Association of HLA class II (-DRB1,-DQB1,-DPB1) alleles and haplotypes on susceptibility to aplastic anemia in northern Chinese Han.

The Human Leukocyte Antigen (HLA) genes, playing key roles in mediating the immune response, especially HLA class II alleles were suggested to play a role in the activation of autoreactive T-cells in aplastic anemia (AA). Previous studies in different ethnic groups have indicated that some of HLA-A,-B,-DRB1 alleles had a protective or susceptive association with the prevalence, pathogenesis and development of AA. HLA class II genes, especially HLA-DQB1 and -DPB1 alleles or haplotypes at high-resolution level associated with AA have not been fully identified in northern Chinese Han populations. The aim of this study was to identify association of the variations in HLA class II region with AA in northern Chinese Han population. A recent case-control study, including 96 AA patients and 824 healthy controls was performed. The high-resolution HLA genotyping was conducted by PCR-SBT, -SSO and NGS-ION S5TM platform. Based on genotypic data of the three loci, haplotype estimation was carried out. HLA-DRB1*15:01 (Pc = 2.87 × 10-3; OR = 2.11, 95% CI = 1.45-3.07) and HLA-DQB1*06:02 (Pc = 1.86 × 10-2; OR = 2.01, 95% CI = 1.32-3.06) were the risk and predisposition alleles to AA in northern Chinese Han after considering multiple testing. Moreover, the HLA-DRB1*15:01-DQB1*06:02 (Pc = 4.90 × 10-3; OR = 2.09, 95% CI = 1.37-3.19) and HLA-DRB1*14:05-DQB1*05:03 (Pc = 2.65 × 10-2; OR = 2.82, 95%CI = 1.45-5.50) haplotypes had direct strong relevance to AA and were the susceptible haplotypes. HLA-DPB1 alleles and 23 polymorphic amino acid residues spanning exon 2 ~ 4 of DPß1 molecules have showed no statistically significant associations between AA and controls. The present findings establish a novel link between inherited HLA-DRB1,-DQB1,-DPB1 risk alleles and haplotypes in northern Chinese Han with AA, and open new avenues for development of targeted therapies to prevent or redirect immunopathology in AA.

Interleukin-2 and Interleukin-8 Gene Polymorphisms and Acquired Aplastic Anemia Risk in a Chinese Population.

BACKGROUND/AIMS: Cytokines IL-2 and IL-8 both participate in immune regulation. However, the relationship between polymorphisms in these two cytokines and the risk of acquired aplastic anemia (acquired AA) has not been explored. METHODS: We selected five SNPs including rs11575812, rs2069772 and rs2069762 of IL-2, rs2227306 and rs2227543 of IL-8. SNaPshot genotyping was used to test the genotypes of IL-2 and IL-8 polymorphisms in a population of 101 acquired AA patients and 165 healthy controls. RESULTS: The rs2069762 G allele appeared to be a protective mutation, but no significant differences were found in other four SNPs. We also found that rs2069762 had an impact on the transcriptional regulation. CONCLUSIONS: It could be assumed that the rs2069762 polymorphism might reduce the risk of acquired aplastic anemia, while the remaining four SNPs might not contribute to susceptibility to acquired AA in a Chinese population.

TNF-α -308 G>A polymorphism and risk of bone marrow failure syndrome: A meta-analysis.

The influence of the TNF-α -308 G>A polymorphism on bone marrow failure syndrome susceptibility is unclear. We have conducted a meta-analysis of all relevant published studies. We searched PubMed, Chinese Biomedical Literature and China National Knowledge Infrastructure databases up to February 2015. Odds ratios (ORs) with 95% confidence intervals (CIs) were applied to assess the strength of associations. Eleven case-control studies with a total sample size of 909 cases and 1803 controls were eligible to assess the association between the TNF-α -308 G>A polymorphism and susceptibility to bone marrow failure syndrome. Overall, the TNF-α -308 G>A polymorphism was significantly associated with an increased risk of bone marrow failure syndrome in any genetic model. In stratified analysis by disease type, there was a significant association between the TNF-α -308 G>A polymorphism and increased risk of aplastic anemia but no significant association with myelodysplastic syndrome (AA vs. GG: OR=2.23, 95% CI=1.23-4.05, P=0.006; recessive model: OR=3.52, 95% CI=1.30-9.53, P=0.010). In subgroup analysis by ethnicity, there were significant associations between the TNF-α -308 G>A polymorphism and increased risk of bone marrow failure syndrome for Caucasians in two models, but not in Asian populations (AA vs. GG: OR=2.66, 95% CI=1.36-5.21, P=0.003; recessive model: OR=2.68, 95% CI=1.37-5.24, P=0.002). In conclusion, our meta-analysis suggests that the TNF-α -308 G>A polymorphism may contribute to the risk of bone marrow failure syndrome, particularly among Caucasian and aplastic anemia patients. Further investigations are needed to clarify the role of the TNF-α -308 G>A polymorphism in bone marrow failure syndrome.

Effect of race on outcomes after allogeneic hematopoietic cell transplantation for severe aplastic anemia.

We compared outcomes after hematopoietic cell transplantation in patients of African American (n = 84) and Caucasian (n = 215) descent with severe aplastic anemia. African Americans and Caucasians were matched for age, donor-recipient human leukocyte antigen match, graft type, and transplantation year. The median follow-up of surviving patients was 5 years. In multivariate analysis, overall mortality risks were higher for African Americans compared to Caucasians (relative risk 1.73, P = 0.01). The 5-year probabilities of overall survival adjusted for interval from diagnosis to transplantation, and performance score was 58% for African Americans and 73% for Caucasians. The day-100 cumulative incidence of grade III-IV, but not grade II-IV acute graft-versus-host disease (GVHD), was higher in African Americans compared to Caucasians (29% vs. 13%, P = 0.006). Although the 5-year cumulative incidence of chronic GVHD was not significantly different between the racial groups, African Americans were more likely to have extensive chronic GVHD compared to Caucasians (72% vs. 49%, P = 0.06). Survival differences between Caucasians and African Americans can be attributed to multiple factors. Our data suggest that some of the observed survival differences between Caucasians and African Americans may be explained by higher rates of acute GVHD and severity of chronic GVHD.

Population pharmacokinetics of ciclosporin in Chinese children with aplastic anemia: effects of weight, renal function and stanozolol administration.

AIM: To develop a population pharmacokinetic model for the immunosuppressant ciclosporin in Chinese children with aplastic anemia and to identify covariates influencing ciclosporin pharmacokinetics. METHODS: A total of 102 children with either acquired or congenital aplastic anemia aged 8.8±3.6 years (range 0.9-17.6 years) were included. Therapeutic drug monitoring (TDM) data for ciclosporin were collected. The population pharmacokinetic model of ciclosporin was described using the nonlinear mixed-effects modeling (NONMEM) VI software. The final model was validated using bootstrap and normalized prediction distribution errors. RESULTS: A one-compartment model with first-order absorption and elimination was developed. The estimated CL/F was 15.1, which was lower than those of children receiving stem cell or kidney transplant reported in the West (16.9-29.3). The weight normalized CL/F was 0.45 (range: 0.27-0.70) Lh(-1)·kg(-1). The covariate analysis identified body weight, serum creatinine and concomitant administration of the anabolic steroid stanozolol as individual factors influencing the CL/F of ciclosporin. CONCLUSION: Our model could be used to optimize the ciclosporin dosing regimen in Chinese children with aplastic anemia.

The ancestry of the HLA-DRB1*15 allele predisposes the Mexican mestizo to the development of aplastic anemia.

UNLABELLED: Aplastic anemia (AA) is a hematological disorder characterized by pancytopenia in peripheral blood and hypoplasia in the bone marrow; the majority of cases have no known etiology, but it is thought that genetic and environmental factors can be involved in its pathogenesis. From the genetic viewpoint, it has been reported a significant increase frequency of the human leukocyte antigen HLA-DRB1(∗)15 in patients with AA as compared to ethnically matched healthy controls, this is true in different populations worldwide, which would suggests that this allele participates in the immune regulation of the disease. OBJECTIVE: To determine gene frequencies of HLA-DRB1 alleles in Mexican mestizo patients with AA. METHODS: We analyzed and compared the HLA-DRB1 alleles in 36 Mexican mestizo patients (female gender, n=13; male gender, n=23) with AA to those present in 201 umbilical cord blood (UCB) samples as a control group, this was done by means of the polymerase chain reaction-single specific primer (PCR-SSP) technique. RESULTS: Analysis of gene frequencies of HLA-DRB1(∗) alleles exhibits a significant increase of HLA-DRB1(∗)15 allele in the group of patients with AA as compared to those present in the control group (15.27% vs. 2.23%, respectively; p=1×10(-5); odds ratio [OR]=9.3; 95% confidence interval [95% CI]=3.2-27.8). CONCLUSIONS: Our results showed a positive association of the DRB1(∗)15 allele in Mexican patients with aplastic anemia, which coincides with that reported internationally. In addition, we think that this allele was introduced to the Mexican population structure inherited from European ancestry.

Polymorphisms in PDCD1 gene are not associated with aplastic anemia in Chinese Han population.

Programmed cell death 1 (PD-1) has recently been reported to have a genetic association in several autoimmune diseases. The object of this study was to investigate the association of PD-1 polymorphisms with aplastic anemia (AA) in the Chinese Han population. In a case-control association study, three single-nucleotide polymorphisms (SNP), PD-1.3 G/A, PD-1.5 C/T, and PD-1.9 T/C, were genotyped in 166 AA patients and 264 healthy controls using polymerase chain reaction-restriction fragment length polymorphism assay. All genotype distributions in the patients and the controls were in Hardy-Weinberg equilibrium. The associations of genotypes and alleles with AA were analyzed. No differences in genotype and allele frequencies were elucidated for SNPs in intron 4 and exon 5. In conclusion, we show no association of selected SNPs in PDCD1 gene with AA in the Chinese Han population.

The polymorphisms of T cell-specific TBX21 and STAT4 genes may contribute to the susceptibility of Chinese individuals to aplastic anemia.

T cell-specific T-box transcription factor gene (TBX21) and signal transducer and activator of transcription 4 (STAT4) have been suggested as 2 candidate genes for conferring susceptibility to autoimmunity. We herein hypothesized that the polymorphisms of TBX21 and STAT4 genes might contribute to the susceptibility of Chinese individuals to aplastic anemia (AA) as T cell-mediated immune disease characterized by hypoplasia and pancytopenia. We investigated the distributions of TBX21 (T-1993C and T-1514C) and STAT4 (rs7574862) polymorphisms in 202 adult patients with AA and 195 healthy controls by polymerase chain reaction-restriction fragment length polymorphism. The frequencies of T-1993C (but not T-1514C) genotype and allele distribution were significantly higher in AA patients than in controls. The T allele (TT + TG genotypes) of STAT4 variant rs7574865 was associated with increased susceptibility of Chinese people to AA. Our results indicated that single nucleotide polymorphisms in TBX21 and STAT4 might contribute to susceptibility to AA in the Chinese population.

Susceptibility to aplastic anemia is associated with HLA-DRB1*1501 in an aboriginal population in Sabah, Malaysia.

The incidence of aplastic anemia is reported to be higher in Asia than elsewhere. We studied the frequency of human leukocyte antigen (HLA) DRB1 alleles in aplastic anemia patients from 2 genetically similar aboriginal groups, the Kadazan and the Dusun, and compared them with genetically matched community and hospital controls. HLA-DRB1*15 was significantly higher in the patients compared with controls (p = 0.005), confirming similar findings in Japanese and Caucasian studies. Further testing indicated a significantly higher frequency of HLA-DRB1*1501 in patients compared with controls (p = 0.0004) but no significant difference in the frequency of HLA-DRB1*1502. The high frequency of HLA-DRB1*15 in the Kadazan and Dusun population combined with the wide variety of environmental factors associated with aplastic anemia could be the reason for the elevated incidence of aplastic anemia in the Kadazan and Dusun in Sabah.

HFE genotype and iron metabolism in Chinese patients with myelodysplastic syndromes and aplastic anemia.

The incidence of HFE gene mutations in myelodysplastic syndrome (MDS) cases remains controversial. In this study, we examined the HFE C282Y and H63D mutations in 271 Chinese patients with MDS, 402 with aplastic anemia (AA) and 1,615 healthy controls by polymerase chain reaction-restriction fragment length polymorphism in combination with DNA sequencing. No C282Y mutations were observed in the entire cohort. The distribution of H63D heterozygous and homozygous genotypes was not significantly different between the AA cases and the controls (9.7% versus 10.2%, 0.25% versus 0.24%, respectively). While the H63D heterozygous genotype in MDS patients was significantly lower than that in the controls (4.1% versus 10.2%, p = 0.002), the H63D homozygous genotype was not detected in the MDS patients. The results suggest that HFE gene mutations are not common genetic factors in Chinese patients with MDS and AA. We also compared iron metabolic parameters, including serum ferritin, serum iron, and transferrin saturation values, between HFE mutant and HFE wild-type groups in the absence of transfusion iron overload, but no significant difference was found in either MDS or AA patients except that the level of serum iron in AA patients was significantly higher in mutant carriers than in those with wild-type HFE (p = 0.011). Similarly, there was no significant difference between HFE mutant and HFE wild-type MDS and AA patients in clinical indices such as alanine aminotransferase, aspartate aminotransferase, fasting blood sugar values, and electrocardiogram. The results suggest that H63D mutations may not have clinical significance in Chinese patients with MDS and AA.

The impact of Asian descent on the incidence of acquired severe aplastic anaemia in children.

Previous studies have suggested an increased incidence of acquired severe aplastic anaemia in Asian populations. We evaluated the incidence of aplastic anaemia in people of Asian descent, using a well-defined paediatric (0-14 years) population in British Columbia, Canada to minimize environmental factors. The incidence in children of East/South-east Asian descent (6.9/million/year) and South Asian (East Indian) descent (7.3/million/year) was higher than for those of White/mixed ethnic descent (1.7/million/year). There appeared to be no contribution by environmental factors. This study shows that Asian children have an increased incidence of severe aplastic anaemia possibly as a result of a genetic predisposition.

Normas para el abordaje de las enfermeddes hemato-oncológicas pediátricas / Norms for the boarding of the illnesses hemato-oncológicas pediátrics

Se presenta documento con el objetivo de contribuir a mejorar el conocimiento sobre el cáncer y otras enfermedades hematológicos en el niño, a fin de poder realizar un diagnóstico mas oportuno, asegurar una más rápida referencia, un mejor abordaje terapeútico, así como enfrentar las posibles complicaciones. Existe un registro desde 1990 hasta el año 2000 de 1,2000 casos en el departamento de Hemato-Oncología del Hospital Infantil "La Macota", diagnosticados de diferentes tipos de cáncer, además de un número de enfermedades hematológicas no oncológicas (principalmente Drepanocitosis, PTI y Anemia Aplástica), los cuales son referidos de todo el territorio. Uno de los principales problemas que encuentran en el abordaje de los niños con enfermedades hemoto-oncológicas es el diagnóstico tardío, la referencia no oportuna y por lo tanto los niños presentan enfermedades avanzadas con el consecuente pronóstico desfavorable, así como la falta de un manejo intrahospitalario mas uniforme y adecuado cuando el paciente ingresa a al centro. En nuestro país se estan diagnosticando cerca de 200 casos anuales y que el cáncer ocupa el quinto lugar cmo causa de muerte en los niños mayores de 4 años

[Glycosilphosphatidylinositol-anchored cell surface protein deficiency in Mexican mestizo patients with aplastic anemia]. / Deficiencia de proteínas de superficie ancladas por glucosilfosfatidilinositol en células de pacientes mestizos mexicanos con hipoplasia medular.

The peripheral blood cells of ten patients with biopsy-proven aplastic anemia were studied by means of flow-cytometry in order to assess the expression of two phosphatidylinositol-anchored surface proteins: CD55/DAF (decay accelerating factor) and CD59/MIRL (membrane inhibitor of reactive lysis). An abnormal expression was found in five of these ten patients, whereas the "traditional" tests for paroxysmal nocturnal hemoglobinuria (PNH) were positive only on two of these five individuals. Five of the aplastic patients were treated with anti-thymocyte globulin and cyclosporin-A and three entered a complete remission; of the latter, one had CD55/CD59 deficiencies whereas two did not. Along the study period one patient with a hemolytic pattern of PNH was identified. It is concluded that CD55 and/or CD59 abnormalities are frequent in Mexican mestizo patients with aplastic anemia, that the aplastic presentation of PNH is more frequent in Mexico than the hemolytic presentation, that the flow-cytometric identification of CPI-anchored proteins is more sensitive than the "traditional" PNH tests, and that some patients with PNH-aplasia may respond to intensive immunosuppressive treatment. The flow-cytometric identification of GPI-anchored cell surface proteins should replace the "traditional" tests in the identification of patients with PNH.

Deficiencia de proteínas de superficie ancladas por glucosilfosfatidilinositol en células de pacientes mestizos mexicanos con hipoplasia medular / Clycosilphosphatidylinositol anchored cell surface proteins deficiency in mexican mestizo patients with aplastic anemia

Se estudiaron de manera prospectiva 10 sujetos con diagnóstico histológico de hipoplasia medular para identificar por medio de citometría de flujo las características de las moléculas de superficie CD55 y CD59, ancladas a la superficie celular a través de glucosilfosfatidilinositol (GPI). En cinco se identificó una distribución anormal de estas moléculas; las pruebas de hemólisis ácida, por insulina y sacarosa, así como la investigación de hemosiderinuria fueron anormales en dos de los cinco pacientes. Cinco de ellos fueron tratados con globulina antitimocito y ciclosporina-A y tres se encuentran en remisión completa, en tanto que cinco enfermos fueron tratados con andrógenos y ninguno logró la remisión. De los pacientes en remisión completa, uno tuvo trastornos en las moléculas ancladas por GPI ocurren con frecuencia en pacientes con hipoplasia medular, que la identificación de estas alteraciones es más sensible que las pruebas tradicionales para investigar hemoglobinuria paroxística nocturna (HPN), que las formas aplásticas de HPN son frecuentes en nuestro país y que el tratamiento con inmunosupresión intensa puede ser efectivos en algunas formas hipoplásicas de la HPN. La identificación citofluorográfica de las alteraciones en las moléculas ancladas por GPI debieran reemplazar a las pruebas ®tradicionales¼ para identificar a la HPN