本文選題：白癜風(fēng) + 全基因組關(guān)聯(lián)分析��； 參考：《安徽醫(yī)科大學(xué)》2010年博士論文

【摘要】：研究背景白癜風(fēng)是一種由于皮膚和毛發(fā)黑素細(xì)胞選擇性破壞而導(dǎo)致的常見(jiàn)色素脫失性皮膚病,該病患病率約為0.1-2.9%,但因地域和種族不同而存在差異。臨床觀察和流行病學(xué)研究發(fā)現(xiàn)白癜風(fēng)是一種多基因遺傳性皮膚病。通過(guò)連鎖分析和關(guān)聯(lián)研究已經(jīng)報(bào)道了許多白癜風(fēng)的易感基因/位點(diǎn),但是只有少數(shù)基因/位點(diǎn)如:NALP1和一些HLA分子在其他人群或者實(shí)驗(yàn)室得到重復(fù)。2006年后,多項(xiàng)復(fù)雜疾病全基因組關(guān)聯(lián)分析(GWAS)研究取得了巨大成功,為白癜風(fēng)易感基因的搜尋提供了新的思路和方法。近來(lái),歐洲人群開(kāi)展了一項(xiàng)大樣本量白癜風(fēng)GWAS研究,發(fā)現(xiàn)酪氨酸酶基因和多個(gè)與自身免疫相關(guān)基因/位點(diǎn)與白癜風(fēng)易感性相關(guān)。由于白癜風(fēng)作為常見(jiàn)的多基因病具有遺傳異質(zhì)性和種族差異性的特點(diǎn),因此在中國(guó)人群中進(jìn)行白癜風(fēng)的GWAS研究,尋找本民族特有的疾病易感基因具有重要的意義。 目的利用GWAS研究方法構(gòu)建中國(guó)人群白癜風(fēng)病例-對(duì)照的全基因組關(guān)聯(lián)分析數(shù)據(jù)庫(kù);從全基因組范圍內(nèi)篩選與白癜風(fēng)可能關(guān)聯(lián)的遺傳變異,并在多個(gè)人群中進(jìn)行驗(yàn)證,鑒定出中國(guó)人群所特有的白癜風(fēng)易感基因/位點(diǎn)。 方法在中國(guó)漢族人群中,首先利用Illumina Human 610-Quad全基因組SNP分型芯片(50,000 SNPs)對(duì)1,149白癜風(fēng)病例和1,468對(duì)照進(jìn)行SNP分型(初篩);經(jīng)過(guò)嚴(yán)格的數(shù)據(jù)質(zhì)控和統(tǒng)計(jì)分析,選擇最有意義的32個(gè)非MHC SNPs和2個(gè)MHC SNPs;然后聯(lián)合應(yīng)用Sequenom和TaqMan兩種SNP分型技術(shù),在漢族人群(5,910病例-9,916對(duì)照)和新疆維吾爾族人群(713病例-824對(duì)照)進(jìn)行重復(fù)試驗(yàn)。 結(jié)果(1)經(jīng)過(guò)多種嚴(yán)格的數(shù)據(jù)質(zhì)控后,本課題組構(gòu)建了一個(gè)包括1,117患者/1,429對(duì)照493,909個(gè)常染色體SNPs的白癜風(fēng)全基因組關(guān)聯(lián)分析數(shù)據(jù)庫(kù)。該數(shù)據(jù)庫(kù)無(wú)明顯的人群分層,并且病例-對(duì)照樣本匹配良好。(2)在MHC區(qū)域發(fā)現(xiàn)了2個(gè)獨(dú)立的關(guān)聯(lián)信號(hào):一個(gè)位于HLA-III類區(qū)域(rs11966200: P_(Chinese Han) =8.77×10~(-43), P_(Chinese Uygur)=1.15×10~(-7));另一個(gè)位于HLA-C/B區(qū)域(rs9468925: P_(Chinese Han) =1.11×10~(-30),P_(Chinese Uygur)=3.65×10~(-4))。進(jìn)一步分析發(fā)現(xiàn)SNP rs11966200所代表的關(guān)聯(lián)信號(hào)反應(yīng)了多個(gè)既往報(bào)道白癜風(fēng)相關(guān)HLA分子,如:HLA-A*3001, B*1302, C*0602以及DRB1*0701。而SNP rs9468925所代表的關(guān)聯(lián)信號(hào)可能來(lái)自一個(gè)未知的HLA分子。MHC區(qū)域單體型分析顯示該區(qū)域存在以SNPs (rs11966200和rs9468925)為代表的2個(gè)與白癜風(fēng)顯著相關(guān)的單體型:H1 (攜帶rs9468925保護(hù)性等位基因A),P=6.71×10~(-8), OR=0.72;H5 (攜帶rs11966200的危險(xiǎn)性等位基因A),P=1.76×10~(-9), OR=1.85。(3)通過(guò)在2個(gè)漢族人群和1個(gè)新疆維吾爾人群的驗(yàn)證,本研究發(fā)現(xiàn)6q27為新的白癜風(fēng)易感位點(diǎn)(漢族:rs2236313, P=1.60×10~(-15);新疆維吾爾人群:rs2236313, P=2.00×10~(-2))。該區(qū)域也是炎性腸病、類風(fēng)濕性關(guān)節(jié)炎等自身免疫性疾病的易感位點(diǎn),共包含了3個(gè)已知基因:RNASET2、FGFR1OP和CCR6。(4)位于10q22區(qū)域的ZMIZ1與漢族人群白癜風(fēng)間存在提示性關(guān)聯(lián)信號(hào)(rs11593576, P=1.82×10~(-7)),ZMIZ1同樣也是炎性腸病易感基因。(5)對(duì)6q27、10q22和2個(gè)MHC SNPs進(jìn)行交互作用分析,但未發(fā)現(xiàn)在各位點(diǎn)間存在交互作用。(6)利用GWAS數(shù)據(jù)對(duì)白癜風(fēng)及常見(jiàn)自身免疫性疾病相關(guān)基因進(jìn)行分析,發(fā)現(xiàn)除去HLA,LPP、MBL2、XBP1、CXCR4、CD69、PTPN2等基因/位點(diǎn)也提示與白癜風(fēng)相關(guān)。 結(jié)論本研究在中國(guó)人群中進(jìn)行了一項(xiàng)大樣本量的GWAS,構(gòu)建了第一個(gè)中國(guó)人群白癜風(fēng)病例-對(duì)照的全基因組關(guān)聯(lián)分析數(shù)據(jù)庫(kù)。通過(guò)在多個(gè)獨(dú)立中國(guó)人群中進(jìn)行驗(yàn)證,報(bào)道了MHC區(qū)域2個(gè)獨(dú)立的位點(diǎn)和6q27區(qū)域的1個(gè)新位點(diǎn)與白癜風(fēng)易感性相關(guān),同時(shí)還提示位于10q22區(qū)域的ZMIZ1與漢族人群白癜風(fēng)可能相關(guān)。本研究首次從遺傳學(xué)上明確提出6q27是白癜風(fēng)與其它自身免疫性疾病(尤其是炎性腸病)共同的易感基因/位點(diǎn),強(qiáng)調(diào)了免疫因素在白癜風(fēng)發(fā)病過(guò)程中的重要性,對(duì)于揭示白癜風(fēng)發(fā)病機(jī)制具有重要意義。
[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 .

【學(xué)位授予單位】：安徽醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2010
【分類號(hào)】：R758.41

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