中国人群白癜风全基因组关联分析研究

发布时间：2018-04-27 18:04

本文选题：白癜风 + 全基因组关联分析　；参考：《安徽医科大学》2010年博士论文

【摘要】：研究背景白癜风是一种由于皮肤和毛发黑素细胞选择性破坏而导致的常见色素脱失性皮肤病,该病患病率约为0.1-2.9%,但因地域和种族不同而存在差异。临床观察和流行病学研究发现白癜风是一种多基因遗传性皮肤病。通过连锁分析和关联研究已经报道了许多白癜风的易感基因/位点,但是只有少数基因/位点如:NALP1和一些HLA分子在其他人群或者实验室得到重复。2006年后,多项复杂疾病全基因组关联分析(GWAS)研究取得了巨大成功,为白癜风易感基因的搜寻提供了新的思路和方法。近来,欧洲人群开展了一项大样本量白癜风GWAS研究,发现酪氨酸酶基因和多个与自身免疫相关基因/位点与白癜风易感性相关。由于白癜风作为常见的多基因病具有遗传异质性和种族差异性的特点,因此在中国人群中进行白癜风的GWAS研究,寻找本民族特有的疾病易感基因具有重要的意义。目的利用GWAS研究方法构建中国人群白癜风病例-对照的全基因组关联分析数据库;从全基因组范围内筛选与白癜风可能关联的遗传变异,并在多个人群中进行验证,鉴定出中国人群所特有的白癜风易感基因/位点。方法在中国汉族人群中,首先利用Illumina Human 610-Quad全基因组SNP分型芯片(50,000 SNPs)对1,149白癜风病例和1,468对照进行SNP分型(初筛);经过严格的数据质控和统计分析,选择最有意义的32个非MHC SNPs和2个MHC SNPs;然后联合应用Sequenom和TaqMan两种SNP分型技术,在汉族人群(5,910病例-9,916对照)和新疆维吾尔族人群(713病例-824对照)进行重复试验。结果(1)经过多种严格的数据质控后,本课题组构建了一个包括1,117患者/1,429对照493,909个常染色体SNPs的白癜风全基因组关联分析数据库。该数据库无明显的人群分层,并且病例-对照样本匹配良好。(2)在MHC区域发现了2个独立的关联信号:一个位于HLA-III类区域(rs11966200: P_(Chinese Han) =8.77×10~(-43), P_(Chinese Uygur)=1.15×10~(-7));另一个位于HLA-C/B区域(rs9468925: P_(Chinese Han) =1.11×10~(-30),P_(Chinese Uygur)=3.65×10~(-4))。进一步分析发现SNP rs11966200所代表的关联信号反应了多个既往报道白癜风相关HLA分子,如:HLA-A*3001, B*1302, C*0602以及DRB1*0701。而SNP rs9468925所代表的关联信号可能来自一个未知的HLA分子。MHC区域单体型分析显示该区域存在以SNPs (rs11966200和rs9468925)为代表的2个与白癜风显著相关的单体型:H1 (携带rs9468925保护性等位基因A),P=6.71×10~(-8), OR=0.72;H5 (携带rs11966200的危险性等位基因A),P=1.76×10~(-9), OR=1.85。(3)通过在2个汉族人群和1个新疆维吾尔人群的验证,本研究发现6q27为新的白癜风易感位点(汉族:rs2236313, P=1.60×10~(-15);新疆维吾尔人群:rs2236313, P=2.00×10~(-2))。该区域也是炎性肠病、类风湿性关节炎等自身免疫性疾病的易感位点,共包含了3个已知基因:RNASET2、FGFR1OP和CCR6。(4)位于10q22区域的ZMIZ1与汉族人群白癜风间存在提示性关联信号(rs11593576, P=1.82×10~(-7)),ZMIZ1同样也是炎性肠病易感基因。(5)对6q27、10q22和2个MHC SNPs进行交互作用分析,但未发现在各位点间存在交互作用。(6)利用GWAS数据对白癜风及常见自身免疫性疾病相关基因进行分析,发现除去HLA,LPP、MBL2、XBP1、CXCR4、CD69、PTPN2等基因/位点也提示与白癜风相关。结论本研究在中国人群中进行了一项大样本量的GWAS,构建了第一个中国人群白癜风病例-对照的全基因组关联分析数据库。通过在多个独立中国人群中进行验证,报道了MHC区域2个独立的位点和6q27区域的1个新位点与白癜风易感性相关,同时还提示位于10q22区域的ZMIZ1与汉族人群白癜风可能相关。本研究首次从遗传学上明确提出6q27是白癜风与其它自身免疫性疾病(尤其是炎性肠病)共同的易感基因/位点,强调了免疫因素在白癜风发病过程中的重要性,对于揭示白癜风发病机制具有重要意义。
[Abstract]:It is found that vitiligo is a kind of multi - gene hereditary skin disease , but only a few genes / sites such as NALP1 and some HLA molecules have been replicated in other populations or laboratories .

Objective To establish a complete genome association analysis database of vitiligo case - control in Chinese population by using GWAS method . The genetic variation associated with vitiligo can be screened from the whole genome , and validated in multiple populations , and the gene / site of vitiligo is identified .

Methods In Chinese Han population , 1 , 149 vitiligo cases and 1 , 468 controls were first screened using Illumina Human 610 - Quad all - genomic SNP genotyping chip ( 50,000 SNPs ) ; 32 non - MHC SNPs and two MHC SNPs were selected by strict data quality control and statistical analysis ; then Sequenom and two kinds of SNP typing techniques were applied to repeat the test in Han population ( 5,910 cases - 9 , 916 control ) and Xinjiang Uygur population ( 713 cases - 824 controls ) .

Results ( 1 ) After a wide variety of strict data quality control , the study group constructed a complete genomic association analysis database including 1,117 patients / 1,429 controls , 493,909 autosomal SNPs . The association signals represented by SNP rs11966200 were found to be in HLA - A * 3001 , B * 1302 , C * 0602 , and DRB1 * 0701 . The MHC region haplotype analysis revealed that there were two independent HLA - C / B regions ( rs11966200 : P _ ( Chinese Han ) = 1.15x10 ~ ( -7 )) ; the other was located in HLA - C / B region ( rs9468925 : P _ ( Chinese Han ) = 1.15x10 ~ ( -7 )) ; the other was located in HLA - C / B region ( rs9468925 : P _ ( Chinese Han ) = 1.15x10 ~ ( -7 )) ; the other was located in HLA - C / B region ( rs9468925 : P _ ( Chinese Han ) = 1.15x10 ~ ( -7 )) ; the other was located in HLA - C / B region ( rs9468925 : P _ ( Chinese Han ) = 1.15x10 ~ ( -7 )) ; the other was located in HLA - C / B region ( rs9468925 : P _ ( Chinese Han ) = 1.15x10 ~ ( -7 )) ; the other was located in HLA - C / B region ( rs9468925 : P _ ( Chinese Han ) = 1.15x10 ~ ( -7 )) ; the other was located in HLA - C / B region ( rs9468925 : P _ ( Chinese Han ) = 1.15x10 ~ ( -7 )) ; and the other was located in HLA - C / B region ( rs9468925 : P _ ( Chinese Han ) = 1.15x10 ~ ( -7 )) ; the other was located in HLA - C / B region ( rs9468925 : P _ ( Chinese Han ) = 1.15x10 ~ ( -7 )) ; and the other was found in HLA - C / B region ( rs9468925 : P _ ( Chinese Han ) = 1.15x10 ~ ( -7 )) ; ( 5 ) There were three known genes : RNASET2 , FGFR1OP and CCR6 . ( 4 ) There were three known genes : RNASET2 , FGFR1OP and CCR6 .

Conclusion This study has carried out a large sample of GWAS in Chinese population , constructed the first Chinese population vitiligo case - control full genome association analysis database . It is reported that two independent loci in the MHC region and 1 new site in the 6q27 region are associated with the susceptibility to vitiligo .

【学位授予单位】：安徽医科大学
【学位级别】：博士
【学位授予年份】：2010
【分类号】：R758.41

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