1q31-32存在新的银屑病易感基因

目的:确定染色体1q是否存在中国汉族寻常型银屑病易感基因位点.方法: 用覆盖染色体1q的12个微卫星标记,对36个寻常型银屑病家系共190个个体(包括92例患者与98例正常亲属)进行基因组扫描研究,并用LINKAGE、ETDT及GENEHUNTER软件进行统计处理.结果:①LINKAGE分析示D1S2891的LOD值为1.0750(θ=0.2),支持连锁;②GENEHUNTER示D1S249、D1S2772和D1S2891的NPL值均大于1.6,相应P<0.05;③ETDT示D1S249 170 bp等位基因和D1S413 258 bp等位基因分别优先传递给正常子代.结论: 中国汉族人1q31-32区存在银屑病易感基因.     

银屑病家系易感基因定位的研究

目的:探讨银屑病易感基因与第4、6、17号染色体上7个微卫星标记的连锁关系,初步对汉族鲁系银屑病易感基因进行定位研究。方法:选择22个银屑病家系中75例患者和正常人51例。选择7个微卫星标记(STR):D6S276、D6S1610、D4S403、D4S424、D4S415、D17S949、D17S784,利用ABI3730测序仪进行电泳测序,并用与之配套的GeneScan、GeneMapper软件进行基因分型。利用GENEHUNTER软件对STR的基因分型数据进行连锁分析。结果:D17S949、D17S784位点的最大两点LOD值,最大两点NPL值均大于1(P<0.05),提示存在连锁关系。结论:染色体17q23~17q25区域内存在寻常型银屑病易感基因。     

染色体4q存在中国汉族人的银屑病易感基因

目的：确定在4号染色体长臂上是否存在中国汉族人寻常性银屑病易感基因。方法：用覆盖4号染色体长臂的12个微卫星标记对64个寻常性银屑病家系共372个个体（包括197例患者和175例非患者）进行基因组扫描研究，并用GENEHUNTER软件（2.0 Version)对基因分型结果进行参数和非参数连锁（NPL）分析。结果：（1）非参数连锁分析：两点连锁分析揭示D4S413和D3S1597的NPL值分别为2．04和2．23，对应的P值分别为0．021和0．014；多点连锁分析在染色体155．1－172．3cM的范围NPL值均大于3，在位点D4S413（157．9cM)处NPL值达最高，为3．44，相应的P值为0．00056。（2）参数连锁分析在显性遗传模式下，外显率10％，基因频率0．0062时在D4S1597位点处得出LOD值＝3．70，异质性LOD（HLOD）值＝4．35和较高的连锁家系比例α=85%。结论：染色体4q存在中国汉族人的寻常性银屑病易感基因。     

6号染色体上可能存在银屑病易感基因

目的 研究中国人寻常型银屑病与6p21.3区域内的六个微卫星标记和4q上的两个微卫星标记是否连锁,以寻找银屑病易感基因位点。方法 利用选取的微卫星位点作为标记,采用微卫星荧光标记-基因扫描及分型技术,选取205例经确诊并符合寻常型银屑病诊断标准的患者,对其中14个银屑病家系进行连锁分析。结果 在研究的家系中未发现4q上的微卫星标记与银屑病易感基因之间的连锁,而在染色体6p21.3区域存在着与之有连锁关系的微卫星标记位点(在D6S273位点上两点分析最大LOD值为1.26)。结论 本研究表明在中国人银屑病患者中,染色体6p21.3区域可能存在银屑病易感基因。     

SPRR2E基因编码区单核苷酸多态性与银屑病

目的通过测定32个中国汉族人寻常性银屑病家系共157人SPRR2E基因的外显子编码区序列,研究SPRR2E基因与银屑病发病的关系。方法提取基因组DNA,对32个银屑病家系DNA进行扩增,产物经377DNA测序电泳仪电泳,用自动测序的方法测定SPRR2E基因的外显子编码区序列,并以ETDT及GENEHUNTER软件进行统计处理。结果SPRR2E基因编码区第156核苷酸( 156bp)处存在A或G二态性,可表现为AA纯合、GG纯合和AG杂合三种基因型,虽然该SNP不改变蛋白质编码,但它与银屑病存在传递不平衡,等位基因A优先传递给患病子代(P<0.05)。结论SPRR2E基因的外显子编码区中的一个核苷酸多态性与中国汉族人寻常性银屑病的发病相关联。     

6号染色体短臂存在银屑病易感基因的证据

目的 鉴定6号染色体短臂上是否存在寻常性银屑病的易感基因.方法用6号染色体短臂上的8个微卫星标记对46个寻常性银屑病家系共272个个体(包括143例患者和129例非患者)进行基因分型研究,并用Genehunter软件(2.0 Version)对基因分型结果进行两点和多点参数和非参数连锁分析.结果①两点连锁分析:非参数连锁分析揭示3个相邻的标记D6S276、D6S1610和D6S1575的NPL值分别为2.69、3.58和2.84,对应的P值分别为0.0 048、0.0 006和0.0 033;参数分析在D6S1610位点处得出HLOD=4.01和较高的连锁家系比例α=70%.②多点连锁分析:在44.9-62.3 cM的染色体区域内,非参数连锁分析的NPL值均＞3,D6S276(44.9 cM)、D6S1610(53.9 cM)和D6S1575(62.3 cM)均位于这个范围内,其中在D6S1610处NPL值达到最高为4.11,对应的P值为0.0 002;参数分析在D6S1610处,得出多点分析的HLOD峰值为3.17,连锁家系比例为60%.结论6号染色体短臂上存在寻常性银屑病的易感基因。     

北方汉族寻常型银屑病与HLA-DRB1及DQB1等位基因相关性研究

目的:探讨HLA-DRB1及DQB1等位基因与北方汉族寻常型银屑病相关性。方法:利用序列特异性引物-聚合酶链反应(PCR-SSP)分型技术,对63例寻常型银屑病患者和102例健康人的HIA-DRB!及DQB1等位基因进行检测。结果:(1)HLA-DRB1*070x、DRB1*1001及DOB`*020x等位基因与北方汉族寻常型银屑病呈正相关(P分别为0.001,0.005,0.009);HLA-DRB1*120x等位基因与北方汉族寻常型银屑病呈负相关(P=0.007)。(2)HLA-DRB1*070x及DQB1*020x等位基因仅与家族史阳性的早发型(Ⅰ型)银屑病发病相关(P<0.001)。(3)HLA-DRBq*1001等位基因频率在Ⅰ型及无家族史的晚发型(Ⅱ型)银屑病均显著性增高(P<0.05)。结论:(1)HLA-DRB1*070x、DRB1*1001及DQB1*020x等位基因可能是北方汉族寻常型银屑病的易感基因或与易感基因相连锁;HLA-DRB1*120x等位基因可能是阻止北方汉族人发生银屑病的保护基因。(2)Ⅰ型及Ⅱ型银屑病的遗传背景存在差异。     

山东地区汉族寻常型银屑病与HLA-DRB1、DQB1等位基因的相关性研究

目的：探讨HLA-DRB1、DQB1位点基因与山东地区汉族寻常型银屑病的相关性。方法：用序列特异性引物-聚合酶链反应（PCR-SSP）方法,对98例山东汉族寻常型银屑病患者进行了HLA-DRB1、DQB1等位基因的分型,并分析了上述基因在各组中的分布。结果：寻常型银屑病患者组HLA-DRB1＊07、DQB1＊0201等位基因频率较正常对照组显著增高;I型寻常型银屑病HLA-DRB1＊07、DQB1＊0201等位基因频率较正常对照组显著增高;II型寻常型银屑病HLA-DRB1＊10基因频率较正常对照组显著增高。结论：HLA-DRB1＊07,HLA-DQB1＊0201和HLA-DRB1＊10可能是山东地区汉族寻常型银屑病的易感相关基因。     

蒙古族寻常性银屑病与HLA-Cw及DRB1位点相关性研究

【摘要】 目的 探讨蒙古族人群寻常性银屑病与HLA-Cw 及DRB1等位基因的相关性,为银屑病病因学研究提供依据。方法 序列特异性引物聚合酶链反应（PCR-SSP）对蒙古族寻常性银屑病患者81例及正常蒙古族100例进行HLA-Cw及DRB1位点的等位基因进行分型。结果 银屑病组HLA- Cw*06,DRB1*07等位基因频率显著高于健康对照组,HLA- Cw*04、DRB1*04等位基因频率显著低于健康对照组（Pc ＜ 0.05或0.01）。在发病年龄 ＜ 40岁银屑病及家族史阴性患者中HLA- Cw*06、DRB1*07等位基因频率显著高于健康对照组,而HLA- Cw*04、DRB1*04显著低于健康对照组（Pc ＜ 0.05）。在发病年龄≥ 40岁的银屑病及家族史阳性患者中只有HLA- Cw*06等位基因频率显著高于健康对照组（Pc ＜ 0.05）。结论 HLA- Cw*06、DRB1*07等位基因可能是内蒙古地区蒙古族人群寻常性银屑病的易感基因。HLA- Cw*04、DRB1*04等位基因可能是内蒙古地区蒙古族人群寻常性银屑病发病的保护因子。HLA- DRB1*07可能是发病年龄 ＜ 40岁的银屑病的易感基因,而HLA- Cw*04、DRB1*04则可能是发病年龄 ＜ 40岁银屑病的保护因子。     

包头地区寻常性银屑病与HLA-Cw* 0602等位基因的相关性研究

目的探讨包头地区汉族寻常性银屑病患者与HLACw0602等位基因的相关性。方法采用聚合酶链反应序列特异引物(PCRSSP)法,检测52例寻常性银屑病患者及60名健康对照者的等位基因频率,并相互比较。结果①HLACw0602与包头地区汉族寻常性银屑病患者具有明显的相关性(OR=3.47,P<0.01);②HLACw0602在Ⅰ型、Ⅱ型寻常性银屑病患者中分布无差异(χ2=0.006,P>0.05)。结论HLACw0602可能是寻常性银屑病易感基因或与易感基因相连锁。     

Evidence for a major psoriasis susceptibility locus at 6p21(PSORS1) and a novel candidate region at 4q31 by genome-wide scan in Chinese hans

Psoriasis is a heterogeneous disease with seven major psoriasis susceptibility loci reported so far on chromosomes 1p, 1q, 3q, 4q, 6p, 17q, and 19p, respectively. To investigate the psoriasis susceptibility loci in Chinese Hans, a genome-wide scan was performed with two-point and multipoint parametric and nonparametric linkage analyses in 61 multiplex families. These families were Chinese Hans residing in east and south-east China, comprising 189 affected and 166 unaffected individuals. We detected evidence for linkage at 6p21 (PSORS1) with nonparametric linkage scores > 3 in the range of 39.9-62.3 cM and a maximum multipoint nonparametric linkage score of 4.58 (p=0.000032). Parametric analysis revealed a maximum two-point heterogeneity lod score of 4.30 with 58% as the proportion of linked families (alpha) and a maximum multipoint heterogeneity lod score of 4.25 (alpha=53%) under the assumption of a dominant model. We could not confirm a previous reported locus (PSORS3) on distal chromosome 4q; however, a region of highly suggestive linkage was identified proximal to this proposed locus. Multipoint nonparametric analysis demonstrated nonparametric linkage scores > 3 throughout a region between 152.5 cM and 165.1 cM (from pter) with a maximum peak of 3.69 (p=0.00033) at 157.9 cM, which locates D4S413. A maximum multipoint heterogeneity lod score of 2.31 (alpha=46%) was reached at 163.1 cM. With two-point parametric linkage analysis, we observed the highest lod score of 2.43 and heterogeneity lod score of 3.94 (alpha=77%) at marker D4S1597. Our results showed that chromosomes 6p and 4q may contain genes involved in the susceptibility to psoriasis vulgaris in a Chinese Han population. Other regions with weaker evidence for linkage could also hide minor susceptibility genes.     

TNIP1基因多态性与中国北方汉族寻常性银屑病关联性分析

目的 探讨人肿瘤坏死因子α诱导蛋白3（TNFAIP3）相互作用蛋白1（TNIP1）基因多态性与中国北方汉族人寻常性银屑病的遗传关联性。 方法 收集寻常性银屑病患者465例,健康对照476例。受试者知情同意后采集外周静脉血5 ml。选择位于TNIP1基因区域的3个单核苷酸多态性（SNP）,即rs17728338、rs3762999和rs999556,利用连接酶检测反应基因分型。利用PLINK1.07软件进行统计分析,卡方检验比较病例组及对照组等位基因频率及基因型频率,计算等位基因的相对危险度估计值比值比OR及其95%可信区间（95% CI）。对 3个SNP间进行连锁不平衡检验,计算两两间的r2和D′值。 结果 位于TNIP1基因区域的3个SNP在病例组和对照组中等位基因频率分布存在差异,但rs3762999和rs999556未达到Bonferroni校正水平。在显性模式下,rs3762999、rs999556的基因型频率在病例组和对照组间差异有统计学意义,达到Bonferroni校正水平（P < 0.016 7）。分层分析发现,3个SNP的等位基因频率、基因型频率在有家族史寻常性银屑病患者与健康对照组间的差异均具有统计学意义（均P < 0.016 7）,rs17728338等位基因A的频率在寻常性银屑病组及各型（早发型、晚发型、有家族史、无家族史）病例组均显著高于对照组（均P < 0.0167）。rs3762999与 rs999556间存在强连锁不平衡（r2 = 0.910,D′ = 0.982）,rs17728338与rs3762999和rs999556之间有中等程度的连锁不平衡（r2分别为0.371和0.353,D′分别为0.989和1）。 结论 TNIP1基因多态性rs17728338、rs3762999及rs999556与汉族人寻常性银屑病具有相关性。     

Follow-up analysis of 180 Chinese Han families: identification of a novel locus for psoriasis at 2p22.3-11.2

BACKGROUND: Psoriasis is a common inflammatory and hyperproliferative skin disease. The pathogenesis of psoriasis remains obscure. Family and twin studies have suggested a strong genetic susceptibility to psoriasis. Eight linkage loci (PSORS1-7, PSORS9) were identified and accepted by the OMIM and an additional 16 susceptibility loci have been suggested so far. OBJECTIVES: To investigate further three suggested psoriasis susceptibility loci at 2p22.3-11.2, 13q21-32 and 17q22-25.3 in a Chinese population. Using an expanded sample of 180 Chinese families with psoriasis and improved marker coverage, we verified whether they were Chinese Han psoriasis susceptibility loci. METHODS: In total, 180 Chinese Han families with psoriasis vulgaris (including the 61 families used in the original genome-wide scan and 119 new families) were recruited from the Dermatology Department at the First Hospital Affiliated to Anhui Medical University. Two-point and multipoint parametric and nonparametric linkage (NPL) analyses were performed at 2p, 13q and 17q in the total 180 families as well as the 61 original and 119 new families separately. RESULTS: At the region 2p, a maximum multipoint NPL score of 4.11 was identified at locus D2S337 (P=0.000003), and a maximum multipoint heterogeneity LOD (HLOD) score of 4.93 (alpha=54%) was identified at the same locus in the analysis of the 180 families. However, the analysis of the 180 families did not identify any significant linkage evidence at the region 13q21-32 [a maximum multipoint HLOD score of 0.10 (alpha=7%) and NPL score of 0.95 (P=0.14)] or the region 17q22-25.3 [a maximum multipoint HLOD score of 0.08 (alpha=6%) and NPL value of 0.94 (P=0.14)]. For these two regions, the LOD scores from the 180 families as well as the 119 new families were much smaller than the ones obtained from the original 61 families. CONCLUSIONS: Our study indicates that 2p22.3-11.2 is a novel psoriasis susceptibility locus in the Chinese Han population and confirms that psoriasis is a genetically heterogeneous disease.     

Evidence for a novel psoriasis susceptibility locus at 9q33-9q34 in Chinese Hans

Psoriasis is a heterogeneous disease for which nine linkage loci (PSORS loci 1-5 and PSORS7-10) have been accepted by the Human Genome Nomenclature Committee and an additional 16 potential susceptibility loci have been reported so far. Our previous genome-wide scan in 61 Chinese Han psoriasis vulgaris families found two susceptibility loci at 6p21.3 and 4q31 and additional suggestive linkage evidence at other regions, including 9q33. In this follow-up study, the linkage evidence at 9q33 was further investigated using an expanded sample of 160 families and improved marker coverage. Our follow-up linkage analysis of the 160 families demonstrated strong linkage evidence (P < or = 0.000022) throughout a region between 133.38 and 146.23 cM with a maximum nonparametric linkage (NPL) score of 4.64 (P = 0.00000023) and a heterogeneity LOD (HLOD) score of 5.03 (alpha = 46%) at 142.39 cM near the marker D9S290. By stratifying the 160 families into the subtypes of 130 early-onset and 30 late-onset families, we revealed stronger linkage evidence in the early-onset psoriasis families with a maximum multipoint HLOD score of 6.48 (alpha = 58%) and a maximum NPL score of 4.69 (P = 0.00000012) near marker D9S290. Our follow-up study has confirmed a novel susceptibility locus at 9q33-34 for early-onset psoriasis in the Chinese population.     

Psoriasis vulgaris in Chinese individuals is associated with PSORS1C3 and CDSN genes

BACKGROUND: Besides the HLA-Cw*0602 allele, the psoriasis susceptibility 1 candidate 3 (PSORS1C3) and corneodesmosin (CDSN) genes are two probable psoriasis susceptibility genes in the PSORS1 locus. The -79C, -26C and +246A alleles of the PSORS1C3 gene, the CDSN*971T allele, CDSN*TTC (619T-1236T-1243C) and CDSN*5 (619T-1240G-1243C) are strongly associated with psoriasis in the caucasian population. Until now, no haplotype study of the PSORS1C3 and CDSN genes has been documented in Chinese patients with psoriasis vulgaris. OBJECTIVES: We aimed to determine whether genetic polymorphisms of the PSORS1C3 and CDSN genes were associated with an increased risk of psoriasis vulgaris in Chinese patients in Taiwan. METHODS: We investigated the PSORS1C3 and CDSN genes for disease association by direct sequencing in 178 patients with psoriasis vulgaris and 203 control subjects. Genotyping for HLA-Cw*0602, alpha-helix coiled-coil rod homologue (HCR) gene and single nucleotide polymorphism (SNP) n.9 was also carried out using a sequence-based typing method. RESULTS: The PSORS1C3*582A allele, an SNP in the 3'-untranslated region of the PSORS1C3 gene, was a major psoriasis vulgaris susceptibility allele in the Chinese population, and the association was much stronger in patients with early-onset psoriasis vulgaris (22.3% vs. 6.9%, odds ratio = 3.87, P(c) =0.0000072). The frequencies of CDSN*TTC and CDSN*971T were also significantly increased in patients with early-onset psoriasis vulgaris. Moreover, PSORS1C3*582A, SNP n.9*C, Cw*0602 and HCR*WWCC were in near complete linkage disequilibrium (LD) with each other; in contrast, the LD with the CDSN gene was not so strong. SNP n.9*C-Cw*0602-PSORS1C3*582A-HCR*WWCC was a major susceptibility haplotype in patients with early-onset psoriasis vulgaris (P < 10(-7)) and this risk haplotype also carried CDSN*TTC and CDSN*971T. CONCLUSIONS: The PSORS1C3 and CDSN genes are important psoriasis susceptibility genes in Chinese patients with psoriasis vulgaris.     

山东汉族寻常性银屑病患者eIF4E、MMP-9基因多态性研究

目的 探讨真核细胞翻译起始因子（eIF4E ）、基质金属蛋白酶-9（MMP-9）基因内的单核苷酸多态性与山东汉族寻常性银屑病的关系。方法 基于群体的病例对照关联分析方法,利用Taqman分型方法对188例银屑病患者及280例正常对照人群MMP-9基因内的2个位点以及eIF4E基因内的1个位点进行分析,对基因型频率及等位基因频率采用PLINK软件进行统计学分析。结果 位于MMP-9基因上游调控区域的 rs4810482等位基因T在银屑病组中的频率显著低于对照组（OR = 1.49,95% CI = 1.12 ~ 1.99,P < 0.01）,在隐性与显性遗传模型分析中,差异具有统计学意义。生物信息学分析表明,该位点可能改变了转录因子的结合位点。在研究中分析的其余两个位点rs3918254和rs11723037与银屑病无相关性。结论 位于MMP-9基因上游调控区域的rs4810482与银屑病具有显著相关性,可能是银屑病的一个易感基因。     

Corneodesmosin (CDSN) gene association with psoriasis vulgaris in Caucasian but not in Japanese populations

PSORS1 on chromosome 6p21.3, which contains the MHC, is a major susceptibility locus for psoriasis vulgaris. This region is characterized by strong linkage disequilibrium and contains the corneodesmosin (CSDN) gene, an attractive candidate for psoriasis susceptibility based on its putative biological function in keratinocyte adhesion, and HLA-Cw6, an established marker for psoriasis susceptibility. We compared two genetically independent populations in order to define the major psoriasis susceptibility gene, a British Caucasian population comprising parent-offspring trios analysed by the transmission disequilibrium test (TDT) and a Japanese case-control population. All individuals were investigated for CDSN polymorphism (+619, +1236, +1240 and +1243) and HLA-C association. Our data confirms strong association with HLA-Cw6 and CDSN allele 5 (+619T, +1240G, +1243C) in the Caucasian cohort (TDT, P = 5.4 x 10(-6)) and in addition defines this region further by identifying a high-risk CDSN haplotype (allele 5 and +1236T, P = 8.5 x 10(-8)). In contrast no association was observed in the Japanese cohort for any HLA-C or CDSN alleles. This data supports a role for the CDSN gene in Caucasian populations with psoriasis. However the lack of association with HLA-Cw6 and CDSN alleles in Japanese psoriasis patients may be because Japanese patients exhibit a form of psoriasis similar to late onset or Type II psoriasis vulgaris in contrast to early onset or Type I disease characterizing our Caucasian population.     

Fine mapping of the PSORS4 psoriasis susceptibility region on chromosome 1q21

Psoriasis is a chronic skin disorder affecting approximately 2% of the Caucasian population. Family clustering of the disease is well established and nonparametric linkage analyzes have mapped disease susceptibility loci on chromosomes 6p (PSORS1) and 17q (PSORS2). Nonconfirmed evidence for linkage is also available for chromosomes 2q 3q, 4q (PSORS3), 8q, 16q, and 20p. We mapped an additional susceptibility locus on chromosome 1q21 (PSORS4). In this study, we have carried out a linkage disequilibrium analysis, in order to achieve a finer localization. We recruited 79 triads from continental Italy and typed them at five loci spanning the 1.6 Mb region generating the highest multipoint LOD scores in our previous linkage study. We observed significant evidence for association with D1S2346 marker (p = 0.004). Results consistent with this data were obtained by typing an independent sample that included 28 patients and 56 controls, originating from Sardinia. In fact, p values of 0.02 were observed with both D1S2346 and D1S2715 markers. We sought further confirmation of our results by typing both samples with two novel markers (140J1C and 140J1D) flanking D1S2346. Marker 140J1D generated a p value of 0.003 in the continental Italy sample where a D1S2346/140J1D haplotype was found with a higher frequency among patients' chromosomes. Altogether our data indicate that the 1q21 susceptibility gene may be localized in the genomic interval spanned by D1S2346 and 140J1D. This report provides evidence supporting the refinement of a non-HLA psoriasis susceptibility locus.