0.009；63.33%比76.66%，P〈0.001）。Haploview 4.2软件分析发现，rs3810936、rs4263839和rs4979462彼此紧密连锁，所构建的单倍型TAC在UC组中的频率低于对照组（40.83%比46.04%，P=0.023）；并且与对照组相比，重度结肠炎患者和广泛性结肠炎患者中，单倍型TAC的频率均显著降低（33.38%比46.04%，P=0.005；37.22%比46.04%，P=0.003）。结论 TNFSF15基因rs4263839位点变异不仅可能降低UC的发病风险，还可能影响UC严重程度和疾病部位。由rs3810936、rs4263839和rs4979462构建的单倍型TAC可能降低UC，尤其是重度结肠炎和广泛性结肠炎的发病风险。

Objective To explore the relationship between ulcerative colitis （UC） susceptibility and tumor necrosis factor superfamily member （TNFSF） 15 gene polymorphisms and haplotypes in Han nationality in Zhejiang province of China.MethodsA total of 408 UC patients and 574 healthy controls were recruited in this study. Three single nucleotide polymorphisms of TNFSF15 （rs3810936, rs4263839, rs4979462） were examined by improved multiple ligase detection reaction （iMLDR） technique. Analyses of linkage disequilibrium （LD） and haplotype were performed by Haploview 4.2 software in all study subjects.ResultsThe variant allele A and genotype （GA＋AA） of rs4263839 were less frequent in UC patients than in controls （45.34% vs. 50.17%, P=0.035;68.38% vs. 76.66%, P=0.004）. According to the severity and location of disease, UC patients were divided into different subgroups. After multiple comparison correction（α=0.012 5）, the frequencies of variant allele A and genotype （GA＋AA） of rs4263839 were lower in patients with severe UC than in the controls （37.69% vs. 50.17%, P=0.007; 60.00% vs. 76.66%, P=0.004）. Similar findings were also drawn for patients with extensive colitis in contrast with the controls （42.22% vs. 50.17%, P=0.009; 63.33% vs. 76.66%, P〈0.001）. Furthermore, the haplotype analysis indicated that three SNPs above were in a strong LD. The frequency of haplotype TAC was lower in UC patients than in the controls（40.83% vs. 46.04%, P=0.023）. Also it was less prevalent in patients with severe UC and patients with extensive colitis when compared with controls respectively （33.38% vs. 46.04%, P=0.005;37.22% vs. 46.04%, P=0.003）.ConclusionsTNFSF15 （rs4263839） variation might not only reduce the risk of UC, but also affect the severity and lesion location of UC. The haplotype TAC formed by rs3810936, rs4263839 and rs4979462 might be related to a lower risk of UC, especially in patients with severe colitis or patients with extensive colitis.