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Analysis of Coding SNPs in the HLA-DRB1 Gene and Association of Selected SNPs with Risk of Cervical Cancer

Author: LiYanZuo
Tutor: ZhangWeiMing；LiuWenTian；XingJun；WangDong
School: Tianjin Medical University
Course: Oncology
Keywords: bioinfonnatics single nucleotide polymorphisms cervical cancer HLA-DRB1 haplotypes linkage disequilibrium genotype
CLC: R737.33
Type: PhD thesis
Year: 2006
Downloads: 184
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Abstract


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.

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CLC: > Medicine, health > Oncology > Genitourinary tumors > Female genital tumors > Uterine tumors
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