A középkorú lakosság morbiditásának és mortalitásának összefüggése az MHC centrális régiójában található egyes génvariánsokkal és haplotipusokkal = Relationship between the morbidity and mortality of the middle-age people with some gene variants and haplotypes in the central region of MHC

A projekt keretében -korábbi adataink utánvizsgálat céljából - a középkorú lakosság morbiditásának és mortalitásának összefüggéseit tanulmányoztuk az MHC centrális régiójában található egyes génvariánsokkal és haplotipusokkal. Fontosabb új eredményeink: 1. Új módszert dolgoztunk ki a C4A és C4B gének kópiaszámának meghatározására 2. A C4B*Q0 (a C4B gén alacsony kópia száma) és a fokozott cardiovascularis morbiditás és mortalitás között kapcsolatot sikerült megerősítenünk az új genotipizálási módszer segítségével, 3. Elsőként sikerült feltérképezni az ősi kiterjesztett MHC haplotípusok előfordulását a magyar populációban és bizonyítottuk, hogy a leggyakoribb, 8.1 j. ősi haplotípus hordozóinak colorectalis carcinoma kockázata lényegesen nagyobb, mint a nem-hordozóké. 4. A C4B*Q0 genotípus és a fokozott cardiovascularis morbiditás és mortalitás között összefüggés egyik lehetséges magyarázata az, hogy a 21-hidroxiláz enzimet kódoló CYP-21 gén funkcionális rendellenessége és a C4A/C4B génszán közötti összefüggés áll fenn. Közel 100 egyén CYP-21 génjének szekvenálása segítségével találtunk ilyen összefüggést: a gén 4-es intronjában taláható két SNP ritka allélje csak a C4B*Q0 hordozókban fordult elő. Projektünk célkitűzéseit sikerült teljesíteni, a kapott eredményeinket 15, rangos nemzetközi folyóiratokban megjelent közleményben publikáltuk. | In order to reexamine our previous findings we studied the possible relationship between the cardiovascular morbidity/mortality of the middle-aged people and some alleles and haplotypes encoded in the central MHC region. Main results of the project: 1. A new method was worked out for direct counting of the copy number of the C4A and C4B genes. 2. Using this new method we have supported by new findings the strong association between the low copy number of the C4B genes (C4B*Q0) and the high rate of cardiovascular morbidity and mortality. 3. We were the first to map the occurrence of the ancestral extended MHC haplotypes in the Hungarian population and found that the carriers of the so-called 8.1 ancestral haplotype have an increased risk to develop colorectal cancer. 4. One of the possible explanation of the strong correlation between the C4B*Q0 genotype and the increased cardiovascular morbidity and mortality could be an association of the functional abnormalities of the CYP-21 gene (that encodes the 21-hydroxylase enzyme) and the C4A/C4B gene counts. We have examined this possibility by sequencing the CYP-21 gene in almost 100 subjects and found that the rare alleles of two SNPs in intron 4 of the gene occurs only in the C4B*Q0 carriers. Aims of the project were satisfied, the results were published in 15 papers in high-ranked international journals

De novo malignant melanoma occurred in renal allograft: DNA typing to determine the origin of the tumour

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HLA-DR genotypes in familial rheumatoid arthritis: increased frequency of protective and neutral alleles in a multicase family

OBJECTIVE: We describe a unique family where each of the 5 siblings in the second generation has rheumatoid arthritis (RA). Two other members of the family have RA and systemic lupus erythematosus (SLE), respectively. No members of previous generations in the family had documented inflammatory arthritis. Due to the suspected genetic predisposition, HLA-DR genotypes were determined in the affected siblings and their parents, children, and grandchildren. We investigated the possible role of various HLA-DR alleles in the evolution of RA in this multicase family. METHODS: HLA-DRB1* alleles were determined by polymerase chain reaction using the sequence-specific primer-Olerup method. RESULTS: The most common alleles in the 6 persons with RA were HLA-DRB1*07 and DRB1*15, which are known to be protective and neutral in RA. No patient or family member carried any HLA-DR4 alleles. CONCLUSION: HLA-DRB1*07 and DRB1*15 alleles are thought to be protective or neutral in RA. However, the majority of RA patients in the family and nearly half of all family members carried these alleles, suggesting a role of these genotypes in susceptibility to RA. No RA patient in this family carried HLA-DR4 alleles. Thus, in our rare family with 6 RA cases, an unexpected genetic background may be involved in the increased susceptibility to inflammatory arthritis

Donor KIR2DS1 reduces the risk of transplant related mortality in HLA-C2 positive young recipients with hematological malignancies treated by myeloablative conditioning.

BackgroundRecognition of HLA-C2 group alleles on recipient cells by activating killer immunoglobulin like receptors, KIR2DS1 on donor natural killer cells may lead to increased graft-versus-leukemia effect or immunomodulation in patients treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT) influencing disease free and overall survival (OS).ObjectiveIn the present study, 314 consecutive, allo-HSCT recipient and donor pairs were included with retrospective donor KIR-genotyping and clinical parameters analyzes.ResultsAfter a median follow-up of 23.6 months, recipients with HLA-C2 group allele (rC2) showed improved (p = 0.046) OS if transplanted with KIR2DS1 positive donors (d2DS1) compared to those without one or both of this genetic attribute. Within the myeloablative conditioning (MAC) subgroup (n = 227), rC2 homozygous+d2DS1 patients (n = 14) showed a 5 years OS of 93% followed by rC2 heterozygous+d2DS1 patients (n = 48, 65%) compared to rC2 and/or d2DS1 negatives (47%, p = 0.018). Multivariate analyses indicated rC2+d2DS1 positivity as an independent predictor of OS (HR:0.47, 0.26-0.86, p = 0.014) besides donor type, presence of CMV-reactivation or chemoresistant disease. Among MAC-treated patients, the combined rC2+d2DS1 presence was associated with a markedly decreased cumulative incidence of transplant related mortality (p = 0.0045).ConclusionThe combination of rC2+d2DS1 may be a favorable genetic constellation in allo-HSCT with MAC potentially reducing transplant related mortality

Prediction of in-vitro developmental competence of early cleavage-stage mouse embryos with compact time-lapse equipment

Single blastocyst transfer is regarded as an efficient way to achieve high pregnancy rates and to avoid multiple pregnancies. Risk of cancellation of transfer due to a lack of available embryos may be reduced by early prediction of blastocyst development. Time-lapse investigation of mouse embryos shows that the time of the first and second cleavage (to the 2- and 3-cell stages, respectively) has a strong predictive value for further development in vitro, while cleavage from the 3-cell to the 4-cell stage has no predictive value. In humans, embryo fragmentation during preimplantation development has been associated with lower pregnancy rates and a higher incidence of developmental abnormalities. Analysis of time-lapse records shows that most fragmentation is reversible in the mouse and is resorbed in an average of 9 h. Daily or bi-daily microscopic checks of embryo development, applied routinely in human IVF laboratories, would fail to detect 36 or 72% of these fragmentations, respectively. Fragmentation occurring in a defined time frame has a strong predictive value for in-vitro embryo development. The practical compact system used in the present trial, based on the ‘one camera per patient’ principle, has eliminated the usual disadvantages of time-lapse investigations and is applicable for the routine follow-up of in-vitro embryo development

HLA-association of serum levels of natural antibodies.

Natural antibodies of IgM or IgG types are present in sera of most healthy individuals and are important participants of the immune response. Little is known, however, about the genetic regulation of their plasma levels in humans. We determined the concentrations of three IgM type natural autoantibodies (NAAbs) reactive to certain conserved self-antigens (citrate synthase (A-CIT), chondroitin sulphate C (A-COS) and 60 kDa heat shock proteins (A-HSP) in the sera of 78 healthy individuals and in their 86 children. In case of all the 164 individuals alleles of several polymorphisms were determined in class II (HLA-DQ, -DR), class III (AGER-429T>C, HSP70-2 1267A>G, TNF-308G>A, CFB S/F, copy number of the C4A and C4B genes), and class I (HLA-A, -B) regions of the major histocompatibility complex (MHC). Since the samples originated from a family study, extended MHC haplotypes were also determined for each study participant. Our results show that children of parents with low NAAb concentration have significantly lower serum concentrations of all the three NAAbs, as compared to offsprings of parents without reduced serum concentration. This indicates that the serum levels of these NAAbs were partly regulated by factors which are inherited from the parents to offsprings. In further studies performed only in genetically independent parents, we found significant differences in the serum levels of the IgM type A-CIT and A-COS antibodies (Abs) between carriers and non-carriers of the HLA-DR2 (15 and 16) antigens. In both cases the Ab concentrations were higher in the HLA-DR15 carriers (p=0.002 and p=0.008, respectively) and lower in DR16 carriers (p=0.029 and p=0.049, respectively) than in the non-carriers. Even more significant differences were found when the levels of two Abs were evaluated together. Frequency of the DR15 carriers was significantly lower among subjects with one or two low (in the lowest quartile) titers of A-CIT/A-COS Abs (p=0.014), A-CIT/A-HSP Abs (p=0.016) and A-COS/A-HSP Abs (p=0.013) as compared to those with normal Ab titers for both antigens. By contrast, frequency of the DR16 carriers was significantly higher among subjects with one or two low A-CIT/A-COS Abs (p=0.001), A-CIT/A-HSP Abs (p=0.002) and A-COS/A-HSP Abs (p=0.021) as compared to those with normal Ab titers for both antigens. Similar differences were found for both IgM type antibodies when carriers and non-carriers of the HLA-DR15-DQ6 and HLA-DR16-DQ5 haplotypes were considered. These novel observations indicate that not only adaptive immune response but also natural autoantibody pattern, as a part of innate immune response, is influenced by the MHC allele composition