早期B细胞因子相关锌指蛋白基因的变异与中国人群狼疮肾炎发病的相关性研究

Variations within OLF1/EBF-associated zinc finger protein gene confer susceptibility to lupus nephritis in Chinese population

目的研究早期B细胞因子相关锌指蛋白(OAZ)基因内部的单核苷酸多态性(SNP)与中国人狼疮肾炎发病的相关性。方法选择OAZ基因内部阳性微卫星D16S517附近的8个SNP标记在184例系统性红斑狼疮(SLE)患者(83例狼疮肾炎患者和101例非狼疮肾炎患者)和286名正常人中进行等位基因分型,以Helixtree软件分析SNP分布情况。结果发现中国汉族人群中(1)SNPrs1344531等位基因(T)频率在SLE患者组(47.0%)和正常对照组(38.1%)中差异存在统计学意义(P=0.008);CC基因型的频率在SLE患者组(25.5%)显著低于正常对照组(38.1%,P=0.005)。(2)SNPrs1344531等位基因(T)频率在狼疮肾炎患者组(53.0%)和正常对照组(38.1%)中差异存在统计学意义(P=0.001);CC基因型的频率在狼疮肾炎患者组(22.9%)显著低于正常对照组(38.1%,P=0.013),TT基因型的频率在狼疮肾炎患者组(28.9%)显著高于正常对照组(14.3%,P=0.003)。(3)rs1420676rs1344531(CT)(P=0.001),rs3803665rs1420676rs1344531(CCT)(P=0.004),rs2292155rs3803665rs1420676rs1344531(CCCT)(P=0.002)等单倍型频率在狼疮肾炎患者组中较高。而rs1344531rs2080353(CA)(P=0.005),rs1344531rs2080353rs933564(CAG)(P=0.006)等单倍型的频率在狼疮肾炎患者组中较低。结论OAZ基因的变异可能在狼疮肾炎发病中发挥作用。

Objective To observe whether single nucleotide polymorphisms (SNPs) within the OLF1/EBF-associated zinc finger protein (OAZ) gene are associated with lupus nephritis (LN) susceptibility in Chinese population.Methods Eight SNPs located around the positive microsatellite marker D16S517 within OAZ gene with relatively high heterozygosity were chosen for genotyping on 184 systemic lupus erythromatosus (SLE) patients, including 101 non-LN patients and 83 LN patients, and 286 normal controls using TaqMan MGB allelic discrimination method. Data were collected by SDS 2.0 software. Haplotypes and their frequencies were constructed and estimated, and linkage disequilibrium analysis between pairs of SNPs was evaluated by calculating the D Prime using Helixtree program. Case-control study was performed between the SLE, LN, and non-LN groups and normal control group.Results (1) The frequency of SNP rs1344531 T allele was 47.0% in the SLE patients, significantly higher than that in the controls [38.1%,; χ2=7.300, P=0.008, OR (95%CI)=1.441 (1.105-1.878)], which showed that the frequency of SNP rs1344531 T allele is associated with SLE susceptibility. The genotypic distribution of SNP rs1344531(CC/CT/TT) differed significantly between the SLE patients(25.5%/54.9%/19.6%)and normal controls(38.1%/47.6%/14.3%)(χ2=8.394, P=0.015). The CC genotype frequency of the SLE patients was 25.5%, significantly lower than that of the normal controls [38.1%; χ2=7.976, P=0.005, OR (95%CI)= 0.557 (0.370-0.838)] (2) The SNP rs1344531 T allele frequency of the SLE patients was 53.0%, significantly higher than that of the normal controls [38.1%; χ2=11.769, P=0.001,OR (95% CI)= 1.832 (1.293-2.596)], which showed an associated between SNP rs1344531 T allele frequency and LN susceptibility. The genotypic distribution of SNP rs1344531 (CC/CT/TT) differed significantly between the LN patients(22.9%/48.2%/28.9%)and the normal controls(38.1%/47.6%/14.3%)(χ2=12.065, P=0.002). The CC genotype frequency of the LN patients was 22.9%, significantly lower than that of the normal controls (38.1%) [χ2=6.578,P=0.013, OR (95% CI)= 0.481(0.274-0.848)]. The TT genotype frequency of the LN patients was 28.9%, significantly higher than that of the normal controls (14.3%) [χ2=9.423,P=0.003,OR (95% CI)= 2.431(1.363-4.334)]. No statistical significance was observed between the non-LN patients and normal controls in TT genotype frequency. (3) The frequencies of haplotypes containing rs1344531:rs1420676-rs1344531(C-T) [χ2=11.731, P=0.001, OR (95% CI)=1.867 (1.302-2.676)], rs3803665-rs1420676-rs1344531(C-C-T) [χ2=8.876, P=0.004, OR (95% CI)=1.772 (1.213-2.589)], and rs2292155-rs3803665-rs1420676-rs1344531 (C-C-C-T) [χ2=9.962, P=0.002, OR (95% CI)=1.915(1.274-2.880)] were all significantly higher in the LN patients in comparison with the normal control group (41.0% versus 27.1%;33.3% versus 21.8%;and 27.0% versus 16.2%); while the frequencies of other haplotypes: rs1344531-rs2080353 (C-A) [χ2=8.06, P=0.005, OR (95% CI)=0.603 (0.424-0.856)],rs1344531-rs2080353-rs933564 (C-A-G) [χ2=7.929, P=0.006, OR (95% CI)=0.602 (0.422-0.859)] were significantly lower than those of the normal control group (39.5% versus 52.2%, and 36.6% versus 49.2%), which produced additional support for such association.Conclusion SNP rs1344531 and some haplotypes containing SNP rs1344531 within OAZ are significantly associated with LN susceptibility. Genetic variants of the OAZ gene are involved in the pathogenesis of LN.