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Background and Purpose: Genetic polymorphisms in ABC transporter A1 (ABCA1) may alter the regulation of plasma high-density lipoprotein (HDL), promoting or protecting from vascular diseases. Methods: We investigated 244 unrelated, consecutively enrolled patients with ischemic stroke, 150 patients with coronary heart disease (CHD) and 193 blood donors for allele frequencies (AFs) of three common ABCA1 polymorphisms (R219K, V771M and I883M). Results: Compared to controls (30.8 ± 4.7 and 4.9 ± 2.2%, respectively), decreased AFs were found in both patient groups for R219K and V771M (28.7 ± 4.1 and 3.1 ± 1.6% in stroke, and 25.7 ± 5.0%; 1.3 ± 1.3% in CHD patients, respectively). In a subset of stroke patients younger than 50, both variants occurred in significantly lower frequencies (22.4 ± 5.5 and 1.8 ± 1.7%, respectively). Similarly, among CHD patients younger than 60, AFs of R219K and V771M (22.6 ± 7.5 and 0 ± 1.6%, respectively) were decreased. V771M was almost exclusively (35/36) found in individuals carrying the R219K allele. Conclusions: Our data confirm earlier observations that ABCA1 R219K and V771M polymorphisms may be associated with a protective role against CHD and extend those to another important pathologic condition, namely stroke.

BackgroundThe acquired form of idiopathic thrombotic thrombocytopenic purpura (TTP) is an autoimmune disease, in which the underlying deficiency of the ADAMTS13 protease is caused by autoantibodies, predominantly of the IgG isotype. Certain HLA-DR-DQ haplotypes were associated with the risk of developing TTP.ObjectivesTo investigate the development of the ADAMTS13-specific antibody response during the course of the disease, we analyzed the concentration, subclass distribution, and inhibitory potential of anti-ADAMTS13 IgG autoantibodies in samples of TTP patients drawn during the first acute phase, in remission, and during relapse. Additionally, we compared the anti-ADAMTS13 IgG levels between patients carrying and not carrying risk and protective HLA-DR-DQ haplotypes.Patients and MethodsWe determined the anti-ADAMTS13 IgG concentration and subclass distribution in 101 antibody-positive samples of 81 acquired TTP patients by ELISA methods. The presence and semi-quantitative amount of anti-ADAMTS13 inhibitors were determined in 97 of 100 deficient samples, and the specific inhibitory potential of anti-ADAMTS13 autoantibodies was determined in 49 selected samples, by mixing ADAMTS13-activity assays. HLA-DR-DQ typing and haplotype prediction were performed in 70 of the above patients.ResultsWe found that IgG1 and IgG4 were the predominant subclasses, present in almost all samples. While IgG1 was the dominant subclass in almost half of the samples taken during the first acute episode, IgG4 was dominant in all samples taken during or following a relapse. The inhibitory potential of the samples correlated with levels of the IgG4 subclass. Anti-ADAMTS13 antibodies of IgG4-dominant samples had higher specific inhibitory potentials than IgG1-dominant samples, independently of disease stage. Interestingly, we found that patients carrying the protective DR7-DQ2 and DR13-DQ6 haplotypes had higher anti-ADAMTS13 IgG levels.ConclusionOur results indicate that IgG4 becomes the dominant subtype at some point of the disease course, apparently before the first relapse, parallel to the increase in inhibitory potential of the anti-ADAMTS13 autoantibodies. Furthermore, we found an association between the genetic background and the antibody response in TTP.

The genotype and phenotype characteristics of Hungarian patients with RET proto-oncogene mutations operated on for hereditary medullary thyroid cancer (MTC) were studied. The genetic screening was performed in two centers and 40 patients with hereditary MTC or C-cell hyperplasia (CCH) from 18 unrelated families were analyzed. One patient having a mutation in exon 16 (Met918Thr) presented with the MEN2B phenotype, six patients from two families had hereditary MTC without pheochromocytoma (pheo) and primary hyperparathyroidism (PHPT), whereas 33 patients from 15 families showed the MEN2A phenotype. Two different mutations were identified in exon 10 (Cys609Tyr and Cys609Ser), five different mutations were present in exon 11 (Cys634Phe, Cys634Arg, Cys634Tyr, Cys634Trp and Cys634Ser), and two different mutations were localized in exon 14 (Val804Met and Val804Leu). Mutations in exon 10 were associated with hereditary MTC (Cys609Tyr) or with MEN2A syndrome (Cys609Ser). Mutations in exon 11 were always associated with the MEN2A phenotype. PHPT was present in one patient with mutation in exon 14 (Val804Met), whereas all other patients affected with mutations in exon 14 had hereditary MTC without PHPT and/or pheos.

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a serious complication of allogeneic haematopoietic stem cell transplantation (allo-HSCT) with high mortality rate. We retrospectively studied the frequency, clinical and genetic associations and prognostic effect of TA-TMA, in a total of 425 consecutive adult patients, who underwent allo-HSCT for a malignant haematological condition between 2007 and 2013 at our single centre. TA-TMA developed in 19% of the patients. Unrelated donor type (P o 0.001), acute GvHD grades II-IV (P o0.001), myeloablative conditioning regimens (P = 0.003), tacrolimus-based GvHD prophylaxis (P = 0.003), CMV infection (P = 0.003) and carriership for HLA-DRB1*11 (P = 0.034) were associated with the development of TA-TMA. Survival was adversely affected by the presence of TA-TMA (P o 0.001). Among patients with TA-TMA, the outcome of HLA-DRB1*11 carriers was significantly better compared with non-carriers (P = 0.003). As a new finding, our observations suggest that the presence of HLA-DRB1*11 antigen contributes to the development of TA-TMA and affects the outcome.

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MDR1 and ABCG2 SNPs were not associated with disease susceptibility or disease phenotype in Hungarian patients, and variant alleles did not predict the response to medical therapy or the need for surgery. Further studies are needed to clarify the association between the presence of ABCG2 variants and arthritis in UC.

Systematic analyses of human leukocyte antigen (HLA) profiles in different populations may increase the efficiency of bone marrow donor selection and help reconstructing human peopling history. We typed HLA-A, -B, and -DRB1 allele groups in two bone marrow donor cohorts of 2402 Hungarians and 186 Hungarian Gypsies and compared them with several Central-European, Spanish Gypsy, and Indian populations. Our results indicate that different European Gypsy populations share a common origin but diverged genetically as a consequence of founder effect and rapid genetic drift, whereas other European populations are related genetically in relation to geography. This study also suggests that while HLA-A accurately depicts the effects of genetic drift, HLA-B, and -DRB1 conserve more signatures of ancient population relationships, as a result of balancing selection.