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PubMed2002

[HLA-DRB1/DQA1/DQB1 alleles and haplotypes in Czech children with celiac sprue].

BACKGROUND: The celiac disease (CD) is a multifactor disease resulting from a life time abnormal immune response to gluten accompanied by autoimmune characteristics, which can in sensitive individuals evoke small bowel mucosa morphologic changes. The genetically sensitive individual to CD has not been defined yet, it is obvious, however, that this illness is closely linked to the HLA class II genes. The objective of our study was to detect associations of HLA class II alleles and haplotypes DRB1/DQA1/DQB1 in Czech CD children. METHODS AND RESULTS: A group of Czech CD children diagnosed according to ESPGHAN criteria was genotyped HLA for alleles of DRB1/DQA1/DQB1 loci. Genotyping of the HLA-DRB1/DQB1 haplotypes proved statistically significant association CD with haplotypes and alleles of this genetic system. 92.9% of patients have in their HLA phenotype allele DQA1*0501 in either cis or trans configuration with the DQB1 allele *0201/*0202. The extended HLA haplotype DRB*0301/DQA1*0501/DRB1*0201 as well as the haplotype DRB1*0701/DQA1*0201/DQB1*0202, are presented in 63.6% or in 61.0% CD patients respectively. The individual HLA class II alleles DRB*0301, *0701, DQA1*0201, *0501, DQB1*0201, *0202 and the above mentioned HLA haplotypes inclusively provide genotypic frequencies significantly different from healthy Czech individuals (P < or = 0.06 +/- 0.001). These results support the opinion that the HLA molecule expressed on the cellular surface as a alpha beta heterodimer encoded by the DQA1*0501 and DQB1*0201/02 alleles in either cis or trans configuration is responsible for the primary sensitivity to this disease. We were, however, not able to find an association of various clinical forms of the CD with a certain HLA haplotype in the followed group. CONCLUSION: The CD patients have in comparison with healthy population significantly different frequency of HLA class II haplotypes. Though the finding of these alleles is not sufficient for an explicit confirmation of this diagnosis, the proof of this risky haplotype/s may notably contribute to it, namely in case of potential or latent forms of this disease.

Adolescent↗

PubMedDate not supplied

Beta-thalassaemia mutations and the underlying beta gene cluster haplotypes in the Greek population.

The polymorphic sites across the beta gene cluster (restriction haplotypes) in association with specific thalassaemic mutations were analyzed in representative samples of normal and thalassaemic Greeks in comparison to similar data of other populations around the mediterranean basin. We studied 316 normal chromosomes, 218 chromosomes from patients with thalassaemia major and 72 chromosomes from patients with thalassaemia intermedia. In the former group, haplotype frequencies followed the order I, IX, II, V etc.. In the group of patients with transfusion-dependent thalassaemia the order was I, II, V and VI, while in those with thalassaemia intermedia the most frequent haplotypes were I and VI. The frequency of haplotypes I and VI was higher among the thalassaemic chromosomes in comparison to those of the normal population; haplotype IX showed the inverse relation. These findings imply that the thalassaemic mutations occurred at a very early stage on haplotypes I and VI and much later on haplotype IX. Micromapping did not reveal any significant variations. Haplotypes I, II, V and VI were associated with the molecular defects IVS-1 nt 110, beta zero-39, IVS-1 nt 1 and IVS-1 nt 6 respectively. A number of other mutations were also identified. The molecular defect was identified also on a random sample of beta-thalassaemia carriers (424 chromosomes). On the basis of the overall data, the feasibility of prenatal diagnosis of thalassaemia by allele specific hybridization is ca. 80%, with the four most common oligomers and 95% when the set of probes expands to eight.

Alleles↗

PubMed2003

[Association of HLA-A, B, and DR haplotypes with genotype in Chinese children with systemic lupus erythematosus].

OBJECTIVE: Development of systemic lupus erythematosus (SLE) is not only associated with single loci of HLA gene, but also possibly related to certain haplotypes and genotypes of MHC. In the present study the authors explored association of HLA-A, B, DR haplotype and genotype with SLE in Chinese children, analyzed a large family with multiple SLE patients and genetic origin of SLE patients with HLA-DRB1 * 15, to discover the influence of linkage disequilibrium of HLA gene on SLE. METHODS: HLA-A, B, DR alleles were tested in 53 patients with SLE and 40 cases with their parents, 35 patients with SLE and HLA-DRB * 15 positive and 27 cases with their parents, a large family with SLE (18 members of three generations) and also 78 normal controls and 43 cases with their parents by microlymphocytotoxicity test and polymerase chain reaction - sequence specific primers (PCR-SSP). HLA-A, B, DR haplotype and genotype of SLE patients and controls were statistically calculated. The SLE patients with HLA-DRB1 * 15 and controls were analyzed for either the gene originated from the paternal or the maternal side. RESULTS: The variety of the haplotype in patient group (64/80) was less than that in control group (74/86). Only 9 haplotypes were found common between the patient group and control group. The frequency of the haplotype HLA-A9B40DRB1 * 15 was significantly higher in patient group than that in control group (P < 0.05), RR was 10.726 0. Five members of the large family had haplotype A9B40DRB1 * 15, 2 of them were patients with SLE, 1 of them was positive for ANA and had Raynaud's phenomenon and 2 of them were normal. The rest of the family members were normal. The frequency of genotypes DRB1 * 09/DRB1 * 15 and DRB1 * 03/DRB1 * 15 in SLE group was significantly higher than that of control group (P < 0.05), RR was 7.772 7 and 14.272 7, respectively. The number of SLE children with gene HLA-DRB1 * 15 derived from their fathers was significantly higher than that of the children with the gene derived from the mothers. CONCLUSION: These findings suggested that haplotype HLA-A9B40DRB1 * 15 and genotypes HLA-DRB1 * 09/DRB1 * 15, HLA-DRB1 * 03/DRB1 * 15 were correlated with SLE. The predisposition of multiple loci seems to have an additive effect. The children with their gene HLA-DRB1 * 15 derived from their fathers might more easily suffer from SLE than those with the gene derived from their mothers, the underlying mechanism needs further studies.

Adolescent↗

PubMed2004

The association between paired basic amino acid cleaving enzyme 4 gene haplotype and diastolic blood pressure.

BACKGROUND: In a previously identified locus linked to hypertension on chromosome 15q, we identified three blood pressure candidate genes: insulin-like growth factor 1 receptor gene (IGF1R), myocyte specific enhancer factor 2A gene (MEF2A), and paired basic amino acid cleaving enzyme 4 gene (PACE4). In this study, we tested their associations with hypertension using haplotype analysis. METHODS: A total of 288 unrelated individuals, including 163 high diastolic blood pressure (DBP) subjects and 125 normal DBP subjects were enrolled in this case-control study. Twenty single nucleotide polymorphisms (SNPs) in the three genes were genotyped using polymerase chain reaction followed by restriction enzyme digestion. Haplotype analysis was accomplished in the following stages: (1) pair-wise linkage disequilibrium test among SNPs on the same gene was performed to explore blocks in which recombination is very unlikely to happen; (2) Estimation-Maximization algorithm was applied to estimate haplotype frequencies in each block; (3) the chi-square test was used to examine the specific haplotype difference, and a permutation test was used to examine the overall haplotype profile difference between cases and controls in each block. RESULTS: An estimated haplotype "CCCCG" frequency in the haplotype block on the PACE4 gene was significantly higher in high DBP cases than in controls (P < 0.01). The overall estimated haplotype profile in this block was also significantly different between the cases and the controls (P < 0.001). This association indicates. CONCLUSIONS: This study for the first time demonstrated that PACE4 gene may play an important role in the regulation of DBP. This association indicates that variations influencing DBP resides in or near this genomic region.

Adult↗

PubMed2004

[The application of DNA sequencing in studying haplotypes of PAI-1 gene in patients with coronary artery disease].

OBJECTIVE: Using simple and efficient DNA sequencing method to determine the haplotypes derived from 4G/5G and G/A polymorphisms in promoter of plasminogen activator inhibitor-1 (PAI-1) gene and trying to associate those haplotypes with coronary artery disease(CAD). METHODS: The frequencies and genotype distribution of the two PAI-1 gene variants in 93 CAD patients and 145 control subjects were determined via denaturing high-performance liquid chromatography (DHPLC) method. The heterozygotes for both polymorphism sites were directly sequenced to define the haplotypes based on the principle that heterozygotes of 4G/5G genotype were one guanine deletion and therefore one base shift from this site in sequencing graph results in particular wave pattern on -844G/A site. RESULTS: Only A-4G and G-5G haplotypes were detected in carriers heterozygous for both -6754G/5G and -844G/A polymorphisms sites though there are G-4G and A-5G haplotypes in carriers homozygous for both sites. No significant differences in haplotypes distribution were seen between CAD patients and control subjects. CONCLUSION: The DNA sequencing is objective and correct in determining haplotypes derived from two polymorphisms with distance less than about 400 bp apart and with one insertion/deletion polymorphism. And the haplotypes derived from -675 4G/5G and -844G/A polymorphisms are not associated with pathogenosis of CAD.

Aged↗

PubMed2005

Multiple sclerosis: a haplotype association study.

Results are presented from a genomewide haplotype association study on multiple sclerosis (MS) cases from Tasmania, an island state of Australia. Cases were ascertained on strict clinical and radiological grounds and on the fact that they had at least one grandparent born in the state. This enriched for early settler chromosomes among present day Tasmanians with MS and increased the chances of finding common haplotype sharing at disease predisposition loci in distant relatives sharing common ancestral haplotypes. Four-to-five close relatives were also collected for each of 170 cases and 105 population-based controls. All were genotyped at a 5cM resolution, haplotypes reconstructed and sharing estimated using an empirical approach based on sorting haplotypes to find the most common at each locus and then generating a test statistic for excess sharing in the cases based on permutation testing. Five initial loci were found where there was an excess sharing in the cases. These were fine-mapped with 10-12 additional markers. Only loci on chromosomes 6 and 10 remained after fine mapping. These loci demonstrate an increase in sharing of multi-marker haplotypes in MS cases compared to both population control transmitted haplotypes and case non-transmitted haplotypes.

Haplotypes↗

PubMed2005

[Construction of standard recombinant plasmids for 7 common mannan-binding lectin gene haplotypes].

OBJECTIVE: To construct the standard recombinant plasmids for 7 common haplotypes of mannan-binding lectin (MBL) gene. METHODS: The DNA samples with known haplotypes and genotypes of MBL gene were used as the templates for amplifying the fragments of MBL gene haplotypes including the promoter region and exon 1 with sequence-specific primer-polymerase chain reaction (SSP-PCR) method. The amplified fragments were cloned into T vector and the bases located at codon 52 and codon 57 of exon 1 in MBL gene were mutated respectively by site-directed mutagenesis. All the 7 recombinant plasmids were identified by PCR and direct sequence analysis. RESULTS: From the DNA samples with known haplotypes and genotypes of MBL gene, the standard plasmids of haplotypes HYPA, LXPA, LYQA, LYPA and LYPB of MBL gene were constructed by SSP-PCR and molecular cloning technique. From the recombinant plasmids of HYPA and LYQA, the standard plasmids of haplotypes HYPD and LYQC of MBL gene were constructed by site-directed mutagenesis, respectively. CONCLUSION: The constructed standard plasmids of haplotypes HYPA, LXPA, LYQA, LYPA, LYPB, HYPD and LYQC of MBL gene provide standard controls for detecting the SNPs, haplotypes and genotypes of MBL gene with such genotyping methods us SSP-PCR and real-time PCR.

Base Sequence↗

PubMed2005

Angiotensin-converting enzyme 2 (ACE2) haplotypes are associated with pulmonary disease phenotypes in sarcoidosis patients.

BACKGROUND AND AIM OF THE STUDY: Angiotensin II (Ang II) formation by angiotensin-converting enzyme (ACE) or other enzymes has shown to exhibit profibrotic properties in a variety of fibrotic diseases. A homologue of ACE called ACE2 has been shown to counteract the formation of Ang II. Genetic variation in the components involved in Ang II formation may underlie the progression of pulmonary sarcoidosis. METHOD: Seven ACE2 SNPs, located on the X-chromosome, were investigated using SSP-PCR and haplotypes were constructed. Gender-matched analyses of sarcoidosis patients (80 males/64 females) and controls (110 males/218 females) were performed to correlate disease susceptibility and pulmonary disease phenotypes with ACE2 genotypes and haplotypes. RESULTS: ACE2 SNPs or haplotypes were not associated with susceptibility for sarcoidosis. Haplotype 4 was only present in sarcoid males without parenchymal involvement (frequency: 0.19) and absent in males with parenchymal involvement (p = 0.006; pcorr. = 0.05; degrees of freedom (df) = 1; OR = 0). No significant difference was observed between haplotype 4 frequencies in females with (0.08) or without (0.13) parenchymal involvement (p = 0.5). Although not significant after correction, analysis of the patient group with fibrosis showed that males with haplotype 5 (0.27) were predominant over those with haplotype 5 of the groups without fibrosis (0.03); p = 0.01; pc = 0.08; df = 1; OR = 11.4. Females with fibrosis vs. no fibrosis revealed no difference between haplotype 5 frequencies: 0.05 vs. 0.03; p = 0.37; pc = 1; df = 1. CONCLUSION: These results suggest that ACE2 might be involved in the progression of pulmonary sarcoidosis which may depend on gender. Subsequent studies using larger groups are needed to confirm these findings.

Angiotensin-Converting Enzyme 2↗

PubMed2006

[Haplotypes of four single nucleotide polymorphisms in caspase-8, -10 genes in Han nationality of Zhejiang province in China].

OBJECTIVE: To investigate single nucleotide polymorphisms (SNPs) and the distribution of their haplotypes in caspase-8, -10 genes in Zhejiang Han nationality in China. METHODS: PCR, denaturing high-performance liquid chromatography (DHPLC) and DNA sequencing were used to detect the SNPs in the 2nd-5th exons of caspase-10 gene, the 8th-10th exons of caspase-8 and their flanking sequences. Expectation Maximization (EM) algorithm was used for haplotype frequencies analysis and pairwise linkage disequilibrium (LD) test. RESULTS: (1) Two SNPs, A2823G and A12799G, were identified in caspase-10 gene, located in exon 2 and exon 5 respectively. A12799G was newly found with low informativeness. Three SNPs were identified in caspase-8 gene; A43466G, G51484A and G52951A were located in exon 8, exon 9 and intron 9, respectively. They do not change the primary structure of the encoded protein. (2) Linkage equilibrium was observed between A2823G in caspase-10 gene and the three sites in caspase-8 gene. A43466G and G52951A, and G51484A and G52951A in caspase-8 gene were also in linkage equilibrium. Their coefficients of disequilibrium were near 0. Whereas strong linkage disequilibrium was observed between A43466G and G51484A, because its coefficient of disequilibrium was near 1. (3) A total of 11 haplotypes were estimated within A2823G in caspase-10 gene and three sites in caspase-8 gene. A-2823/A-43466/G-51484/G-52951 was the main haplotype with a frequency of 0.3811. A-2823/A-43466/G-51484/A-52951 was the second haplotype with a frequency of 0.2536. The polymorphism information content of their haplotypes was 0.7106. CONCLUSION: The SNPs of caspase-8, -10 genes in Han Chinese of Zhejiang could be parsed into at least three different haplotype blocks. The polymorphism information content can be improved by using haplotype analysis of several SNPs.

Alleles↗

PubMed1990

Missense mutations associated with RFLP haplotypes 1 and 4 of the human phenylalanine hydroxylase gene.

We report missense mutations associated with haplotype 1 and haplotype 4 alleles of the human phenylalanine hydroxylase (PAH) gene. Individual exon-containing regions were amplified by polymerase chain reaction from genomic DNA of a PKU patient who was a haplotype 1/4 compound heterozygote. The amplified DNA fragments were subcloned into M13 for sequence analysis. Missense mutations were observed in exons 5 and 7, resulting in the substitution of Arg by Gln at residues 158 and 261 of the enzyme, respectively. Expression analysis in heterozygous mammalian cells after site-directed mutagenesis demonstrated that the Arg158-to-Gln158 mutation is a PKU mutation, whereas the Arg261-to-Gln261 mutation is apparently silent in the assay system. Hybridization analysis using allele-specific oligonucleotide probes demonstrated that the Arg158-to-Gln158 mutation is present in two of six mutant haplotype 4 alleles among the Swiss and constitutes about 40% of all mutant haplotype 4 alleles in the European population. The mutation is not present in normal alleles or in any mutant alleles of other haplotypes. The results provide conclusive evidence that there is linkage disequilibrium between mutation and haplotype in the PAH gene and that multiple mutations have occurred in the PAH gene of a prevalent haplotype among Caucasians.

Base Sequence↗

PubMed1987

The hematologic characteristics of sickle cell anemia bearing the Bantu haplotype: the relationship between G gamma and HbF level.

Previous work has demonstrated that the HbS gene has appeared and expanded three times in Africa in three separate geographic locations and that these three distinct mutational events can be identified by linked DNA polymorphic sites (haplotypes) surrounding the abnormal gene. We have reported that the Senegalese and Beninian haplotypes differ in G gamma expression, mean percentage of HbF, and percentage of dense cells. We now report on the third haplotype, the Bantu, and find that it has intermediate features, namely, the high mean percentage of HbF and low percentage of dense cells associated with the Senegalese haplotype, but with a low percentage of G gamma expression similar to the Beninian haplotype. The distribution of percent HbF is quite different from Senegal haplotype-bearing sickle cell anemia patients since it covers a much wider range. The low G gamma expression is also different from the Beninians since it contains a significant and unique cluster of individuals with lower than 38% G gamma. Interestingly, among the Bantu there is a strong correlation between HbF levels and G gamma expression, which is not seen with the other haplotypes. These findings open the possibility that among the Bantu haplotype-bearing individuals two chromosomal types exist that define different levels of G gamma and HbF expression. Further structural exploration of these two potential subhaplotypes is needed.

Anemia, Sickle Cell↗

PubMed1989

A novel association of DQ alpha and DQ beta genes in the DRw10 haplotype. Determination of a DQw1 specificity by the DQ beta-chain.

The association of the class II genes of the DRw10 haplotype from a cell line, NASC, initiated from a member of a well characterized family, was analyzed by sequencing cDNA clones corresponding to DR beta I, DQ alpha, and DQ beta genes. An identical haplotype was also identified in the Raji cell line. In addition to typing as DRw10 and DQw1 with HLA typing sera both, the NASC and Raji cell lines were shown to react strongly with the monoclonal antibodies 109d6 (specific for DRw10 beta 1 and DRw53 beta 2 gene products) and Genox 3.5.3 (specific for DQw1) and exhibited the restriction fragment length polymorphism indicative of a DRw10, DQw1 haplotype. The DR beta 1 gene corresponding to the DRw10 specificity was found to have a first domain sequence different from all other DR beta I genes. Sequence analysis of the 3'-untranslated region of this DR beta-chain gene showed a significant divergence from the 3' untranslated region of the DRw53 family of haplotypes and a lesser divergence from that of the DRw52 and DR1/DR2 families. The sequence of the DQ beta genes corresponding to the DQw1 specificity in the DRw10 haplotype was found to be identical to the DQ beta gene from a DR1, DQw1 haplotype. Surprisingly, however, the DQ alpha gene did not resemble other DQw1-like DQ alpha genes, but was identical in sequence to the DQ alpha gene found in DR4 haplotypes. The novel association of DQ alpha and DQ beta genes in the DRw10 haplotype revealed in these studies may result from a double recombinational event. More consequentially, these studies strongly suggest that the DQw1 specificity recognized by Genox 3.5.3 is determined by the DQ beta chain and is not affected by the DQ alpha-chain.

Amino Acid Sequence↗

PubMed1989

[Novel partial t-haplotypes of domestic mouse: characteristics of basic properties].

The paper concerns the description of new partial t-haplotypes. One of them, tN1, arose as a result of recombination from t12. The rest ones, tN2-tN5, arose from t6. All the haplotypes described are viable in homozygotic state and when present with T (Brachyury) cause the offspring to be tailless. The tN1-heterozygous males transmit the chromosome with this haplotype to their offspring at the rate of 33%, the t12/tN1 compounds being subfertile. Transmission of chromosome with tN2-tN5 haplotype from heterozygous males does not deviate from 1:1, the t6/tN2 (-tN5) being fertile. The data obtained point out to additional genes (distorters) in the model of t-haplotype, offered by M. Lyon (1984, 1986), that agrees with suggestion of L. Silver (1985). Recombination analysis showed that tN1-tN5 haplotypes suppress crossing over at the strech of 4-5 cM, distally to the T mutation. In tN1 homozygous stock the short-tailed mice appear at the rate of 6-7%. Manifestation of the fused gene is sufficiently modified in a greater part of the animals having genotype tN1Fu/tN1+. That is likely to be the result of gene interaction in early ontogenesis. It has been shown earlier, that penetrance of Fu gene is reduced in the progeny of Fu/t12 females. The results are in favor of the fact that this effect is connected with the distal part of t12-haplotype, the proximal tN1-haplotype having no such effect.

Animals↗

PubMed1988

Polymorphism of the HLA-D region in American blacks. A DR3 haplotype generated by recombination.

The polymorphism of HLA class II molecules in man is particularly evident when comparisons between population groups are made. This study describes a DR3 haplotype commonly present in the American black population. Unlike the Northern European population in which almost all DR3 individuals are DQw2, approximately 50% of DR3-positive American blacks express a serologically undefined DQ allelic product. DNA restriction fragment analysis with the use of several unrelated individuals and an informative family has allowed us to identify unique DQ alpha- and beta-fragments associated with the DR3, DQw- haplotype. Based on fragment size, the DQ alpha genes of the DR3, DQw- and DRw8, DQw- haplotypes are similar as are the DQ beta genes of DR3, DQw-; DRw8, DQw-; and DR4, DQw- haplotypes. In addition, a DX beta gene polymorphism has been identified which is associated with some DR3 haplotypes including the American black DR3, DQw- haplotype. cDNA sequence analysis has revealed a DQw2-like alpha gene and a DQ beta gene which is similar to that previously described for a DR4, DQw- haplotype. It is postulated that recombination between DQ alpha and DQ beta genes and between the DQ and DX subregions has generated the various DR3 haplotypes and has played an important role in creating diversity in the HLA-D region.

Amino Acid Sequence↗

PubMed1989

Structural relationships among the H-2 D-regions of murine MHC haplotypes.

The number of genes encoding functional Ag-presenting molecules in the D region of the murine MHC differs among haplotypes. For example, the H-2b D region contains a single "D/L" gene, H-2Db, whereas the d-haplotype encodes two, H-2Dd and Ld. Using D/L specific oligonucleotide probes, we have found that, as with H-2d, the q- and v-haplotypes contain two D/L genes, whereas the other haplotype examined have one. Hybridization analysis using cloned probes that map between H-2Dd and Ld revealed similar structures in each of the three haplotypes (d, q, and v) which have "duplicated" D regions. Two approaches were used to examine allelic relationships among the D/L genes. First, the 5' region of the H-2Db gene was sequenced, and found to be more similar to H-2Ld than to H-2Dd. Second, oligonucleotide probes that distinguish H-2Ld from H-2Dd revealed H-2Ld-related genes in several haplotypes, including the duplicated haplotypes H-2q and H-2v. Analogous probes specific for H-2Dd, however, did not detect similar sequences in the other haplotypes. We interpret these results to mean that the three duplicated D regions arose from a common duplication event, and share the five gene structure of the D region cluster defined in H-2d. However, subsequent events have generated sequence divergence at the D-locus.

Alleles↗

PubMed1994

The heterogeneity of the beta s cluster haplotypes in Brazil.

The beta s cluster haplotypes were determined for 74 Brazilian patients with sickle cell anemia from three cities separated by 1,400 to 2,300 km. The cities are representative of the regions which have the largest Black populations of the country. All 138 chromosomes with typical haplotypes had one of the three most common African haplotypes. No example of the Asian or of the Cameroon haplotypes was found. The Bantu haplotype predominates in all three regions (54.8 to 73.1%), followed by the Benin haplotype (25.4 to 45.2%) and a small number of cases with the Senegal haplotype (0 to 6.9%). The mean prevalence of the Bantu haplotype of 65.9% agrees closely with historical data which indicate that 70% of the African slaves brought to Brazil originated from regions of Bantu populations.

Anemia, Sickle Cell↗

PubMed1994

Identification of a specific HLA class II haplotype strongly associated with susceptibility to cyclosporine-dependent aplastic anemia.

Hematopoietic function of some aplastic anemia (AA) patients is dependent on the administration of cyclosporine (CyA). To investigate whether certain HLA class II genes are associated with susceptibility to such CyA-dependent AA, we determined the HLA class II alleles of 59 AA patients treated with CyA. Among 26 patients successfully treated with CyA, 13 required a small dose of CyA to maintain stable hematopoiesis. Of these 13 AA patients, 10 shared an HLA class II haplotype of DRB1*1501-DQA1*0102-DQB1*0602. None of the 13 responders who obtained a sustained remission off CyA therapy possessed this haplotype. In the 10 patients who shared the HLA class II haplotype, single-strand conformation polymorphism analysis of each gene fragment of this haplotype failed to detect a polymorphism in the nucleotide sequence. When the AA patients were assessed for their likelihood to respond to CyA therapy, the response rate in patients with this haplotype (71%) was significantly higher than that of patients with another haplotype associated with HLA-DR2, DRB1*1502-DQA1*0103-DQB1*0601 (36%) and that of patients without HLA-DR2 (35%). These findings indicate that the CyA-dependent response of AA is closely related to an HLA class II haplotype of DRB1*1501-DQA1*0102-DQB1*0602 and suggest that, in AA patients with this haplotype, immune mechanisms play an important role in the pathogenesis of bone marrow failure.

Adolescent↗

PubMed1996

DNA haplotypes in Africans and West Indians with sickle cell anaemia or SC disease.

Considering that genetic variation linked to the beta S mutation may influence the clinical manifestations of sickle cell disease, we have analyzed the beta globin cluster haplotypes in 47 patients with this condition (33 SS homozygotes, one S/beta thal (0), and 13 SC) living in London (30 West Indian, 17 West African). Of the 80 chromosomes tested, 82.5% had the Benin haplotype and of the 13 C chromosomes tested, 85% had the Bantu-A4 haplotype. A minority of patients had Bantu or Senegal haplotypes, and in 5 patients we found new haplotypes called E, H and O which may have arisen through mutation or recombination. Because of the predominance of a single haplotype (Benin) nearly all our homozygous S patients were either homozygous or heterozygous for this haplotype. We concluded that the beta globin haplotype is unlikely to be an important determinant of the clinical severity in this patient population.

Africa, Western↗