Relative predispositional effects of HLA class II DRB1-DQB1 haplotypes and genotypes on type 1 diabetes: a meta-analysis.

The direct involvement of the human leukocyte antigen class II DR-DQ genes in type 1 diabetes (T1D) is well established, and these genes display a complex hierarchy of risk effects at the genotype and haplotype levels. We investigated, using data from 38 studies, whether the DR-DQ haplotypes and genotypes show the same relative predispositional effects across populations and ethnic groups. Significant differences in risk within a population were considered, as well as comparisons across populations using the patient/control (P/C) ratio. Within a population, the ratio of the P/C ratios for two different genotypes or haplotypes is a function only of the absolute penetrance values, allowing ranking of risk effects. Categories of consistent predisposing, intermediate ('neutral'), and protective haplotypes were identified and found to correlate with disease prevalence and the marked ethnic differences in DRB1-DQB1 frequencies. Specific effects were identified, for example for predisposing haplotypes, there was a statistically significant and consistent hierarchy for DR4 DQB1*0302s: DRB1*0405 =*0401 =*0402 > *0404 > *0403, with DRB1*0301 DQB1*0200 (DR3) being significantly less predisposing than DRB1*0402 and more than DRB1*0404. The predisposing DRB1*0401 DQB1*0302 haplotype was relatively increased compared with the protective haplotype DRB1*0401 DQB1*0301 in heterozygotes with DR3 compared with heterozygotes with DRB1*0101 DQB1*0501 (DR1). Our results show that meta-analyses and use of the P/C ratio and rankings thereof can be valuable in determining T1D risk factors at the haplotype and amino acid residue levels.

HLA associations, microsatellite instability and epigenetic changes in thyroid lymphoma in Chinese.

In Chinese, autoimmune thyroid disease (AITD) is very common but lymphoma of the thyroid is a rare disease. Southern Chinese AITD is common in females and is strongly linked to the HLA haplotype A2B46DR9. We studied the HLA association, aberration p15, p16 and p73 promoter methylation and microsatellite instability in Chinese primary thyroid lymphoma patients to elucidate their relationship with AITD and the relationship between thyroid diffuse large cell lymphoma (DLCL) and marginal zone lymphomas (MZL). Despite a female preponderance (8:1) and the finding of cases with histological and immunological evidence of AITD, a significant HLA association was not found. MSI was absent, but aberrant promoter methylation was found in both thyroid MZL and DLCL and p73 methylation was unexpectedly common.

HLA-B67 may be a male-specific HLA marker of susceptibility to relapsed childhood ALL in Hong Kong Chinese and HLA-A33 or HLA-B17 signifies a higher presentation leukocytosis: A retrospective analysis on 53 transplant candidates (1989-2003).

We performed a retrospective analysis on the human leukocyte antigen (HLA) data of 53 consecutive Chinese patients with high-risk childhood acute lymphoblastic leukemia (ALL) diagnosed from 1989 to 2003. A significantly higher frequency of HLA-B67 in the male relapse group of patients [OR, 23.08; 95% CI, 5.31-100.36; p = 0.0042; for statistical significance after Bonferroni correction (Bc) p (Bc) < 0.0083] was identified after Bonferroni correction. Although not surviving the Bonferroni correction, gender effects on the association were also observed with HLA-A11, HLA-A32, HLA-A33, and HLA-B22, which were however more prevalent in the female patients and particularly those developing relapse. Two patients with HLA-A29 and HLA-B7 revealed significantly shortened survivals, suggestive of their potential prognostic impacts. Notably, for the first time, we found a significant correlation of leukocyte count with HLA types, where HLA-A33 (p = 0.006) or HLA-B17 (p < 0.001) signifies higher leukocytosis at presentation. Taken together, our findings support the involvement of HLA in Chinese high-risk childhood ALL.

Autoimmune thyroid dysfunction after hematopoietic stem cell transplantation.

Autoimmune thyroid disease (AITD) may occur in patients after hematopoietic stem cell transplantation (HSCT). In all, 10 cases of AITD (seven allogeneic and three autologous HSCT) were diagnosed among 721 HSCT recipients, including two patients with sequential hyper- and hypothyroidism. The 5-year actuarial rates for AITD after allogeneic and autologous HSCT were 2.9 and 4%, respectively. Significant risk factors included HSCT for chronic myeloid leukemia, the HLA B46 and DR9 loci and the A2B46DR9 haplotype, while female donors showed trend to significance. On multivariate analysis, only female donors and HLA DR9 remained significant. For autologous HSCT, the associations with HLA B46 and DR9 were also significant. Only three donors had a family history of AITD. A review of other reported cases confirmed the predominance of female donors, although the other associations including graft-versus-host disease, familial AITD and other autoimmune phenomena might be related to reporting bias. Since the actuarial incidence of AITD from female donors with predisposing HLA alleles may be over 30%, susceptible recipients should be carefully monitored. Owing to the small number of reported cases and different HLA associations with AITD in different populations, our observations await confirmatory data from other registries.

HLA class I allele distribution of a Hong Kong Chinese population based on high-resolution PCR-SSOP typing.

A stem cell registry population from Hong Kong, of Chinese ethnicity, was examined for HLA-A and HLA-B alleles using a two-stage sequence-specific oligonucleotide probe system. Comparison of the HLA-A and HLA-B frequencies with different populations showed a close relationship with a Chinese population from Singapore, although there were several differences in the presence/absence of alleles at the HLA-B locus. Having the data available on these registry donors will influence the search strategy and the ongoing compilation of new donors to the registry. In addition, knowing which alleles do/do not occur in this population will aid in the distinction of ambiguities which result from the use of many of the typing kits available.

Emergency living related liver transplantation for fulminant reactivation of hepatitis B virus after unrelated marrow transplantation.

We report a unique case of emergency living related donor orthotopic liver transplantation (OLT) for late fulminant reactivation of hepatitis B virus (HBV) after matched unrelated bone marrow transplantation (BMT) for chronic myeloid leukemia (CML). Cessation of lamivudine after BMT for HBV positive patients may carry risks of late fatal HBV reactivation. Similar to fulminant HBV reactivation in the general population, OLT under resumption of lamivudine can be life saving. In our case, concomitantly molecular relapse of CML at the time of liver failure was also cleared by OLT, possibly via a 'liver-graft vs. leukemia' effect. Liver rejection (graft vs. graft disease) was mild due to inherent immunocompromise of the marrow graft. Hence BMT recipients in stable remission should not be denied the opportunity for life-saving solid organ transplantation. A choice of marrow and liver donors with innate HBV immunity may be needed to give the additional advantage of long-term HBV clearance.

Post-transplantation lymphoproliferative disease in Chinese: the Queen Mary Hospital experience in Hong Kong.

Post-transplantation lymphoproliferative disease (PTLD) is an unique iatrogenic complication after bone marrow transplantation (BMT) and solid organ transplantation (SOTx). The pattern of EBV related lymphoma in Chinese is different from Caucasians. We surveyed the incidence, clinical and pathological spectrum of PTLD among 541 cases of allogeneic BMT, 145 cases of renal transplant, 35 cases of heart/lung transplantation and 146 cases of orthotopic liver transplantation (OLT). From 1994 to 2001, 13 consecutive cases of PTLD were diagnosed, ranging from disseminated NK cell lymphoma to localized plasmacytoma. Both donor and recipient derived PTLD was documented. Disease was often heralded by cytomegaloviral disease and antithymocyte globulin (ATG) usage. Two cases were diagnosed post-mortem, and six patients died of PTLD at a median of 3 months. Complete and partial remission was only achieved in 3 and 2 cases, respectively, despite a range of treatment (reduced immunosuppression, explantation, radiotherapy, combination chemotherapy, donor lymphocytes, autologous marrow infusion and rituximab). Most responding patients died subsequently of rejection, infection and graft versus host disease (GVHD). The incidence of PTLD is not increased in Chinese patients. However, some patients may be at increased risk, especially mismatched allogeneic BMT, parental OLT (especially involving young infants) and heavy ATG exposure.

Ten years of unrelated bone marrow transplantation in Hong Kong.

The Hong Kong Marrow Match Foundation was established as a charity in 1991 to set up and operate an unrelated bone marrow donor registry for the largely Chinese population of Hong Kong and to assist patients requiring bone marrow transplantation to locate donors in Hong Kong or elsewhere. In the 10 years that followed, the registry has recruited over 42000 predominantly Chinese donors and has provided donors for 150 patients in Hong Kong and overseas requiring transplantation. This report describes the current status of the Foundation.

Association of the HLA A2-B46-DR9 haplotype with autoimmune thyroid dysfunction after bone marrow transplantation in Chinese patients.

Autoimmune thyroid disease (AITD) may occur in patients after bone marrow transplantation (BMT). At a median follow-up of 4 years, among 194 allografts and 28 autografts, four patients (three allografts, one autograft) developed AITD. All carried the human leucocyte antigen (HLA) A2-B46-DR9 haplotype, strongly associated with AITD in the Chinese population. No significant thyroid disorder was detected in 190 patients without this haplotype. The frequency of AITD in BMT patients with the HLA A2-B46-DR9 haplotype was 12.5%, with a relative risk of 7.8 times that of non-carriers (P < 0.001). The risk of AITD should be recognized in recipients with high-risk HLA haplotypes, and regular screening might be warranted.

Risk of haematological malignancies in HLA-B27 carriers.

Human leucocyte antigen (HLA)-B27 carriers are predisposed to inflammatory and autoimmune diseases. Among 1137 patients with haematological diseases, 59 HLA-B27 carriers were identified. Compared with 18 774 volunteers, the incidence of HLA-B27 was increased in patients with acute leukaemia (relative risk RR = 1.67, P = 0.002), for both acute myeloid leukaemia (AML) (RR) = 1.67, P = 0.007) and acute lymphoblastic leukaemia (ALL) (RR = 1.68, P = 0.094). Of all the HLA-B27 carriers, four patients had ankylosing spondylitis (AS), all with lymphoid malignancies (three ALL, one Hodgkin's disease), whereas no HLA-B27 carriers with myeloid leukaemia had AS symptoms (P = 0.006). This suggests that HLA-B27 carriers may have an increased risk of acute leukaemia and those with concomitant AS may be predisposed to lymphoid malignancies.

Evans' syndrome complicating chronic graft versus host disease after cadaveric liver transplantation.

Acute graft versus host disease (GVHD) occurred in a patient after cadaveric liver transplantation from an HLA disparate donor. Immunosuppression resulted in a remission, but chronic GVHD with a scleroderma-like syndrome ensued. This was further complicated by immune hemolytic anemia and thrombocytopenia (Evan's syndrome). Semi-quantitative microsatellite analysis of circulating lymphoid cells showed that T cells were predominantly of donor origin, thereby explaining the chronic GVHD. The marrow hematopoietic cells remained recipient, so that the immune cytopenias were expected to be alloimmune in nature. However, the red cell antibodies were shown to have anti-C and anti-e specificity, with both the donor (R1R1) and recipient (R1r) possessing the C and e antigens. Therefore, the immune hemolysis might be considered both alloimmune and autoimmune. The patient finally died of sepsis. This case illustrates that chronic GVHD due to stable donor T cell engraftment may rarely occur in liver transplantation despite HLA disparity. Immunosuppression may result in dysregulation of T cell functions, leading to alloimmune and autoimmune problems.

Unmanipulated bone marrow transplantation from one-HLA locus mismatched siblings carries high transplant-related mortality in Chinese patients.

BACKGROUND AND OBJECTIVES: We compared the outcome of bone marrow transplantation (BMT) from HLA-identical siblings (MSD) and one HLA-locus mismatched siblings (PMSD) in Chinese patients with hematologic malignancies in terms of transplant-related mortality (TRM) and disease relapse to see whether PMSD can feasibly increase the availability of donors in our population. DESIGN AND METHODS: Medical records of patients who had received a BMT from sibling donors in the Queen Mary Hospital, Hong Kong, from March 1990 to February 2000 were reviewed (MSD 326, PMSD 20). Patients and their donors were matched for HLA-A, -B and DRB1 loci using standard serologic methods as well as polymerase chain reaction-sequence specific primers. All patients received standard anti-microbials and graft -versus host disease (GVHD) prophylaxis including cyclosporin A and a short course of methotrexate. RESULTS: A total of 346 BMT patients were analyzed of whom 326 and 20 patients had received transplants from matched and one locus mismatched siblings, respectively. Patients receiving BMT from PMSD had a significantly higher TRM than those receiving their BMT from MSD (p=0.0016). Six patients received BMT from HLA-DR PMSD: one died 2 months post-BMT as a result of post-transplantation-related lymphoproliferative disease. Fourteen patients received BMT from HLA-A or -B PMSD: 11 of these patients died after a median of 5.6 months (range 0.6-13.7 months) due to severe GVHD (n=5), graft failure (n=2), bleeding (n=1), leukemic relapse (n=2) and thrombotic thrombocytopenic purpura (n=1). Two out of the three survivors had primary graft failure: one of these two required infusion of back-up marrow and the other had autologous regeneration. Patients in the PMSD group were at greater risk of developing severe GVHD than their MSD-recipient counterparts (p<0.001). There was no significant difference in the probability of disease relapse between patients who received BMT from MSD or PMSD. INTERPRETATION AND CONCLUSIONS: BMT from PMSD (especially those with mismatches at HLA class I loci) carried a higher risk of TRM and morbidity than BMT from MSD in our population.

Metabolic and immunologic features of Chinese patients with atypical diabetes mellitus.

OBJECTIVE: To determine whether atypical diabetes mellitus (ADM) is present in the Chinese population in Hong Kong. RESEARCH DESIGN AND METHODS: The records of Chinese patients who attended the Diabetes Clinic at Queen Mary Hospital were reviewed. We identified 11 patients who initially presented with acute diabetic ketoacidosis but subsequently displayed clinical features more typical of type 2 diabetes. Metabolic studies and HLA typing were performed to characterize this group of Chinese patients with ADM. RESULTS: C-peptide response of the patients with ADM 1 h after a standard meal was intermediate between that of type 1 diabetic patients (matched for age and duration of diabetes) and that of nondiabetic control subjects (matched for age and BMI) (analysis of variance, P = 0.02). Insulin sensitivity measured by a short insulin tolerance test was not significantly different between patients with ADM and their matched nondiabetic control subjects. HLA typing showed that none of the patients with ADM had the DR3 allele and that the frequency of DR9 was not increased. Only one patient had significantly increased levels of antibodies to GAD and islet cell antigen 512. CONCLUSIONS: ADM, which was first described in African-Americans, is seen also in Chinese subjects. These patients have significant residual C-peptide secretory capacity and should not be misdiagnosed and treated as patients with type 1 diabetes with life-long insulin therapy.

Graft-versus-host disease after liver transplantation: documentation by fluorescent in situ hybridisation and human leucocyte antigen typing.

Graft-versus-host disease (GVHD) after liver transplantation is uncommon and the outcome is often fatal. A firm diagnosis of GVHD is difficult because the clinical triad of skin rash, marrow failure and diarrhoea can be indistinguishable from drug reaction or viral infection, and the presence of donor lymphocyte chimerism is not specific. We describe a case of severe GVHD in a female patient after liver transplantation from a male cadaveric donor. Skin biopsy showed characteristic changes of GVHD. Using Y-chromosome-specific fluorescent in situ hybridisation (FISH), male lymphocytes were demonstrated in 10% of marrow cells and in 90% of lymphocytes infiltrating the dermal epidermal junction. Donor human leucocyte antigens (HLAs) were detected in the peripheral blood, buccal mucosa and skin by polymerase chain reaction. The GVHD subsided with steroid and anti-thymocyte globulin, but recurred on tailing off of treatment. Despite maximum supportive therapy, including random donor leucocyte infusion, and marrow infusion from a HLA-identical sibling, the patient succumbed to sepsis. Our results showed the utility of combining morphological features with molecular techniques using FISH and HLA typing in confirming a diagnosis of GVHD.

Sibling HLA-matched cord blood transplant for beta-thalassemia: report of two cases, expression of fetal hemoglobin, and review of the literature.

PURPOSE: A program of cord blood stem cell (CBSC) transplants for patients with beta-thalassemia major was initiated in conjunction with the prenatal diagnostic service in 1994. Two patients who received HLA-matched related CBSC transplants with posttransplant fetal hemoglobin (HbF) expression are described and the literature is reviewed. PATIENTS AND METHODS: After screening 12 pregnancies, matched sibling CBSC transplants were performed for 2 girls with beta-thalassemia major when they were 3.8 and 2.2 years old, respectively. Their HbF was assayed serially. RESULTS: The nucleated cell counts/kg were 11.4 x 10(7) and 6.2 x 10(7), which engrafted on days 19 and 24, respectively. The children are now transfusion-independent at 3 years and 1.2 years posttransplant. Their HbF levels showed a rapid rise posttransplant and reached peak levels of 37.2% and 42.2% on day 83 and day 88, respectively. The HbF levels declined to 1.0% and 3.8% on day 581 and day 305, respectively. Nine other sibling CBSC transplants for thalassemias have been reported with an engraftment rate of approximately 50%. Graft rejection was related to insufficient CBSC number in one. CONCLUSIONS: HbF levels in patients with beta-thalassemia major after CBSC transplants could be influenced by many factors, including reactivation of HbF synthesis, intrinsic rate of Hb switching of CBSC, and mixed chimerism.

Strong association between DQA1/DQB1 genotype and early-onset IDDM in Chinese: the association is with alleles rather than specific residues.

We report on the role of HLA-DQA1 and DQB1 alleles in determining susceptibility to insulin-dependent diabetes mellitus (IDDM) in Hong Kong Chinese and investigate whether these alleles affect the age of onset of the disease. We studied 76 unrelated Chinese patients and 250 controls. There was no apparent predisposing effect of non-aspartic acid residues at position 57 of the DQ beta chain (Asp57-) but there was an excess of homozygous genotypes containing arginine at position 52 of the DQ alpha chain (Arg52+). This excess was mainly attributable to the genotype DQA1*0301/DQA1*05011 in early-onset disease. There was a significant excess of heterodimers of DQ alpha and DQ beta carrying Arg52+ and Asp57- in both early-onset and late-onset disease, but the excess in early-onset disease was mainly attributable to a single heterodimer formed by DQA1*05011 and DQB1*0201. Of three DQA1/DQB1 genotypes containing a double dose of Arg52+ and Asp57-, only one had a strong association with both early-onset and late-onset disease. We show that early-onset IDDM and late-onset IDDM in Chinese may be separated on the basis of their associated DQA1 and DQB1 genotypes and we conclude that previously reported associations of IDDM with Arg52+ and Asp57- residues in Chinese are secondary to specific combinations of DQA1 and DQB1 alleles. We also show that DRB1 molecules play a distinct role in determining susceptibility to early-onset IDDM but the greatest effect is exerted by specific DR/DQ genotypic combinations.

Distribution of human platelet antigens in a Chinese population.

We report the distribution of the human platelet antigens HPA-1, -2, -3, -4 and -5 as determined using the polymerase chain reaction with sequence-specific primers in 100 random, healthy Chinese in Hong Kong. The HPA-1a, -2a, -4a and -5a genes were present in every sample tested, HPA-1b, -2b and -5b were rare, and the sample was monomorphic for HPA-4a. HPA-3a and -3b genes showed frequencies of 0.525 and 0.475 respectively. There was no departure from Hardy-Weinberg equilibrium in any of the five HPA systems studied.