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PubMed1990

Phenylketonuria mutation in Chinese haplotype 44 identical with haplotype 2 mutation in northern-European Caucasians.

DNA amplification with the polymerase chain reaction was employed to identify the phenylketonuria (PKU) mutation in Chinese PKU families. The amplified DNA was hybridized with oligonucleotides corresponding to the two most common mutant alleles, i.e., mutations associated with PKU haplotype 2 and 3 among Caucasians of northern-European ancestry. The results of analysis demonstrate that the mutation in Chinese haplotype 44 is a single-base substitution corresponding to the mutation associated with haplotype 2 in Caucasians, whereas the mutations of the phenylalanine hydroxylase gene in haplotypes 4, 7, 11 and 28 among Chinese do not correlate with either of the two mutations identified in northern-European Caucasians.

Asian People↗

PubMed2005

ATM haplotypes and associated mutations in Iranian patients with ataxia-telangiectasia: recurring homozygosity without a founder haplotype.

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder caused by mutations in the ATM gene. The ATM gene spans more than 150 kb at chromosomal region 11q23.1 and encodes a product of 3,056 amino acids. The ATM protein is a serine/threonine protein kinase and is involved in oxidative stress, cell cycle control, and DNA repair. We analyzed the 11q22-23 haplotypes and associated mutations of 16 Iranian families. We utilized standardized short tandem repeat (STR) haplotypes to enhance mutation identification. In addition to the STR markers, single-nucleotide polymorphism haplotypes were determined, using three critical polymorphisms. The entire gene was screened sequentially by protein truncation testing, single-strand conformation polymorphism, and denaturing high-performance liquid chromatography to identify the disease-causing mutations. Of the expected 32 mutations, 25 (78%) were identified. All but two mutations led to a truncated or null form of the ATM protein (nonsense, splice site, or frameshift). Twelve mutations were identified for 15 haplotypes. Five mutations were novel. Mutations were located throughout the entire gene, with no clustering. Despite the absence of an Iranian founder mutation, three-fourths of the families were homozygous, suggesting that many undetected ATM mutations still exist in Iran. This study establishes a database for Iranian A-T families, and extends the global spectrum of ATM mutations.

Ataxia Telangiectasia↗

PubMed1997

The relative importance of the X-linked FCP locus and beta-globin haplotypes in determining haemoglobin F levels: a study of SS patients homozygous for beta S haplotypes.

Five factors have been hypothesized to influence the 20-fold variation in fetal haemoglobin (Hb F) levels in sickle cell anaemia (SS): age sex, alpha-globin gene number, beta-globin haplotype, and the X-linked F-cell production locus (FCP) that regulates the production of Hb F containing erythrocytes (F cells). We analysed the association of these factors with Hb F levels in 112 SS patients living in France who are homozygous for the three common African beta-globin haplotypes (Benin, Bantu or Central African Republic and Senegal). We found that: (1) FCP accounts for about 40% of the overall variation in Hb F levels, (2) when the FCP influence is removed, beta-globin haplotype is associated with 14% of the remaining Hb F variation, and (3) the other factors have little influence. Comparison with our previous study of SS individuals in Jamaica leads to the following conclusions: (1) the X-linked FCP locus is a major determinant of Hb F levels in SS disease, (2) factors linked to the beta-globin haplotype have only a small effect on the variation in Hb F levels, in either the homozygous or heterozygous state, and (3)approximately half of the variation in Hb F levels still remains to be explained.

Adolescent↗

PubMed2005

Distribution of human chemokine (C-X3-C) receptor 1 (CX3CR1) gene polymorphisms and haplotypes of the CC chemokine receptor 5 (CCR5) promoter in Chinese people, and the effects of CCR5 haplotypes on CCR5 expression.

Two chemokine (C-X3-C) receptor 1 (CX3CR1) gene polymorphisms, V249I and T280M, and 10 CC chemokine receptor 5 (CCR5) promoter haplotypes, P1-P10, have recently been reported to influence the progression of acquired immune-deficiency syndrome (AIDS). As these studies were performed mainly with Caucasian and African-American subjects, we determined the distribution of these alleles in Chinese people for the purpose of predicting possible clinical responses to the human immunodeficiency virus type 1 (HIV) epidemics in countries with significant Chinese populations, as well as to establish their effects on the expression of surface CCR5. Ninety-six HIV-negative Chinese individuals in Taiwan were subjected to genotyping, and we thus determined that the allelic frequencies of CX3CR1V249I and T280M changes were 2.6% and 2.1%, respectively, which were lower than found in Caucasians (25.5% and 14.0%, respectively). Unlike the previous reports, we only detected CCR5P1 and P4 haplotypes in Taiwanese people, and the P1/P1, P1/P4 and P4/P4 genotype frequencies were 21.0%, 41.1% and 37.9%, respectively. The sequencing data confirmed the results of previous studies, showing that CCR5P1 exhibited a complete linkage disequilibrium with a polymorphic allele 59029A present in the CCR5 promoter. Furthermore, fluorescence-activated cell sorter analysis revealed that, in the absence of the CCR2-64I mutation, individuals carrying CCR5P1 tended to express more surface CCR5 on monocytes and CD4+ cells. Therefore, this study not only reports the frequencies for the CX3CR1 and CCR5 promoter haplotypes in a Chinese population living in Taiwan, but also identifies a statistical link between the P1/P1 haplotype and the elevated CCR5 expression levels in the study group.

Adult↗

PubMedDate not supplied

Microsatellite haplotypes of Polish cystic fibrosis alleles: delta F508 chromosomes demonstrate a North-South haplotype frequency gradient.

Analysis of haplotypes of three intragenic, highly polymorphic microsatellite markers (IVS8CA, IVS17BTA, IVS17BCA) of the CFTR gene was performed on a sample of 96 CF chromosomes of Polish origin. Twenty different haplotypes were detected in delta F508 chromosomes. Of these, four haplotypes (23-31-13; 23-32-13; 17-31-13; 17-32-13) represent 67.1% of the overall pool of delta F508 chromosomes. Distribution of these haplotypes, together with frequencies of the delta F508 mutation, are intermediate between Northern- and Southern-European populations and correlate with established gradients.

Cystic Fibrosis↗

PubMed2006

iHAP--integrated haplotype analysis pipeline for characterizing the haplotype structure of genes.

BACKGROUND: The advent of genotype data from large-scale efforts that catalog the genetic variants of different populations have given rise to new avenues for multifactorial disease association studies. Recent work shows that genotype data from the International HapMap Project have a high degree of transferability to the wider population. This implies that the design of genotyping studies on local populations may be facilitated through inferences drawn from information contained in HapMap populations. RESULTS: To facilitate analysis of HapMap data for characterizing the haplotype structure of genes or any chromosomal regions, we have developed an integrated web-based resource, iHAP. In addition to incorporating genotype and haplotype data from the International HapMap Project and gene information from the UCSC Genome Browser Database, iHAP also provides capabilities for inferring haplotype blocks and selecting tag SNPs that are representative of haplotype patterns. These include block partitioning algorithms, block definitions, tag SNP definitions, as well as SNPs to be "force included" as tags. Based on the parameters defined at the input stage, iHAP performs on-the-fly analysis and displays the result graphically as a webpage. To facilitate analysis, intermediate and final result files can be downloaded. CONCLUSION: The iHAP resource, available at http://ihap.bii.a-star.edu.sg, provides a convenient yet flexible approach for the user community to analyze HapMap data and identify candidate targets for genotyping studies.

Algorithms↗

PubMed1985

Haplotype study on C4 polymorphism in Japanese. Associations with MHC alleles, complotypes, and HLA-complement haplotypes.

Genetic polymorphism of the fourth component of human complement (C4) was investigated in 83 Japanese families which have been typed for HLA-A,-B,-C,-DR, C2, and BF. Four common C4A alleles and four common C4B alleles were observed. The allele frequencies estimated from unrelated parents were as follows: C4A3, 0.686; A4, 0.132; A2, 0.106; AQ0, 0.067; ARares, 0.009; C4B1, 0.587; B2, 0.167; B5, 0.088; and BQ0, 0.158. Eight different C4 haplotypes were observed with frequencies of more than 0.01. The estimated haplotype frequencies were as follows: C4A3-B1, 0.513; A4-B2, 0.114; A2-BQ0, 0.106; A3-B5, 0.088; AQ0-B1, 0.059; A3-BQ0, 0.047; A3-B2, 0.038; A4-B1, 0.015; and Rares, 0.021. Strong positive gametic associations were found in the following C4-HLA haplotypes: C4A2BQ0-A24, C4A2BQ0-Bw52, C4A3B5-Bw54, C4A3B5-Bw59, C4A4B2-Bw46, C4A3B5-Cw1, C4A2BQ0-DR2, and C4A3B5-DR4. Eleven complotypes were observed with frequencies of more than 0.01. C4A2BQ0 and C4A3B5 were exclusively associated with BFS-C2C. BFF was associated with C4A3B1. C2AT, C2B, and C2BH were associated with C4A3B1, A4B2, and C4A3B1, respectively. Eight different HLA-complement haplotypes were found to be characteristic of Japanese. These combinations are considerably different from those reported in Caucasoid populations.

Alleles↗

PubMed1979

Comparison of the haplotypes of the major histocompatibility complex in the rat. IV. The six original Ag-B haplotypes.

The six original haplotypes described in the Ag-B system were compared with their counterparts in the H-1 system. Antisera to the Ag-B haplotypes raised in inbred rats and antisera to H-1 haplotypes raised in congenic lines were tested against various panels of cell from inbred and congenic lines by the dextran and Ficoll haemagglutination methods. The private and strong public specificities detected in both systems were the same, but there were some minor differences in the intermediate and weak reactivities detected. The cross-reactivity of the antisera raised in inbred rats was broader than that of antisera raised in congenic lines. The identity of the antigenic products detected in the two systems by the dextran and Ficoll tests was further confirmed by a variety of absorption analyses and by F1 tests. This study completes the systematic serological comparison of the haplotypes of the major histocompatibility complex of the rat described originally in the Ag-B and H-1 systems.

Animals↗

PubMed1990

Frequency of the delta F508 mutation and XV2c,KM19 haplotypes in cystic fibrosis families from The Netherlands: haplotypes without delta F508 still in disequilibrium.

We have determined the frequency of the major cystic fibrosis (CF) three base pair deletion (delta F508) mutation in 152 CF chromosomes from patients originating from the northern part of The Netherlands. In these patients, the deletion represents approximately 76% of CF mutations. Meconium ileus is strongly associated with homozygosity for the delta F508 mutation. The XV2c,KM19 haplotypes on the CF chromosomes without the delta F508 mutation are in disequilibrium with the population frequency, although showing an increased frequency of the 1 2 haplotype. The surplus of this haplotype is almost entirely made up by the pancreatic insufficient patients.

Cystic Fibrosis↗

PubMed2005

Haplotype XV of the Y-chromosome is the main haplotype in West-Europe.

We have analyzed Y-chromosome variation in a large sample of males from Western Europe by surveying p49a,f TaqI polymorphisms. Haplotype XV (A3, Cl, D2, Fl, Il) is the main Y-chromosome haplotype in West Europe, with a Basque focus in Southwestern Europe. This study demonstrates that the geographic distribution of Y-chromosome variation for p49a,f TaqI haplotype XV reveals an important genetic identity for populations that live in the Occidental part of Europe.

Adult↗

PubMed2003

Pathogenesis of autoimmune diseases associated with 8.1 ancestral haplotype: a genetically determined defect of C4 influences immunological parameters of healthy carriers of the haplotype.

Subjects with certain HLA alleles have a higher risk of specific autoimmune diseases than those without these alleles. The 8.1 ancestral haplotype (AH) is a common Caucasoid haplotype carried by most people who type for HLA-B8,DR3. It is unique in its association with a wide range of immunopathological diseases. To gain insight into the identification of the mechanism(s) of disease susceptibility of 8.1 AH carriers, we have investigated the prevalence of circulating immune complexes and non-organ-specific autoantibodies in healthy carriers of the haplotype. The results show that carriers of 8.1 AH display both a significant increased prevalence of immune complexes and higher titers of anti-nuclear autoantibodies. This AH carries a single segment characterized by no C4A gene. This null allele does not code for a functional C4A protein that likely plays an anti-inflammatory role being specialized in the opsonization and immunoclearance processes. So, this genetic defect has been claimed to allow that an increased production of autoantibodies directed vs. cells that have undergone apoptosis and are not efficiently disposed because a reduced antigenic clearance. The results obtained in the present study fit very well with this hypothesis. In the AH carriers the simultaneous high setting of tumor necrosis factor (TNF)-alpha may supply the autoantigens (providing an excess of apoptotic cells) that drive the autoimmune response. In conclusion, the C4 defect associated to the increased spontaneous release of TNF-alpha, modifying a certain number of immunological parameter may be the most characterizing feature of the 8.1 AH. In the majority of individuals, an autoimmune response clinically relevant will develop only in the presence of other immunological abnormalities.

Adult↗

PubMed1999

Introduction of SLG (S locus glycoprotein) alters the phenotype of endogenous S haplotype, but confers no new S haplotype specificity in Brassica rapa L.

Self-incompatibility (SI) in Brassicaceae is genetically controlled by the S locus complex in which S locus glycoprotein (SLG) and S receptor kinase (SRK) genes have been identified, and these two genes encoding stigma proteins are believed to play important roles in SI recognition reaction. Here we introduced the SLG43 gene of Brassica rapa into a self-incompatible cultivar, Osome, of B. rapa, and examined the effect of this transgene on the SI behavior of the transgenic plants. Preliminary pollination experiments demonstrated that Osome carried S52 and S60, and both were codominant in stigma, but S52 was dominant to S60 in pollen. S43 was found to be recessive to S52 and codominant with S60 in stigma. The nucleotide sequence of SLG43 was more similar to that of SLG52 (87.8% identity) than to that of SLG60 (74.8% identity). Three of the ten primary transformants (designated No. 1 to No. 10) were either completely (No. 9) or partially (No. 6 and No. 7) self-compatible; the SI phenotype of the stigma was changed from S52S60 to S60, but the SI phenotype of the pollen was not altered. In these three plants, the mRNA and protein levels of both SLG43 and SLG52 were reduced, whereas those of SLG60 were not. All the plants in the selfed progeny of No. 9 and No. 6 regained SI and they produced a normal level of SLG52. These results suggest that the alteration of the SI phenotype of the stigma in the transformants Nos. 6, 7, and 9 was the result of specific co-suppression between the SLG43 transgene and the endogenous SLG52 gene. Three of the transformants (Nos. 5, 8 and 10) produced SLG43 protein, but their SI phenotype was not altered. The S60 homozygotes in the selfed progeny of No. 10 which produced the highest level of SLG43 were studied because S43 was codominant with S60 in the stigma. They produced SLG43 at approximately the same level as did S43S60 heterozygotes, but did not show S43 haplotype specificity at the stigma side. We conclude that SLG is necessary for the expression of the S haplotype specificity in the stigma but the introduction of SLG alone is not sufficient for conferring a novel S haplotype specificity to the stigma.

Blotting, Southern↗

PubMed2003

A Gambian TNF haplotype matches the European HLA-A1,B8,DR3 and Chinese HLA-A33,B58,DR3 haplotypes.

Caucasians carry TNFA-308*2 in the 8.1 ancestral haplotype (AH) (HLA-A1,B8,DR3). In Gambians, TNFA-308*2 occurs without HLA-B8 or -DR3, suggesting an independent effect of TNFA-308 on disease. Hence we sought a segment of the 8.1 AH in Gambians. BAT1 (intron 10)*2 was selected as a specific marker of the haplotype and was found with TNFA-308*2 in Gambians. Samples homozygous at TNFA-308 and BAT1 (intron 10) demonstrated identity between the African TNFA-308*2 haplotype, the 8.1AH and the Asian diabetogenic 58.1AH (HLA-A33,B58,DR3) across a region spanning BAT1, ATP6G, IKBL, LTA, TNFA, LTB, LST-1 and AIF-1. Conservation of this block in geographically distinct populations suggests a common evolutionary origin and challenges current views of the role of TNFA-308*2 in disease.

Asian People↗

PubMed2003

Haplotype block partition with limited resources and applications to human chromosome 21 haplotype data.

Recent studies have shown that the human genome has a haplotype block structure such that it can be decomposed into large blocks with high linkage disequilibrium (LD) and relatively limited haplotype diversity, separated by short regions of low LD. One of the practical implications of this observation is that only a small fraction of all the single-nucleotide polymorphisms (SNPs) (referred as "tag SNPs") can be chosen for mapping genes responsible for human complex diseases, which can significantly reduce genotyping effort, without much loss of power. Algorithms have been developed to partition haplotypes into blocks with the minimum number of tag SNPs for an entire chromosome. In practice, investigators may have limited resources, and only a certain number of SNPs can be genotyped. In the present article, we first formulate this problem as finding a block partition with a fixed number of tag SNPs that can cover the maximal percentage of the whole genome, and we then develop two dynamic programming algorithms to solve this problem. The algorithms are sufficiently flexible to permit knowledge of functional polymorphisms to be considered. We apply the algorithms to a data set of SNPs on human chromosome 21, combining the information of coding and noncoding regions. We study the density of SNPs in intergenic regions, introns, and exons, and we find that the SNP density in intergenic regions is similar to that in introns and is higher than that in exons, results that are consistent with previous studies. We also calculate the distribution of block break points in intergenic regions, genes, exons, and coding regions and do not find any significant differences.

Chromosomes, Human, Pair 21↗

PubMed2005

The association between HLA DR, DQ antigens, and vulval lichen sclerosus in the UK: HLA DRB112 and its associated DRB112/DQB10301/04/09/010 haplotype confers susceptibility to vulval lichen sclerosus, and HLA DRB10301/04 and its associated DRB10301/04/DQB10201/02/03 haplotype protects from vulval lichen sclerosus.

Lichen sclerosus (LS) is considered to have an immunogenetic background. Several small studies, using serological typing, have reported that HLA-DR11, DR12, and DQ7 were increased in LS, with DR17 less frequent. This study aimed to validate and detect new HLA-DR and DQ associations with LS in females and its characteristic clinical parameters. The cases, 187 female LS patients, and 354 healthy controls were all UK North Europeans. PCR-sequence specific primers method was applied to genotype the HLA-DR, DQ polymorphisms that correspond to 17 serologically defined DR and seven DQ antigens. Statistical analysis was performed with two-tailed Fisher's exact test with Bonferroni adjustment (p value after Bonferrroni adjustment, Pc). We found increased frequency of DRB1*12 (DR12) (11.2%vs 2.5%, pc < 0.01) and the haplotype DRB1*12/DQB1*0301/04/09/010 (11.2%vs 2.5%, p < 0.001, pc < 0.05), and a lower frequency of DRB1*0301/04 (DR17) (11.8%vs 25.8%, pc < 0.01) and the haplotype DRB1*03/DQB1*02DRB1*0301/DQB1*0201/02/03 (11.2%vs 24.6%, pc < 0.0001) in patients compared with controls. HLA DR and DQ antigens were not associated with time of onset of disease, site of involvement, structural changes of genitals, and response to treatment with potent topical steroids. In conclusion, HLA-DR and DQ antigens or their haplotypes appear to be involved in both susceptibility to and protection from LS.

Adolescent↗

PubMed1991

Testing for haplotype sharing by siblings with incomplete information of parental haplotypes.

Testing for the inheritance of a disease susceptibility gene by analysis of haplotype sharing among affected siblings has been well established for the case where all four parental haplotypes have been ascertained. This paper presents a modification of a published method to cover the situation where there is incomplete information concerning parental haplotypes and this new test is applied in a worked example.

Female↗

PubMed2001

Three-loci HLA haplotypes in Spanish celiac children and healthy subjects: estimation of linkage disequilibrium and haplotype frequencies.

OBJECTIVES: The aim of this study was to compare the linkage disequilibrium parameters and the frequencies of the three-loci HLA haplotypes in children with celiac disease and in a control population within the same geographical area. METHODS: A total of 38 celiac children were studied. HLA typing was performed by microlymphocytotoxicity assay using T and B cells separated by monoclonal antibody labeled immunomagnetic particles (IMB). Three-loci haplotype frequency (pABC) depend on each gene frequency (pA, pB, and pC), and a correction factor (delta) and takes the form: pABC = pA x pB x pC + delta ABC. The existence of a linkage disequilibrium was assessed by chi2 test using 2 x 2 x 2 contingency tables for gametic association. RESULTS: There was a higher frequency of A1/B8/Cw7, A1/B8/DR3, A1/B8/DQ2, A19/B12/DQ2, B8/Cw7/DR3, B8/Cw7/DQ2, B8/DR3/DQ2, and B12/DR7/DQ2 in celiac children than in the control population. CONCLUSIONS: From the comparative study of celiac and healthy population within the same area, we conclude that these three-loci haplotypes could determine genetic susceptibility to celiac disease.

Adolescent↗

PubMed2003

[Analysis of haplotype-based haplotype relative risk and transmission disequilibrium test in childhood absence epilepsy].

OBJECTIVE: Childhood absence epilepsy (CAE), a common form of idiopathic generalized epilepsy, accounts for 8% - 15% of all childhood epilepsies. A positive family history of epilepsy, a hereditary factor being one of the pathogeneses, is found in 15% - 44% of children with absence seizures. The phenotype of CAE is specific (including seizure forms and EEG), therefore it is suitable for genetic study. The purpose of this study was to confirm the linkage of childhood absence epilepsy to chromosome 8q24 in China. METHODS: Twenty-nine trios families (a patient and his/her parents) as patient group and 10 normal trios families as control group were investigated for chromosome 8q24 by haplotype analysis with 5 microsatellite DNA markers (D8S554, D8S534, D8S1100, D8S1783, D8S1753). Genomic DNA was isolated from 4 ml human peripheral blood by using the conventional procedure, and then was treated using the PCR method. PCR products were analyzed by gene scan. Statistical methodology included haplotype-based haplotype relative risk (HHRR) and transmission disequilibrium test (TDT). RESULTS: In this study, the polymorphism information content (PIC) of 5 microsatellite DNA markers were: 0.519, 0.828, 0.528, 0.654 and 0.772. HHRR showed D8S554(4) (chi(2) = 5.939, P < 0.05), D8S1100(3) (chi(2) = 5.081, P < 0.05), D8S1783(6) (chi(2) = 4.308, P < 0.05). TDT showed D8S554(4) (chi(2) = 4.46, P < 0.05), D8S1783(6) (chi(2) = 4, P < 0.05). In order to exclude false association results, the authors analyzed every family in detail. Four trios families transmitted allele D8S1783(6) to their offspring, and the same allele hasn't been found in controls. The further work showed that locus D8S1783 had transmission disequilibrium with CAE, the other two loci were a false association. CONCLUSION: (1) Childhood absence epilepsy in the Chinese population may be linked to chromosome 8q24, the CAE gene is transmitted disequilibrium on locus D8S1783. Combined with other research results, we suppose that CAE gene may be in the ECA1 area on chromosome 8q24. (2) The CAE gene perhaps has a genetic heterogeneity in the population of different areas and different races. (3) HHRR and TDT seem to be the best statistical methods to do linkage disequilibrium study in the trios family.

Child↗