中国汉族人特应性皮炎全基因组关联研究
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摘要
研究背景:
特应性皮炎(atopic dermatitis, AD) ,是一种反复发作的慢性炎症性皮肤病。其特征是皮肤瘙痒,皮损多形性并有渗出倾向,常伴有哮喘、过敏性鼻炎及血清IgE增高等,在儿童和青少年中较多见。近三十年来,AD发病率呈逐年上升趋势,较之前增长达2-3倍之多,在儿童中已达到15%-30%,在成人中达到2%-10%。本病病因和发病机制尚不清楚。国内外通过大量的人群、家系及双生子研究均表明遗传因素是构成AD易感性的主要因素,属多基因遗传病。
多年来,国内外学者主要应用全基因组连锁研究(Genome-wide linkage studies)、候选基因研究(Candidate genes studies)等研究策略搜寻AD的易感基因,并取得了一些进展。但这些研究均存在着一定的局限性,如全基因组连锁研究应用的微卫星标记信息量有限,所定位区域往往较大,很难从其中找出真正的易感基因。同时,全基因组连锁研究主要是针对家系研究,因而所发现的疾病易感位点是否能够代表散发病例尚不清楚。对于候选基因研究,其选取候选基因主要根据研究者们认为最有可能导致疾病发生的易感基因,其分析的位点过少,故不可避免的存在着局限性,不可能全面搜寻到AD的易感基因。
2005年以后,随着人类基因组计划(HGP)和人类基因组单体型图计划(HapMap)的相继完成,以及高通量基因分型技术的飞速发展和分型费用的降低,使得在大规模人群中开展全基因组关联研究(genome-wide association study, GWAS)成为可能。这种研究方法对全基因组范围内的SNP(single nucleotide polymorphism)进行总体的分析,能够更有效的发现和疾病有关联的基因。GWAS是目前寻找复杂疾病易感基因的最有效方法之一。多项研究的成功有力证明了GWAS搜寻复杂疾病易感基因的有效性,也为AD易感基因的搜寻提供了新的思路和方法。2009年,Esparza-Gordillo等对德国人群进行了大规模的GWAS研究,发现11q13.5(C11orf30)为AD的易感位点。
AD在不同人种间存在遗传异质性,主要表现在发病率和患病率以及临床表现存在一定的差异。由于多数AD研究主要是在欧洲高加索白人中进行的,因而这些AD遗传易感基因/位点与中国人群的关联性尚不清楚。因此对AD在中国人群中的易感基因研究很有必要。本研究首次在中国汉族人群中应用GWAS方法在全基因组范围内对AD的易感基因进行筛查,以期发现AD的易感基因。
目的:
在中国汉族人群中,利用全基因组关联分析研究方法在全基因组范围内搜寻与AD关联的遗传变异,鉴定中国汉族人AD的易感基因/位点。
方法:
(1)初筛阶段:在中国汉族人群中,利用Illumina Human 610-Quad全基因组SNP分型芯片对1012个AD病例和1362个对照进行SNPs分型。
(2)验证阶段:①验证第一阶段:经过严格的数据质控和统计分析,从初筛阶段选择最有意义的67个SNPs,使用Sequenom平台在二个独立的中国人群中进行验证(北部人群:1119个病例和1203个对照;南部人群:2505个病例和6762个对照);
②验证第二阶段:从验证第一阶段中选取了19个SNPs,进一步加大样本量使用Sequenom平台在二个独立的中国人群中进行验证(北部人群:276个正常对照;南部人群:3956个正常对照)。之后,将上述附加的对照和之前已分型的对照数据及病例进行合并分析(验证第一、二阶段北部人群总计:1119个病例和1479个对照;验证第一、二阶段南部人群总计:2505个病例和10718个对照;GWAS初筛阶段人群总计:1012个病例和1362个对照),以发现了达到全基因组显著关联性水平SNPs(P<5×10~(-8));
③验证第三阶段:将上一阶段发现的有意义的SNPs进一步在德国的人群中使用TaqMan进行验证(1,806个病例和3,256个正常对照)。
结果:
(1)在验证第一阶段中,在中国汉族人群的3624例患者和7965例对照中对67个SNPs进行基因分型。将验证第一阶段的结果和GWAS结果合并分析后显示,位于2个易感位点的3个SNPs达到了全基因组关联显著水平(P<5×10~(-8)):①位于1q21.3(FLG)易感位点上的2个SNPs的rs3126085/rs11204971 (关联性分别为P_(combined)=5.75×10~(-12), OR=0.83; P_(combined)=5.02×10~(-9), OR=0.86);②位于5q22.1(TMEM232 /SLC25A46)易感位点上的1个SNP rs7701890 (P_(combined)=4.33×10~(-8), OR=1.23);
(2)在验证第二阶段中,对从验证第一阶段中选取的19个SNPs在附加的4232对照中进行分型,之后与第一阶段的样本进行合并分析,最后再与GWAS数据综合分析后发现了位于3个易感位点区域(1q21.3, 5q22.1和20q13.33)内的7个SNPs达到全基因组显著水平:①位于1q21.3(FLG)易感位点上的2个SNPs rs3126085/rs11204971 (关联性分别为P_(combined)=5.90×10~(-12), OR=0.82; P_(combined)=1.20×10~(-10), OR=0.85);②位于5q22.1(TMEM232/SLC25A46)易感位点上的4个SNPs rs7701890/rs10067777/rs13360927/rs13361382 (关联性分别为P_(combined)=3.15×10~(-9), OR=1.24; P_(combined)=1.20×10~(-8), OR=1.24; P_(combined)=2.45×10~(-8), OR=1.22; P_(combined)=4.02×10~(-8), OR=1.22);③位于20q13.33(TNFRSF6B/ZGPAT)易感位点上的1个SNP rs6010620 (P_(combined)=3.0×10~(-8), OR=1.17)。此外,尚有1个提示性的易感位点,即位于10q21.2(ZNF365)易感位点上的SNP rs2393903 (P_(combined)=1.05×10~(-7), OR=1.15);
(3)在验证第三阶段中,发现20q13.33(TNFRSF6B/ZGPAT)也与德国AD存在关联性(rs6010620, P=2.87×10~(-5), OR=1.25)。
结论:
本研究通过大样本量的全基因组关联研究搜寻中国汉族人群AD易感基因,构建了第一个中国汉族人群AD病例-对照的全基因组关联分析数据库。在中国人群中发现了2个新的AD易感基因/位点:5q22.1 (TMEM232/SLC25A46),20q13.33 (TNFRSF6 / ZGPAT);验证出既往欧洲人群和亚洲人群报道的1q21.3(FLG)易感位点;发现了AD一个提示易感位点10q21.2(ZNF365)。此外,发现20q13.33 (TNFRSF6B / ZGPAT)与德国人群AD发病也存在关联性。
Background:
Atopic dermatitis (AD) is a chronic, relapsing form of inflammatory skin disorder, characterized by a skin itching, skin pantomorphous lesions with exudative tendencies and often accompanied by asthma, allergic rhinitis and elevated serum IgE. Atopic dermatitis is a common skin disease in children and adolescents. The prevalence of atopic dermatitis has doubled or tripled during the past three decades; 15% to 30% of children and 2% to 10% of adults are affected. The etiology and pathogenesis of atopic dermatitis is not clear. The results of a large number of people, family and twin studies show that the genetic factors are the main susceptibility factors to AD, and AD is a polygenic disease.
In the past years, researches mainly used genome-wide linkage studies, candidate genes studies or other research strategies to search AD susceptibility genes and some progress was made. However, there are limitations in these studies. For example, there are few microsatellite markers in genome-wide linkage studies and the targeted region is large, which is why it is often difficult to identify the real susceptibility genes. Meanwhile, the genome linkage method is a family-based approach, which identified the diseases susceptibility locus. Whether it can represent the sporadic cases is unknown. Similar to candidate genes studies, researchers often selected candidate genes based on available data which suggest an implication of this gene in the disease. So, there are some limitations in candidate genes study, which could not uncover susceptibility genes of AD with a genome wide coverage.
After 2005, completion of the Human Genome Project (HGP) and the Human Genome Haplotype Mapping Project (HapMap) facilitated the rapid development of high-throughput gene genotyping technologies and the reduction of genotyping costs, which made genome-wide association study become possible in large-scale approaches. The method of genome wide SNP analysis is highly effective to uncover disease susceptibility genes. GWAS is one of the most effective ways currently described to identify susceptibility genes of complex diseases. The success of a large number of GWAS shows a strong efficiency to uncover susceptibility genes of complex diseases, which provide new ideas and methods to search susceptibility genes of AD. In 2009, Esparza-Gordillo et. al. performed a large-scale GWAS study in German population and found that 11q13.5 (C11orf30) is a AD susceptibility locus.
AD is genetically heterogeneous among different ethnic populations, which is mainly showed by differences in clinical manifestations, the incidence and prevalence rates. However, Many studies were performed in the Caucasian population. It is not clear whether these susceptibility genes/loci have the same function in the Chinese population. Therefore, AD susceptibility genes studies are necessary in the Chinese population. This is the first GWAS realized in the Chinese Han population which identified susceptibility genes of AD in the whole genome.
Objective:
To screen for AD associated SNPs with genome-wide coverage and identify susceptibility genes/loci for AD, using the GWAS approach in Chinese Han population.
Methods:
(1) Initial GWAS stage: Samples were genotyped by Illumina Human 610-Quard BeadChips in 1,012 cases and 1,362 controls of Chinese Han.
(2) Replication stage:①Replication in the first stage: After quality control and statistical analysis, we selected 67 SNPs for replication in two independent samples of Chinese Han (Northern population: 1,119 cases and 1,203 controls; Southern population: 2,505 cases and 6,762 controls) by using the Sequenom(?) MassARRAY platform.
②Replication in the second stage: we further genotyped the most promising 19 (of the 67 selected) SNPs that showed supportive association evidence in the initial validation study in additional 276 controls for the northern Chinese population and 3,956 controls for the southern Chinese population by using Sequenom(?) MassARRAY platform. Then, for statistical analysis we combined GWAS, replication of the first stage and replication of the second stage together and found several SNPs reached genome-wide significance.
③Replication in the third stage: the most significant SNPs of the 67 SNPs were further genotyped in German population (1,806 cases and 3,256 controls) by using TaqMan assays.
Results:
(1) In the first stage replication, we genotyped 67 SNPs in 3624 cases and 7965 controls of Chinese Han population. Then, a joint analysis was carried out in the combined GWAS and replication samples of Chinese Han. The replication analysis revealed 3 SNPs within 2 loci showing association with AD at genome-wide significance (P_(combined)<5×10?8): rs3126085/rs11204971 at 1q21.3 (P_(combined)=5.75×10~(-12), OR=0.83; P_(combined)=5.02×10~(-9), OR=0.86, respectively); and rs7701890 at 5q22.1 (P_(combined)=4.33×10~(-8), OR=1.23).
(2) In the second stage replication, we selected 19 SNPs from the first stage replication and genotyped in additional 4232 controls. Then a joint analysis was carried out in the combined GWAS and two stage replications samples of Chinese Han. The associations at 7 SNPs located in 3 loci (1q21.3, 5q22.1 and 20q13.33) reached genome-wide significance: rs3126085/rs11204971 at 1q21.3 (P_(combined)=5.90×10~(-12), OR=0.82; P_(combined)=1.20×10~(-10), OR=0.85, respectively); rs7701890/rs10067777/rs13360927/ rs13361382 at 5q22.1 (P_(combined)=3.15×10~(-9), OR=1.24; P_(combined)=1.20×10~(-8), OR=1.24; P_(combined)=2.45×10~(-8), OR=1.22; P_(combined)=4.02×10~(-8), OR=1.22, respectively); rs6010620 at 20q13.33. In addition, one promising SNP (rs2393903 at 10q21.2) showed a genome-wide association barely below significance (P_(combined)=1.05×10~(-7), OR=1.15). (3) In the third replication stage, the 20q13.33 locus also showed evidence for association in the Germany sample (rs6010620, P=2.87×10~(-5), OR=1.25).
Conclusion:
This study was the first large scale GWAS of AD to uncover susceptibility genes in the Chinese Han population and successfully constructed the first AD cases-controls database of GWAS. Two new susceptibility genes/loci: 5q22.1(TMEM232 /SLC25A46),20q13.33(TNFRSF6B/ZGPAT) were identified in this study. Furthermore, this study identified a susceptibility locus 1q21.3(FLG) which had been reported previously in European population and Asian population. We also found a suggestive susceptibility locus 10q21.2(ZNF365).In addition, the 20q13.33(TNFRSF6B/ZGPAT) locus also showed evidence for association in the German sample.
特应性皮炎(atopic dermatitis, AD) ,是一种反复发作的慢性炎症性皮肤病。其特征是皮肤瘙痒,皮损多形性并有渗出倾向,常伴有哮喘、过敏性鼻炎及血清IgE增高等,在儿童和青少年中较多见。近三十年来,AD发病率呈逐年上升趋势,较之前增长达2-3倍之多,在儿童中已达到15%-30%,在成人中达到2%-10%。本病病因和发病机制尚不清楚。国内外通过大量的人群、家系及双生子研究均表明遗传因素是构成AD易感性的主要因素,属多基因遗传病。
多年来,国内外学者主要应用全基因组连锁研究(Genome-wide linkage studies)、候选基因研究(Candidate genes studies)等研究策略搜寻AD的易感基因,并取得了一些进展。但这些研究均存在着一定的局限性,如全基因组连锁研究应用的微卫星标记信息量有限,所定位区域往往较大,很难从其中找出真正的易感基因。同时,全基因组连锁研究主要是针对家系研究,因而所发现的疾病易感位点是否能够代表散发病例尚不清楚。对于候选基因研究,其选取候选基因主要根据研究者们认为最有可能导致疾病发生的易感基因,其分析的位点过少,故不可避免的存在着局限性,不可能全面搜寻到AD的易感基因。
2005年以后,随着人类基因组计划(HGP)和人类基因组单体型图计划(HapMap)的相继完成,以及高通量基因分型技术的飞速发展和分型费用的降低,使得在大规模人群中开展全基因组关联研究(genome-wide association study, GWAS)成为可能。这种研究方法对全基因组范围内的SNP(single nucleotide polymorphism)进行总体的分析,能够更有效的发现和疾病有关联的基因。GWAS是目前寻找复杂疾病易感基因的最有效方法之一。多项研究的成功有力证明了GWAS搜寻复杂疾病易感基因的有效性,也为AD易感基因的搜寻提供了新的思路和方法。2009年,Esparza-Gordillo等对德国人群进行了大规模的GWAS研究,发现11q13.5(C11orf30)为AD的易感位点。
AD在不同人种间存在遗传异质性,主要表现在发病率和患病率以及临床表现存在一定的差异。由于多数AD研究主要是在欧洲高加索白人中进行的,因而这些AD遗传易感基因/位点与中国人群的关联性尚不清楚。因此对AD在中国人群中的易感基因研究很有必要。本研究首次在中国汉族人群中应用GWAS方法在全基因组范围内对AD的易感基因进行筛查,以期发现AD的易感基因。
目的:
在中国汉族人群中,利用全基因组关联分析研究方法在全基因组范围内搜寻与AD关联的遗传变异,鉴定中国汉族人AD的易感基因/位点。
方法:
(1)初筛阶段:在中国汉族人群中,利用Illumina Human 610-Quad全基因组SNP分型芯片对1012个AD病例和1362个对照进行SNPs分型。
(2)验证阶段:①验证第一阶段:经过严格的数据质控和统计分析,从初筛阶段选择最有意义的67个SNPs,使用Sequenom平台在二个独立的中国人群中进行验证(北部人群:1119个病例和1203个对照;南部人群:2505个病例和6762个对照);
②验证第二阶段:从验证第一阶段中选取了19个SNPs,进一步加大样本量使用Sequenom平台在二个独立的中国人群中进行验证(北部人群:276个正常对照;南部人群:3956个正常对照)。之后,将上述附加的对照和之前已分型的对照数据及病例进行合并分析(验证第一、二阶段北部人群总计:1119个病例和1479个对照;验证第一、二阶段南部人群总计:2505个病例和10718个对照;GWAS初筛阶段人群总计:1012个病例和1362个对照),以发现了达到全基因组显著关联性水平SNPs(P<5×10~(-8));
③验证第三阶段:将上一阶段发现的有意义的SNPs进一步在德国的人群中使用TaqMan进行验证(1,806个病例和3,256个正常对照)。
结果:
(1)在验证第一阶段中,在中国汉族人群的3624例患者和7965例对照中对67个SNPs进行基因分型。将验证第一阶段的结果和GWAS结果合并分析后显示,位于2个易感位点的3个SNPs达到了全基因组关联显著水平(P<5×10~(-8)):①位于1q21.3(FLG)易感位点上的2个SNPs的rs3126085/rs11204971 (关联性分别为P_(combined)=5.75×10~(-12), OR=0.83; P_(combined)=5.02×10~(-9), OR=0.86);②位于5q22.1(TMEM232 /SLC25A46)易感位点上的1个SNP rs7701890 (P_(combined)=4.33×10~(-8), OR=1.23);
(2)在验证第二阶段中,对从验证第一阶段中选取的19个SNPs在附加的4232对照中进行分型,之后与第一阶段的样本进行合并分析,最后再与GWAS数据综合分析后发现了位于3个易感位点区域(1q21.3, 5q22.1和20q13.33)内的7个SNPs达到全基因组显著水平:①位于1q21.3(FLG)易感位点上的2个SNPs rs3126085/rs11204971 (关联性分别为P_(combined)=5.90×10~(-12), OR=0.82; P_(combined)=1.20×10~(-10), OR=0.85);②位于5q22.1(TMEM232/SLC25A46)易感位点上的4个SNPs rs7701890/rs10067777/rs13360927/rs13361382 (关联性分别为P_(combined)=3.15×10~(-9), OR=1.24; P_(combined)=1.20×10~(-8), OR=1.24; P_(combined)=2.45×10~(-8), OR=1.22; P_(combined)=4.02×10~(-8), OR=1.22);③位于20q13.33(TNFRSF6B/ZGPAT)易感位点上的1个SNP rs6010620 (P_(combined)=3.0×10~(-8), OR=1.17)。此外,尚有1个提示性的易感位点,即位于10q21.2(ZNF365)易感位点上的SNP rs2393903 (P_(combined)=1.05×10~(-7), OR=1.15);
(3)在验证第三阶段中,发现20q13.33(TNFRSF6B/ZGPAT)也与德国AD存在关联性(rs6010620, P=2.87×10~(-5), OR=1.25)。
结论:
本研究通过大样本量的全基因组关联研究搜寻中国汉族人群AD易感基因,构建了第一个中国汉族人群AD病例-对照的全基因组关联分析数据库。在中国人群中发现了2个新的AD易感基因/位点:5q22.1 (TMEM232/SLC25A46),20q13.33 (TNFRSF6 / ZGPAT);验证出既往欧洲人群和亚洲人群报道的1q21.3(FLG)易感位点;发现了AD一个提示易感位点10q21.2(ZNF365)。此外,发现20q13.33 (TNFRSF6B / ZGPAT)与德国人群AD发病也存在关联性。
Background:
Atopic dermatitis (AD) is a chronic, relapsing form of inflammatory skin disorder, characterized by a skin itching, skin pantomorphous lesions with exudative tendencies and often accompanied by asthma, allergic rhinitis and elevated serum IgE. Atopic dermatitis is a common skin disease in children and adolescents. The prevalence of atopic dermatitis has doubled or tripled during the past three decades; 15% to 30% of children and 2% to 10% of adults are affected. The etiology and pathogenesis of atopic dermatitis is not clear. The results of a large number of people, family and twin studies show that the genetic factors are the main susceptibility factors to AD, and AD is a polygenic disease.
In the past years, researches mainly used genome-wide linkage studies, candidate genes studies or other research strategies to search AD susceptibility genes and some progress was made. However, there are limitations in these studies. For example, there are few microsatellite markers in genome-wide linkage studies and the targeted region is large, which is why it is often difficult to identify the real susceptibility genes. Meanwhile, the genome linkage method is a family-based approach, which identified the diseases susceptibility locus. Whether it can represent the sporadic cases is unknown. Similar to candidate genes studies, researchers often selected candidate genes based on available data which suggest an implication of this gene in the disease. So, there are some limitations in candidate genes study, which could not uncover susceptibility genes of AD with a genome wide coverage.
After 2005, completion of the Human Genome Project (HGP) and the Human Genome Haplotype Mapping Project (HapMap) facilitated the rapid development of high-throughput gene genotyping technologies and the reduction of genotyping costs, which made genome-wide association study become possible in large-scale approaches. The method of genome wide SNP analysis is highly effective to uncover disease susceptibility genes. GWAS is one of the most effective ways currently described to identify susceptibility genes of complex diseases. The success of a large number of GWAS shows a strong efficiency to uncover susceptibility genes of complex diseases, which provide new ideas and methods to search susceptibility genes of AD. In 2009, Esparza-Gordillo et. al. performed a large-scale GWAS study in German population and found that 11q13.5 (C11orf30) is a AD susceptibility locus.
AD is genetically heterogeneous among different ethnic populations, which is mainly showed by differences in clinical manifestations, the incidence and prevalence rates. However, Many studies were performed in the Caucasian population. It is not clear whether these susceptibility genes/loci have the same function in the Chinese population. Therefore, AD susceptibility genes studies are necessary in the Chinese population. This is the first GWAS realized in the Chinese Han population which identified susceptibility genes of AD in the whole genome.
Objective:
To screen for AD associated SNPs with genome-wide coverage and identify susceptibility genes/loci for AD, using the GWAS approach in Chinese Han population.
Methods:
(1) Initial GWAS stage: Samples were genotyped by Illumina Human 610-Quard BeadChips in 1,012 cases and 1,362 controls of Chinese Han.
(2) Replication stage:①Replication in the first stage: After quality control and statistical analysis, we selected 67 SNPs for replication in two independent samples of Chinese Han (Northern population: 1,119 cases and 1,203 controls; Southern population: 2,505 cases and 6,762 controls) by using the Sequenom(?) MassARRAY platform.
②Replication in the second stage: we further genotyped the most promising 19 (of the 67 selected) SNPs that showed supportive association evidence in the initial validation study in additional 276 controls for the northern Chinese population and 3,956 controls for the southern Chinese population by using Sequenom(?) MassARRAY platform. Then, for statistical analysis we combined GWAS, replication of the first stage and replication of the second stage together and found several SNPs reached genome-wide significance.
③Replication in the third stage: the most significant SNPs of the 67 SNPs were further genotyped in German population (1,806 cases and 3,256 controls) by using TaqMan assays.
Results:
(1) In the first stage replication, we genotyped 67 SNPs in 3624 cases and 7965 controls of Chinese Han population. Then, a joint analysis was carried out in the combined GWAS and replication samples of Chinese Han. The replication analysis revealed 3 SNPs within 2 loci showing association with AD at genome-wide significance (P_(combined)<5×10?8): rs3126085/rs11204971 at 1q21.3 (P_(combined)=5.75×10~(-12), OR=0.83; P_(combined)=5.02×10~(-9), OR=0.86, respectively); and rs7701890 at 5q22.1 (P_(combined)=4.33×10~(-8), OR=1.23).
(2) In the second stage replication, we selected 19 SNPs from the first stage replication and genotyped in additional 4232 controls. Then a joint analysis was carried out in the combined GWAS and two stage replications samples of Chinese Han. The associations at 7 SNPs located in 3 loci (1q21.3, 5q22.1 and 20q13.33) reached genome-wide significance: rs3126085/rs11204971 at 1q21.3 (P_(combined)=5.90×10~(-12), OR=0.82; P_(combined)=1.20×10~(-10), OR=0.85, respectively); rs7701890/rs10067777/rs13360927/ rs13361382 at 5q22.1 (P_(combined)=3.15×10~(-9), OR=1.24; P_(combined)=1.20×10~(-8), OR=1.24; P_(combined)=2.45×10~(-8), OR=1.22; P_(combined)=4.02×10~(-8), OR=1.22, respectively); rs6010620 at 20q13.33. In addition, one promising SNP (rs2393903 at 10q21.2) showed a genome-wide association barely below significance (P_(combined)=1.05×10~(-7), OR=1.15). (3) In the third replication stage, the 20q13.33 locus also showed evidence for association in the Germany sample (rs6010620, P=2.87×10~(-5), OR=1.25).
Conclusion:
This study was the first large scale GWAS of AD to uncover susceptibility genes in the Chinese Han population and successfully constructed the first AD cases-controls database of GWAS. Two new susceptibility genes/loci: 5q22.1(TMEM232 /SLC25A46),20q13.33(TNFRSF6B/ZGPAT) were identified in this study. Furthermore, this study identified a susceptibility locus 1q21.3(FLG) which had been reported previously in European population and Asian population. We also found a suggestive susceptibility locus 10q21.2(ZNF365).In addition, the 20q13.33(TNFRSF6B/ZGPAT) locus also showed evidence for association in the German sample.
引文
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[17]. Chang YT, Lee WR, Yu CW,et al. No association of cytokine gene polymorphisms in Chinese patients with atopic dermatitis. Clin Exp Dermatol. 2006 ;31(3):419-23.
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[29]. Lander E, Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet. 1995; 11(3): 241-7.
[30]. Goring HH, Terwilliger JD, Blangero J. Large upward bias in estimation of locus-specific effects from genomewide scans. Am J Hum Genet 2001; 69(6): 1357-69.
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