Pre-miRNA基因单核苷酸多态性与系统性红斑狼疮遗传易感性的关联研究
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摘要
研究背景
系统性红斑狼疮（systemic lupus erythematosus, SLE）是一种临床表现多样、累及全身多器官、病程迁延反复的典型的自身免疫性疾病，血清中以抗核抗体为代表的多种自身抗体的出现是SLE患者的突出表现。SLE的病因和发病机制较为复杂，目前尚未完全阐明，也无特异的治疗方法，患者生存质量差、病死率高。
已有研究表明，同卵双生子和异卵双生子的疾病一致率差异较大，提示遗传因素在SLE发病中发挥重要作用，多项研究已发现并确证了多个SLE的易感基因或区域，如BANK1、BLK、IRF5、ITGAM、STATA4、HLA区域、1q23、1q25-31、2q35-37、6q21、6p11-21、12q24、16q12、22q11.21等。而环境因素在SLE的发病中也不容忽视，遗传和环境共同作用导致机体固有免疫和适应性免疫紊乱，最终导致SLE的发生。
近年来，越来越多的研究关注于微小RNA（microRNA, miRNA）在疾病发生发展中的作用。MiRNAs是一类约22nt的、具有调控功能的、高度保守的内源性非编码RNA，它们主要通过与靶mRNA3′端的非翻译区（untranslated regions, UTR）不完全性互补配对来抑制mRNA的翻译，介导转录后基因调控，具有广泛的生物学功能。
多项研究表明miRNA在SLE患者和正常对照中存在表达差异，miRNA在SLE的发生发展中发挥着重要作用。MiRNAs整体的成熟受限可以导致细胞的恶性转化，而前体miRNAs上的遗传突变可以导致miRNAs由前体向成熟的转化受到限制，从而影响miRNAs的表达，进而影响下游mRNA的表达、转录后基因调控等，最终影响疾病的发生、发展和预后。
鉴于miRNA功能的重要性，人们认为位于miRNA基因区域内的单核苷酸多态性（single nucleotide polymorphisms, SNP）可能会影响miRNA的功能，进而会影响疾病的易感性。近年来，已有研究发现miRNA前体区域内的基因SNPs与克罗恩病、溃疡性结肠炎等自身免疫疾病、肝癌、肺癌、结直肠癌等肿瘤以及哮喘和先天性心脏病等的遗传易感性有关。
以上证据显示，miRNA基因前体区域的遗传突变在SLE的发生发展中可能发挥着重要作用。本研究拟采用病例对照研究，利用Sequenom MassArray SNP检测技术，检测SLE患者和正常对照pre-miRNA基因区域内的SNPs，探讨其与SLE遗传易感性的关系。本课题的完成将有助于阐明pre-miRNA基因区域的遗传突变在SLE发病中的作用，进一步揭示SLE的发病机制，并为寻找SLE新的诊断和治疗靶点提供科学依据。
目的
比较SLE患者和正常对照之间、狼疮肾炎（lupus nephritis, LN）患者和SLE未合并肾炎患者之间以及SLE患者出现某种首发症状和未出现某种首发症状之间hsa-miRNA-146a、hsa-miRNA-149和hsa-miRNA-196a2前体区域的多态性位点rs2910164、rs2292832和rs11614913等位基因和基因型频率分布的差异，探讨miRNA基因前体区域单核苷酸多态性与系统性红斑狼疮遗传易感性关联。
方法
SLE患者为安徽医科大学第一附属医院风湿免疫科和安徽省立医院风湿免疫科的门诊和住院患者，所有患者均符合1997年美国风湿病学会修订的SLE分类标准并由两名副主任以上级别的专科医生确诊，共1479例。LN患者的诊断符合SLE分类标准的同时，有持续2周以上不同程度的肾损害表现，如血尿、脓尿、蛋白尿、氮质血症等。对照为不具备SLE诊断标准中的任何一条、本人及其直系亲属无自身免疫性疾病史、最近一个月内身体健康，未使用激素和免疫抑制剂等药物、以及无重大疾病史的健康志愿者，共2268例。在获取研究对象知情同意后采用自行设计的问卷进行调查，同时抽取5ml外周静脉血，提取基因组DNA。利用Sequenom MassArray SNP检测技术对研究对象pre-miRNA区域的SNPs进行分型检测。
数据录入采用Epi Data3.0软件，建立数据库，双重录入并检错；统计分析采用SPSS10.01软件，符合正态分布的定量资料采用均数±标准差表示，χ~2检验用于计数资料的分析，t检验用于两组间计量资料的分析，Logistic回归分析用于计算校正性别、年龄等因素后的OR值和P值；哈迪-温伯格平衡（Hardy-Weinbergequilibrium, HWE）的计算采用Stata10.0软件；单倍型分析采用在线遗传分析软件SHEsis；应用Power and Sample Size Calculation3.0软件计算SNPs的把握度。检验水准=0.05。
结果
（1）HWE检验3个SNPs位点rs2910164、rs2292832和rs11614913基因型频率在SLE病例组和对照组中均已达到遗传平衡（rs2910164对照组：2=1.179，P=0.278，病例组：2=0.392，P=0.531；rs2292832对照组：2=0.096，P=0.757，病例组：2=0.652，P=0.419；rs11614913对照组：2=0.080，P=0.777，病例组：2=0.450，P=0.502）。
（2）Pre-miRNA基因单核苷酸多态性与SLE遗传易感性的关联Hsa-miRNA-146a基因rs2910164位点GG、GC和CC三种基因型频率在1479例SLE患者组中分别为262例（17.7%）、707例（47.8%）和510例（34.5%），在2268例对照组中分别为416例（18.3%）、1081例（47.7%）和771例（34.0%），该位点的等位基因和基因型频率在病例组和对照组中差异均无统计学意义（P>0.05）；hsa-miRNA-149基因rs2292832位点CC、CT和TT三种基因型频率在SLE患者组中分别为159例（10.8%）、631例（42.7%）和689例（46.6%），在对照组中分别为234例（10.3%）、979例（43.2%）和1055例（46.5%），两组的等位基因和基因型频率差异均无统计学意义（P>0.05）；hsa-miRNA-196a2基因rs11614913位点CC、CT和TT三种基因型频率在SLE患者组中分别为309例（20.9%）、720例（48.7%）和450例（30.4%），对照组中分别为486例（21.4%）、1135例（50.0%）和647例（28.5%），两组的等位基因和基因型频率差异均无统计学意义（P>0.05）。（3）Pre-miRNA基因单核苷酸多态性与LN的关系在1392例有是否为LN资料的SLE患者中，LN患者557例，占40.0%，非LN患者835例，占60.0%。Hsa-miRNA-146a基因rs2910164位点GG、GC和CC基因型频率在LN患者组分别为14.9%、46.9%和38.2%，在非LN患者组分别为19.3%、48.5%和32.2%，LN患者组与非LN患者组等位基因和基因型频率差异均有统计学意义（C vs. G：χ~2=7.453，P=0.006，OR=1.240，95%CI：1.063-1.448；CC vs. GG：χ~2=7.860，P=0.005，OR=1.621，95%CI：1.156-2.272；GC+CC vs. GG：χ~2=4.958，P=0.026，OR=1.416，95%CI：1.043-1.924）；hsa-miRNA-149基因rs2292832位点CC、CT和TT基因型频率在LN患者组分别为9.7%、40.0%和50.3%，在非LN患者组分别为12.0%、45.9%和42.2%，LN患者组与非LN患者组等位基因频率差异有统计学意义（T vs.C：χ~2=8.186，P=0.004，OR=1.269，95%CI：1.078-1.494），两组基因型频率比较提示纯合突变基因型TT为LN的风险基因型（TT vs. CC：χ~2=4.560，P=0.033，OR=1.517，95%CI：1.035-2.225）；hsa-miRNA-196a2基因rs11614913位点CC、CT和TT基因型频率在LN组分别为22.1%、49.6%和28.4%，非LN患者组分别为20.0%、48.1%和31.9%，LN患者组与非LN患者组等位基因和基因型频率差异均无统计学意义（P>0.05）。
（4）Pre-miRNA基因单核苷酸多态性与SLE患者首发症状的关系在成功分型的1479例SLE患者中首发症状资料齐全的有1382例（93.4%），分析9种主要首发症状（颧部红斑、盘状红斑、光敏感、口腔溃疡、关节炎、胸腺炎、心包炎、肾损害和神经系统异常）与3个SNPs位点的关系发现：hsa-miRNA-146a基因rs2910164位点与SLE患者首发症状的关节炎（GC vs. GG：χ~2=4.809，P=0.028，OR=1.423，95%CI：1.038-1.950；GC+CC vs. GG：χ~2=4.583，P=0.032，OR=1.383，95%CI：1.028-1.860）和肾损害（C vs. G：χ~2=7.973，P=0.005，OR=1.548，95%CI：1.141-2.101； GC vs. GG：χ~2=5.167，P=0.023，OR=2.596，95%CI：1.140-5.910；CC vs. GG：χ~2=7.915，P=0.005，OR=3.295，95%CI：1.436-7.561；GC+CC vs. GG：χ~2=6.809，P=0.009，OR=2.887，95%CI：1.302-6.402）有关，与其他首发症状均无关；hsa-miRNA-149基因rs2292832多态性与SLE患者9种主要首发症状间均不存在统计学关联；hsa-miRNA-196a2基因rs11614913多态性与SLE患者首发关节炎（T vs. C：χ~2=4.580，P=0.032，OR=0.849，95%CI：0.731-0.986；TT vs. CC：χ~2=4.273，P=0.039，OR=0.715，95%CI：0.521-0.983）有关，与其他首发症状均不存在统计学关联。
（5）Pre-miRNA基因单倍型分析本研究对3个hsa-miRNA前体区域的多态性位点rs2910164-rs2292832-rs11614913进行了单倍型分析，构建了8个单倍型，分别为CCC、CCT、CTC、CTT、GCC、GCT、GTC和GTT，其频率分布在SLE患者组和对照组间差异均无统计学意义（P>0.05）。
（6）Pre-miRNA基因交互作用分析本研究对3个hsa-miRNA前体区域内的多态性位点rs2910164、rs2292832和rs11614913进行了两两交互作用分析，结果未发现pre-miRNA SNPs在SLE和LN中存在交互作用。
结论
（1）Hsa-miRNA-146a、hsa-miRNA-149和hsa-miRNA-196a2前体区域内的SNPsrs2910164、rs2292832和rs11614913及其构建的单倍型与中国人群SLE的遗传易感性无关，且未发现基因间存在交互作用。
（2）Hsa-miRNA-146a和hsa-miRNA-149前体区域的多态性位点rs2910164和rs2292832与中国人群LN的遗传易感性有关，但未发现基因间存在交互作用。
（3）Hsa-miRNA-146a前体区域的多态性位点rs2910164与SLE患者首发关节炎和肾脏损害有关，hsa-miRNA-196a2前体区域的多态性位点rs11614913与中国人群SLE患者首发关节炎有关。
Background
Systemic lupus erythematosus (SLE) is a typical systemic autoimmune disease,which has different clinical manifestation, affects multiple organ systems such as kidneyand has a complex process. The outstanding performance of SLE patients was theemergence of variety autoantibodies such as anti-nuclear antibody in serum. At present,the pathogenesis of SLE remains unclear and no specific treatment aimed at controllingsymptoms. The patients have a poor quality of life and high mortality.
Studies have shown that the disease concordance rate was significantly different inmonozygotic and dizygotic twins. It suggests that genetic factors play an important rolein the pathogenesis of SLE. Many SLE susceptibility genes or regions have beendiscovered and confirmed by different studies, such as BANK1, BLK, IRF5, ITGAM,STATA4, HLA,1q23,1q25-31,2q35-37,6q21,6p11-21,12q24,16q12and22q11.21.Environmental factors can’t be ignored in the pathogenesis of SLE. The combinedeffects of genetic and environmental lead to the innate and adaptive immune disorders,and eventually lead to the occurrence of SLE.
In recent years, more researches have been focused on the role of miRNA(microRNA) in disease development. MiRNAs are approximately22nt, having aregulatory function, highly conserved and endogenous non-coding RNA. They aremainly through incomplete complementary pairing with the target mRNA3'untranslated region (3’UTR) to inhibit mRNA’s translation, mediate post-transcriptionalgene regulation, and have a wide range of biological functions.
Several studies have shown that the expressions of miRNAs were significantdifference in SLE patients and normal controls and miRNAs play an important role in the occurrence and development of SLE. The limitation of miRNAs’ maturation canlead to malignant transformation of cells. The genetic mutation in pre-miRNA can leadto the limitation of miRNAs conversion from pre-miRNA to mature miRNA, affect theexpression of miRNAs and regulation of post-transcriptional gene, and ultimately affectthe incidence, development and prognosis of the disease
Given the importance of miRNA function, single nucleotide polymorphisms (SNPs)in miRNA gene region were considered to affect the function of miRNAs and diseasesusceptibility. Several studies have found that the genetic mutations in pre-miRNAswere associated with Crohn's disease, ulcerative colitis, liver cancer, lung cancer,colorectal cancer, asthma, congenital heart disease and so on.
Therefore, in this research, we carried out a case-control association study toexamine the single nucleotide polymorphisms in pre-miRNAs by using the SequenomMassArray SNP detection technology and investigate whether or not allele andgenotype frequencies of pre-miRNAs gene confer susceptibility to SLE in the Chinesepopulation. In addition, we analyzed whether SLE patients with nephritis (LN) and SLEinitial symptoms were associated with SNPs or not. The completion of this study wouldhelp to clarify the role of pre-miRNA gene mutations in the pathogenesis of SLE, andprovide a scientific basis for looking for new diagnostic and therapeutic targets in SLE.
Objectives
To compare the allele distributions and genotype frequencies about SNPs(rs2910164, rs2292832and rs11614913) in the precursor region of hsa-miRNA-146,hsa-miRNA-149and hsa-miRNA-196a2gene between SLE patients and normal controls,lupus nephritis (lupus nephritis, LN) patients and SLE patients without nephritis, SLEpatients with an initial symptom and those without it, and to explore the association ofpre-miRNA gene polymorphisms with SLE susceptibility.
Methods
One thousand four hundred and seventy-nine SLE patients were recruited fromDepartment of Rheumatology and Immunology of the First Affiliated Hospital of AnhuiMedical University and Anhui Provincial Hospital. All SLE patients were according tothe1997revised American College of Rheumatology (ACR) classification criteria anddiagnosed by the two vice-director level and above specialists. LN patients werediagnosed as SLE and have renal impairment for2weeks or more, such as hematuria,pyuria, proteinuria and azotemia. Two thousand two hundred and sixty-eight normalcontrols were recruited from healthy volunteers, all of them were fulfilled these criteria:I without one of the diagnostic criteria for SLE; II themselves and their immediatefamily members without a history of autoimmune disease; III health in the last monthand no use of hormones and immunosuppressant drugs; IV no history of major diseases;After obtaining the informed consent, we collected data by self-designed questionnaireand5ml EDTA anti-coagulated venous blood samples from all studied subjects.Sequenom MassArray SNP detection technology was used to study SNPs genotypingin pre-miRNA.
Epi Data3.0software was used for the database establishment, double entry anderror detection. SPSS10.01software was used to analyze data. The chi-square test wasused to count data analyses; t-test was used for the data analysis of the measurementdata; Logistic regression analysis was used to calculate odds ratios (ORs) and P valueswith adjustment for gender, age etc. Stata10.0software was used to calculate theHardy-Weinberg equilibrium (HWE). Haplotype analysis was assessed by using onlineSHEsis software. The powers of SNPs were calculated by Power and Sample Sizecalculation3.0software. The statistical significance defined as P value <0.05andcalculated based on two-sided tests.
Results
(1) HWE test There were no deviations from HWE observed in both SLE patients andnormal controls in each polymorphism (rs2910164controls:2=1.179, P=0.278; SLEpatients:2=0.392, P=0.531; rs2292832controls:2=0.096, P=0.757; SLE patients:
2=0.652, P=0.419; rs11614913controls:2=0.080, P=0.777; SLE patients:2=0.450,P=0.502).
(2) Association analysis of pre-miRNA gene SNPs and SLE susceptibility To SNPrs2910164of hsa-miRNA-146a, genotype frequencies for GG, GC and CC were17.7%,47.8%and34.5%in the SLE patients and18.3%,47.7%and34.0%in the normalcontrols, and no significant differences were exhibited either in the allele distributionsor in the genotype frequencies between SLE patients and normal controls (P>0.05); ToSNP rs2292832of hsa-miRNA-149, genotype frequencies for CC, CT and TT were10.8%,42.7%and46.6%in the SLE patients and10.3%,43.2%and46.5%in thenormal controls, and significant differences were existed neither in the alleledistributions nor in the genotype frequencies between SLE patients and normal controls(P>0.05); To SNP rs11614913of hsa-miRNA-196a2, genotype frequencies for CC, CTand TT were20.9%,48.7%and30.4%in the SLE patients and21.4%,50.0%and28.5%in the normal controls, and there were no significant differences existed in alleleand genotype frequencies between SLE patients and normal controls (P>0.05).
(3) Association analysis of pre-miRNA gene SNPs and LN The present study included1392SLE patients with LN information,557patients of whom were LN patients(40.0%). To SNP rs2910164of hsa-miRNA-146a, genotype frequencies for GG, GC andCC were14.9%,46.9%and38.2%in the LN patients and19.3%,48.5%and32.2%inthe SLE patients without nephritis, and significant differences were exhibited in theallele and genotype frequencies between LN patients and SLE patients without nephritis(C vs. G: χ~2=7.453, P=0.006, OR=1.240,95%CI:1.063-1.448; CC vs. GG: χ~2=7.860,P=0.005, OR=1.621,95%CI:1.156-2.272; GC+CC vs. GG: χ~2=4.958, P=0.026, OR=1.416,95%CI:1.043-1.924); To SNP rs2292832of hsa-miRNA-149, genotypefrequencies for CC, CT and TT were9.7%,40.0%and50.3%in the LN patients and12.0%,45.9%and42.2%in the SLE patients without nephritis, and significantdifferences were existed both in allele frequencies and in genotype frequencies betweenLN patients and SLE patients without nephritis (T vs. C: χ~2=8.186, P=0.004, OR=1.269,95%CI:1.078-1.494; TT vs. CC: χ~2=4.560, P=0.033, OR=1.517,95%CI:1.035-2.225);To SNP rs11614913of hsa-miRNA-196a2, genotype frequencies for CC, CT and TTwere22.1%,49.6%and28.4%in the LN patients and20.0%,48.1%and31.9%in theSLE patients without nephritis, and there were no significant differences existed inallele and genotype frequencies between LN patients and SLE patients without nephritis(P>0.05).
(4) Association analysis of pre-miRNA gene SNPs and SLE patients with an initialsymptom There were1382SLE patients (93.4%) with information of initial symptomsof1479SLE patients. Analyze of the associations between nine main initial symptoms(malar rash, discoid rash, photosensitivity, oral ulcers, arthritis, pleuritis, pericarditis,renal involvement and nervous system involvement) and three SNPs, we found thatrs2910164of hsa-miRNA-146a was associated with the initial symptoms of arthritis(GC vs. GG: χ~2=4.809, P=0.028, OR=1.423,95%CI:1.038-1.950; GC+CC vs. GG:χ~2=4.583, P=0.032, OR=1.383,95%CI:1.028-1.860）and renal involvement (C vs. G:χ~2=7.973, P=0.005, OR=1.548,95%CI:1.141-2.101; GC vs. GG: χ~2=5.167, P=0.023,OR=2.596,95%CI:1.140-5.910; CC vs. GG: χ~2=7.915, P=0.005, OR=3.295,95%CI:1.436-7.561; GC+CC vs. GG: χ~2=6.809, P=0.009, OR=2.887,95%CI:1.302-6.402),rs2292832of hsa-miRNA-149was associated with the initial symptoms of arthritis (T vs.C: χ~2=4.580, P=0.032, OR=0.849,95%CI:0.731-0.986; TT vs. CC: χ~2=4.273, P=0.039,OR=0.715,95%CI:0.521-0.983) and rs11614913of hsa-miRNA-196a2was notassociated with the initial symptoms.
(5) Pre-miRNA haplotype analysis We analyzed the haplotypes constructed of rs2910164-rs2292832-rs11614913and determined eight haplotypes: CCC, CCT, CTC,CTT, GCC, GCT, GTC and GTT, and found that eight haplotypes frequencies were notsignificantly different between SLE patients and those in controls (P>0.05).(6) Pre-miRNA gene-gene interaction analysis We analyzed gene-gene interaction ofthree SNPs (rs2910164, rs2292832and rs11614913) in pre-miRNA, and found nogene-gene interaction exist in pre-miRNA in SLE and LN.
Conclusions
(1) No significant differences existed between the SLE patients and controls in SNPs(rs2910164, rs2292832and rs11614913) in the precursor region of hsa-miRNA-146,hsa-miRNA-149and hsa-miRNA-196a2, their haplotypes and gene-gene interaction,which suggests that the polymorphisms of pre-miRNA genes might not contribute toSLE susceptibility in the Chinese population.
(2) The SNPs rs2910164and rs2292832in hsa-miRNA-146a and hsa-miRNA-149maybe associated with susceptibility to LN, and there was no interaction between genes.
(3) The SNPs rs2910164in hsa-miRNA-146a may be associated with the initialsymptom of arthritis and renal involvement in SLE patients and the SNPs rs11614913inhsa-miRNA-196a2may be associated with the initial symptom of arthritis in SLEpatients.
系统性红斑狼疮（systemic lupus erythematosus, SLE）是一种临床表现多样、累及全身多器官、病程迁延反复的典型的自身免疫性疾病，血清中以抗核抗体为代表的多种自身抗体的出现是SLE患者的突出表现。SLE的病因和发病机制较为复杂，目前尚未完全阐明，也无特异的治疗方法，患者生存质量差、病死率高。
已有研究表明，同卵双生子和异卵双生子的疾病一致率差异较大，提示遗传因素在SLE发病中发挥重要作用，多项研究已发现并确证了多个SLE的易感基因或区域，如BANK1、BLK、IRF5、ITGAM、STATA4、HLA区域、1q23、1q25-31、2q35-37、6q21、6p11-21、12q24、16q12、22q11.21等。而环境因素在SLE的发病中也不容忽视，遗传和环境共同作用导致机体固有免疫和适应性免疫紊乱，最终导致SLE的发生。
近年来，越来越多的研究关注于微小RNA（microRNA, miRNA）在疾病发生发展中的作用。MiRNAs是一类约22nt的、具有调控功能的、高度保守的内源性非编码RNA，它们主要通过与靶mRNA3′端的非翻译区（untranslated regions, UTR）不完全性互补配对来抑制mRNA的翻译，介导转录后基因调控，具有广泛的生物学功能。
多项研究表明miRNA在SLE患者和正常对照中存在表达差异，miRNA在SLE的发生发展中发挥着重要作用。MiRNAs整体的成熟受限可以导致细胞的恶性转化，而前体miRNAs上的遗传突变可以导致miRNAs由前体向成熟的转化受到限制，从而影响miRNAs的表达，进而影响下游mRNA的表达、转录后基因调控等，最终影响疾病的发生、发展和预后。
鉴于miRNA功能的重要性，人们认为位于miRNA基因区域内的单核苷酸多态性（single nucleotide polymorphisms, SNP）可能会影响miRNA的功能，进而会影响疾病的易感性。近年来，已有研究发现miRNA前体区域内的基因SNPs与克罗恩病、溃疡性结肠炎等自身免疫疾病、肝癌、肺癌、结直肠癌等肿瘤以及哮喘和先天性心脏病等的遗传易感性有关。
以上证据显示，miRNA基因前体区域的遗传突变在SLE的发生发展中可能发挥着重要作用。本研究拟采用病例对照研究，利用Sequenom MassArray SNP检测技术，检测SLE患者和正常对照pre-miRNA基因区域内的SNPs，探讨其与SLE遗传易感性的关系。本课题的完成将有助于阐明pre-miRNA基因区域的遗传突变在SLE发病中的作用，进一步揭示SLE的发病机制，并为寻找SLE新的诊断和治疗靶点提供科学依据。
目的
比较SLE患者和正常对照之间、狼疮肾炎（lupus nephritis, LN）患者和SLE未合并肾炎患者之间以及SLE患者出现某种首发症状和未出现某种首发症状之间hsa-miRNA-146a、hsa-miRNA-149和hsa-miRNA-196a2前体区域的多态性位点rs2910164、rs2292832和rs11614913等位基因和基因型频率分布的差异，探讨miRNA基因前体区域单核苷酸多态性与系统性红斑狼疮遗传易感性关联。
方法
SLE患者为安徽医科大学第一附属医院风湿免疫科和安徽省立医院风湿免疫科的门诊和住院患者，所有患者均符合1997年美国风湿病学会修订的SLE分类标准并由两名副主任以上级别的专科医生确诊，共1479例。LN患者的诊断符合SLE分类标准的同时，有持续2周以上不同程度的肾损害表现，如血尿、脓尿、蛋白尿、氮质血症等。对照为不具备SLE诊断标准中的任何一条、本人及其直系亲属无自身免疫性疾病史、最近一个月内身体健康，未使用激素和免疫抑制剂等药物、以及无重大疾病史的健康志愿者，共2268例。在获取研究对象知情同意后采用自行设计的问卷进行调查，同时抽取5ml外周静脉血，提取基因组DNA。利用Sequenom MassArray SNP检测技术对研究对象pre-miRNA区域的SNPs进行分型检测。
数据录入采用Epi Data3.0软件，建立数据库，双重录入并检错；统计分析采用SPSS10.01软件，符合正态分布的定量资料采用均数±标准差表示，χ~2检验用于计数资料的分析，t检验用于两组间计量资料的分析，Logistic回归分析用于计算校正性别、年龄等因素后的OR值和P值；哈迪-温伯格平衡（Hardy-Weinbergequilibrium, HWE）的计算采用Stata10.0软件；单倍型分析采用在线遗传分析软件SHEsis；应用Power and Sample Size Calculation3.0软件计算SNPs的把握度。检验水准=0.05。
结果
（1）HWE检验3个SNPs位点rs2910164、rs2292832和rs11614913基因型频率在SLE病例组和对照组中均已达到遗传平衡（rs2910164对照组：2=1.179，P=0.278，病例组：2=0.392，P=0.531；rs2292832对照组：2=0.096，P=0.757，病例组：2=0.652，P=0.419；rs11614913对照组：2=0.080，P=0.777，病例组：2=0.450，P=0.502）。
（2）Pre-miRNA基因单核苷酸多态性与SLE遗传易感性的关联Hsa-miRNA-146a基因rs2910164位点GG、GC和CC三种基因型频率在1479例SLE患者组中分别为262例（17.7%）、707例（47.8%）和510例（34.5%），在2268例对照组中分别为416例（18.3%）、1081例（47.7%）和771例（34.0%），该位点的等位基因和基因型频率在病例组和对照组中差异均无统计学意义（P>0.05）；hsa-miRNA-149基因rs2292832位点CC、CT和TT三种基因型频率在SLE患者组中分别为159例（10.8%）、631例（42.7%）和689例（46.6%），在对照组中分别为234例（10.3%）、979例（43.2%）和1055例（46.5%），两组的等位基因和基因型频率差异均无统计学意义（P>0.05）；hsa-miRNA-196a2基因rs11614913位点CC、CT和TT三种基因型频率在SLE患者组中分别为309例（20.9%）、720例（48.7%）和450例（30.4%），对照组中分别为486例（21.4%）、1135例（50.0%）和647例（28.5%），两组的等位基因和基因型频率差异均无统计学意义（P>0.05）。（3）Pre-miRNA基因单核苷酸多态性与LN的关系在1392例有是否为LN资料的SLE患者中，LN患者557例，占40.0%，非LN患者835例，占60.0%。Hsa-miRNA-146a基因rs2910164位点GG、GC和CC基因型频率在LN患者组分别为14.9%、46.9%和38.2%，在非LN患者组分别为19.3%、48.5%和32.2%，LN患者组与非LN患者组等位基因和基因型频率差异均有统计学意义（C vs. G：χ~2=7.453，P=0.006，OR=1.240，95%CI：1.063-1.448；CC vs. GG：χ~2=7.860，P=0.005，OR=1.621，95%CI：1.156-2.272；GC+CC vs. GG：χ~2=4.958，P=0.026，OR=1.416，95%CI：1.043-1.924）；hsa-miRNA-149基因rs2292832位点CC、CT和TT基因型频率在LN患者组分别为9.7%、40.0%和50.3%，在非LN患者组分别为12.0%、45.9%和42.2%，LN患者组与非LN患者组等位基因频率差异有统计学意义（T vs.C：χ~2=8.186，P=0.004，OR=1.269，95%CI：1.078-1.494），两组基因型频率比较提示纯合突变基因型TT为LN的风险基因型（TT vs. CC：χ~2=4.560，P=0.033，OR=1.517，95%CI：1.035-2.225）；hsa-miRNA-196a2基因rs11614913位点CC、CT和TT基因型频率在LN组分别为22.1%、49.6%和28.4%，非LN患者组分别为20.0%、48.1%和31.9%，LN患者组与非LN患者组等位基因和基因型频率差异均无统计学意义（P>0.05）。
（4）Pre-miRNA基因单核苷酸多态性与SLE患者首发症状的关系在成功分型的1479例SLE患者中首发症状资料齐全的有1382例（93.4%），分析9种主要首发症状（颧部红斑、盘状红斑、光敏感、口腔溃疡、关节炎、胸腺炎、心包炎、肾损害和神经系统异常）与3个SNPs位点的关系发现：hsa-miRNA-146a基因rs2910164位点与SLE患者首发症状的关节炎（GC vs. GG：χ~2=4.809，P=0.028，OR=1.423，95%CI：1.038-1.950；GC+CC vs. GG：χ~2=4.583，P=0.032，OR=1.383，95%CI：1.028-1.860）和肾损害（C vs. G：χ~2=7.973，P=0.005，OR=1.548，95%CI：1.141-2.101； GC vs. GG：χ~2=5.167，P=0.023，OR=2.596，95%CI：1.140-5.910；CC vs. GG：χ~2=7.915，P=0.005，OR=3.295，95%CI：1.436-7.561；GC+CC vs. GG：χ~2=6.809，P=0.009，OR=2.887，95%CI：1.302-6.402）有关，与其他首发症状均无关；hsa-miRNA-149基因rs2292832多态性与SLE患者9种主要首发症状间均不存在统计学关联；hsa-miRNA-196a2基因rs11614913多态性与SLE患者首发关节炎（T vs. C：χ~2=4.580，P=0.032，OR=0.849，95%CI：0.731-0.986；TT vs. CC：χ~2=4.273，P=0.039，OR=0.715，95%CI：0.521-0.983）有关，与其他首发症状均不存在统计学关联。
（5）Pre-miRNA基因单倍型分析本研究对3个hsa-miRNA前体区域的多态性位点rs2910164-rs2292832-rs11614913进行了单倍型分析，构建了8个单倍型，分别为CCC、CCT、CTC、CTT、GCC、GCT、GTC和GTT，其频率分布在SLE患者组和对照组间差异均无统计学意义（P>0.05）。
（6）Pre-miRNA基因交互作用分析本研究对3个hsa-miRNA前体区域内的多态性位点rs2910164、rs2292832和rs11614913进行了两两交互作用分析，结果未发现pre-miRNA SNPs在SLE和LN中存在交互作用。
结论
（1）Hsa-miRNA-146a、hsa-miRNA-149和hsa-miRNA-196a2前体区域内的SNPsrs2910164、rs2292832和rs11614913及其构建的单倍型与中国人群SLE的遗传易感性无关，且未发现基因间存在交互作用。
（2）Hsa-miRNA-146a和hsa-miRNA-149前体区域的多态性位点rs2910164和rs2292832与中国人群LN的遗传易感性有关，但未发现基因间存在交互作用。
（3）Hsa-miRNA-146a前体区域的多态性位点rs2910164与SLE患者首发关节炎和肾脏损害有关，hsa-miRNA-196a2前体区域的多态性位点rs11614913与中国人群SLE患者首发关节炎有关。
Background
Systemic lupus erythematosus (SLE) is a typical systemic autoimmune disease,which has different clinical manifestation, affects multiple organ systems such as kidneyand has a complex process. The outstanding performance of SLE patients was theemergence of variety autoantibodies such as anti-nuclear antibody in serum. At present,the pathogenesis of SLE remains unclear and no specific treatment aimed at controllingsymptoms. The patients have a poor quality of life and high mortality.
Studies have shown that the disease concordance rate was significantly different inmonozygotic and dizygotic twins. It suggests that genetic factors play an important rolein the pathogenesis of SLE. Many SLE susceptibility genes or regions have beendiscovered and confirmed by different studies, such as BANK1, BLK, IRF5, ITGAM,STATA4, HLA,1q23,1q25-31,2q35-37,6q21,6p11-21,12q24,16q12and22q11.21.Environmental factors can’t be ignored in the pathogenesis of SLE. The combinedeffects of genetic and environmental lead to the innate and adaptive immune disorders,and eventually lead to the occurrence of SLE.
In recent years, more researches have been focused on the role of miRNA(microRNA) in disease development. MiRNAs are approximately22nt, having aregulatory function, highly conserved and endogenous non-coding RNA. They aremainly through incomplete complementary pairing with the target mRNA3'untranslated region (3’UTR) to inhibit mRNA’s translation, mediate post-transcriptionalgene regulation, and have a wide range of biological functions.
Several studies have shown that the expressions of miRNAs were significantdifference in SLE patients and normal controls and miRNAs play an important role in the occurrence and development of SLE. The limitation of miRNAs’ maturation canlead to malignant transformation of cells. The genetic mutation in pre-miRNA can leadto the limitation of miRNAs conversion from pre-miRNA to mature miRNA, affect theexpression of miRNAs and regulation of post-transcriptional gene, and ultimately affectthe incidence, development and prognosis of the disease
Given the importance of miRNA function, single nucleotide polymorphisms (SNPs)in miRNA gene region were considered to affect the function of miRNAs and diseasesusceptibility. Several studies have found that the genetic mutations in pre-miRNAswere associated with Crohn's disease, ulcerative colitis, liver cancer, lung cancer,colorectal cancer, asthma, congenital heart disease and so on.
Therefore, in this research, we carried out a case-control association study toexamine the single nucleotide polymorphisms in pre-miRNAs by using the SequenomMassArray SNP detection technology and investigate whether or not allele andgenotype frequencies of pre-miRNAs gene confer susceptibility to SLE in the Chinesepopulation. In addition, we analyzed whether SLE patients with nephritis (LN) and SLEinitial symptoms were associated with SNPs or not. The completion of this study wouldhelp to clarify the role of pre-miRNA gene mutations in the pathogenesis of SLE, andprovide a scientific basis for looking for new diagnostic and therapeutic targets in SLE.
Objectives
To compare the allele distributions and genotype frequencies about SNPs(rs2910164, rs2292832and rs11614913) in the precursor region of hsa-miRNA-146,hsa-miRNA-149and hsa-miRNA-196a2gene between SLE patients and normal controls,lupus nephritis (lupus nephritis, LN) patients and SLE patients without nephritis, SLEpatients with an initial symptom and those without it, and to explore the association ofpre-miRNA gene polymorphisms with SLE susceptibility.
Methods
One thousand four hundred and seventy-nine SLE patients were recruited fromDepartment of Rheumatology and Immunology of the First Affiliated Hospital of AnhuiMedical University and Anhui Provincial Hospital. All SLE patients were according tothe1997revised American College of Rheumatology (ACR) classification criteria anddiagnosed by the two vice-director level and above specialists. LN patients werediagnosed as SLE and have renal impairment for2weeks or more, such as hematuria,pyuria, proteinuria and azotemia. Two thousand two hundred and sixty-eight normalcontrols were recruited from healthy volunteers, all of them were fulfilled these criteria:I without one of the diagnostic criteria for SLE; II themselves and their immediatefamily members without a history of autoimmune disease; III health in the last monthand no use of hormones and immunosuppressant drugs; IV no history of major diseases;After obtaining the informed consent, we collected data by self-designed questionnaireand5ml EDTA anti-coagulated venous blood samples from all studied subjects.Sequenom MassArray SNP detection technology was used to study SNPs genotypingin pre-miRNA.
Epi Data3.0software was used for the database establishment, double entry anderror detection. SPSS10.01software was used to analyze data. The chi-square test wasused to count data analyses; t-test was used for the data analysis of the measurementdata; Logistic regression analysis was used to calculate odds ratios (ORs) and P valueswith adjustment for gender, age etc. Stata10.0software was used to calculate theHardy-Weinberg equilibrium (HWE). Haplotype analysis was assessed by using onlineSHEsis software. The powers of SNPs were calculated by Power and Sample Sizecalculation3.0software. The statistical significance defined as P value <0.05andcalculated based on two-sided tests.
Results
(1) HWE test There were no deviations from HWE observed in both SLE patients andnormal controls in each polymorphism (rs2910164controls:2=1.179, P=0.278; SLEpatients:2=0.392, P=0.531; rs2292832controls:2=0.096, P=0.757; SLE patients:
2=0.652, P=0.419; rs11614913controls:2=0.080, P=0.777; SLE patients:2=0.450,P=0.502).
(2) Association analysis of pre-miRNA gene SNPs and SLE susceptibility To SNPrs2910164of hsa-miRNA-146a, genotype frequencies for GG, GC and CC were17.7%,47.8%and34.5%in the SLE patients and18.3%,47.7%and34.0%in the normalcontrols, and no significant differences were exhibited either in the allele distributionsor in the genotype frequencies between SLE patients and normal controls (P>0.05); ToSNP rs2292832of hsa-miRNA-149, genotype frequencies for CC, CT and TT were10.8%,42.7%and46.6%in the SLE patients and10.3%,43.2%and46.5%in thenormal controls, and significant differences were existed neither in the alleledistributions nor in the genotype frequencies between SLE patients and normal controls(P>0.05); To SNP rs11614913of hsa-miRNA-196a2, genotype frequencies for CC, CTand TT were20.9%,48.7%and30.4%in the SLE patients and21.4%,50.0%and28.5%in the normal controls, and there were no significant differences existed in alleleand genotype frequencies between SLE patients and normal controls (P>0.05).
(3) Association analysis of pre-miRNA gene SNPs and LN The present study included1392SLE patients with LN information,557patients of whom were LN patients(40.0%). To SNP rs2910164of hsa-miRNA-146a, genotype frequencies for GG, GC andCC were14.9%,46.9%and38.2%in the LN patients and19.3%,48.5%and32.2%inthe SLE patients without nephritis, and significant differences were exhibited in theallele and genotype frequencies between LN patients and SLE patients without nephritis(C vs. G: χ~2=7.453, P=0.006, OR=1.240,95%CI:1.063-1.448; CC vs. GG: χ~2=7.860,P=0.005, OR=1.621,95%CI:1.156-2.272; GC+CC vs. GG: χ~2=4.958, P=0.026, OR=1.416,95%CI:1.043-1.924); To SNP rs2292832of hsa-miRNA-149, genotypefrequencies for CC, CT and TT were9.7%,40.0%and50.3%in the LN patients and12.0%,45.9%and42.2%in the SLE patients without nephritis, and significantdifferences were existed both in allele frequencies and in genotype frequencies betweenLN patients and SLE patients without nephritis (T vs. C: χ~2=8.186, P=0.004, OR=1.269,95%CI:1.078-1.494; TT vs. CC: χ~2=4.560, P=0.033, OR=1.517,95%CI:1.035-2.225);To SNP rs11614913of hsa-miRNA-196a2, genotype frequencies for CC, CT and TTwere22.1%,49.6%and28.4%in the LN patients and20.0%,48.1%and31.9%in theSLE patients without nephritis, and there were no significant differences existed inallele and genotype frequencies between LN patients and SLE patients without nephritis(P>0.05).
(4) Association analysis of pre-miRNA gene SNPs and SLE patients with an initialsymptom There were1382SLE patients (93.4%) with information of initial symptomsof1479SLE patients. Analyze of the associations between nine main initial symptoms(malar rash, discoid rash, photosensitivity, oral ulcers, arthritis, pleuritis, pericarditis,renal involvement and nervous system involvement) and three SNPs, we found thatrs2910164of hsa-miRNA-146a was associated with the initial symptoms of arthritis(GC vs. GG: χ~2=4.809, P=0.028, OR=1.423,95%CI:1.038-1.950; GC+CC vs. GG:χ~2=4.583, P=0.032, OR=1.383,95%CI:1.028-1.860）and renal involvement (C vs. G:χ~2=7.973, P=0.005, OR=1.548,95%CI:1.141-2.101; GC vs. GG: χ~2=5.167, P=0.023,OR=2.596,95%CI:1.140-5.910; CC vs. GG: χ~2=7.915, P=0.005, OR=3.295,95%CI:1.436-7.561; GC+CC vs. GG: χ~2=6.809, P=0.009, OR=2.887,95%CI:1.302-6.402),rs2292832of hsa-miRNA-149was associated with the initial symptoms of arthritis (T vs.C: χ~2=4.580, P=0.032, OR=0.849,95%CI:0.731-0.986; TT vs. CC: χ~2=4.273, P=0.039,OR=0.715,95%CI:0.521-0.983) and rs11614913of hsa-miRNA-196a2was notassociated with the initial symptoms.
(5) Pre-miRNA haplotype analysis We analyzed the haplotypes constructed of rs2910164-rs2292832-rs11614913and determined eight haplotypes: CCC, CCT, CTC,CTT, GCC, GCT, GTC and GTT, and found that eight haplotypes frequencies were notsignificantly different between SLE patients and those in controls (P>0.05).(6) Pre-miRNA gene-gene interaction analysis We analyzed gene-gene interaction ofthree SNPs (rs2910164, rs2292832and rs11614913) in pre-miRNA, and found nogene-gene interaction exist in pre-miRNA in SLE and LN.
Conclusions
(1) No significant differences existed between the SLE patients and controls in SNPs(rs2910164, rs2292832and rs11614913) in the precursor region of hsa-miRNA-146,hsa-miRNA-149and hsa-miRNA-196a2, their haplotypes and gene-gene interaction,which suggests that the polymorphisms of pre-miRNA genes might not contribute toSLE susceptibility in the Chinese population.
(2) The SNPs rs2910164and rs2292832in hsa-miRNA-146a and hsa-miRNA-149maybe associated with susceptibility to LN, and there was no interaction between genes.
(3) The SNPs rs2910164in hsa-miRNA-146a may be associated with the initialsymptom of arthritis and renal involvement in SLE patients and the SNPs rs11614913inhsa-miRNA-196a2may be associated with the initial symptom of arthritis in SLEpatients.
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