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M T Dorak

Publications and source records attributed to M T Dorak.

At least 19 recordsLinked to original sources
PubMed2006

Conserved extended haplotypes of the major histocompatibility complex: further characterization.

Since the complete sequencing of a human major histocompatibility complex (MHC) haplotype, interest in non-human leucocyte antigen (HLA) genes encoded in the MHC has been growing. Non-HLA genes, which outnumber the HLA genes, may contribute to or account for HLA and disease associations. Most information on non-HLA genes has been obtained in separate studies of individual loci. To comprehensively address polymorphisms of relevant non-HLA genes in 'conserved extended haplotypes' (CEH), we investigated 101 International Histocompatibility Workshop reference cell lines and nine additional anonymous samples representing all 37 unambiguously characterized CEHs at MICA, NFKBIL1, LTA, NCR3, AIF1, HSPA1A, HSPA1B, BF, NOTCH4 and a single nucleotide polymorphism (SNP) at HLA-DQA1 as well as MICA, NOTCH4, HSPA1B and all five tumour necrosis factor short tandem repeat (STR) polymorphisms. This work (1) provides an extensive catalogue of MHC polymorphisms in all CEHs, (2) unravels interrelationships between HLA and non-HLA haplotypical lineages, (3) resolves reported typing ambiguities and (4) describes haplospecific markers for a number of CEHs. Analysis also identified a DQA1 SNP and segments containing MHC class III polymorphisms that corresponded with class II (DRB3 and DRB4) lineages. These results portray the MHC where lineages containing non-HLA and HLA variants in linkage disequilibrium may operate in concert and can guide more thorough design and interpretation of HLA-disease relationships.

3' Untranslated Regions↗
PubMed2004

MICA intron 1 sequences of conserved extended HLA haplotypes: implications for sequencing-based typing.

The human major histocompatibility complex (MHC) class I chain-related gene A (MICA) has a high degree of genetic diversity. Several methods have been used in MICA typing. Recent studies reported different results for the same reference cell lines typed by different methods. By searching the GenBank, we found an indel polymorphism in MICA intron 1 corresponding to the area where one of the sequencing-based typing primers used by others is located. We investigated this polymorphism in 43 reference samples by primer cycle sequencing. This approach revealed three haplotype-specific patterns of polymorphisms in intron 1. This study provided evidence that one of the primers commonly used in MICA typing may fail to amplify both alleles in certain heterozygous combinations. Our data showed a correlation between the three patterns in MICA intron 1 and exon 5 short tandem repeat (STR) alleles. Being neutral ones, the intron 1 and STR polymorphisms appeared to mark the ancestral lineages better than the coding region polymorphisms.

Base Sequence↗
PubMed2004

Molecular typing of human leukocyte antigen and related polymorphisms following whole genome amplification.

Reliable, high-resolution genotyping of human leukocyte antigen (HLA) polymorphisms is often compromised by DNA samples of suboptimal quality or limited quantity. We tested the feasibility of molecular typing for variants at HLA and neighboring loci using whole genome amplification (WGA) strategy facilitated by the Phi29 DNA polymerase. With little (5-100 ng) starting genomic DNA of varying quality and source materials, WGA was deemed successful in 167 of 169 DNA from 47 cell lines, 100 European Americans, and 22 native Africans. The Phi29-processed DNA provided adequate templates for polymerase chain reaction (PCR)-based analyses of several HLA (A, B, C, DRB1, and DQB1) and related loci (HFE, MICA, and 10 microsatellites) in the 6p24.3-6p21.3 region, with PCR amplicons ranging from 92 to 2200 bp. Five different genotyping techniques resolved and confirmed 364 genotypes when both original and Phi29-processed DNA worked in PCRs. General population genetic analyses provided additional evidence that WGA may represent a reliable and simple approach to securing ample genomic DNA for typing HLA, MICA, and related variants.

Africa↗
PubMed2004

Human leukocyte antigen-A, -B and -C alleles and human leukocyte antigen haplotypes in Turkey: relationship to other populations.

In this study, we present, for the first time, human leukocyte antigen (HLA) class I allele and haplotype frequencies at the DNA level in a sample of 142 donors from Turkey. HLA typing was performed by medium-to-high resolution polymerase chain reaction sequence-specific oligonucleotide probes method. The most frequent HLA alleles at class I locus were A*0201(0.257), -B*35(0.204) and -Cw*04(0.173). A*0201-B*35-Cw*04(0.056) was the most common three-locus haplotype. Allele and haplotype frequency comparisons and neighbour-joining dendrograms, constructed using DA genetic distances and correspondence analysis using HLA-A, -B and -C, and -DRB1 allele frequencies, revealed similarities with other Mediterranean and European populations, but not with Mongol populations. These results agree with previous studies and confirm that the present day Turkish population is genetically more similar to its geographic neighbours than its historical neighbours in central Asia. The comprehensive HLA data on the Turkish population at the DNA level including up to six-locus putative haplotypes generated in this study will be useful for further studies.

Alleles↗
PubMed2003

Genetic affinities among Mongol ethnic groups and their relationship to Turks.

The central Asian country Mongolia is home to more than 20 tribes and ethnic groups, some of which are related to neighboring Turkic populations. The main Mongolian people, Khalkha, live in central and eastern Mongolia while the Tsaatan minority lives in the north of the country. The Oold minority is from the western Altai mountain region and live in close proximity with Turkic people. We have typed the HLA-A, -B, -Cw, -DRB1 and -DQB1 loci by PCR-SSP in these three Mongolian populations as well as a sample of the German population. To examine their genetic relationships, a sample of the Turkish population already typed at the HLA-A, -B and -DRB1 loci were used. Altogether five populations were analyzed: Khalkha (n = 100), Tsaatan (n = 72), Oold (n = 52), German (n = 260) and (Anatolian) Turkish (n = 498). Nei's unbiased genetic identity (GI) and genetic distance (GD) were estimated from genotypes using PopGene v1.31, and dendrograms were constructed using phylip. The results suggested a close relationship of the Khalkha to the Tsaatan. The Turks and Germans were equally distant to all three Mongolian populations. These results confirmed the lack of strong genetic relationship between the Mongols and the Turks despite the close relationship of their languages (Altaic group) and shared historical neighborhood. This study has provided useful population data for genetic and anthropologic studies bridging eastern and western populations.

Gene Frequency↗
PubMed2002

Increased heterozygosity for MHC class II lineages in newborn males.

In plants, fungi and marine invertebrates, there are genetic compatibility systems to ensure diversity in the offspring. The importance of genetic compatibility in gametic union and selective abortion in vertebrate animals has also been appreciated recently. There have been suggestions that the major histocompatibility complex (HLA in humans) may be a compatibility system in vertebrates. HLA class II haplotypes often contain a second expressed DRB locus which can be either DRB3, DRB4 or DRB5. These encode the supertypical specificities and mark the ancestral lineages. The members of each lineage have related DNA sequences at the main class II locus HLA-DRB1. We analysed 415 newborns at all expressed DRB loci by PCR analysis to seek evidence for sex-specific prenatal selection events. While there was no significant change in heterozygosity rates between males and females at DRB1, the proportion of males carrying two DRB1 specificities from different ancestral lineages was significantly increased (53.7% in males vs 39.3% in females, P = 0.003). The genotypes consisting of phylogenetically most distinct ones, namely the DRB3 and DRB4 haplotypes, showed the most striking difference between sexes (P = 0.007). These results suggested a more favourable outcome for male concepti heterozygous for supertypical haplotypes. Heterozygosity for most divergent haplotypical families ensures the highest degree of functional heterozygosity at the main HLA class II locus DRB1 while increasing the likelihood of heterozygosity also at other MHC loci. Our observations agree with the previously reported heterozygote excess in male newborn rats and mice. Correlations between MHC class II heterozygosity and advertised male quality in deer and pheasant as well as increased reproductive success in MHC class II heterozygous male macaques are examples of postnatal benefits of heterozygosity in males that may be behind the development of prenatal selection mechanisms. The MHC-mediated prenatal selection of males may also be one of the selective events suggested by the very high primary (male-to-female) sex ratio at fertilization reaching close to unity at birth in humans. These results provide an appealing working hypothesis for further studies in humans and other vertebrates.

Alleles↗
PubMed1999

Unravelling an HLA-DR association in childhood acute lymphoblastic leukemia.

Genetic and environmental factors play an interactive role in the development of childhood acute lymphoblastic leukemia (ALL). Since the demonstration of a major histocompatibility complex (MHC) influence on mouse leukemia in 1964, an HLA association has been considered as a possible genetic risk factor. Despite extensive efforts, however, no strong evidence comparable to the H-2(k) influence on mouse leukemia has been shown. The number of negative serological studies resulted in a loss of interest and consequently, no molecular HLA-DR association study has been published to date. We reconsidered the HLA-DR association in childhood ALL in 114 patients from a single center and 325 local newborn controls by polymerase chain reaction (PCR) analysis of the HLA-DRB1/3/4/5 loci. With conventional analysis, there was a moderate allelic association with the most common allele in the HLA-DR53 group, HLA-DRB1*04, in the whole group that was stronger in males (P =.0005, odds ratio = 2.9). When the other expressed HLA-DRB loci were examined, homozygosity for HLA-DRB4*01, encoding the HLA-DR53 specificity, was increased in patients (21.1% v 8.3%; odds ratio = 2.9, P =.0005). Consideration of gender showed that all of these associations were reflections of a male-specific increase in homozygosity for HLA-DRB4*01 (32.8% v 4. 0%; odds ratio = 11.7, 95% confidence interval [CI] = 4.9 to 28.0; P = 3 x 10(-8)). This highly significant result provided the long-suspected evidence for the HLA-DR influence on the development of childhood ALL while confirming the recessive nature of the MHC influence on human leukemogenesis as in experimental models. The cross-reactivity between HLA-DR53 and H-2Ek, extensive mimicry of the immunodominant epitope of HLA-DR53 by several carcinogenic viruses, and the extra amount of DNA in the vicinity of the HLA-DRB4 gene argue for the case that HLA-DRB4*01 may be one of the genetic risk factors for childhood ALL.

Abortion, Habitual↗
PubMed1996

Influence of the major histocompatibility complex on age at onset of chronic lymphoid leukaemia.

The major histocompatibility complex is one of the interactive factors in the multifactorial model of carcinogenesis. Its main influence in experimental models is on the age at onset of malignancies. We have previously shown a similar effect of homozygosity for HLA-DR53 in CML. In the present study, we investigated 79 patients with CLL and 329 local controls from Germany. In addition to full serotyping, all patients and 116 of controls were also typed by HLA-DRB PCR analysis. The homozygosity rates for DR53 in patients under and over the median age (60 years) were 18.6% and 2.9%, respectively (p = 0.03). Eight of the 9 homozygous patients were under the median age. The sex ratio in the DR53 homozygous group was reversed in favour of females. The homozygosity rates for DR53 were different in the overall groups of patients and controls, yielding a relative risk (RR) of 2.4 (p = 0.03). This association was stronger in the early-onset group compared to age-matched controls (RR = 4.4; p = 0.008) and for females with an early onset compared to age- and sex-matched controls (RR = 17.9; p = 0.0008). The simultaneous occurrence of the alleles of the haplotype A2B62DR4 showed a strong association with CLL (RR = 4.1; p = 0.002). This was probably the reason behind the association with HLA-DRB1*0401 (RR = 2.4; p = 0.009). Compared to the accelerating effect of HLA-DR53, HLA-DR52 showed a significant delaying effect on the onset of CLL. These findings confirmed the influence of the HLA complex on the development of another leukaemia.

Adult↗
PubMed1996

The implications for childhood leukemia of infection with adenovirus.

Adenoviruses have mechanisms that allow persistence in lymphoid cells and immunoevasion. They downregulate major histocompatibility complex (MHC) class I antigen expression and may trigger an autoimmune reaction against MHC class II antigens through mimicry. Adenoviral persistence could be facilitated by human leukocyte antigens A2 and DR53, thereby allowing a preleukemic clone to escape immune surveillance and progress to leukemia.

Adenoviridae↗
PubMed1996

The frequency of the haemochromatosis-associated genotype D6S265-1:D6S105-8 in blood donors.

Homozygosity for HLA-A3 and the microsatellite markers D6S265 allele 1 and D6S105 allele 8 is associated with a high relative risk for genetic haemochromatosis-indeed we and others have suggested that a haplotype including D6S265-1, HLA-A3 and D6S105-8 is specific for haemochromatosis. To determine the frequency of this haplotype and examine its specificity for haemochromatosis we have analysed data from 7820 blood donors from South Wales. The frequency of homozygosity for D6S265-1, HLA-A3 and D6S105-8 was 1 in 280. Calculations based on the prevalence of haemochromatosis suggest that about 50% of chromosomes carrying D6S265-1:HLA-A3:D6S105-8 also carry the haemochromatosis gene. This information is of value for assessing the risk that the partner of a patient with haemochromatosis also carries the haemochromatosis gene.

Adult↗
PubMed1995

A molecular analysis of the telomeric end of the major histocompatibility complex. DNA typing of HLA-A3 subtypes and -B7.

A molecular investigation of the HLA-A, -B, -C, I82, D6S128, and D6S265 loci was carried out using RFLP and PCR analyses in 331 healthy individuals, 21 HLA-A3B7 homozygous subjects, and 17 HLA homozygous cell lines. New polymorphic RFLP patterns were noted at the HLA-A and -B loci which were useful for distinguishing subtypes of HLA-A3 and -B44. Strictly specific bands were observed for HLA-A3, -A11, -B7, -B57. and -Cw4. Molecular identification of two HLA-A3 subtypes was possible by HLA-A RFLP and D6S265 PCR analyses. The two alleles of the I82 locus were associated with different HLA-A3 subtypes. It was shown that the serologically HLA-A3 homozygous cell line EHM was heterozygous for the two subtypes. The common subtype formed 91% of HLA-A3 antigens. Some serologically HLA-A3 homozygous healthy individuals were heterozygous for the subtypes. Using these new polymorphisms, a thorough molecular analysis of the haplotype HLA-A3B7DR15 at the three regions of the MHC was performed. The results have implications on HLA matching in transplantation, population genetics of the MHC, and disease association studies.

Base Sequence↗
PubMed1995

Nature of HLA-associated predisposition to childhood acute lymphoblastic leukemia.

A molecular analysis was carried out in 63 sequentially diagnosed childhood acute lymphoblastic leukemia (ALL) patients and 1011 controls to investigate the homozygosity rate for HLA-DR53. HLA-DR53 is associated with acute myeloblastic leukemia at the protein level, and our previous study has shown its association with early-onset chronic myeloid leukemia only in homozygous form at the DNA level. In the present study, the homozygosity rates for DR53 were 17.5 and 13.6% in patients and controls, respectively. Ten of the 11 homozygous patients were boys. In the common ALL group (n = 40), all seven DR53 homozygous patients were boys, and among 19 girls this genotype was not observed (P = 0.006). For males, homozygosity for DR53 revealed a relative risk (RR) of 3.29 (P = 0.008) for common ALL. Five of the 11 relapsed patients were homozygous for DR53. Heterozygous frequencies for HLA-DR53 were not different between patients and controls. Homozygosity for DR53 was associated with a very high relapse rate (45.5 vs 7.7%, P = 0.002, RR = 9.1). These results extended our findings in chronic myeloid leukemia and showed the recessive nature and the male predominance of the interactive HLA influence on the development of childhood leukemia. Molecular mimicry of an HLA-DR53 epitope by oncogenic (retro)viruses or putative susceptibility genes in linkage disequilibrium with HLA-DR53 may be responsible for this association.

Adolescent↗