【作者】 刘晔；

【导师】 项蕾红；

【作者基本信息】 复旦大学 ， 皮肤病与性病学， 2012， 博士

【摘要】 研究背景寻常型痤疮是一种常见的累及毛囊皮脂腺的慢性炎症性疾病。雄激素在痤疮发生过程中起着至关重要的作用,但其具体机制至今仍不十分明了。已有两个雄激素合成酶和雄激素受体的编码基因的多态性被证明和痤疮的发病有关。芳香化酶可将雄激素转化为雌激素,并可在皮脂腺表达。CYP19a1为编码此酶的基因,该基因序列的变异可能会影响芳香化酶的表达,进而影响雄雌激素的比例,最终导致痤疮的发生。目的初步探索CYP19a1基因的单核苷酸多态性与中国汉族成人寻常型痤疮发病、严重程度的关系。方法本研究共纳入了309例Pillsbury I-IV°的患者,均为中国华东地区汉族人群,分为轻度组(I°，99例)和中重度组(Ⅱ-Ⅳ。,210例)。从患者外周静脉血中抽取DNA组,多重PCR获取目的基因片段后,采用SNaPshot分型技术检测CYP19al基因上的10个候选SNP位点的基因型,对比其分布频率在两组患者中的差异,并进行单倍型分析,统计分析采用SPSS16.0、Unphase、Hapstata等软件。结果1.rs6493497位点不符合Hardy-Weinberg平衡检验(轻度组p=2.659e-08,中重度组p=3.097e-11),将其剔除。2.rs28892002位点(总基因频率为CC54.7%,CT38.2%,CT7.1%)的基因频率在轻度组和中重度组之间存在显著差异(p值<0.05)。显性遗传模式下,CC基因型的分布频率在中重度组(58.6%)显著高于轻度组(46.5%)(p=0.046),OR=0.614,95%CI=0.379-0.993；相乘遗传模式下,等位基因T的分布频率在中重度组(23.8%)显著低于轻度组(31.3%)(p=0.048),OR=0.685,95%CI=0.471-0.997。余SNP位点基因频率分布两组间未得到阳性结果。3.连锁不平衡结果显示, rs2255192-rs4646-rs10064-rs700519间rs2414096-rs4775936间、rs28892002-rs752760间有着良好的连锁不平衡效应,单倍型分析显示,rs2255192-rs4646-rs10064-rs700519这组单倍型在显性模式下,其C-C-A-C、T-C-A-C基因型在两组间分布有统计学差异,P值分别为0.0000、0.0216,OR值分别为5.0198和2.0707。结论结果提示,中国汉族人群中,CYP19a1基因上的rs28892002位点CC野生纯合子基因型可能增加中重度寻常型痤疮的患病风险；rs2255192-rs4646-rs10064-rs700519这组单倍型在显性模式下,其C-C-A-C、T-C-A-C可能减少中重度寻常型痤疮的患病风险。更多还原

【Abstract】 BackgroundAcne vulgaris is a common chronic inflammatory skin disorder that involves pilosebaceous unit. Androgen plays an essential role in the pathophysiology of acne however which is not yet well understood up to now. Coding gene polymorphism of two synthetic enzymes for androgen and androgen receptor (AR) has been proved to be associated with acne. The aromatase enzyme converts androgens to estrogens and is expressed in sebaceous gland. Sequence variation in the gene encoding aromatase, CYP19A1, might change expression of aromatase, and then imbalance androgen/estrogen, and finally influence the risk of developing acne.ObjectiveOur aim is to explore the association between a genetic polymorphism in CYP19al gene and the development of acne in Chinese Han ethnic group.Methods309Chinese of Han ethnic group with Pillsbury Ⅰ-Ⅳ°acne were enrolled in our study, who were divided into two groups, mild group (Ⅰ°acne,99cases) and moderate-server group (Ⅱ-Ⅳ°acne,210cases). Genomic DNA was extracted from peripheral venous blood of individual patients. SNaPshot technique was used to detect the10candidate SNPs in CYP19al gene after obtaining target segments. Statistics were done by SPSS16.0, Unphase, Hapstata, comparing gene distribution among two groups and analyzing haplotype.Results1. rs6493497was excited as it wasn’t coincident with Hardy-Weinberg equilibrium(p=2.659e-08vs p=3.097e-11for mild group and moderate-server group respectively).2. For SNP rs28892002(overall genotype frequencies, CC54.7%, CT38.2%, CT7.1%), there exists a significant difference between mild group and moderate-server group (p-value<0.05). According to dominant model, the genotype CC was more frequent in moderate-server group (58.6%) than mild group (46.5%)(p-value=0.046). According to allelic model, the allele T was less frequent in moderate-server group (23.8%) than mild group (31.3%)(p-value=0.048). No positive results were drew for the remaining loci.3. Dates showed that there existed a good linkage disequilibrium between rs2255192, rs4646, rs10064,rs700519, and between rs2414096, rs4775936, and between rs28892002, rs752760. According to dominant model, the genotype frequency of C-C-A-C and T-C-A-C for the first haplotype showed a significant difference between mild group and moderate-server group, for p-value0.0000and0.0216respectively, and for OR5.0198and2.0707respectively.ConclusionsThese findings suggest that rs28892002genotype CC might be associated with predisposition to moderate-server acne vulgaris in Chinese Han ethnic group; the genotype C-C-A-C and T-C-A-C for haplotype of rs2255192-rs4646-rs10064-rs700519might be associated with low risk for moderate-server acne vulgaris in Chinese Han ethnic group.更多还原