中华骨髓库四川分库汉族人群HLA-C等位基因分布
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摘要
目的：
研究四川骨髓库中川籍汉族人群HLA-C等位基因的分布特征。
方法：
样本来源于2008.12--2009.3四川骨髓库街头采集的川籍汉族无血缘关系志愿者血样244份,采用PCR-SBT对样本HLA-C位点第2-4外显子进行序列分析。对得到的模棱两可分型结果通过组特异性测序和加测相应外显子来确认。采用直接计数法计算HLA-C等位基因频率,并通过卡方检验比较HLA-C等位基因在不同人群中的分布差异。采用最大似然法计算HLA-A-C、HLA-C-B和HLA-A-C-B-DRB1单体型频率,并对两座位单体型进行了连锁不平衡参数分析。
结果：
244份标本中,可直接得到HLA-C位点高分辨分型结果的68份,呈现模棱两可结果的176份,其中通过组特异性测序及加测外显子确认的90份,单通过加测外显子确认的59份,通过组特异性测序确认的27份,这27份中含新等位基因标本1份。本研究共检出HLA-C位点已知等位基因24种及新等位基因1种。HLA-C等位基因频率>10%的3种：C*01：02(21.93%)、C*07：02(18.65%)和C*03：04(13.11%),累积频率53.68%。HLA-C等位基因频率>1%的12种,累积频率95.69%。同其他人群资料相比,四川骨髓库汉族人群HLA-C等位基因的分布与国内南方人群最为接近,而与欧裔美国人和美国黑人差异最大。经最大似然法计算,四川骨髓库汉族人群中HLA-A-C、HLA-C-B和HLA-A-C-B- DRB1单体型分别有100条、96条和302条,且相应的优势单体型为A*02：07-C*01：02(9.7125%)、C*01：02-B*46：01(15.1043%)和A*02：07-C*01：02-B*46：01-DRB1*09：01(5.1708%)。另外,分别有9条HLA-A-C单体型和23条HLA-C-B单体型呈现显著的连锁不平衡。同时,本次研究发现了1例HLA-C新等位基因1C*06：45,其与同源性最高的C*06：02在第187位碱基存在1个点突变：G>T,使密码子39由GAC>TAC,导致编码的氨基酸由天门冬氨酸(Asp)>酪氨酸(Tyr)。在此之前此位点尚未发现过碱基突变。
结论：
本研究建立了针对HLA-C等位基因第2-4外显子的直接测序法,并通过组特异性测序和加测外显子解决了模棱两可结果,得到了四川骨髓库汉族人群C等位基因的分布特征,其总体分布符合南方地区人群特征,并有其自身特点。
Objective
To investigate the allelic distribution of HLA-C locus in Han individuals from Sichuan branch of Chinese Marrow Donor Program (CMDP).
Methods
A total of 244 peripheral blood DNA samples, consecutively collected from unrelated donors during Dec.2008 and Mar.2009, were randomly chosen. Exon 2,3 and 4 of each sample were sequenced using PCR-SBT. Additional exon sequencing and group-specific sequencing were performed to resolve the allele ambiguities. Allele frequencies were calculated by direct counting and the chi-square values of allele frequencies from different populations were also analyzed. Haplotype frequencies of HLA-A-C, HLA-C-B and HLA-A-C-B-DRB1 were calculated by expectation-maximization method, and the linkage disequilibrium for two-locus haplotypes was analyzed.
Results
Of the 244 samples,68 showed conclusive typing results, and the remaining 176 samples showed ambiguity results. As to the 176 inconclusive samples,90 samples were resolved by group-specific sequencing and additional exon sequencing both, and 59 were resolved just by additional exon sequencing, and 27 were resolved by group-specific sequencing, including one sample with a novel HLA-C allele. In our study, a total of 24 different HLA-C alleles and a novel allele were identified. The most common alleles, with the allele frequency of more than 10%, were C*01:02 (21.93%), C*07:02 (18.65%) and C*03:04 (13.11%), which comprised 53.68% of the total alleles identified in our study. And 12 kinds of allele were detected with the allele frequency of more than 1%, which comprised 95.69% of the total alleles identified in our study. Comparison of the HLA-C allelic distribution with different populations showed that little difference was observed between Sichuan Han and southern Chinese population, whereas there were many significant differences between Sichuan Han and Eastern European American /African American populations. Expectation-maximization revealed 100 kinds of HLA-A-C,96 of HLA-C-B and 302 of HLA-A-C-B-DRB1 haplotypes, and the most frequent haplotype for A-C, C-B and A-C-B-DRB1 haplotype was A*02:07-C*01:02 (9.7125%), C*01:02-B*46:01 (15.1043%) and A*02:07-C*01:02-B*46:01-DRB1*09:01 (5.1708%), respectively. Linkage disequilibrium estimation of the association of two alleles from different two loci showed that 9 of HLA-A-C, and 23 of HLA-C-B had significant LD. In additional, a novel HLA-C allele C*06:45 was found in our study. This novel allele differed from the closet matching allele C*06:02 by a missense nucleotide substitution at the first position of codon 39(GAC>TAC), resulting in an amino acid changed from Asp to Tyr. Interestingly, no substitution at this conserved codon had ever been found before.
Conclusion
A reliable HLA-C SBT technique, from exon 2 through exon 4, has been established in our study. In additional, all the allele ambiguities are resolved by group-specific sequencing and additional exon sequencing. The HLA-C allelic distribution and haplotype analysis demonstrate that the Sichuan Han population share HLA patterns with southern Chinese, while it also retains unique characteristics.
研究四川骨髓库中川籍汉族人群HLA-C等位基因的分布特征。
方法：
样本来源于2008.12--2009.3四川骨髓库街头采集的川籍汉族无血缘关系志愿者血样244份,采用PCR-SBT对样本HLA-C位点第2-4外显子进行序列分析。对得到的模棱两可分型结果通过组特异性测序和加测相应外显子来确认。采用直接计数法计算HLA-C等位基因频率,并通过卡方检验比较HLA-C等位基因在不同人群中的分布差异。采用最大似然法计算HLA-A-C、HLA-C-B和HLA-A-C-B-DRB1单体型频率,并对两座位单体型进行了连锁不平衡参数分析。
结果：
244份标本中,可直接得到HLA-C位点高分辨分型结果的68份,呈现模棱两可结果的176份,其中通过组特异性测序及加测外显子确认的90份,单通过加测外显子确认的59份,通过组特异性测序确认的27份,这27份中含新等位基因标本1份。本研究共检出HLA-C位点已知等位基因24种及新等位基因1种。HLA-C等位基因频率>10%的3种：C*01：02(21.93%)、C*07：02(18.65%)和C*03：04(13.11%),累积频率53.68%。HLA-C等位基因频率>1%的12种,累积频率95.69%。同其他人群资料相比,四川骨髓库汉族人群HLA-C等位基因的分布与国内南方人群最为接近,而与欧裔美国人和美国黑人差异最大。经最大似然法计算,四川骨髓库汉族人群中HLA-A-C、HLA-C-B和HLA-A-C-B- DRB1单体型分别有100条、96条和302条,且相应的优势单体型为A*02：07-C*01：02(9.7125%)、C*01：02-B*46：01(15.1043%)和A*02：07-C*01：02-B*46：01-DRB1*09：01(5.1708%)。另外,分别有9条HLA-A-C单体型和23条HLA-C-B单体型呈现显著的连锁不平衡。同时,本次研究发现了1例HLA-C新等位基因1C*06：45,其与同源性最高的C*06：02在第187位碱基存在1个点突变：G>T,使密码子39由GAC>TAC,导致编码的氨基酸由天门冬氨酸(Asp)>酪氨酸(Tyr)。在此之前此位点尚未发现过碱基突变。
结论：
本研究建立了针对HLA-C等位基因第2-4外显子的直接测序法,并通过组特异性测序和加测外显子解决了模棱两可结果,得到了四川骨髓库汉族人群C等位基因的分布特征,其总体分布符合南方地区人群特征,并有其自身特点。
Objective
To investigate the allelic distribution of HLA-C locus in Han individuals from Sichuan branch of Chinese Marrow Donor Program (CMDP).
Methods
A total of 244 peripheral blood DNA samples, consecutively collected from unrelated donors during Dec.2008 and Mar.2009, were randomly chosen. Exon 2,3 and 4 of each sample were sequenced using PCR-SBT. Additional exon sequencing and group-specific sequencing were performed to resolve the allele ambiguities. Allele frequencies were calculated by direct counting and the chi-square values of allele frequencies from different populations were also analyzed. Haplotype frequencies of HLA-A-C, HLA-C-B and HLA-A-C-B-DRB1 were calculated by expectation-maximization method, and the linkage disequilibrium for two-locus haplotypes was analyzed.
Results
Of the 244 samples,68 showed conclusive typing results, and the remaining 176 samples showed ambiguity results. As to the 176 inconclusive samples,90 samples were resolved by group-specific sequencing and additional exon sequencing both, and 59 were resolved just by additional exon sequencing, and 27 were resolved by group-specific sequencing, including one sample with a novel HLA-C allele. In our study, a total of 24 different HLA-C alleles and a novel allele were identified. The most common alleles, with the allele frequency of more than 10%, were C*01:02 (21.93%), C*07:02 (18.65%) and C*03:04 (13.11%), which comprised 53.68% of the total alleles identified in our study. And 12 kinds of allele were detected with the allele frequency of more than 1%, which comprised 95.69% of the total alleles identified in our study. Comparison of the HLA-C allelic distribution with different populations showed that little difference was observed between Sichuan Han and southern Chinese population, whereas there were many significant differences between Sichuan Han and Eastern European American /African American populations. Expectation-maximization revealed 100 kinds of HLA-A-C,96 of HLA-C-B and 302 of HLA-A-C-B-DRB1 haplotypes, and the most frequent haplotype for A-C, C-B and A-C-B-DRB1 haplotype was A*02:07-C*01:02 (9.7125%), C*01:02-B*46:01 (15.1043%) and A*02:07-C*01:02-B*46:01-DRB1*09:01 (5.1708%), respectively. Linkage disequilibrium estimation of the association of two alleles from different two loci showed that 9 of HLA-A-C, and 23 of HLA-C-B had significant LD. In additional, a novel HLA-C allele C*06:45 was found in our study. This novel allele differed from the closet matching allele C*06:02 by a missense nucleotide substitution at the first position of codon 39(GAC>TAC), resulting in an amino acid changed from Asp to Tyr. Interestingly, no substitution at this conserved codon had ever been found before.
Conclusion
A reliable HLA-C SBT technique, from exon 2 through exon 4, has been established in our study. In additional, all the allele ambiguities are resolved by group-specific sequencing and additional exon sequencing. The HLA-C allelic distribution and haplotype analysis demonstrate that the Sichuan Han population share HLA patterns with southern Chinese, while it also retains unique characteristics.
引文
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8. Itoh Y, Mizuki N, Shimada T, et al. High-throughput DNA typing of HLA-A,-B,-C and -DRB1 loci by a PCR-SSOP-Luminex method in the Japanese population. Immunogenet,2005,57(10):717-729.
9. Mack SJ, Tu B, Lazaro A, et al. HLA-A,-B,-C. and -DRB1 allele and haplotype frequencies distinguish Eastern European American from the general European American population. Tissue Antigens,2009,73(1):17-32.
10. Tu B, Mack SJ, Lazaro A, et al. HLA-A,-B,-C,-DRB1 allele and haplotype frequencies in an African American population. Tissue Antigens,2007, 69(1):73-85.
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17. Petersdorf EW, Longton GM, Anasetti C, et al. Association of HLA-C disparity with graft failure after marrow transplantation from unrelated donors. Blood,1997,89(5):1818-1823.
18. Sasazuki T, Juji T, Morishima Y, et al.Effect of Matching of Class I HLA Alleles on Clinical Outcome after Transplantation of Hematopoietic Stem Cells from an Unrelated Donor. N Engl J Med,1998,339(17):1177-1185.
19. Morishima Y, Sasazuki T, Inoko H, et al. The clinical significant of human leukocyte antigen(HLA) allele compatibility in patients receiving a marrow transplant from serologically HLA-A, HLA-B, and HLA-DR matched unrelated donors. Blood,2002,99(11):4200-4206.
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21. Bray AR, Hurley KC, Kamani RN, et al. National marrow donor program HLA matching guidelines for unrelated adult donor hematopoietic cell transplantation. Biol of Blood and Marrow Transplant,2008,14(1):45-53.
22. Flomenberg N. Baxter-Lowe LA, Confer D, et al. Impact of HLA class Ⅰ and Ⅱ high resolution matching on outcomes of unrelated donor bone marrow transplantation:HLA-C mismatching is associated with a strong adverse effect on transplantation outcome. Blood,2004,104(7):1923-1930.
23. Petersdorf EW, Anasetti C, Martin PJ, et al. Limits of HLA mismatching in unrelated hematopoietic cell transplantation. Blood,2004, 104(9):2976-2980.
24. Ho VT, Kim HT, Liney D, et al. Post-Transplant Events HLA-C mismatch is associated with inferior survival after unrelated donor non-myeloablative hematopoietic stem cell transplantation. Bone Marrow Transplant,2006,37(9):845-850.
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27. Kawase T, Morishima Y, Matsuo K, et al. High-risk HLA allele mismatch combinations responsible for severe acute graft-versus-host disease and implication for its molecular mechanism. Blood,2007,110(19):2235-2241.
28. Kawase T, Matsuo K, Kashiwase K, et al. HLA mismatch combination associated with decreased risk of relapse:implication for the molecular mechanism. Blood,2009,113(6):2851-2858.
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33. Ruggeri L, Capanni M, Urbani E, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science,2002, 295(5562):2097-2100.
34. Hsu KC, Pinto-Agnello C, Gooley T, et al.Hematopoietic stem cell transplantation:killer immunoglobulin-like receptor component. Tissue Antigens, 2007,69 (Suppl S1):42-45.
2. HLA database:statistics. http://www.ebi.ac.uk/imgt/hla/ambig.html http://www.ebi.ac.uk/imgt/hla.html
3. Petersdorf EW, Longton GM, Anasetti C, et al. Association of HLA-C disparity with graft failure after marrow transplantation from unrelated donors. Blood,1997,89(5):1818-1823.
4. Sasazuki T. Juji T, Morishima Y, et al. Effect of matching of Class I HLA alleles on clinical outcome after transplantation of hematopoietic stem cells from an unrelated donor. N Engl J Med,1998,339(17):1177-1185.
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