MHC区域单核苷酸多态性rs9468925与汉族人寻常型白癜风表型的相关性研究

发布时间：2018-05-15 01:11

本文选题：白癜风 + MHC　；参考：《安徽医科大学》2011年硕士论文

【摘要】：背景白癜风(OMIM,#193200)属于一种多基因遗传病,因不同种族不同地域而呈现不同的患病率[2-4]。白癜风是一种常见的色素减退性皮肤病,主要侵犯皮肤及毛发的发病机制不明的复杂性疾病。其发病机制迄今尚未完全阐明,目前认为机制包括遗传学说、自身免疫学说、黑素细胞自身破坏学说、神经化学因子学说等,但均未定论。其中遗传因素在白癜风的发病中具有重要作用。以往主要通过连锁分析和候选基因方法研究白癜风的易感基因。现在我们通过全基因组关联分析研究发现在MHC区域上发现两个独立的关联信号即突变位点(rs11966200, rs9468925 ),进一步研究发现rs1196200可能与HLA-A*3001, HLA-B*1302, HLA-C*0602以及HLA-DRB1*0701的等位基因相关联,而rs9468925可能代表了一个以前所未知的易感基因。同时还发现了一个以前未被描述的风险位点位于6q27(rs2236313),此处包含了三个基因RNASET2, FGFR1OP和CCR6。为探讨该SNP位点是否与汉族人白癜风表型相关,本研究应用课题组白癜风易感基因的GWA研究结果,分析MHC区域上的一个SNPrs9468925的单核苷酸多态性与汉族人寻常型白癜风表型的关系。目的对寻常型白癜风发病年龄、发病面积、家族史、伴发自身免疫疾病及临床类型进行分层分析,在汉族人群中研究寻常型白癜风MHC区域一个SNPrs9468925单核苷酸多态性与白癜风表型的相关性,为进一步探讨白癜风的发病机制提供重要的遗传学依据。方法5,566例白癜风患者和6,462例正常对照的MHC区域单核苷酸多态性rs9468925位点基因分型(AA、AG、GG)资料均来源于本课题组白癜风全基因组关联分析的Illumina 610芯片分型数据,数据资料经适当转化后应用社会科学统计软件包SPSS10.0对资料进行统计学分析。结果1.病例组与对照组的基因型总体分布差异具有统计学意义(χ~2=138.4,df=2,P=8.85×10~(-31)),病例组与对照组的等位基因分布差异亦具有统计学意义(χ~2=136.49,df=1,P=1.56×10~(-31),OR= 0.73,95%CI:0.69-0.77)。2.发病患者年龄≤20岁与对照比较,rs9468925位点基因型和等位基因分布差异均有统计学意义(χ~2=140.93,df=2,P=2.50×10~(-31);χ~2=140.42,df=1,P=2.16×10~(-32),OR= 0.68,95%CI:0.63-0.72)。发病患者年龄20岁与对照比较,rs9468925位点基因型和等位基因分布差异亦具有统计学意义(χ~2=43.87,df=2,P=2.97×10~(-10);χ~2=43.23,df=1,P=4.87×10~(-11),OR 0.80,95%CI 0.74-0.85)。发病患者≤20岁和发病患者20岁之间rs9468925位点基因型和等位基因分布差异均有统计学意义(χ~2=16.53,df=2,P=2.57×10~(-4);χ~2=16.1,df=1,P=6.01×10~(-5),OR= 0.80,95%CI:0.74-0.85)。3.涉及皮损面积5%的患者与对照比较,rs9468925位点基因型和等位基因分布差异均有统计学意义(χ~2=109.4,df=2,P=1.72×10~(-24);χ~2=109.67,df=1,P=1.16×10~(-25),OR= 0.73,95%CI:0.69-0.77)。涉及皮损面积≥5%的患者与对照比较,rs9468925位点基因型和等位基因分布差异均有统计学意义(χ~2=63.79,df=2,P=1.41×10~(-14);χ~2=58.71,df=1,P=1.83×10~(-14),OR= 0.72,95%CI:0.66-0.78)。涉及皮损面积5%的患者和涉及皮损面积≥5%的患者之间rs9468925位点基因型有统计学意义(χ~2=7.39,df=2,P=0.025),等位基因分布差异无统计学意义(χ~2=0.3,df=1,P=0.58,OR= 1.03,95%CI:0.94-1.12)。4.家族史阳性患者与对照比较,rs9468925位点基因型和等位基因分布差异均有统计学意义(χ~2=34.97,df=2,P=2.55×10~(-8);χ~2=32.92,df=1,P=9.59×10~(-9),OR= 0.70,95%CI:0.63-0.79)。家族史阴性患者与对照比较,rs9468925位点基因型和等位基因分布差异亦具有统计学意义(χ~2=63.79,df=2,P=1.41×10~(-14);χ~2=58.71,df=1,P=1.83×10~(-14),OR= 0.72,95%CI:0.66-0.78)。家族史阳性患者和阴性患者间rs9468925位点基因型和等位基因分布差异均无统计学意义(χ~2=3.28,df=2,P=0.19;χ~2=0.38,df=1,P=0.54,OR =0.96,95%CI:0.85-1.09)。5.伴发自身免疫疾病的患者与对照比较,rs9468925位点基因型和等位基因分布差异均有统计学意义(χ~2=14.23,df=2,P=0.001;χ~2=13.94,df=1,P=1.88×10~(-4),OR= 0.72,95%CI:0.60-0.85)。不伴发自身免疫疾病的患者与对照比较,rs9468925位点基因型和等位基因分布差异亦具有统计学意义(χ~2=132.93,df=2,P=1.36×10~(-29);χ~2=131.18,df=1,P=1.93×10~(-30),OR= 0.73,95%CI:0.69-0.77)。伴发自身免疫疾病的患者和不伴发自身免疫疾病的患者之间rs9468925位点基因型和等位基因分布差异均无统计学意义(χ~2=0.43,df=2,P=0.81;χ~2=0.57,df=1,P=0.45,OR= 1.09,95%CI:0.87-1.37)。6.局限型患者与对照比较,rs9468925位点基因型和等位基因分布差异均有统计学意义(χ~2=38.04,df=2,P=5.48×10~(-9);χ~2=37.06,df=1,P=1.14×10~(-9),OR= 0.79,95%CI:0.73-0.85)。散发型患者与对照比较,rs9468925位点基因型和等位基因分布差异亦具有统计学意义(χ~2=121.83,df=2,P=3.51×10~(-27);χ~2=119.87,df=1,P=6.76×10~(-28),OR= 0.70,95%CI:0.66-0.75)。泛发型患者与对照比较,rs9468925位点基因型和等位基因分布差异亦具有统计学意义(χ~2=14.41,df=2,P=0.001;χ~2=13.31,df=1,P=2.64×10~(-4),OR= 0.79,95%CI:0.73-0.85)。面肢型患者与对照比较,rs9468925位点基因型和等位基因分布差异亦具有统计学意义(χ~2=17.00,df=2,P=2.04×10~(-4);χ~2=16.05,df=1,P=6.17×10~(-5),OR= 0.72,95%CI:0.62-0.85)。各临床类型患者rs9468925位点基因型分布差异有统计学意义(χ~2=13.98,df=6,P=0.03),等位基因分布差异无统计学意义(χ~2=6.74,df=3,P=0.08)。结论1.MHC区域rs9468925遗传多态性与汉族人寻常型白癜风的易感性相关。2.汉族人白癜风患者MHC区域rs9468925遗传多态性与发病年龄有显著相关性。3.汉族人白癜风患者MHC区域rs9468925遗传多态性与发病面积有显著相关。4.MHC区域rs9468925遗传多态性与汉族人白癜风的临床发病类型有显著相关性。MHC区域rs9468925遗传多态性均对白癜风的有无家族史,是否伴发自身免疫性疾病的影响作用较弱,可能与白癜风具有不同的遗传学基础和不同的发病机制有关。
[Abstract]:Background OMIM (#193200) belongs to a polygenic disease. The incidence of vitiligo in different races and different regions [2-4]. is a common pigmented dermatosis, which mainly invades the complicated and complex diseases of the skin and hair. Its pathogenesis has not yet been fully elucidated, and the mechanism is now considered to be the mechanism. It includes genetic theory, autoimmune theory, melanocyte self destruction theory, neurochemical factor theory, etc. but the genetic factors play an important role in the pathogenesis of vitiligo. Past linkage analysis and candidate gene methods have been used to study the susceptibility genes of vitiligo. The study found that two independent correlation signals, rs11966200 (rs9468925), were found in the MHC region. Further studies found that rs1196200 might be associated with HLA-A*3001, HLA-B*1302, HLA-C*0602 and HLA-DRB1*0701 alleles, and rs9468925 may represent a previously unknown susceptibility gene. A previously unknown risk locus is located in 6q27 (rs2236313), which contains three genes RNASET2, FGFR1OP and CCR6. to investigate whether the SNP locus is associated with the phenotype of vitiligo in Han people. This study applies the results of the GWA study on the susceptible gene of vitiligo to analyze a single nucleotide polymorphisms on a SNPrs9468925 in MHC region. The relationship between sex and the phenotype of vitiligo vulgaris.
Objective to analyze the age, area, family history, autoimmune diseases and clinical types of vitiligo vulgaris, and to study the correlation of a single nucleotide polymorphism of SNPrs9468925 in the MHC area of vitiligo vulgaris to the phenotype of vitiligo, and to provide an important approach to further explore the pathogenesis of vitiligo. Genetic basis.
Methods the MHC regional single nucleotide polymorphic rs9468925 loci genotyping (AA, AG, GG) data from 5566 patients with vitiligo and 6462 normal controls were derived from the Illumina 610 chip data of the whole genome association analysis of vitiligo in our group. The data were properly converted to the data of the social science statistics software package and SPSS10.0 to the data. Make a statistical analysis.
Results the total distribution of genotypes between the 1. cases group and the control group was statistically significant (x ~2=138.4, df=2, P=8.85 x 10~ (-31)), and the difference of allele distribution between the case group and the control group was also statistically significant (x ~2=136.49, df=1, P=1.56 * 10~ (-31), OR= 0.73,95%CI:0.69-0.77) and the age of the patients was less than 20 years old and compared with the control. The differences in the distribution of genotypes and alleles at 25 loci were statistically significant (x ~2=140.93, df=2, P=2.50 x 10~ (-31), X ~2=140.42, df=1, P=2.16 * 10~ (-32), OR= 0.68,95%CI:0.63-0.72). The difference of genotype and allele distribution between the age 20 and the control was also statistically significant. 10~ (-10); X ~2=43.23, df=1, P=4.87 * 10~ (-11), OR 0.80,95%CI 0.74-0.85). There are significant differences in the genotype and allele distribution of the rs9468925 loci between the 20 years of age and the 20 year old patients. The differences in genotype and allele distribution of rs9468925 loci were statistically significant (x ~2=109.4, df=2, P=1.72 x 10~ (-24), X ~2=109.67, df=1, P=1.16 x 10~ (-25), OR=). Statistical significance (x ~2=63.79, df=2, P=1.41 x 10~ (-14); Chi ~2=58.71, df=1, P=1.83 * 10~ (-14), OR= 0.72,95%CI:0.66-0.78). There were statistical significance in the genotype between patients involving skin lesion area 5% and patients involving skin lesion area more than 5%. P=0.58, OR= 1.03,95%CI:0.94-1.12).4. family history positive patients compared with the control, rs9468925 locus genotype and allele distribution difference were statistically significant (x ~2=34.97, df=2, P=2.55 x 10~ (-8)). The difference of allele distribution was also statistically significant (x ~2=63.79, df=2, P=1.41 x 10~ (-14), X ~2=58.71, df=1, P=1.83 * 10~ (-14), OR= 0.72,95%CI:0.66-0.78). =0.96,95%CI:0.85-1.09) the differences in genotype and allele distribution of rs9468925 loci in.5. patients with autoimmune diseases were statistically significant (x ~2=14.23, df=2, P=0.001; Chi ~2=13.94, df=1, P=1.88 * 10~ (-4), OR=). The distribution of genotypes and alleles also had statistical significance (x ~2=132.93, df=2, P=1.36 x 10~ (-29), X ~2=131.18, df=1, P=1.93 * 10~ (-30), OR= 0.73,95%CI:0.69-0.77). There was no statistical difference between the genotype and allele distribution in patients with autoimmune diseases and patients without autoimmune disease. Significance (chi ~2=0.43, df=2, P=0.81; Chi ~2=0.57, df=1, P=0.45, OR= 1.09,95%CI:0.87-1.37).6. localized patients compared with the control, the differences in the genotype and allele distribution of the rs9468925 loci were statistically significant (x ~2=38.04, df=2). The distribution of genotypes and alleles of rs9468925 loci was also statistically significant (x ~2=121.83, df=2, P=3.51 x 10~ (-27), X ~2=119.87, df=1, P=6.76 x 10~ (-28), OR=). P=0.001; X ~2=13.31, df=1, P=2.64 x 10~ (-4), OR= 0.79,95%CI:0.73-0.85). Compared with the control, the differences in the genotype and allele distribution of the rs9468925 loci were also statistically significant (chi ~2=17.00, df=2, P=2.04 x). The distribution of genotype was statistically significant (x ~2=13.98, df=6, P=0.03), and allele distribution was not statistically significant (x ~2=6.74, df=3, P=0.08).
Conclusion the genetic polymorphism of rs9468925 in 1.MHC region is associated with susceptibility to vitiligo vulgaris in Han people. The genetic polymorphism of rs9468925 in the MHC region of patients with vitiligo in.2. Han people is significantly related to the age of onset.3., the genetic polymorphism of rs9468925 in the MHC region of the Han people with vitiligo is significantly related to the.4.MHC region rs9468925 inheritance. There is a significant correlation between polymorphism and the clinical type of vitiligo in Han people..MHC region rs9468925 genetic polymorphism has no family history of vitiligo, and it has a weak influence on autoimmune diseases. It may be related to different genetic basis and different pathogenesis of vitiligo.

【学位授予单位】：安徽医科大学
【学位级别】：硕士
【学位授予年份】：2011
【分类号】：R758.41

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