Advance in the diagnosis and treatment of hereditary thrombotic thrombocytopenic purpura / 中华医学遗传学杂志

Congenital thrombotic thrombocytopenic purpura, also known as Upshaw-Schulman syndrome, is a rare autosomal recessive genetic disorder. The main pathogenesis is homozygous or compound heterozygous variants of von Willebrand factor lyase (ADAMTS13) gene mapped to chromosome 9q34, which may result in severe lack of ADAMTS13 which cleaves von Willebrand factor (vWF) multimers in the plasma and increase the risk of microvascular thrombosis, leading to various complications. The advance of research on the pathogenesis of cTTP, recombinant human ADAMTS13 and gene therapy have made breakthroughs which may lead to cure of cTTP. This article has provided a review for the latest progress made in the diagnosis and treatment of cTTP.

Recurrent thrombocytopenia with hemolytic anemia in a boy aged 3 years / 中国当代儿科杂志

A boy, aged 3 years and 8 months, had recurrent thrombocytopenia with hemolytic anemia for more than 3 years. The physical examination showed no enlargement of the liver, spleen, and lymph nodes or finger deformities. Laboratory results showed a negative result of the direct antiglobulin test, normal coagulation function, and increases in bilirubin, lactate dehydrogenase and reticulocytes. The results of von Willebrand factor-cleaving protease ADAMTS13 activity assay showed extreme deficiency, and antibody assay showed negative ADAMTS13 inhibitory autoantibodies. Next-generation sequence showed compound heterozygous mutation in the

Association between ADAM metallopeptidase domain 33 gene polymorphism and risk of childhood asthma: a meta-analysis

This study aimed to investigate the association between ADAM metallopeptidase domain 33 (ADAM33) gene polymorphisms and the risk of childhood asthma. The relevant studies about the relationship between ADAM33 gene polymorphisms and childhood asthma were searched from electronic databases and the deadline of retrieval was May 2016. The single nucleotide polymorphisms (SNPs) of ADAM33 (rs511898, rs2280092, rs3918396, rs528557, rs2853209, rs44707, rs2280091 and rs2280089) were analyzed based on several models including the allele, codominant, recessive and dominant models. The results showed that the ADAM33 rs2280091 polymorphism in all four genetic models was associated with an increased risk of childhood asthma. Positive associations were also found between the polymorphisms rs2280090, rs2787094, rs44707 and rs528557 and childhood asthma in some genetic models. This meta-analysis suggested that ADAM33 polymorphisms rs2280091, rs2280090, rs2787094, rs44707 and rs528557 were significantly associated with a high risk of childhood asthma.

Polimorfismos de nucleótidos simples V4 y T1 del gen ADAM33 en pacientes venezolanos con asma o enfermedad pulmonar obstructiva crónica / Single nucleotide polymorphisms V4 and T1 of the ADAM33 gene in Venezuelan patients with asthma or chronic obstructive pulmonary disease

ADAM33 es una metaloproteinasa de la matriz extracelular involucrada en la remodelación tisular y, por ello, en el asma y la enfermedad pulmonar obstructiva crónica (EPOC). Se han reportado varios polimorfismos del gen de ADAM33 asociados a la actividad enzimática. Los polimorfismos más estudiados son el V4, citosina por una guanina en la región 3’ UTR, y el T1, adenina por una guanina en el exón 19 del gen. El objetivo del presente trabajo fue determinar la posible asociación de los polimorfismos de nucleótido simple de ADAM33, V4 y T1, con la presencia de asma o EPOC en pacientes venezolanos. Los polimorfismos V4 y T1 fueron analizados en 303 individuos (103 asmáticos, 100 EPOC, y 100 controles) mediante PCR-RFLP (reacción en cadena de la polimerasa y análisis de polimorfismos por longitud de fragmentos de restricción enzimática). La frecuencia genotípica del polimorfismo V4 fue significativamente mayor (p<0,05) en ambos grupos de pacientes, asmáticos y EPOC, con respecto al control. No se encontraron diferencias significativas (P=0,4) en el polimorfismo T1. Sin embargo, se evidenció una diferencia significativa (p<0,05) cuando los haplotipos y diplotipos de ADAM33 V4/T1 se compararon entre los tres grupos. Se concluye que el polimorfismo ADAM33 V4 está asociado con la presencia de asma o EPOC en pacientes venezolanos.

ADAM33 is a metalloproteinase important in the extracellular matrix for tissue remodeling, and, consequently, in asthma and chronic obstructive pulmonary disease (COPD). Several polymorphisms of the ADAM33 gene have been associated with enzyme activity. One of the most studied polymorphisms is V4, cytosine for guanine in the 3’UTR region, and T1, adenine for guanine in the exon 19 of the gen. The aim of this study was to ascertain the possible association among single polymorphisms of ADAM33, V4 and T1, in Venezuelan patients with asthma or COPD. The polymorphisms V4 and T1 were analyzed in 303 individuals (103 asthmatic, 100 COPD and 100 controls) by PCR-RFLP (polymerase chain reaction and restriction fragment length polymorphisms). There was a significant difference (P<0.05) in the frequency of ADAM33 V4 polymorphism in both, asthmatic and COPD patients groups, as compared to controls. No significant differences (P=0.4) were found for T1 polymorphism. However, there were significant differences (P<0.05) when haplotypes and diplotypes of ADAM33 V4/T1 were compared in all three groups. It can be concluded that the polymorphism V4 of ADAM33 is associated with asthma or COPD in Venezuelan patients.

Genetic polymorphisms and asthma: findings from a case - control study in the Madeira island population

BACKGROUND: Asthma is a complex disease influenced by multiple genetic and environmental factors. While Madeira has the highest prevalence of asthma in Portugal (14.6%), the effect of both genetic and environmental factors in this population has never been assessed. We categorized 98 asthma patients according to the Global Initiative for Asthma (GINA) guidelines, established their sensitization profile, and measured their forced expiratory volume in 1second (FEV1) and forced vital capacity (FVC) indexes. Selected single nucleotide polymorphisms (SNPs) were analysed as potential markers for asthma susceptibility and severity in the interleukin 4 (IL4), interleukin 13 (IL13), beta-2-adrenergic receptor (ADRB2), a disintegrin and metalloprotease 33 (ADAM33), gasdermin-like (GSDML) and the signal transducer and activator of transcription 6 (STAT6) genes comparatively to a population reference set. RESULTS: Although mites are the major source of allergic sensitization, no significant difference was found amongst asthma severity categories. IL4-590*CT/TT and IL4-RP2*253183/183183 were found to predict the risk (2-fold) and severity (3 to 4-fold) of asthma and were associated with a lower FEV1 index. ADRB2-c.16*AG is a risk factor (3.5-fold), while genotype GSDML-236*TT was protective (4-fold) for moderate-severe asthma. ADAM33-V4*C was associated to asthma and mild asthma by the transmission disequilibrium test (TDT). Finally, ADAM33-V4*CC and STAT6-21*TT were associated with higher sensitization (mean wheal size ≥10mm) to house dust (1.4-fold) and storage mite (7.8-fold). CONCLUSION: In Madeira, IL4-590C/T, IL4-RP2 253/183, GSDML-236C/T and ADAM33-V4C/G SNPs are important risk factors for asthma susceptibility and severity, with implications for asthma healthcare management.

ADAMTS13 Gene Mutations in Children with Hemolytic Uremic Syndrome

We investigated ADAMTS13 activity as well as the ADAMTS13 gene mutation in children with hemolytic uremic syndrome (HUS). Eighteen patients, including 6 diarrhea-negative (D-HUS) and 12 diarrhea-associated HUS (D+HUS) patients, were evaluated. The extent of von Willebrand factor (VWF) degradation was assayed by multimer analysis, and all exons of the ADAMTS13 gene were PCR-amplified using Taq DNA polymerase. The median and range for plasma activity of ADAMTS13 in 6 D-HUS and 12 D+HUS patients were 71.8% (22.8-94.1%) and 84.9% (37.9-119.9%), respectively, which were not statistically significantly different from the control group (86.4%, 34.2-112.3%) (p>0.05). Five ADAMTS13 gene mutations, including 2 novel mutations [1584+2T>A, 3941C>T (S1314L)] and 3 polymorphisms (Q448E, P475S, S903L), were found in 2 D-HUS and one D+HUS patients, which were not associated with deficiency of ADAMTS13 activity. Whether these mutations without reduced ADAMTS13 activity are innocent bystanders or predisposing factors in HUS remains unanswered.

Association between ADAM33 polymorphisms and asthma in a Thai population.

ADAM33 (A Disintegrin And Metalloprotease 33) is an asthma susceptibility gene found across several human populations. However, no information on ADAM33 exists for Thai population. The objective of this study was to determine the association, if any, between ADAM33 polymorphisms and asthma in Thai subjects. Genotyping revealed 8 single nucleotide polymorphisms (SNPs) within the 3' region of the ADAM33 gene among 200 asthmatics and 100 control subjects. Asthmatic subjects were further sub-categorized into high and low severity groups. Multiple genetic model statistic tests for single-marker and haplotype association were carried out. Differences in allele frequencies at the SNPs rs528557/S2, rs598418 and rs44707/ST+4 in asthmatics were statistically significant compared to controls. The SNP rs528557/S2 could also be linked to the low severity group and the SNPs rs598418 and rs44707/ST+4 with the high severity group. Two-SNP haplotype analysis at the SNPs rs528557/S2 and rs598418 revealed a significant association with asthma. This study in a Thai population confirmed a positive association between ADAM33 polymorphisms and asthma susceptibility.

Associação dos polimorfismos dos genes TGF-beta1, CD14, IL-4, IL-4R e ADAM33 com a gravidade da asma em crianças e adolescentes / Association of TGF-beta1, CD14, IL-4, IL-4R and ADAM33 gene polymorphisms with asthma severity in children and adolescents

OBJETIVO: Verificar, em uma amostra de pacientes com asma atópica persistente leve, moderada e grave, a associação entre os polimorfismos dos genes fator de crescimento transformante-beta1 (TGF-beta1) (C-509T e T869C), CD14 (C-159T), IL-4 (C-590T), IL-4R (ILe50Val) e ADAM33 (S_2) com a gravidade da asma. MÉTODOS: Realizou-se um estudo clínico laboratorial prospectivo em pacientes com asma atópica persistente, comparados a um grupo controle no Hospital Universitário da Universidade Estadual de Campinas nos anos de 2006 e 2007. A análise do polimorfismo T869C do gene TGF-beta1 foi realizada pela técnica de reação em cadeia da polimerase (PCR) + sistema de amplificação refratária de mutação (ARMS). Os outros polimorfismos, C-509T do gene TGF-beta1, C-159T do gene CD14, C-590T da IL-4, ILe50Val da IL-4Ra e S2 do gene ADAM33, foram detectados por PCR e enzima de restrição. RESULTADOS: Foram incluídos 88 pacientes com asma atópica persistente (27 leves, 23 moderados e 38 graves) e 202 indivíduos saudáveis, doadores de sangue. Em relação ao polimorfismo T869C (TGF-beta1), observou-se uma associação entre o genótipo CC e os pacientes com asma grave. Nenhuma associação foi encontrada com os polimorfismos C-509T (TGF-beta1), C-590T (IL4) e S_2 (ADAM33). Quando se comparou a distribuição da freqüência genotípica do polimorfismo C-159T (CD14) na asma grave com o grupo controle, foi observado um resultado significativo com o genótipo TT. Houve associação significativa do genótipo Val/Val (IL-4R) com a asma leve. CONCLUSÃO: Nossos resultados indicam que os polimorfismos T869C (TGF-beta1), C-159T (CD14) e Val/Val (IL-4R) podem estar envolvidos na modulação da gravidade da asma.

OBJECTIVE: To verify the association of transforming growth factor-beta1 (TGF-beta1) (C-509T and T869C), CD14 (C-159T), IL-4 (C-590T), IL-4R (ILe50Val) and ADAM33 (S_2) gene polymorphisms with asthma severity in a sample of patients with mild, moderate and severe persistent atopic asthma. METHODS: A clinical, laboratory, prospective study was performed in patients with persistent atopic asthma, compared to a control group at Hospital Universitário da Universidade Estadual de Campinas between 2006 and 2007. Analysis of the TGF-beta1 T869C gene polymorphism was performed using the technique polymerase chain reaction (PCR) + amplification refractory mutation system (ARMS). TGF-beta1 C-509T, CD14 C-159T, IL-4 C-590T, IL-4Ra ILe50Val, and ADAM33 S2 gene polymorphisms were detected by PCR and restriction enzyme. RESULTS: This study included 88 patients with persistent atopic asthma (27 mild, 23 moderate and 38 severe) and 202 healthy blood donors. As to T869C polymorphism (TGF-beta1), there was an association between the CC genotype and patients with severe asthma. There was no association in polymorphisms C-509T (TGF-beta1), C-590T (IL-4) and S_2 (ADAM33). When distribution of C-159T polymorphism genotype frequency (CD14) in severe asthma was compared with the control group, there was a significant result with the TT genotype. There was significant association of the Val/Val genotype (IL-4R) with mild asthma. CONCLUSION: Our results indicate that T869C (TGF-beta1), C-159T (CD14) and Val/Val (IL-4R) polymorphisms might be involved in modulation of asthma severity.