HLA-DRB1基因编码区SNPs的分析及其与宫颈癌的相关性研究
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摘要
第1部分 HLA-DRB1基因编码区SNPs的筛选和预测
目的:HLA(human leukocyte antigen)基因多态性的差异在宫颈癌(cervical cancer,CC)的发病过程中发挥重要作用,本研究用生物信息学的方法筛选宫颈癌易感基因HLA-DRB1编码区的单核苷酸多态性(coding single nucleotide polymorphisms,cSNPs),并对其多态性的变异所引发的氨基酸变化是否会导致基因的功能异常进行分析和预测。
方法:以dbSNP数据库的SNPs为来源,用SNPper软件收集HLA-DRB1基因编码区的SNPs,使用PARSESNP软件对SNPs进行评价和分析,对候选SNPs位点在dbMHC数据库进行初步印证,然后对候选SNPs位点的相关信息进行收集和综合分析。
结果:在HLA-DRB1基因的编码区发现3个SNPs(rs1059582、rs1059576、rs1059586),其单核苷酸的变化会引发错义突变,PSSM Difference值(接近或大于10)较高,预测该SNPs为有害突变。另有两个SNPs(rs9269958、rs9269957)引发终止密码子的产生,经综合分析后调整为两组共同变异的SNPs(rs9269959-rs9269958、rs9269957-rs9269956),作为下游实验验证的候选SNPs。
小结:建立的生物信息学的方法可以对基因编码区的SNPs进行分析,在众多SNPs中搜寻出序列保守区的变异,并给出评价标准以衡量变异的有害程度,但是所得结果需要在宫颈癌患者与对照人群进行实验验证。
第2部分 HLA-DRB1基因EXON2的nsSNPs和单体型与宫颈癌的相关性研究
目的:探讨HLA-DRB1基因EXON2的非同义SNPs(non-synonymous SNPs,nsSNPs)和部分单体型与宫颈癌发病的相关性。
Part 1 Screening and Prediction for Coding SNPs of HLA-DRB1 Gene Involved in Susceptibility for Cervical CancerBACKGROUND & OBJECTIVE: Polymorphisms of human leukocyte antigen (HLA) gene play an important role in the development of cervical cancer (CC). To analyze coding single nucleotide polymorphisms (cSNPs) of the HLA-DRB1 gene involved in susceptibility for CC by a bioinformatics approach, we chose some SNPs that might have association with CC and predict variations that were likely to have functional effects.METHODS: By a SNPper tool we extracted cSNPs of HLA-DRB1 gene from a public database (dbSNP). Then we used PARSESNP as a tool for the analysis of cSNPs. These cSNPs needed to be validated from dbMHC database and other information about these cSNPs was also selected and analyzed.RESULTS: In cSNPs of the HLA-DRB1 gene, we found that rs1059582、 rs1059576 and rs1059586, were made up of missense mutations which convert a codon for one amino acid into a codon for another different amino acid. We chose a PSSM Difference as a level for the scores of changes predicted to be deleterious. The other two SNPs led to stop codons. We adjusted them as two groups (rs9269959 and rs9269958、 rs9269957 and rs9269956) after comprehensive analysis. CONCLUSION: We used a bioinformatics approach for cSNPs analysis of the HLA-DRB1 gene. This method can select the variants in a conserved region, and give a PSSM Difference score. But the results need to be verified in CC patients and a control population.Part 2 Association between nsSNPs and Haplotypes of HLA-DRB1 Gene exon2 and Cervical CancerBACKGROUND & OBJECTIVE: Polymorphisms of human leukocyte antigen (HLA) gene play an important role in the development of cervical cancer. In this study we investigated whether the distribution of non-synonymous SNPs (nsSNPs) and some haplotypes of HLA-DRB1 exon2 were associated with cervical cancer.
METHODS: Direct DNA sequencing of HLA-DRB1 gene exon2 and its intron flanking sequence was used to genotype the 55 nsSNPs in 30 cervical cancer patients and 66 control patients. Allele frequency and genotype frequency were analyzied. If the distribution were different, we would further analyze the haplotype associated with CC. RESULTS:1. The results of the cSNPs screened by bioinformatics tools.Rs9269959 and rs9269958, rs9269957 and rs9269956 belonged to triallelic or tetroallelic variations. They did not change to stop codons, which were different from bioinformatics prediction. We didn't further analyze them. Rs 1059582 locus was not detected, because it might be a SNP with very low frequency in population. The distribution of rslO59576 locus had not been found different between case-control patients. The distribution of rslO59586 locus was different between case-control patients (P=0.029,OR=2.657).2. Among the 55 SNPs of HLA-DRB1 exon2, 21 SNPs were not found in case-control patients, 9 SNPs were triallelic or tetroallelic variations, only 25 SNPs were biallelic variations. Among 25 SNPs successfully typed, 4 SNPs showed association with CC. Rs 17880292 (P=0.033,OR=0.322) and rslO59586 (P=0.029,OR=2.657) were associated with increased risk of CC. Rsl7879702 (P=0.016,OR=0.222) and rsl7882525 (P=0.025,OR=0.128) were associated with decreased risk ofCC.3. Pairwise linkage disequilibrium test was analyzed among rsl7879702-rs 17882525 (D' =0.9236, r2=0.5295) and rsl7880292-rsl059586 (D' = -0.0345, r2=0.0345).4. The haplotype of rsl7880292> rslO59586 and rsl7882525 loci were analyzied. The frequency of haplotype 5582A-5592A-5667T was significantly different between case-control patients (P=0.043, OR=2.735).CONCLUSION:1 Rsl7880292 heterzygous genotype G/A (5582A carriers) had higher risk than genotype G/G for CC. RslO59586 homozygous genotype A/A had higher risk than heterzygous genotype A/C and homozygous genotype C/C for CC. The results suggested these SNPs might confer susceptibility to CC. Rsl7879702 and rsl7882525 might be haplotype-tag SNPs (htSNPs) or belonged to some haplotypes, which might exert a protective effect against CC.
2. The result of pairwise linkage disequilibrium test suggested region of HLA-DRBl exon2 was recombination hot spot. There are a lot of haplotypes in this region. It is more complicated to investigate the association between the DNA variants and the development of CC.3. The results suggested that specific 5582A-5592A-5667T haplotype combinations, rather than individual rsl7880292 or rs!059586 alleles, might be a risk factor of CC.Part 3 Study of Association between HLA-DRBl Genotype and Cervical CancerBACKGROUND & OBJECTIVE: Polymorphisms of human leukocyte antigen (HLA) geneplay an important role in the development of cervical cancer. In this study we investigated theassociations between HLA-DRBl genotypes and CC.METHODS: 30 CC patients and 66 control patients were selected for the study. PCR-SBTmethod was used to genotyped for HLA-DRB1 gene.RESULTS:1. All of 13 different HLA-DRBl genotypes were detected for low resolution typing. DRBl*15s DRB1*O9, DRB1*12, DRB1*1K DRB1*O7, DRB 1*03 were the most common alleles. Their gene frequencies were 19.4%. 13.4%, 11.2%, 9.7%> 9.7% and 3.7% respectively.2. Thirty HLA-DRBl genotypes were detected for high resolution typing, 21 of those came from CC patients, 26 of those came from controls. The distribution of allele frequencies was different. The frequencies of HLA-DRB 1*1001 (OR, 7.222;95%C1, [0.719-72.559]) andDRBl*1101 (OR, 1.929;95%C1, [0.709-5.245]) were significantly increased in the CC patients. The frequencies of HLA-DRB1*12O2 (OR, 0.193;95%C1, [0.024-1.583]) and DRB1*13O2 were significantly decreased in the CC patients.CONCLUSION:1. The results were compared with other population in East Southern Asia and Beijing. The frequencies of HLA-DRBl genotypes were significantly different from that of East Southern Asia population, but similar to that of Beijing.2. Observations from this study confirmed earlier findings that HLA-DRB 1*1001 and HLA-DRB1*1101 might increase the risk for CC, but the results need to be further evaluated in different populations.
3. Observations from this study confirmed earlier findings that HLA-DRB 1*1202 and HLA-DRB 1*1302 might decrease the risk for CC, but the result need to be further evaluated in different populations. These results supported the hypothesis that multiple risk alleles were needed in order to increase risk for cervical neoplasia.
目的:HLA(human leukocyte antigen)基因多态性的差异在宫颈癌(cervical cancer,CC)的发病过程中发挥重要作用,本研究用生物信息学的方法筛选宫颈癌易感基因HLA-DRB1编码区的单核苷酸多态性(coding single nucleotide polymorphisms,cSNPs),并对其多态性的变异所引发的氨基酸变化是否会导致基因的功能异常进行分析和预测。
方法:以dbSNP数据库的SNPs为来源,用SNPper软件收集HLA-DRB1基因编码区的SNPs,使用PARSESNP软件对SNPs进行评价和分析,对候选SNPs位点在dbMHC数据库进行初步印证,然后对候选SNPs位点的相关信息进行收集和综合分析。
结果:在HLA-DRB1基因的编码区发现3个SNPs(rs1059582、rs1059576、rs1059586),其单核苷酸的变化会引发错义突变,PSSM Difference值(接近或大于10)较高,预测该SNPs为有害突变。另有两个SNPs(rs9269958、rs9269957)引发终止密码子的产生,经综合分析后调整为两组共同变异的SNPs(rs9269959-rs9269958、rs9269957-rs9269956),作为下游实验验证的候选SNPs。
小结:建立的生物信息学的方法可以对基因编码区的SNPs进行分析,在众多SNPs中搜寻出序列保守区的变异,并给出评价标准以衡量变异的有害程度,但是所得结果需要在宫颈癌患者与对照人群进行实验验证。
第2部分 HLA-DRB1基因EXON2的nsSNPs和单体型与宫颈癌的相关性研究
目的:探讨HLA-DRB1基因EXON2的非同义SNPs(non-synonymous SNPs,nsSNPs)和部分单体型与宫颈癌发病的相关性。
Part 1 Screening and Prediction for Coding SNPs of HLA-DRB1 Gene Involved in Susceptibility for Cervical CancerBACKGROUND & OBJECTIVE: Polymorphisms of human leukocyte antigen (HLA) gene play an important role in the development of cervical cancer (CC). To analyze coding single nucleotide polymorphisms (cSNPs) of the HLA-DRB1 gene involved in susceptibility for CC by a bioinformatics approach, we chose some SNPs that might have association with CC and predict variations that were likely to have functional effects.METHODS: By a SNPper tool we extracted cSNPs of HLA-DRB1 gene from a public database (dbSNP). Then we used PARSESNP as a tool for the analysis of cSNPs. These cSNPs needed to be validated from dbMHC database and other information about these cSNPs was also selected and analyzed.RESULTS: In cSNPs of the HLA-DRB1 gene, we found that rs1059582、 rs1059576 and rs1059586, were made up of missense mutations which convert a codon for one amino acid into a codon for another different amino acid. We chose a PSSM Difference as a level for the scores of changes predicted to be deleterious. The other two SNPs led to stop codons. We adjusted them as two groups (rs9269959 and rs9269958、 rs9269957 and rs9269956) after comprehensive analysis. CONCLUSION: We used a bioinformatics approach for cSNPs analysis of the HLA-DRB1 gene. This method can select the variants in a conserved region, and give a PSSM Difference score. But the results need to be verified in CC patients and a control population.Part 2 Association between nsSNPs and Haplotypes of HLA-DRB1 Gene exon2 and Cervical CancerBACKGROUND & OBJECTIVE: Polymorphisms of human leukocyte antigen (HLA) gene play an important role in the development of cervical cancer. In this study we investigated whether the distribution of non-synonymous SNPs (nsSNPs) and some haplotypes of HLA-DRB1 exon2 were associated with cervical cancer.
METHODS: Direct DNA sequencing of HLA-DRB1 gene exon2 and its intron flanking sequence was used to genotype the 55 nsSNPs in 30 cervical cancer patients and 66 control patients. Allele frequency and genotype frequency were analyzied. If the distribution were different, we would further analyze the haplotype associated with CC. RESULTS:1. The results of the cSNPs screened by bioinformatics tools.Rs9269959 and rs9269958, rs9269957 and rs9269956 belonged to triallelic or tetroallelic variations. They did not change to stop codons, which were different from bioinformatics prediction. We didn't further analyze them. Rs 1059582 locus was not detected, because it might be a SNP with very low frequency in population. The distribution of rslO59576 locus had not been found different between case-control patients. The distribution of rslO59586 locus was different between case-control patients (P=0.029,OR=2.657).2. Among the 55 SNPs of HLA-DRB1 exon2, 21 SNPs were not found in case-control patients, 9 SNPs were triallelic or tetroallelic variations, only 25 SNPs were biallelic variations. Among 25 SNPs successfully typed, 4 SNPs showed association with CC. Rs 17880292 (P=0.033,OR=0.322) and rslO59586 (P=0.029,OR=2.657) were associated with increased risk of CC. Rsl7879702 (P=0.016,OR=0.222) and rsl7882525 (P=0.025,OR=0.128) were associated with decreased risk ofCC.3. Pairwise linkage disequilibrium test was analyzed among rsl7879702-rs 17882525 (D' =0.9236, r2=0.5295) and rsl7880292-rsl059586 (D' = -0.0345, r2=0.0345).4. The haplotype of rsl7880292> rslO59586 and rsl7882525 loci were analyzied. The frequency of haplotype 5582A-5592A-5667T was significantly different between case-control patients (P=0.043, OR=2.735).CONCLUSION:1 Rsl7880292 heterzygous genotype G/A (5582A carriers) had higher risk than genotype G/G for CC. RslO59586 homozygous genotype A/A had higher risk than heterzygous genotype A/C and homozygous genotype C/C for CC. The results suggested these SNPs might confer susceptibility to CC. Rsl7879702 and rsl7882525 might be haplotype-tag SNPs (htSNPs) or belonged to some haplotypes, which might exert a protective effect against CC.
2. The result of pairwise linkage disequilibrium test suggested region of HLA-DRBl exon2 was recombination hot spot. There are a lot of haplotypes in this region. It is more complicated to investigate the association between the DNA variants and the development of CC.3. The results suggested that specific 5582A-5592A-5667T haplotype combinations, rather than individual rsl7880292 or rs!059586 alleles, might be a risk factor of CC.Part 3 Study of Association between HLA-DRBl Genotype and Cervical CancerBACKGROUND & OBJECTIVE: Polymorphisms of human leukocyte antigen (HLA) geneplay an important role in the development of cervical cancer. In this study we investigated theassociations between HLA-DRBl genotypes and CC.METHODS: 30 CC patients and 66 control patients were selected for the study. PCR-SBTmethod was used to genotyped for HLA-DRB1 gene.RESULTS:1. All of 13 different HLA-DRBl genotypes were detected for low resolution typing. DRBl*15s DRB1*O9, DRB1*12, DRB1*1K DRB1*O7, DRB 1*03 were the most common alleles. Their gene frequencies were 19.4%. 13.4%, 11.2%, 9.7%> 9.7% and 3.7% respectively.2. Thirty HLA-DRBl genotypes were detected for high resolution typing, 21 of those came from CC patients, 26 of those came from controls. The distribution of allele frequencies was different. The frequencies of HLA-DRB 1*1001 (OR, 7.222;95%C1, [0.719-72.559]) andDRBl*1101 (OR, 1.929;95%C1, [0.709-5.245]) were significantly increased in the CC patients. The frequencies of HLA-DRB1*12O2 (OR, 0.193;95%C1, [0.024-1.583]) and DRB1*13O2 were significantly decreased in the CC patients.CONCLUSION:1. The results were compared with other population in East Southern Asia and Beijing. The frequencies of HLA-DRBl genotypes were significantly different from that of East Southern Asia population, but similar to that of Beijing.2. Observations from this study confirmed earlier findings that HLA-DRB 1*1001 and HLA-DRB1*1101 might increase the risk for CC, but the results need to be further evaluated in different populations.
3. Observations from this study confirmed earlier findings that HLA-DRB 1*1202 and HLA-DRB 1*1302 might decrease the risk for CC, but the result need to be further evaluated in different populations. These results supported the hypothesis that multiple risk alleles were needed in order to increase risk for cervical neoplasia.
引文
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