Impact of hHLA-DPB1 matching on clinical outcomes after haploidentical-related hematopoietic stem cell transplantation

ABSTRACT Background: The impact of HLA-DPB1 compatibility and its role as a transplantation antigen in haploidentical-related hematopoietic stem cell transplant (haplo-R-HSCT) have not been established, and a negative effect on survival has been suggested. Objective: The objective of the determine was to study the frequency and clinical effects of incompatibility at the HLA-DPB1 locus in the haplo-R-HSCT setting. Methods: Clinical records and electronic files of 91 patients with a hematological disease who underwent haplo-HSCT from January 2009 to October 2017 in a university medical center were scrutinized. Overall survival (OS) was estimated by the Kaplan-Meier method; the cumulative incidence of transplant-related mortality (TRM) and relapse rates was determined. Acute graft-versus-host disease was assessed by binary logistic regression. Cox regression model with a 95% confidence interval was used to examine the association between the different variables and their effect on OS. Results: Of the 91 donor-recipient pairs, 24 (26.37%) shared complete DPB1 identity, 60 (65.93%) had a mismatch at one allele, and 7 (7.70%) were mismatched at two alleles. Twenty-four different HLA-DPB1 alleles were found; the most frequent were DPB1*04:01 (34.1%) and DPB1*04:02 (27.5%). Two-year OS, the cumulative incidence of TRM and relapse was 51.3 ± 6.8%, 28 ± 6% and 60 ± 7.8% for all haplo-related transplants, respectively, with no statistical difference between HLA-DPB1 matched and partially matched patients. In Cox regression analysis, no risk factors associated with OS, TRM, or relapses were identified. Conclusion: HLA-DPB1 mismatching in the haplo-R-HSCT setting did not influence transplant outcomes and was clinically tolerable. A high degree of homozygosity was found.

Establishment of a polymerase chain reaction sequencing based typing method for HLA-DPB1 exons 2 and 3 and investigation of their polymorphisms / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To establish a polymerase chain reaction sequencing-based typing (PCR SBT) method for HLA-DPB1 exons 2 and 3, and to analyze their polymorphisms.</p><p><b>METHODS</b>Based on the sequences of HLA-DPB1 loci, locus-specific primers were designed and applied to amplify the target sequences encompassing the entire exons 2 and 3 of HLA-DPB1. The amplification products were digested by enzymes and directly sequenced in both directions. The genotype was assigned by Assign 3.5+ SBT software.</p><p><b>RESULTS</b>Specific target fragment was obtained with the PCR amplification, and good quality electropherogram was derived by direct sequencing. Among 242 individuals from Zhejiang Han population, 18 HLA-DPB1 alleles were detected. Alleles with a frequency of > 0.05 have included DPB1*05:01:01/135:01 (0.4112), DPB1*02:01:02 (0.1901), DPB1*04:01:01 (0.1136) and DPB1*02:02 (0.0620). A novel HLA-DPB1*168:01 allele has also been identified. Nine polymorphism sites were founded in the exon 3 region, which included a new SNP site 517 A>T.</p><p><b>CONCLUSION</b>The PCR-SBT method for exons 2 and 3 of HLA-DPB1 is reliable, which allowed detection of polymorphisms in exon 3 of the HLA-DPB1 gene.</p>

Association of HLA-DPA1 and -DPB1 polymorphisms with Posner-Schlossman syndrome among southern Chinese Han population / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To assess the association of HLA-DPA1 and -DPB1 polymorphisms with Posner-Schlossman syndrome (PSS) in southern Chinese Han population.</p><p><b>METHODS</b>A total of 100 randomly selected PSS patients of southern Chinese Han origin were served as the experimental group, while 128 unrelated healthy blood donors of the same origin were served as the control group. All samples were subjected to sequencing-based typing (SBT) for exon 2 of HLA-DPA1 and -DPB1 loci in both directions. HLA genotype was assigned using an Assign 3.5 HLA SBT software. The allele frequencies and haplotype frequencies of HLA-DPA1 and -DPB1 of the two groups were compared. x² test, P value and odds ratio (OR) value were calculated.</p><p><b>RESULTS</b>Six HLA-DPA1 alleles in the experimental group and 4 HLA-DPA1 alleles in the healthy control group were identified. The allelic frequency for HLA-DPA1*02:01 in the experimental group was significantly lower than the control group (4.50% vs. 12.109%; x²=8.124, P=0.004). Sixteen HLA-DPB1 alleles were identified in both the experimental and control groups. The allelic frequencies for HLA-DPB1*14:01 and - DPB1*17:01 in the experimental group were significantly lower than those of the control group ( DPB1*14:01: 1.00% vs. 4.688%, x²=5.130, P=0.024; DPB1*17:01: 0% vs. 2.344%, x²=3.897, P=0.048). The DPA1-DPB1 haplotypes for the experimental and control groups were 23 and 25, respectively. The haplotype frequencies for both DPA1*02:01- DPB1*14:01 and DPA1*02:01- DPB1*17:01 were significantly lower than those of the control group.</p><p><b>CONCLUSION</b>DPA1*02:01- DPB1*14:01 and DPA1*02:01- DPB1*17:01 haplotypes may provide considerable protection effect against PSS in the southern Chinese Han population.</p>

Clinical significance of HLA-DRB1 and HLA-DPB1 gene polymorphisms in cirrhosis patients / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To investigate the genetic association between cirrhosis and polymorphisms in the genes encoding major histocompatibility complex, class II (HLA)-DR beta 1 (DRB1) and HLA-DP beta 1 (DPB1).</p><p><b>METHODS</b>A population of 168 parent/offspring trios, in which the proband had a diagnosis of hepatitis B virus infection with clinical signs of cirrhosis.The HLA-DRB1 and DPB 1 gene polymorphisms of rs24755213 and rs202176660 were detected by PCR and single nucleotide polymorphism (SNP) genotyping.Correlation analysis and haplotype relative risk analysis were carried out.</p><p><b>RESULTS</b>A/G genotypes were detected in rs24755213 of HLA-DRB1 and C/T genotypes were detected in rs202176660 of DPB1.The rs24755213 allele was associated with cirrhosis (P=0.014), with the G allele identified as a protective factor (Z=-2.33) and the A allele identified as a hazard factor (Z=2.33).The rs202176660 allele was also associated with cirrhosis (P =0.026), with the T allele identified as a protective factor (Z=-2.06) and the C allele identified as a hazard factor (Z=2.06).The haplotypes of G/T and A/C in rs24755213 and rs202176660 respectively were associated with cirrhosis (P =0.037 and 0.002, Z=-2.12 and 2.09 respectively).</p><p><b>CONCLUSION</b>In this group of Chinese patients with hepatitis B virus-related cirrhosis, polymorphisms in the HLA-DRB 1 and DPB1 genes were associated with cimhosis.</p>

A study of HLA-DPA1 and DPB1 matching status for unrelated donor-recipient pairs matched at allele level for HLA-A, -B, -C, -DRB1 and -DQB1 loci / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To analyze the status of HLA-DPA1 and DPB1 matching for unrelated donor-recipient pairs matched at high-resolution allele level for HLA-A, B, C, DRB1 and DQB1 loci.</p><p><b>METHODS</b>A total of 76 unrelated donor-recipient pairs matching at allele level for HLA-A, B, C, DRB1 and DQB1 loci were subjected to HLA-DPA1 and DPB1 sequence-based typing (SBT). HLA-DPA1and DPB1 matching status at high-resolution allelic level was also analyzed.</p><p><b>RESULTS</b>The allelic identity ratio for single HLA-DPA1 and DPB1 were 17.1% and 9.2%, respectively. HLA-DPA1 and DPB1 allelic identity ratio were both very low. The majority of unrelated donor-recipient pairs (73.7%) had an incompatibility at 1 HLA-DPA1 allele, 9.2% of pairs had an incompatibility at 2 DPA1 alleles. As for the high-polymorphic HLA-DPB1 gene, 57.9% of studied donor-recipient pairs had an incompatibility at 1 HLA-DPB1 allele, almost 1/3 (32.9%) of them were completely incompatible. When HLA-DPA1 and DPB1 genes were analyzed together, the donor-recipient pairs matched at 2/4 was the most common (51.4%), 4/4 allelic complete matched pairs accounted for 5.6%, and 0/4 matched pairs accounted for 8.3%.</p><p><b>CONCLUSION</b>Our results indicated that the ratio of HLA-DPA1 and DPB1 complete match in the unrelated donor-recipient pairs matching at allelic level for HLA-A, B, C, DRB1 and DQB1 loci were very low. The effect of HLA-DPA1 and DPB1 matching status on clinical unrelated stem cell transplantation still needs to be elucidated.</p>

Development of a high-throughput sequence-based typing assay for human leukocyte antigen loci / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To develop a reliable assay for simultaneous sequence-based typing (SBT) of HLA-DPA1 and HLA-DPB1, and to apply it for the study of allelic polymorphisms in southern Chinese Han population.</p><p><b>METHODS</b>Based on full-length HLA-DPA1 and HLA-DPB1 allelic sequences, locus-specific PCR primers were designed and applied to amplify the target sequence encompassing the entire exon 2 of HLA-DPA1 and HLA-DPB1. PCR products were purified with magnetic beads, and run through an ABI 3730 DNA sequencer. Genotypes were assigned with an Assign 3.5 SBT software.</p><p><b>RESULTS</b>The target sequences of HLA-DPA1 and HLA-DPB1 were both amplified with the PCR procedure. Little background and noise was observed in the derived sequences. Among 176 non-related healthy individuals, 4 HLA-DPA1 alleles with the frequencies of DPA1*02:02 (0.589) > DPA1*01:03 (0.284) > DPA1*02:01 (0.096) > DPA1*04:01 (0.031) were identified. In addition, 14 HLA-DPB1 alleles, including 4 common alleles (with a frequency of more than 5%, namely DPB1*05:01, DPB1*02:01, DPB1*04:01 and DPB1*02:02), 7 alleles with a frequency ranging from 1%-5% and 3 alleles with a frequency of less than 1% were identified. The results of HLA-DPB1 genotyping were all in accordance with the typing results derived from an Atria AlleleSEQR HLA-DPB1 kit.</p><p><b>CONCLUSION</b>A reliable technique has been established for simultaneous genotyping of HLA-DPA1 and HLA-DPB1, which may have a broad application in population and disease association studies.</p>

Analysis of the HLA-DPA1 and HLA-DPB1 polymorphism of Zhejiang Han population by PCR-sequence based typing / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To investigate the polymorphisms of HLA-DPA1 and HLA-DPB1 loci of Han population in Zhejiang province of China.</p><p><b>METHODS</b>The alleles of HLA-DPA1 and HLA-DPB1 loci in 100 unrelated healthy individuals were analyzed using polymerase chain reaction-sequence based typing.</p><p><b>RESULTS</b>Eight HLA-DPA1 alleles and 19 HLA-DPB1 alleles were found in the population. The HLA-DPA1 alleles with higher frequencies were DPA1*020202 (47.0%), DPA1*010301 (38.5%) and DPA1*020101(10.5%). The HLA-DPB1 alleles with higher frequencies were DPB1*0501, DPB1*020102 and DPB1*040101. The frequencies were 39.5%, 13.5% and 13.0%, respectively. A total of 44 estimated DPA1-DPB1 haplotypes were detected. The HLA-DPA1*020202-DPB1*0501(29.5%) was the most frequent haplotype.</p><p><b>CONCLUSION</b>The polymorphism data of the HLA-DPA1 and -DPB1 were obtained in Han population in Zhejiang province of China. There was linkage disequilibrium between the two loci.</p>

Association of regulatory region of HLA-DPB1 with nasopharyngeal carcinoma in southern Chinese Hans / 临床耳鼻咽喉头颈外科杂志

OBJECTIVE@#To clarify the association between regulatory region of HLA-DPB1 (3'UTR) with Naso pharyngeal carcinoma in Guangdong Province Hans.@*METHOD@#The allelic types of HLA-DPB1-3'UTR were detected by sequence specific primer (SSP) in 104 patients with NPC and 105 control individuals from Guangdong Province Hans.@*RESULT@#The frequencies of allelic types B/B, haplotype B were higher in patients with NPC than those of the control individuals.@*CONCLUSION@#Positive association may exist between certain HLA-DPB1 alleles and NPC in Guangdong Province Hans.

cDNA microarray and cluster analysis to identify the significance of immune genes associated with benzene poisoning / 中华劳动卫生职业病杂志

<p><b>OBJECTIVE</b>To delineate the immune regulatory pathway of benzene poisoning by using gene expression profile analysis.</p><p><b>METHODS</b>Peripheral white blood cell gene expression profile of 7 benzene poisoning patients, including one aplastic anemia, was determined by microarray. Seven chips from normal workers were served as controls. Cluster analysis of gene expression profile was performed. Differentially expressed immune genes associated with benzene poisoning were determined.</p><p><b>RESULTS</b>Among the 2 779 target genes, 38 genes differentially expressed were identified, including 10 up-regulated genes such as CD59, TRA@, MCP etc, and 14 down-regulated genes such as HLA-DMB, HLA-DQA1, HLA-DPB1, ITGB2, PFC etc. Cluster analysis showed that the expression profiles of 38 genes were associated with benzene poisoning.</p><p><b>CONCLUSION</b>Differentially expressed immune genes may play an important role in the pathogenesis of benzene poisoning.</p>

Association of HLA-DPB1 alleles with chronic myelogenous leukemia in southern Chinese Hans / 中国实验血液学杂志

To clarify the association between HLA-DPB1 alleles and chronic myelogenous leukemia (CML) in South Chinese, the allelic types of HLA-DPB1 were detected by sequence based typing (SBT) in 86 patients with CML and 82 healthy individuals from Southern China. The results showed that the frequencies of HLA-DPB1 * 1301 and DPB1 * 20011 were higher in patients with CML in comparison with those of healthy individuals. It is concluded that positive association may exist between certain HLA-DPB1 alleles and CML.