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PubMed1989

The absence of 21-OH A and C4 B genes is a constant characteristic of the "Sardinian" HLA extended haplotype A30 Cw5 B18 BfF1 DR3 DRw52 DQw2.

The genomic DNA of 25 unrelated individuals with HLA haplotype A30 Cw5 B18 BfF1 DR3 D w52 DQw2 was digested with the restriction enzyme Taq I and hybridized with cDNA probes for C4 and 21-OH genes. Eighteen individuals and a non-Sardinian reference cell (DUCAF) were homozygous for the entire extended haplotype, six individuals were heterozygous for the HLA-A locus and homozygous for the rest of the same haplotype. All of the 18 homozygous individuals, four of the six heterozygous subjects and the DUCAF cell revealed the absence of two fragments at 3.2 and 2.4 kb corresponding to the 21-OH A gene, and the absence of fragments corresponding to the C4 B "long" or "short" gene. The contemporary absence of the 21-OH A and C4 B genes seems to be a constant characteristic of this extended haplotype in the Sardinian population and suggests that this and other extended haplotypes bearing C4 A or C4 B null alleles could be ancestral haplotypes which never duplicated at these loci.

Alleles↗

PubMed1989

HLA-DQ antigens and DQ beta amino acid 57 of Japanese patients with insulin-dependent diabetes mellitus: detection of a DRw8DQw8 haplotype.

DQw8 (DQw3.2) on DR4 haplotypes is a susceptibility gene for development of insulin-dependent diabetes mellitus (IDDM) in Caucasoids, possibly because it encodes a non-Asp amino acid (aa) (i.e. Ala) at residue 57 of the DQ beta chain (non-Asp-57). Most Caucasoid IDDM patients are homozygous non-Asp-57. We have examined 14 Japanese IDDM patients, selected to be either DR4 or DRw9 (associated to IDDM among Japanese). Their DQB1 alleles and the aa encoded by their DQB1 codons 57 were identified, using 11 different sequence-specific oligonucleotide probes. Secondly, they were examined with DQw8 specific T lymphocyte clones and with anti-DQ monoclonal antibodies. The DQB1 genes on their DR4 and DRw9 haplotypes in all cases encoded Asp-57. Two patients were Asp-57 homozygous, the rest were Asp-57/non-Asp-57 heterozygous. The DR4 haplotypes all carried DQw4 (rather than DQw8), and the DRw9 haplotypes all carried DQw9. Furthermore, five of six DRw8 positive patients carried a previously undetected DRw8DQw8 haplotype, where both the DQA1 and DQB1 genes were similar to those usually found on the DR4DQw8 haplotype. Thus, the DR/DQ allele combinations and aa residue 57 of the DQ beta chain of Caucasoid and Japanese IDDM patients are largely different.

Antibodies, Monoclonal↗

PubMed1990

Large haplotype-specific differences in inter-genic distances in human MHC shown by pulsed field electrophoresis mapping of healthy and type 1 diabetic subjects.

Type 1 diabetes is associated with extended haplotypes defined by combinations of specific alleles of genes in the MHC. We have used pulsed field gel electrophoresis mapping to examine the gross structure of the Class II region of the MHC and its relationship to susceptibility to Type 1 diabetes. We have studied heterozygous members of a family in which susceptibility to Type 1 diabetes is associated with an A1/B8/DR3 haplotype and resistance with A2/B7/DR2, an unrelated diabetic DR3,4 patient and a healthy DR4,w10 subject and a DR2/Dw2 cell line. Digestion was performed with the enzymes Sst II, Mlu I, and Pvu I and hybridization with 21-hydroxylase, DRA, DQB, DOB and DPA probes. Within the DQ/DR region the DR4- and DR7-bearing haplotypes studied contain insertions of 140-150kb relative to the DR3 haplotypes whilst the DR2 haplotype in the family was smaller than the DR3 haplotypes by 130kb, whilst that in the cell line was smaller by up to 220kb. This cell line, previously thought to be homozygous by consanguinity, was also shown to be heterozygous in the DP region. Although no differences between diabetic and healthy subjects were observed within the family, these differences in long-range structure may be of importance to the etiology of Type 1 diabetes, as well as to the evolution of the MHC.

Chromosome Mapping↗

PubMed1991

Association of four HLA class III region genomic markers with HLA haplotypes.

We have studied restriction fragment length polymorphism (RFLP) in the region 300 kb centromeric to the HLA-B locus. Four probes were used: one was genomic DNA derived from the tumor-necrosis factor (TNF)-beta gene, one was a cDNA for the BAT3 gene, and two single-copy genomic probes, R5A and M20A. The order of these markers from HLA-B towards the centromere is M20A, R5A, TNF and BAT3. The BAT3 and TNF-beta probes each detected two allelic bands with Taq I and Nco I digestion, respectively; the R5A and M20A probes each detected three polymorphic allelic bands with BstEII digestion. To determine if these restriction polymorphisms are preferentially associated with certain HLA-B and -DR haplotypes, a total of 153 HLA haplotypes was analyzed. The haplotypes A1, B8, DR3 and A3, B7, DR2 were each associated with a distinct combination of polymorphisms identified at these four sites, thereby demonstrating that the strong linkage disequilibrium characteristic of these haplotypes extends also to this segment of the class III region. In contrast, haplotypes that are not in positive linkage disequilibrium, such as A1,B8,DR4 and A2,B7,DR3, showed no preferential association with any of these polymorphisms. The antigens HLA-B27 and B35 were also found to be in positive linkage disequilibrium with RFLP patterns at three of these sites, and HLA-B14,B35,B44,Bw57 and Bw62 were found preferentially associated with polymorphisms at one or two of these sites, independent of the DR antigen present. These data further demonstrate that genetic linkage disequilibrium in the HLA class III region is complex and variable among different HLA haplotypes.

Chromosome Mapping↗

PubMed1992

HLA structure of the Sardinian population: a haplotype study of 551 families.

A study on the HLA structure of the Sardinian population was carried out on 551 healthy unrelated families representing all of the island districts. Altogether 2202 HLA-A, B, Cw, DR individual haplotypes and 853 different haplotypes were determined. Cavalli-Sforza and Edwards' genetic distance index for the total of 62 tested alleles showed a modest heterogeneity between one district and another (0.09-0.16). The genetic distance between Sardinians and the rest of the Italian population was 0.23 (0.22-0.26) and progressively increased in comparisons with caucasoids (0.26), negroids (0.34) and mongoloids (0.41). Sixty-three two-locus haplotypes with a high positive linkage disequilibrium were observed in our family sample. The percentages of two-locus haplotypes in LD shared with other populations turned out to be 45% with caucasoids, 20% with negroids and 10% with mongoloids. The distribution of the A, B, Cw, DR haplotypes is shown with 673 of them represented only once or twice, and 10 (1.2%) 14-322 times each. Of the latter, 8 are extended haplotypes, 6 of which characterize the Sardinian population. The analysis of our data suggests that the present-day Sardinian population is the result of a superposition of different populations, mainly consisting of caucasoids on a pre-caucasoid paleo-Mediterranean substratum.

Adult↗

PubMed1995

Distribution of HLA antigens and haplotypes in the Buryat population of Siberia.

Polymorphisms of HLA-A, B, C, DR, and DQ antigens were investigated in a Mongoloid population named Buryat living in Siberia. HLA gene and haplotype frequencies were calculated from the population data obtained from 141 unrelated healthy Buryat adults. Gene frequencies of class I antigens A2, A24, A1, B61, Cw10, and Cw6 were estimated to be more than 10%. For class II, DR4, DR7, DR13, DQ7, and DQ1 antigens were predominant. A phylogenetic tree was constructed based on HLA gene frequencies, and the Buryat population was clustered with the Mongoloid groups in Northeast Asia. In the analysis of HLA-A, C, B, DR, and DQ five-locus haplotype frequencies, seven kinds of haplotypes were calculated to occur at frequencies of more than 2%. Five of the seven common haplotypes have also been described in the other human populations thus far. Some of the haplotypes have been described in European populations, while the others were shared with Northeast Asian Mongoloids as well as Amerindians. Similar situation was also found in the analysis of class I (HLA-A, C, B) three locus haplotypes. These observations suggest the unique genetic background of this Buryat population.

Ethnicity↗

PubMed1997

HLA-B44 subtypes and the chance of finding HLA compatible donor/recipient pairs for bone marrow transplantation: a haplotype study of 303 Italian families.

A total of 1176 HLA-A,B,DR haplotypes were reconstructed by typing 303 unrelated families referred to our laboratory during the last seven years for the search of HLA identical sibs in view of bone marrow transplantation. A total of 614 different three-locus haplotypes were found. Most of them (83.6%) were present only once or twice, whereas 24/614 (3.9%) were found 6-28 times each. HLA-B44 was present in 4 of these most frequent haplotypes. HLA-B44 has been implicated as the molecular target for bone marrow allograft rejection. Therefore, a better knowledge of the HLA-B44 haplotype relationships might prove useful for the programming of registries of unrelated bone marrow donors. Eighty five serologically defined HLA-B44 unrelated subjects, either one or both parents from the above families, were subtyped by a high-resolution sequence-specific oligonucleotide probing approach. Moreover, 34 unrelated potential donors recruited for those patients that did not find a suitable donor among their siblings were subtyped also for HLA-B44. B*4403, which accounted for 47/85 (55.3%) serologically defined B44 alleles, appeared in strong, statistically significant, linkage disequilibrium with HLA-A29, -A23 and -DR7. On the other hand, B*4402, which covered virtually all other B44 alleles, showed prevalent gametic associations with HLA-A2 and HLA-A24. The linkage disequilibrium between HLA alleles is the key for the low frequency of HLA-B44 mismatches in donors selected as HLA-A,B,DRB1 identical to patients waiting for unrelated bone marrow transplantation. If a given patient presents unusual haplotypes, the chance of finding HLA-B44 mismatches may be higher because of the presence of different haplotype relationships in the donors.

Bone Marrow Transplantation↗

PubMed1998

HLA-Cw alleles associated with HLA extended haplotypes and C2 deficiency.

There are four MHC-linked complement genes, BF, C2, C4A and C4B, that are inherited as single DNA units, known as complotypes. Extended haplotypes were initially defined by studying the distribution of complotypes in relation to HLA-B and HLA-DR loci in Caucasian families. In order to analyze the distribution of HLA-Cw alleles in relation to extended haplotypes, we studied a large panel of MHC homozygous and heterozygous cell lines representing previously described Caucasian-derived extended haplotypes and 14 patients with complete C2 deficiency. HLA alleles were assigned using sequence-specific oligonucleotide probe hybridization (SSOP). Family analysis served to assign haplotypes for heterozygous samples. We found distinctive HLA-Cw alleles for each independent extended haplotype. Their association in each instance was statistically significant. All patients with C2 deficiency carrying the haplotype [HLA-B18, S042, DR2] were associated with HLA-Cw*1203. These conserved allelic combinations may become an important tool for the study of human evolution and may contribute to the expeditious selection of prospective donors in clinical transplantation.

Alleles↗

PubMed2004

A psoriasis vulgaris protective gene maps close to the HLA-C locus on the EH18.2-extended haplotype.

We determined the molecular haplotypes of the HLA-A, HLA-C and HLA-B loci and the MHC class I-B-related (MIB) microsatellite in 179 unrelated psoriatic patients (72 familial cases) and in 120 controls. The HLA-A*3002-Cw*0501-B*1801-MIB1 haplotype showed a strong negative association with psoriasis vulgaris (PV) and in particular with familial PV, revealing the presence of a PV-protective gene. Analysis of association and linkage disequilibrium of the single alleles and the various two-three-four-locus segments of this haplotype indicated the presence of a protective gene telomeric to the HLA-C locus. This finding was confirmed in 13 informative multiplex PV families, in which at least one parent carried the EH18.2 haplotype. In two families, an affected sibling presented HLA-A/C recombination on the EH18.2 haplotype. A study of 12 polymorphic microsatellites in all members of the informative families, 145 PV patients, 120 controls and 32 EH18.2 homozygous healthy individuals demonstrated that the protection conferred by the EH18.2 haplotype lies within a 170 kb interval between the C143 and C244 loci, most probably in a 60 kb segment between the C132 and C244 loci.

Adolescent↗

PubMed2005

Association of HYPA haplotype in the mannose-binding lectin gene-2 with Behçet's disease.

Behcet's disease (BD) is a multisystemic, recurrent inflammatory disease caused by the combinations of multiple genetic and environmental factors. Moreover, the MBL2 gene single-nucleotide polymorphisms and haplotypes are known to increase the susceptibility to inflammatory disease and to alter the serum levels of mannose-binding lectin (MBL. We postulated that the haplotypes of the MBL2 gene influence therapeutic response in BD, thus affecting the clinical symptoms in 282 BD patients. The promoter region, MBL2-550*C/*C (L/L) homozygote was found to have a lower frequency in BD patients than that in controls. No difference was observed in the allele frequencies of G-221C (Y/X), C+4T (P/Q) or Gly54Asp (A/B) of the MBL2 gene in BD patients and in controls. The HYPA haplotype contributed to BD occurrence, whereas the LYPA haplotype was negatively associated with BD. BD patients with several symptoms and with an earlier disease-onset age had a higher HYPA haplotype frequency. BD patients showing poor response (S) to therapy had a higher HYPA frequency than those showing good response (M). It seems that possessing HYPA increases the risk of BD and that the MBL2 HYPA haplotype plays a role in MBL levels and increases the susceptibility to BD.

Adolescent↗

PubMed2005

Human leukocyte antigen class I and II haplotypes and risk of cervical cancer.

Human leukocyte antigen (HLA) variations may affect immune response to human papillomavirus infection and subsequent cervical neoplasia risk. We investigated the frequency and relationship between HLA-A-B and HLA-A-B-DR haplotypes among women with cervical cancer/high-grade lesions (n=365) and cytologically normal population controls (n=681) within three cervical neoplasia studies in the US and Costa Rica. Notable differences in haplotype frequencies were observed; the HLA-A*01-B*08 haplotype occurred in >5% of US Caucasians but in <1% of Costa Ricans. The most prevalent HLA-A*24-B*40-DR*04 haplotype in Costa Rica (5%) was found in <1% of US Caucasians. No HLA haplotype was significantly associated with cervical neoplasia, suggesting that individual allele associations reported to date (e.g. HLA-DR*13) are not likely explained by underlying haplotypes.

Costa Rica↗

PubMed2006

Association of a common dog leucocyte antigen class II haplotype with canine primary immune-mediated haemolytic anaemia.

Immune-mediated haemolytic anaemia (IMHA) is the commonest immune-mediated disease of the dog, representing a major health concern to this species. The aim of this investigation was to determine whether genetic susceptibility to IMHA is associated with genes of the canine major histocompatibility complex (MHC; dog leucocyte antigen system, DLA). Samples were collected from 108 dogs with primary idiopathic, Coombs' positive IMHA. This diseased population was subdivided on the basis of Coombs' test results into two groups: 1) dogs with dominant warm-reactive immunoglobulin (Ig) G haemagglutinins and (2) dogs with an additional or dominant cold-reactive IgM haemagglutinin. The DLA class II alleles and haplotypes of the diseased population were characterised, and these data were compared with those derived from a breed-matched control cohort and a much larger group of DLA-typed dogs. Two haplotypes were increased in the patient group: DLA-DRB1*00601/DQA1*005011/DQB1*00701 (in the group with warm-reactive IgG haemagglutinins only) and DLA-DRB1*015/DQA1*00601/DQB1*00301 (in both groups, but more so in the group with cold-reactive IgM haemagglutinins). One haplotype, DLA-DRB1*001/DQA1*00101/DQB1*00201, was decreased in the total patient group, but this decrease was limited to the warm-reactive IgG haemagglutinins group, and it was actually increased in the cold-reactive IgM haemagglutinins group. A second haplotype, DLA-DRB1*015/DQA1*00601/DQB1*02301, was also decreased in the total patient group, and this decrease was found in both subgroups. In addition, all haplotypes carrying DLA-DRB1*001 were significantly increased in the cold-reactive IgM haemagglutinins group. When the overall patient group was divided on the basis of individual breeds with more than six animals represented, each of the haplotypes could be shown to be implicated in one of the breeds. Thus, it was apparent that different breeds had different MHC associations with canine IMHA, which is similar to the observation that different human ethnic groups can have different HLA associations with the same immune-mediated disease.

Alleles↗

PubMed2005

IL-10 promoter haplotype influence on interferon treatment response in multiple sclerosis.

The level of interleukin-10 (IL-10) expression is related to polymorphisms -1082 (G/A), -819 (T/C) and -592 (A/C) in the promoter region of the IL-10 gene, which constitute three haplotypes, GCC, ATA, and ACC. The ATA (a non-GCC) haplotype, which is associated with low IL-10 expression, has been shown to improve interferon (IFN) treatment response in hepatitis C. We analysed the distribution of IL-10 promoter haplotype combinations to determine whether they could influence initial IFN treatment response in 63 patients with relapsing-remitting multiple sclerosis (MS). The patients were grouped into non-GCC or GCC haplotypes, and the clinical and magnetic resonance imaging (MRI) disease activity was compared in the two groups. During the first 6 months of treatment, MS patients with non-GCC haplotypes experienced fewer new MRI T1-contrast enhancing lesions [0.77+/-0.36 (SEM)] than patients with the GCC haplotype (2.45+/-0.57) (P=0.05, Mann-Whitney U test). No differences were detected on clinical disease activity. The results suggest an influence of IL-10 promoter polymorphisms on IFN treatment response in MS.

Adult↗

PubMed2006

Case-parent triads: estimating single- and double-dose effects of fetal and maternal disease gene haplotypes.

Case-parent triad data are considered a robust basis for studying association between variants of a gene and a disease. Methods evaluating statistical significance of association, like the TDT-test and its extensions, are frequently used. When there are prior hypotheses of a causal effect of the gene under study, however, methods measuring penetrance of alleles or haplotypes as relative risks will be more informative. Log-linear models have been proposed as a flexible tool for such relative risk estimation. We demonstrate an extension of the log-linear model to a natural framework for also estimating effects of multiple alleles or haplotypes, incorporating both single- and double-dose effects. The model also incorporates effects of single- and double-dose maternal haplotypes on a fetus during pregnancy. Unknown phase of haplotypes as well as missing parents are accounted for by the EM algorithm. A number of numerical improvements to maximum likelihood estimation are also implemented to facilitate a larger number of haplotypes. Software for these analyses, HAPLIN, is publicly available through our web site. As an illustration we have re-analyzed data on the MSX1 homeobox-gene on chromosome 4 to show how haplotypes may influence the risk of oral clefts.

Cleft Lip↗

PubMed2006

Genotypic heterogeneity and correlation to intergenic haplotype within high HbF beta-thalassemia intermedia.

OBJECTIVES: A molecular study was carried out of beta-thalassemia intermedia patients, compound heterozygotes for mutations usually found in beta-thalassemia major, with high levels of HbF in the absence of hereditary persistence of fetal hemoglobin (HPFH) syndrome. Our objective was to locate cis-DNA structures, DNA haplotypes, motifs, or polymorphisms that may correlate with the presence of high HbF. METHODS: Allele-specific oligonucleotide (ASO) hybridization was used for the detection of mutations and restriction fragment length polymorphism (RFLP) analysis and automated sequencing for motifs, haplotypes, and polymorphisms. Southern blot was used for investigating alpha-thalassemia and/or alpha- or gamma-globin genes triplications. RNA extracted from burst forming unit-erythroid (BFU-e) colonies of peripheral blood mononuclear cell cultures was used in reverse transcriptase-polymerase chain reaction (RT-PCR) to investigate intergenic transcription. RESULTS: We established that (i) the combination: T haplotype of the Agamma-delta-globin intergenic region, the motif (TA)9N10(TA)10 in the HS2 site of locus control region (LCR), and TAG pre-Ggamma haplotype is sufficient but not necessary for high HbF, (ii) the genetic determinant(s) for high HbF involves an element associated with this combination and must be present in the specific R haplotype occurring in beta-thalassemia intermedia and (iii) the genetic determinant(s) for high HbF does not involve the abolition of intergenic transcription in the Agamma-delta-globin intergenic region. CONCLUSIONS: The genetic determinant(s) of high HbF in the absence of HPFH is linked to intergenic haplotype T and does not disrupt intergenic transcription.

Adult↗

PubMedDate not supplied

Novel HLA-DR2-related haplotypes in Hong Kong Chinese implicate the DQB1*0602 allele in susceptibility to multiple sclerosis.

Multiple sclerosis (MS) is strongly associated with the HLA-Dw2 haplotype DRw15.DQw6 in Caucasoids, although the relative contributions of DR and DQ loci to disease susceptibility are unknown. The situation is further complicated by the apparent lack of an association between DR2 and MS in Orientals. This study examined 42 DR2-positive chromosomes in healthy Chinese and 12 DR2-positive chromosomes in MS patients from Hong Kong, using oligonucleotide hybridizations of DQA1, DQB1, DRB1, and DRB5 polymerase chain reaction (PCR) products. There was marked heterogeneity in DR2-related haplotypes in controls (ten types), where the most frequent haplotype, confirmed in one family, involved the novel arrangement DRB1*1501, DQB1*0601. Another common haplotype had the unusual combination of DRB1*1602, DRB5*0101 as confirmed by DNA sequencing of the DRB5 allele. In contrast, the most common DR2-related haplotype in MS patients was the 'classical' Dw2 haplotype DRB1*1501, DQB1*0602, with a frequency of 50% compared with 12% in controls (P = 0.01). Novel DR,DQ linkage disequilibrium relationship in Hong Kong Chinese have permitted recognition of DQB1*0602 as a susceptibility allele in DR2-positive MS patients, although a role for the DRB1*1501 allele in MS pathogenesis has not been excluded by this study.

Alleles↗

PubMed1994

PCR SSCP reveals haplotype related polymorphism of PERB1: a new marker for MHC beta block typing.

Many new Major Histocompatibility Complex (MHC) genes have been discovered in the last 5 years. Defining the polymorphism of these new genes may elucidate their function and their relevance to diseases with MHC associations. Polymerase chain reaction and single stranded conformation polymorphism (PCR SSCP) analyses were used to detect sequence polymorphisms of PERB1 demonstrated by comparing the available genomic sequence of four haplotypes. This study showed that PCR SSCP of PERB1 is reproducible. In addition, PERB1 alleles segregate within families together with MHC haplotypes. Typing results from the Forth Asia and Oceania Histocompatibility Workshop (4AOHW) cell panel indicate that the identified polymorphisms of PERB1 are "haplotypic', i.e., unrelated individuals carrying the same MHC ancestral haplotypes carry the same PERB1 SSCP pattern. Interestingly, PERB1 SSCP patterns allow the distinction of ancestral haplotypes which share HLA-B serological specificities, such as HLA-B44 and therefore this analysis can be used to further define MHC haplotypes and thus to improve our understanding of the evolution of this complex.

Alleles↗

PubMed2005

Poly (ADP-ribose) polymerase-1 haplotypes are associated with coeliac disease.

In coeliac disease (CD) there is an inflammatory status of the intestinal mucosa because of a high expression of proinflammatory mediators. The nuclear protein poly (ADP-ribose) polymerase-1 (PARP-1) has been implicated in the initial inflammatory response by modulating transcription of inflammation-related genes. The aim of this work was to investigate the role of PARP-1 gene promoter region haplotypes in relation to coeliac disease susceptibility. We analysed a coeliac population consisting of a case-control panel with 120 CD patients and 311 healthy blood donors. A CA microsatellite, as haplotype-defining variant of the whole PARP-1 promoter, was typed using a polymerase chain reaction (PCR) method combined with fluorescence technology. We considered two promoter haplotypes: A defined by short CA alleles (83-87 bp) and B defined by long CA alleles (89-101 bp). Haplotype A was significantly increased within the coeliac patients group (P = 0.007 OR 1.6 95%CI 1.12-2.35). Additionally, we observed a significant dose effect, showing homozygous individuals for haplotype A higher risk for CD susceptibility (P = 0.007, OR 1.79 95%CI 1.14-2.82). Our results provide the first evidence that PARP-1 haplotypes are related with coeliac disease susceptibility.

Autoimmune Diseases↗