SEARCH · PubMed Health

Results for “Haplotypes”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,333 records · Page 74Linked to original sources

PubMed2003

A functional haplotype in the 5' flanking region of the factor VII gene is associated with an increased risk of coronary heart disease.

AIMS: The aim of this study was to investigate associations between coronary heart disease risk and polymorphisms in the coagulation factor (F)VII gene in participants of a large prospective study. METHODS: One thousand nine hundred and fifty-seven men were genotyped for four FVII polymorphisms, -670A-->C, -402G-->A, a 10 base pair insertion at -323 (0 > 10) in the promoter, and R353Q in the structural gene. Associations among genotypes and estimated haplotypes, plasma FVII levels, and coronary heart disease risk were evaluated, and the function of the promoter polymorphisms was assessed in reporter gene assays. RESULTS: The -670A-->C and -402G-->A polymorphisms were in complete allelic association. The haplotype containing -670C and -402A (frequency =0.23) was associated with significantly increased plasma FVII coagulant activity and increased risk of an initial coronary event, particularly acute myocardial infarction, which remained after correction for conventional risk factors. In contrast, the -323 insertion and Q353 alleles (frequency =0.11 and 0.10, respectively) were associated with decreased plasma FVII levels, but hazard ratios for coronary events in carriers of these alleles were not significantly different from unity. In transiently transfected hepatoma cells, increased basal expression of the reporter gene was directed by a promoter fragment with rare haplotype -670C/-630G/-402A rather than by a promoter fragment with common haplotype -670A/-630A/-402G; -402A was not responsible for this effect. CONCLUSIONS: The promoter haplotype, -670C/-630G/402A, was associated with significantly increased plasma FVII coagulant activity, risk of an initial coronary event, particularly acute myocardial infarction, and reporter gene expression.

Alleles↗

PubMed2005

Haplotype analysis improves molecular diagnostics of autosomal recessive polycystic kidney disease.

BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) is characterized by wide phenotypic variability, ranging from in utero detection with enlarged, echogenic kidneys to an adult presentation with congenital hepatic fibrosis. The ARPKD gene, PKHD1 , covers about 470 kb of DNA (67 exons), and mutation studies have found marked allelic heterogeneity with a high level of novel missense changes and neutral polymorphisms. To improve the prospects for molecular diagnostics and to study the origin of some relatively common mutations, the authors have developed a strategy for improved ARPKD haplotyping. METHODS: A protocol of multiplex PCR and fluorescence genotyping in a single capillary has been developed to assay 7 highly informative simple sequence repeat (SSR) markers that are intragenic or closely flanking PKHD1. RESULTS: Examples in which haplotype analysis, used in combination with mutation screening, improved the utility of molecular diagnostics, especially in families in which just a single PKHD1 mutation has been identified, are illustrated. The new markers also allow screening for larger DNA deletions, detecting unknown consanguinity and exploring the disease mechanism. Analysis of 8 recurring mutations has shown likely common haplotypes for each, and the divergence from the ancestral haplotype, by recombination, can be used to trace the history of the mutation. The common mutation, T36M, was found to have a single European origin, about 1,225 years ago. CONCLUSION: Improved haplotype analysis of ARPKD complements mutation-based diagnostics and helps trace the history of common PKHD1 mutations.

3' Flanking Region↗

PubMed2001

Tumour necrosis factor alpha (-238 and -308) and beta gene polymorphisms in pulmonary tuberculosis: haplotype analysis with HLA-A, B and DR genes.

SETTING: A study of tumour necrosis factor alpha and beta (TNFalpha and beta) gene polymorphism and haplotype analysis with HLA in pulmonary tuberculosis. OBJECTIVE: To determine whether TNFalpha (-238 and -308) and TNFbeta (Nco I polymorphism in intron 2) genes either alone or in combination with human leucocyte antigens (HLA) as haplotypes afford susceptibility or resistance to pulmonary tuberculosis as well as bacteriological relapse of the disease. DESIGN: Tumour necrosis factor alpha -238, -308 (TNFalpha -238, -308) and TNFbeta (Nco I) gene polymorphisms were carried out in HLA-A,B and DR typed pulmonary tuberculosis patients (n=210) and 120 normal healthy control subjects. RESULTS: No difference in the genotype frequencies of TNFalpha-238 and -308 and TNFbeta was seen between control subjects and pulmonary tuberculosis patients. Of the HLA-TNF haplotypes analysed, the infrequent allele (A) of TNFalpha238 was in strong linkage disequilibrium with HLA-A1 (P corrected: Pc=0.001), B17 (Pc<0.0001) and DR7 (Pc=0.01) in control subjects and with B17 (Pc<0.0001) in pulmonary tuberculosis. The infrequent allele 2 of TNFalpha-308 and the infrequent allele 2 of TNFbeta were in strong linkage disequilibrium with HLA-B21. An increased haplotype frequency of HLA-B17-TNFalpha-238/A (P=0.05), B17-TNFalpha308/2 (P=0.03) and B17-TNFalpha308/2 (P=0.01) was observed in bacteriological relapse patients than quiescent patients. CONCLUSION: The present study suggests that TNFalpha (-238 and -308) and TNFbeta gene variants are not associated independently with the susceptibility to pulmonary tuberculosis. However, in combination with the HLA genes/gene products such as HLA-A1, B17, B21 and DR7, the TNFalpha and beta genes as haplotypes are associated with protection against the disease as well as an increased susceptibility to bacteriological relapse.

Adult↗

PubMed1987

A Gm haplotype study in relation with HLA-DR in 155 insulin-dependent diabetic patients and their affected and non affected siblings.

In order to assess interaction between HLA and Gm for susceptibility to IDDM, the families of 155 IDDM probands were typed for HLA class I, II, III antigens and 16 Gm allotypes (including G2m23). Haplotypes were obtained for both systems. Individuals bearing the equivocal haplotype Gm (formula; see text) were excluded. The frequencies of the 6 Gm haplotypes detected were comparable in IDDM patients, sibling controls and unrelated controls. The number of Gm haplotypes was compatible with random segregation whether or not the HLA genotype was taken into account. However, analysis of the HLA-DR allelic combinations showed an increase of the uncommon haplotype Gm (formula; see text) in IDDM patients bearing DR3 in the absence of DR4 (Gm (formula; see text) phenotype frequency 43% vs 24% in other allelic combinations, p less than 0.04). When 21 diabetic and 154 non diabetic siblings of the probands were compared, the combined presence of DR3/ non 4 and Gm (formula; see text) was observed in 7 (33%) affected and 11 (7%) unaffected siblings (p less than 0.001), conferring a relative risk of 6.4 to siblings who bear both markers. All DR3/non 4 positive affected siblings (7/7) also carried Gm (formula; see text) compared with 27% (11/41) of unaffected siblings (p less than 0.001). This result suggests, that in spite of the absence of segregation distortion, interaction between Gm and HLA gene products may play a role in the familial penetrance of IDDM.

Adolescent↗

PubMed2005

No association between microsomal triglyceride transfer protein (MTP) haplotype and longevity in humans.

Human longevity is a multifactorial condition with a significant genetic contribution. A recent association study in two independent samples of long-lived U.S. Caucasians [long-lived individuals (LLI)] identified a SNP haplotype of the microsomal triglyceride transfer protein (MTP, 4q25) that was underrepresented among LLI when compared with younger controls. This suggested that variation in the MTP gene might modify human longevity. Because of its function in lipid metabolism, the MTP gene product could plausibly play a pivotal role in the physiology of aging. However, the association observed in the U.S. samples could not be replicated by the same authors in a larger French LLI sample. We have therefore investigated the MTP "risk" haplotype in our own collection of 1,589 German nonagenarians, centenarians, and appropriately matched controls. No statistically significant differences were observed between LLI and controls at the allele, genotype, or haplotype level. This indicates that a noteworthy influence of the respective MTP haplotype on human longevity in the German population is unlikely. Furthermore, in comparison with all other U.S. and European samples analyzed, the MTP "risk" haplotype was found to be overrepresented only in the U.S. controls. This implies that the putative association is more likely to reflect recent changes in the genetic structure of the U.S. Caucasian population as a whole, rather than genetic effects upon survival to old age. In our view, the original study therefore highlights potential problems that arise when the case-control design is used as a means to map longevity genes in humans.

Aged↗

PubMed2006

Long-range multilocus haplotype phasing of the MHC.

Haplotypes are a powerful tool for identifying the genetic basis of common complex diseases. Disease-association mapping requires molecular methods for haplotyping biallelic SNP variation and highly complex polymorphisms. We developed a method for phasing HLA-A, HLA-B, and HLA-DRB1 alleles on chromosome 6 in unrelated individuals. This method uses the highly polymorphic HLA-B locus to discriminate the two HLA haplotypes in heterozygous individuals and its ideal location 1.4 Mbp telomeric to HLA-DRB1 and 1.2 Mbp centromeric to HLA-A to capture 2-Mbp-long genomic DNA. Genomic DNA representing a single HLA-B-captured haplotype is genotyped for HLA-A and HLA-DRB1 alleles and linkage to HLA-B is established. Proof of principle was established in a large blinded study of phase-known samples. Availability of an efficient method for MHC haplotype phase determination will facilitate the mapping of causative MHC-resident genes in many human diseases and has the potential to be broadened to other polymorphic gene complexes.

Genes, MHC Class I↗

PubMed1986

Polymorphism of HLA-DR beta chains in DR4, -7, and -9 haplotypes: implications for the mechanisms of allelic variation.

We have isolated and sequenced cDNA clones corresponding to the DR beta 1 and DR beta 2 loci from two homozygous B-cell lines typed as DR7 (Burkhart) and DR9 (ISK). These nucleotide sequences were compared to beta 1 and beta 2 chains of other DR haplotypes. The first-domain sequences of beta 2 chains are identical in DR4 and DR7 haplotypes. In addition, there is strong sequence homology within the 3' untranslated regions of beta 1 genes from DR4, -7, and -9 haplotypes, thus confirming the close evolutionary relationship among these three haplotypes. In contrast, the first-domain sequences of beta 1 molecules from these haplotypes are very different from each other and do not reflect the DR4, -7, -9 family relationship. Two explanations for the differences in degree of diversity between beta 1 and beta 2 chains are suggested. The differences may be a consequence of selection pressures; this implies functional differences for products of the beta 1 and beta 2 loci. Alternatively, closely linked segments of the human class II region may differ in their underlying rates of variation, independent of selection pressures, and this may in part account for the extraordinary diversity found in the beta 1 first domain.

Alleles↗

PubMed1992

Evolution of the mouse t haplotype: recent and worldwide introgression to Mus musculus.

Mouse t haplotypes are variants of chromosome 17, consisting of four inversions. Despite the homozygous lethality and pleiotropic effect on embryonic development, sperm production, and recombination, they have widely spread in natural populations of the house mouse (10-40% in frequency) because of the meiotic drive advantage. We sequenced 14 Tcp-1 (t-complex polypeptide 1) genes from four t haplotypes, nine wild mice, and a rat as a reference. From a comparison of intron sequences of 610 base pairs, we dated the origin of t haplotypes to 2.9 +/- 0.7 million years ago, which predates the splitting of Mus musculus subspecies (approximately 1 million years ago). However, the Tcp-1 intron sequences of t haplotypes from different M. musculus subspecies from various parts of the world show no divergence, indicating the recent introgression (no earlier than 0.8 million years ago) of a single ancestral type. Nucleotide changes in coding regions are also consistent with this conclusion. Hence, polymorphisms among t haplotypes including lethality factors have accumulated during this short time period independently in each M. musculus subspecies.

Animals↗

PubMed1998

Determination of gene organization in individual haplotypes by analyzing single DNA fragments from single spermatozoa.

To determine human Ig heavy chain variable region (VH) gene segment organization on individual homologous chromosomes, an efficient approach has been developed. Single spermatozoa were used as subjects for the study. Upon sperm lysis, VH regions in each sperm were randomly sheared into fragments by the random Brownian force. The fragments were separated from each other by aliquoting the lysate into a certain number of tubes. The gene segments in the VH1 and VH4 families in each tube were identified by denaturing gradient gel electrophoresis after PCR amplification. The polymorphic VH sequences were used to determine the parental origins of the analyzed sperm. VH segment organization in the parental haplotypes was determined by aligning the overlapping fragments from the spermatozoa with the corresponding haplotypes. Based on this comparison between the resulting haplotype maps and the composite map reported previously, the VH region on chromosome 14 could be subdivided into four portions. The numbers and compositions of the VH gene segments differ considerably among the maps in two portions, but are highly conserved in the other two. The data also indicate that the VH region on chromosome 15 may contain a large duplicated block with copy number varying among haplotypes. The approach used in the present study may be used to construct high-resolution haplotype maps without molecular cloning.

Chromosomes, Human, Pair 14↗

PubMed1999

Race-specific HIV-1 disease-modifying effects associated with CCR5 haplotypes.

Genetic variation in CC chemokine receptor 5 (CCR5), the major HIV-1 coreceptor, has been shown to influence HIV-1 transmission and disease progression. However, it is generally assumed that the same CCR5 genotype (or haplotype) has similar phenotypic effects in different populations. To test this assumption, we used an evolutionary-based classification of CCR5 haplotypes to determine their associated HIV-1 disease-modifying effects in a large well-characterized racially mixed cohort of HIV-1-seropositive individuals. We demonstrate that the spectrum of CCR5 haplotypes associated with disease acceleration or retardation differs between African Americans and Caucasians. Also, we show that there is a strong interactive effect between CCR5 haplotypes with different evolutionary histories. The striking population-specific phenotypic effects associated with CCR5 haplotypes emphasize the importance of understanding the evolutionary context in which disease susceptibility genes are expressed.

Acquired Immunodeficiency Syndrome↗

PubMed1995

Response of three class-IV major histocompatibility complex haplotypes to Eimeria acervulina in meat-type chickens.

1. The importance of MHC genes and background genes in controlling disease resistance, including resistance to avian coccidiosis, has not been clarified in meat-type chickens. 2. The role of class IV MHC genes in resistance to Eimeria acervulina was assessed in F2 progeny of a cross between 2 meat-type lines, selected divergently for immune response to Escherichia coli. 3. Disease susceptibility was assessed by lesion score, body weight, packed cell volume and carotene absorption. 4. Chickens with the "K" class IV MHC haplotype had lower lesion scores than chickens with "F" and "A" haplotypes. 5. Plasma carotene concentrations were higher in chickens with "K" haplotype and lower in chickens with "F" and "A" haplotypes whereas body weight and packed cell volume were less sensitive measures of Eimeria infection. 6. Eimeria acervulina resistance appears to be associated with MHC class IV genes; information about MHC haplotypes may be useful in selecting for increased resistance of meat-type chickens to coccidiosis.

Animals↗

PubMed2004

A study of the genetic basis of C4A protein deficiency. Detection of C4A gene deletion by long-range PCR and its associated haplotypes.

OBJECTIVE: To study the frequency of a C4A gene deletions as the genetic basis of C4A protein deficiency (C4AQ0) and its associated haplotypes in Icelandic families with systemic lupus erythematosus (SLE). METHODS: Nine multiplex SLE families were genotyped for C4A gene deletions using a long-range polymerase chain reaction (LR-PCR) method, and major histocompatibility complex (MHC) haplotypes were defined. RESULTS: Of the SLE patients, first-degree and second-degree relatives, 53.8%, 47.9%, and 28.6% had C4AQ0, respectively. A C4A gene deletion was found to be the genetic basis for C4AQ0 in 64.3% of SLE patients, 60.0% of first-degree and 50.0% of second-degree relatives. All individuals carrying haplotype B8-C4AQ0-C4B1-DR3 had a deletion, and the deletion was also found on haplotypes B8-C4AQ0-C4B1-DR7 and B7-C4AQ0-C4B1-DR3. CONCLUSION: The study shows that a C4A gene deletion is the most common genetic basis for C4AQ0. It accounts for two-thirds of C4AQ0 and is found on different MHC haplotypes. One-third of C4AQ0 is due to other as yet undefined genetic changes. The results demonstrate a heterogeneous genetic background for C4AQ0, giving further support for the hypothesis that C4AQ0 may be an independent risk factor for SLE.

Age Distribution↗

PubMed1998

Haplotype distribution of class II MHC genes in Mexican patients with systemic lupus erythematosus.

The objective of this project was to determine the association of the DQA1*0501 allele in the susceptibility to develop systemic lupus erythematosus (SLE) in Mexicans. Frequencies of generic MHC Class II genes (HLA-DR, DQA and DQB1) were determined by DNA typing in 58 Mexican mestizo SLE patients and 96 ethnically matched controls. Statistical analysis was performed by chi-square and Fisher's exact tests. The DQA1*0501 allele was found to be in linkage disequillibrium with H LA-DR3, DR11, and DR14. This explains the lack of association with the allele alone, and the evident strong association of SLE with the [HLA-DR3-DQA1*0501-DQB1*0201] and [HLA-DR1-DQA1*0101-DQB1*0501] haplotypes. It was also found a significant decrease (protection) of the [HLA-DR8-DQA1*0401-DQB1*0402] haplotype which is known to be a characteristic haplotype among the indigenous population of Mexico. These data shows that the susceptibility to SLE in Mexicans is more strongly influenced by the MHC haplotypes than by single alleles. The suggestion that these genes do not act alone but in combination, makes the identification of haplotypes mandatory.

DNA↗

PubMedDate not supplied

Genetic relationships among Berbers and South Spaniards based on CD4 microsatellite/Alu haplotypes.

BACKGROUND: CD4 STR/Alu haplotype diversity, both for its qualitative and quantitative properties, has been widely used in molecular anthropology to clarify the degree of genetic relationships among human populations. AIM: CD4 STR/Alu variation was studied in two West Mediterranean samples, Andalusians from La Alpujarra region on the north side of the Gibraltar Strait and Berbers from the south, to ascertain the pattern of affinities between them. SUBJECTS AND METHODS: Alu and microsatellite alleles were tested in 99 Andalusians from La Alpujarra region (Southeast Spain) and 124 Middle Atlas Berbers (Morocco). RESULTS: Two new combinations of Alu and STR alleles (75(+) and 80(-)) were found in Berbers. The CD4 STR/Alu haplotype distribution in South Spaniards is similar to that of other Europeans, the only special feature is the slight presence of the 90(+) and 130(+) typical Sub-Saharan haplotypes. The Berber sample is characterized by a high number of different haplotypes (18) with intermediate heterozygosity values (0.846) in comparison with other North African groups, and by a high frequency of the 110(-) combination that has been proposed as representative of an ancient Northwest African population. CONCLUSION: A geographical gradient of Sub-Saharan gene contribution has been detected in North Africa. The Middle Atlas Berbers showed an intermediate value in comparison with the high and low values found in Mauritanians and Moroccan Berbers, respectively. The analysis of the CD4 STR/Alu haplotype variation failed to indicate any particular relationship between South Spaniards and North Africans.

Alu Elements↗

PubMed2006

Haplotypes linked to three rare beta-thalassemia mutations, originally reported in Tunisia.

The polymorphism of the beta-globin gene haplotypes and frameworks are useful in the determination of the unicentric and multicentric origin of a mutational event. In order to improve our knowledge of the chromosomal background of the beta-globin gene in three beta-thalassemia (thal) mutations originally reported in Tunisia, namely codons 25/26 (+T), codon 30 (G-->C) and IVS-I-2 (T-->G), we have investigated 13 unrelated individuals. There were five non transfusion-dependent patients homozygous for the IVS-I-2 (T-->G) mutation, five others were homozygous for the codon 30 (G-->C) mutation, one was a homozygote for the codons 25/26 (+T) insertion mutation and one patient was a compound heterozygote for the codon 39 (C-->T) and codon 25/26 (+T) mutations; the last patient had a betaS/codon 25/26 (+T) compound heterozygous genotype. Haplotype analysis was carried out by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) based methods. The framework polymorphism was established by direct sequencing. beta-Globin gene analyses demonstrated that all IVS-I-2 (T-->G) cases were associated with haplotype IX; the codon 30 (G-->C) mutation was supported by haplotype I, while the codons 25/26 (+T) mutation was linked to haplotypes I and IX.

Codon↗

PubMed2006

Haplotypic variation in MRE11, RAD50 and NBS1 and risk of non-Hodgkin's lymphoma.

The MRE11-RAD50-NBS1 tri-complex is involved in the cellular response to DNA double strand breaks, detecting DNA damage, activating cell cycle checkpoints and apoptosis. Defects in members of the tri-complex are linked to increased chromosomal instability and in lymphoma predisposition. Using genotyping data from six intronic or gene flanking variants in MRE11, five in NBS1 and six in RAD50 in 461 non-Hodgkin's lymphoma cases and 461 age, sex matched controls, Phase 2.1 was used to impute haplotypes for each of these genes. It was observed that the average variant density (12 kb) was dense enough to capture the majority of genetic variation for each locus examined, encoded by four or five common haplotypes. There were no significant differences in allele or genotype frequency, global haplotype distribution between the cases and control, nor effect for individual haplotypes when analysed by unconditional logistic regression for either RAD50 or NBS1. A protective effect against follicular lymphoma was seen for the MRE11 rs601341 variant, the homozygous T allele being associated with an odds ratio (OR) of 0.50, 95% confidence interval (95% CI) 0.26 - 0.97, while a protective effect was seen for the MRE11 haplotype GCTCA (OR 0.72, 95% CI 0.53 - 0.97) for diffuse large B-cell lymphoma. While reproduction of this data in other datasets is indicated, the results are indicative for a role for MRE11 in non-Hodgkin's lymphoma.

Acid Anhydride Hydrolases↗

PubMed2000

Haplotype fine mapping by evolutionary trees.

To refine the location of a disease gene within the bounds provided by linkage analysis, many scientists use the pattern of linkage disequilibrium between the disease allele and alleles at nearby markers. We describe a method that seeks to refine location by analysis of "disease" and "normal" haplotypes, thereby using multivariate information about linkage disequilibrium. Under the assumption that the disease mutation occurs in a specific gap between adjacent markers, the method first combines parsimony and likelihood to build an evolutionary tree of disease haplotypes, with each node (haplotype) separated, by a single mutational or recombinational step, from its parent. If required, latent nodes (unobserved haplotypes) are incorporated to complete the tree. Once the tree is built, its likelihood is computed from probabilities of mutation and recombination. When each gap between adjacent markers is evaluated in this fashion and these results are combined with prior information, they yield a posterior probability distribution to guide the search for the disease mutation. We show, by evolutionary simulations, that an implementation of these methods, called "FineMap," yields substantial refinement and excellent coverage for the true location of the disease mutation. Moreover, by analysis of hereditary hemochromatosis haplotypes, we show that FineMap can be robust to genetic heterogeneity.

Algorithms↗

PubMed2000

Unbiased application of the transmission/disequilibrium test to multilocus haplotypes.

When the transmission/disequilibrium test (TDT) is applied to multilocus haplotypes, a bias may be introduced in some families for which both parents have the same heterozygous genotype at some locus. The bias occurs because haplotypes can only be deduced from certain offspring, with the result that the transmissions of the two parental haplotypes are not independent. We obtain an unbiased TDT for individual haplotypes by calculating the correct variance for the transmission count within a family, using information from multiple siblings if they are available. An existing correction for dependence between siblings in the presence of linkage is retained. To obtain an unbiased multihaplotype TDT, we must either count transmissions from one randomly chosen parent or count all transmissions and estimate the significance level empirically. Alternatively, we may use missing-data techniques to estimate uncertain haplotypes, but these methods are not robust to population stratification. An illustration using data from the insulin-gene region in type 1 diabetes shows that the validity and power of the TDT may vary by an order of magnitude, depending on the method of analysis.

Bias↗