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 1,063 records · Page 59Linked to original sources

PubMed2006

The frequent BRCA1 mutation 1135insA has multiple origins: a haplotype study in different populations.

BACKGROUND: Analysis of the chromosomal background upon which a mutation occurs can be used to reconstruct the origins of specific disease-causing mutations. The relatively common BRCA1 mutation, 1135insA, has been previously identified as a Norwegian founder mutation. We performed haplotype analysis of individuals from breast and ovarian cancer families from four different ethnic backgrounds who had been identified as carriers of the BRCA1: 1135insA mutation. METHODS: Four microsatellite markers (D17S855, D17S1322, D17S1323 and D17S1325) located within or near the BRCA1 gene were genotyped in mutation carriers from 6 families of French Canadian, Italian and Dutch descent. Haplotypes were inferred from the genotype data and compared between these families and with the previously reported Norwegian founder haplotype. RESULTS: The 1135insA mutation was found to occur on three distinct haplotype backgrounds. The families from Norway shared a distinct haplotype while the families of French Canadian, Italian, and Dutch descent were found to occur on one of two additional, distinct backgrounds. CONCLUSION: Our results indicate that while the Norwegian haplotype including 1135insA represents an ancient Norwegian mutation, the same mutation has occurred independently in the other populations examined. In centres where targeted mutation testing is performed, exclusively or prior to gene sequencing, our findings suggest that this recurring mutation should be included in targeted mutation panels, irrespective of the ethnic origin of the persons tested.

Breast Neoplasms↗

PubMed2006

Haplotype analysis suggest common founders in carriers of the recurrent BRCA2 mutation, 3398delAAAAG, in French Canadian hereditary breast and/ovarian cancer families.

BACKGROUND: The 3398delAAAAG mutation in BRCA2 was recently found to recur in breast and/or ovarian cancer families from the French Canadian population of Quebec, a population that has genetic attributes consistent with a founder effect. To characterize the contribution of this mutation in this population, this study established the frequency of this mutation in breast and ovarian cancer cases unselected for family history of cancer, and determined if mutation carriers shared a common ancestry. METHODS: The frequency was estimated by assaying the mutation in series of French Canadian breast cancer cases diagnosed before age 41 (n = 60) or 80 (n = 127) years of age, and ovarian cancer cases (n = 80) unselected for family history of cancer by mutation analysis. Haplotype analysis was performed to determine if mutation carriers shared a common ancestry. Members from 11 families were analyzed using six polymorphic microsatellite markers (cen-D13S260-D13S1699-D13S1698-D13S1697-D13S1701-D13S171-tel) spanning approximately a 3.6 cM interval at the chromosomal region 13q13.1, which contains BRCA2. Allele frequencies were estimated by genotyping 47 unaffected female individuals derived from the same population. Haplotype reconstruction of unaffected individuals was performed using the program PHASE. RESULTS: The recurrent BRCA2 mutation occurred in 1 of 60 (1.7%) women diagnosed with breast cancer before 41 years of age and one of 80 (1.3%) women with ovarian cancer. No mutation carriers were identified in the series of breast cancer cases diagnosed before age 80. Mutation carriers harboured one of two haplotypes, 7-3-9-3 - [3/4]-7, that varied with marker D13S1701 and which occurred at a frequency of 0.001. The genetic analysis of D13S1695, a polymorphic marker located approximately 0.3 cM distal to D13S171, did not favour a genetic recombination event to account for the differences in D13S1701 alleles within the haplotype. Although mutation carriers harbour genotypes that are frequent in the French Canadian population, neither mutation-associated haplotype was plausible in reconstructed haplotypes of 47 individuals of French Canadian descent. CONCLUSION: These results suggest that mutation carriers share a related ancestry; further supporting the concept that recurrent BRCA1 and BRCA2 mutations in the French Canadian population could be attributed to common founders. This finding provides further support for targeted screening of recurrent mutations in this population before large-scale mutation analyses are performed.

Adult↗

PubMed2004

Association of a specific haplotype across the genes MMP1 and MMP3 with radiographic joint destruction in rheumatoid arthritis.

The genetic background of rheumatoid arthritis (RA) is only partly understood, and several genes seem to be involved. The matrix metalloproteinases MMP1 (interstitial collagenase) and MMP3 (stromelysin 1) are thought to be important in destructive joint changes seen in RA. In the present study, functional relevant promoter polymorphisms of MMP1 and MMP3 were genotyped in 308 patients and in 110 controls, to test whether the polymorphisms contribute to the severity of the disease measured by radiographic progression of joint destruction. For comparison, the shared epitope of HLA DR4 and DR1 (SE) was determined by polymerase chain reaction. There was no association of MMP polymorphisms with susceptibility to RA. However, a strong linkage disequilibrium was observed between the 1G/2G (MMP1) and the 5A/6A (MMP3) polymorphisms (P << 10(-6); linkage disequilibrium index D' = 0.46). In factorial regression, the degree of radiographic joint destruction correlated significantly with the 1G-5A haplotype (P = 0.0001) and the interaction term 'estimated number of 1G-5A haplotypes x duration of disease' (P = 0.0007). This association was phasic, indicating that possession of the 1G-5A haplotype has a protective effect over a period of about 15 years of RA, but might be associated with a more pronounced radiographic progression later on. Similar results were also found with the 1G allele of MMP1 alone (P = 0.015) and with the interaction term 'estimated number of 1G alleles x duration of disease' (P = 0.014). The correlation of SE with the Ratingen score was comparable (0.044). The regression model of MMP haplotypes explained 35% of the variance of the radiographic score, whereas the SE explained 29%. The 1G-5A haplotype across the closely linked MMP1 and MMP3 gene loci is a newly described genetic factor strongly associated with the progression of joint damage in RA. Our findings suggest that there are haplotypes in a MMP cluster region that modify the joint destruction in RA in a phasic manner.

Adult↗

PubMed2006

Association of FCGR2A and FCGR2A-FCGR3A haplotypes with susceptibility to giant cell arteritis.

The Fc gamma receptors have been shown to play important roles in the initiation and regulation of many immunological and inflammatory processes and to amplify and refine the immune response to an infection. We have investigated the hypothesis that polymorphism within the FCGR genetic locus is associated with giant cell arteritis (GCA). Biallelic polymorphisms in FCGR2A, FCGR3A, FCGR3B and FCGR2B were examined for association with biopsy-proven GCA (n = 85) and healthy ethnically matched controls (n = 132) in a well-characterised cohort from Lugo, Spain. Haplotype frequencies and linkage disequilibrium (D') were estimated across the FCGR locus and a model-free analysis performed to determine association with GCA. There was a significant association between FCGR2A-131RR homozygosity (odds ratio (OR) 2.10, 95% confidence interval (CI) 1.12 to 3.77, P = 0.02, compared with all others) and carriage of FCGR3A-158F (OR 3.09, 95% CI 1.10 to 8.64, P = 0.03, compared with non-carriers) with susceptibility to GCA. FCGR haplotypes were examined to refine the extent of the association. The haplotype showing the strongest association with GCA susceptibility was the FCGR2A-FCGR3A 131R-158F haplotype (OR 2.84, P = 0.01 for homozygotes compared with all others). There was evidence of a multiplicative joint effect between homozygosity for FCGR2A-131R and HLA-DRB1*04 positivity, consistent with both of these two genetic factors contributing to the risk of disease. The risk of GCA in HLA-DRB1*04 positive individuals homozygous for the FCGR2A-131R allele is increased almost six-fold compared with those with other FCGR2A genotypes who are HLA-DRB1*04 negative. We have demonstrated that FCGR2A may contribute to the 'susceptibility' of GCA in this Spanish population. The increased association observed with a FCGR2A-FCGR3A haplotype suggests the presence of additional genetic polymorphisms in linkage disequilibrium with this haplotype that may contribute to disease susceptibility. These findings may ultimately provide new insights into disease pathogenesis.

Alleles↗

PubMed2004

Determination of sequence variation and haplotype structure for the gonadotropin-releasing hormone (GnRH) and GnRH receptor genes: investigation of role in pubertal timing.

Because GnRH and its receptor (GnRHR) are pivotal regulators of the reproductive endocrine axis and mutations in GNRHR lead to hypogonadotropic hypogonadism, we investigated whether genetic variation in GNRHR or GNRH1 affects pubertal timing in the general population. To screen for missense mutations in these genes that might affect pubertal timing, we resequenced the coding regions of these genes in 48 probands with late but otherwise normal pubertal development. No missense variants were found in either gene, except for a previously identified single nucleotide polymorphism (SNP) in GNRH1 that was not associated with late pubertal development. To search for common variants that might affect pubertal timing, we took a haplotype-based association approach. To identify common haplotypes in these genes, we genotyped 41 SNPs in DNA from commercially available European-derived multigenerational pedigrees and participants in a multiethnic cohort (MEC). Two blocks of strong linkage disequilibrium were identified that spanned GNRHR and one was identified spanning GNRH1; within each block, more than 80% of chromosomes carried one of a few common haplotypes. A set of haplotype-tagging SNPs that mark these common haplotypes in all five ethnic groups within the MEC were defined and used to perform association studies among 125 trios (probands with late pubertal development and their parents) and 506 women from the MEC who had early (menarche < 11 yr of age, n = 216) or late (menarche > or = 15 yr of age, n = 290) pubertal development. Three SNPs in GNRHR showed modest association with late pubertal development in the trios; among the 506 women, a different SNP was associated with late menarche, and one rare haplotype was associated with early age of menarche. All of the observed associations were relatively modest and only nominally statistically significant; replication is needed to determine their validity. We conclude that genetic variation in GNRH1 and GNRHR is not likely to be a substantial modulator of pubertal timing in the general population.

Age Factors↗

PubMed1995

Geographical distribution of the Hbb haplotypes in the Mus musculus subspecies in eastern Asia.

We surveyed the geographical distribution of Hbb haplotypes of the house mouse, Mus musculus, in the former USSR and the northern part of China. Mice with the w1 haplotype were distributed from the coastal area of the Black Sea to the Maritime Province of Siberia in the former USSR and in the area north of the Yangtze River in China. Mice with the p haplotype were found in the areas surrounding those populated with the w1 haplotype mice. In the Maritime Province and the southern part of Siberia, the d haplotype was predominant. The correlation between the geographical variation of the Hbb haplotypes and the distribution of the Mus musculus subspecies in the eastern part of the Eurasian Continent, is discussed.

Animals↗

PubMed2003

Haplotype analysis of the prostacyclin synthase gene and essential hypertension.

Previously, we discovered 3 polymorphisms in the prostacyclin synthase (PGIS) gene: 1) T-192G, in the 5-flanking region, a novel single-nucleotide polymorphism (SNP) that is not associated with essential hypertension (EH); 2) a variable number of tandem repeat (VNTR) polymorphism, 6 nucleotides upstream from the ATG start codon, that is associated with risk of cerebral infarction; and 3) C1117A, in exon 8, an SNP that does not cause an amino acid change in codon 373, and that is associated with risk of myocardial infarction (MI). The purpose of the present study was to establish haplotypes of the PGIS gene consisting of these 3 polymorphisms, and to assess the association between these haplotypes and EH. We detected 19 haplotypes. There was no significant difference in the overall distribution of haplotypes between EH and normotensive subjects. To summarize, we successfully identified haplotypes of the PGIS gene, and these haplotypes were not associated with EH.

Adult↗

PubMed2001

North African genes in Iberia studied by Y-chromosome DNA haplotype 5.

The frequency of haplotype 5 at the Y-chromosome-specific DNA polymorphism (p49/TaqI) was reported in a study of 487 males originating from five different geographic locations in Iberia and North Africa. The highest frequency of haplotype 5 (68.9%) was previously observed in Berbers from Morocco, and it has been established that this haplotype is a characteristic Berber haplotype in North Africa. The relative frequencies of haplotype 5 distribution show a geographical gradient of decreasing frequency according to latitude in Iberia: 40.8% in Andalusia, 36.2% in Portugal, 12.1% in Catalonia, and 11.3% in the Basque Country; such a cline of decreasing frequency of haplotype 5 from the south to the north in Iberia clearly establishes a gene flow from North Africa towards Iberia.

Adult↗

PubMed2003

Paternal European ancestry in French Polynesia detected by Y-chromosome haplotypes.

Y-chromosome-specific polymorphisms p49f-a/TaqI were studied in a sample of 68 French Polynesians, and five haplotypes were observed. Three of them were haplotypes characteristic of European ancestry. The mean haplotype (45.6%) in French Polynesia is haplotype XV, a typical western European haplotype. Such an elevated frequency of European haplotypes is due to male gene flow from Europeans in French Polynesia.

Chromosomes, Human, Y↗

PubMed2006

Sequestosome 1: mutation frequencies, haplotypes, and phenotypes in familial Paget's disease of bone.

UNLABELLED: Mutations of the SQSTM1/p62 gene are commonly observed in PDB. Screening an updated sample from Quebec and using previously published data from other populations, we compared frequency estimates for SQSTM1/p62 mutations and haplotype distribution. The P392L mutation was the most prevalent, embedded in two different haplotypes, possibly shared by other populations. We also examined the phenotype and penetrance of P392L. INTRODUCTION: There is accumulating evidence that supports a contribution of genetic factors in the etiology of Paget's disease of bone (PDB), and several genetic loci have been suggested for the disorder. The sequestosome1/p62 (SQSTM1/p62) gene was the first gene identified to have a role in PDB, with 14 mutations reported to date. MATERIAL AND METHODS: To evaluate the importance of the SQSTM1/p62 mutations in PDB, we recruited, sequenced, and genotyped a total of 123 carriers from 20 families in addition to 214 unrelated PDB patients. We compared the frequency of SQSTM1/p62 mutations in familial and unrelated cases among different populations. Finally, we examined the phenotypic expression and penetrance of the P392L mutation in the Quebecois families. RESULTS AND CONCLUSIONS: The 14 mutations reported in SQSTM1/p62 all affect the ubiquitin-associated domain of the protein. The P392L mutation is the most commonly observed mutation in PDB patients and was consistently found in unrelated and familial PDB cases in the populations tested. Analysis of adjacent polymorphisms suggests that P392L is associated with two different haplotypes in the Quebecois patients, similar to what has been observed in European populations. In Quebec, both haplotypes had similar frequencies in unrelated P392L carriers, whereas one haplotype was predominant in the other populations studied. These data suggest that these two haplotypes, possibly introduced by European founders in the Quebecois population, were equally distributed in the succeeding generations. Finally, the P392L mutation is transmitted as an autosomal dominant trait in the Quebecois families, with a high but incomplete penetrance peaking after age 60. The large phenotypic variability and similarity between unrelated and familial cases, respectively, remain unexplained and require further research.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Estrogen receptor alpha gene polymorphisms and bone mineral density: haplotype analysis in women from the United Kingdom.

Genetic factors are important in the pathogenesis of osteoporosis and the estrogen receptor has been suggested as a possible candidate gene for regulation of bone mineral density (BMD). We investigated the relationship between PvuII, XbaI, and dinucleotide (TA)n repeat polymorphisms of the estrogen receptor alpha (ER-alpha) gene and BMD in a study of women from northeast Scotland in the United Kingdom. No significant association was observed between BMD values at the lumbar spine (LS) and femoral neck (FN) in relation to PvuII and XbaI polymorphisms individually, but haplotype analysis showed that BMD values (Z score) were significantly lower in those who carried the Px haplotype (n = 36) compared with those who did not (n = 170) at both the LS (mean +/- SEM; -0.775 +/- 0.125 vs. -0.285 +/- 0.082;p = 0.002) and the FN (-0.888 +/- 0.130 vs. -0.335 +/- 0.083; p = 0.0006). In keeping with this, the Px haplotype also was found to be an independent predictor of LS BMD (p = 0.019) and FN BMD (p = 0.005) in a multiple regression analysis model that included other possible predictors of BMD including age, years since menopause (YSM), hormone-replacement therapy (HRT) use, weight, and height. This model explained 15.7% and 23.4% of the total observed variance in LS and FN BMD, respectively, with the Px haplotype accounting for approximately 3% of the variance at both sites. Although the TA repeat polymorphism was in strong linkage disequilibrium (LD) with the PvuII (chi2 = 109.8; p < 0.0001) and XbaI (chi2 = 97.2; p < 0.0001) polymorphisms, there was no overall association between TA repeat number and BMD. We conclude that polymorphisms of the ER-alpha gene are significantly related to BMD in our population and that this association is dependent on the Px haplotype, suggesting that it is the Px haplotype, or a linked polymorphism, that confers risk.

Alleles↗

PubMed2002

HLA haplotypes in dizygotic twin pairs: are dizygotic twins more similar than sibs?

It has been suggested that dizygotic twin pairs share two HLA haplotypes more often than ordinary siblings and thus might be genetically more alike. We tested this hypothesis in dizygotic twin pairs from the Danish Twin Registry. A total of 114 (60 female and 54 male) same-sexed healthy twin pairs aged 18-45 years participated. Dizygosity was established by means of DNA sequencing of nine polymorphic markers. HLA-A, B and Cw specificities were typed with serology, and if data were inconclusive, with DNA typing. If twin partners had the same HLA-types, they were assumed to share two haplotypes. If they had 1 HLA A, B and C antigen group in common they were assumed to share one haplotype and if they had no HLA types in common they were assumed to share zero haplotypes. Since HLA-types from parents were unavailable we could not test for identity-by-descent and thus had a risk of overestimating the number of twins sharing two haplotypes. A Chi-square test was used to compare observed numbers in each haplotype sharing group with the expected numbers. Twenty-nine (expected 28.5) twin pairs had two HLA-types in common, 52 (expected 57) had one HLA-type in common and 33 (expected 28.5) had zero HLA-types in common, p = 0.56. Our data show that DZ twins are not more similar than sibs from different pregnancies in general.

Adolescent↗

PubMed2004

Conditional probability methods for haplotyping in pedigrees.

Efficient haplotyping in pedigrees is important for the fine mapping of quantitative trait locus (QTL) or complex disease genes. To reconstruct haplotypes efficiently for a large pedigree with a large number of linked loci, two algorithms based on conditional probabilities and likelihood computations are presented. The first algorithm (the conditional probability method) produces a single, approximately optimal haplotype configuration, with computing time increasing linearly in the number of linked loci and the pedigree size. The other algorithm (the conditional enumeration method) identifies a set of haplotype configurations with high probabilities conditional on the observed genotype data for a pedigree. Its computing time increases less than exponentially with the size of a subset of the set of person-loci with unordered genotypes and linearly with its complement. The size of the subset is controlled by a threshold parameter. The set of identified haplotype configurations can be used to estimate the identity-by-descent (IBD) matrix at a map position for a pedigree. The algorithms have been tested on published and simulated data sets. The new haplotyping methods are much faster and provide more information than several existing stochastic and rule-based methods. The accuracies of the new methods are equivalent to or better than those of these existing methods.

Animals↗

PubMed2005

Efficient inference of haplotypes from genotypes on a large animal pedigree.

We present a simple algorithm for reconstruction of haplotypes from a sample of multilocus genotypes. The algorithm is aimed specifically for analysis of very large pedigrees for small chromosomal segments, where recombination frequency within the chromosomal segment can be assumed to be zero. The algorithm was tested both on simulated pedigrees of 155 individuals in a family structure of three generations and on real data of 1149 animals from the Israeli Holstein dairy cattle population, including 406 bulls with genotypes, but no females with genotypes. The rate of haplotype resolution for the simulated data was >91% with a standard deviation of 2%. With 20% missing data, the rate of haplotype resolution was 67.5% with a standard deviation of 1.3%. In both cases all recovered haplotypes were correct. In the real data, allele origin was resolved for 22% of the heterozygous genotypes, even though 70% of the genotypes were missing. Haplotypes were resolved for 36% of the males. Computing time was insignificant for both data sets. Despite the intricacy of large-scale real pedigree genotypes, the proposed algorithm provides a practical rule-based solution for resolving haplotypes for small chromosomal segments in commercial animal populations.

Algorithms↗

PubMed2006

Accurate haplotype inference for multiple linked single-nucleotide polymorphisms using sibship data.

Sibships are commonly used in genetic dissection of complex diseases, particularly for late-onset diseases. Haplotype-based association studies have been advocated as powerful tools for fine mapping and positional cloning of complex disease genes. Existing methods for haplotype inference using data from relatives were originally developed for pedigree data. In this study, we proposed a new statistical method for haplotype inference for multiple tightly linked single-nucleotide polymorphisms (SNPs), which is tailored for extensively accumulated sibship data. This new method was implemented via an expectation-maximization (EM) algorithm without the usual assumption of linkage equilibrium among markers. Our EM algorithm does not incur extra computational burden for haplotype inference using sibship data when compared with using unrelated parental data. Furthermore, its computational efficiency is not affected by increasing sibship size. We examined the robustness and statistical performance of our new method in simulated data created from an empirical haplotype data set of human growth hormone gene 1. The utility of our method was illustrated with an application to the analyses of haplotypes of three candidate genes for osteoporosis.

Algorithms↗

PubMed2006

An ancestral haplotype defines susceptibility to doxorubicin nephropathy in the laboratory mouse.

Haplotype analysis was used to refine of the DOXNPH locus, which harbors the susceptibility gene for doxorubicin (DOX; Adriamycin) nephropathy, a Mendelian form of selective podocyte injury. Analysis of haplotype structure in three strains with contrasting susceptibility (148 single-nucleotide polymorphisms at 101-kb spacing) was complementary to analysis of recombinants in 176 F2 mice. For example, haplotype analysis but not meiotic mapping could exclude the Abcc1 multidrug transporter, and this was confirmed further by phenotypic evaluation of Abcc1 null mice. Next, comparison of haplotype structure (55 single-nucleotide polymorphisms at 44-kb spacing) with phenotype in 15 inbred strains revealed a risk haplotype that was shared by susceptible strains (P = 0.00017), thereby reducing the DOXNPH region to a 1.3-Mb interval. These data demonstrate that susceptibility to DOX nephropathy represents a founder mutation in the laboratory mouse. Haplotype analysis can be used for identification of the DOXNPH gene and prediction of strain susceptibility pattern.

Animals↗

PubMed2006

Interactions between noncontiguous haplotypes in the adiponectin gene ACDC are associated with plasma adiponectin.

Adiponectin, an adipocyte protein important in insulin sensitization and cardioprotection, has a strong genetic component. We hypothesized that variants in the adiponectin gene (adipocyte collagen-domain containing [ACDC]) contribute to adiponectin levels in a biracial adolescent cohort. We genotyped 11 ACDC single nucleotide polymorphisms (SNPs) in 631 non-Hispanic white and 553 African-American unrelated adolescents in grades 5-12 randomly selected from the Princeton School District Study. ACDC SNPs -11,391 (A allele), -10,068 (G allele), and +276 (T allele) were associated with higher adiponectin, adjusting for sex, puberty stage, BMI Z score, and waist Z score. Contiguous two-SNP haplotypes of promoter variants -11,391/-10,068 were significantly associated with adiponectin levels in whites and African Americans (P < 0.0001 and 0.03, respectively). Extended haplotypes from the promoter through the second intron (-11,391 to +349) strongly associated with adiponectin in whites (P = 6 x 10(-11)) and African Americans (P = 0.004), but haplotypes of first intron SNPs -4,521 to -657 did not (P > 0.2). Noncontiguous haplotypes or interactions between two-SNP (-11,391/-10,068) and three-SNP (+45, +276, and +349) haplotypes predicted adiponectin better than either region alone. Variants of ACDC are associated with adiponectin levels in whites and African Americans. Interactions between noncontiguous ACDC haplotypes strongly influence adiponectin levels, suggesting nonadditive and potentially cis relationships between these regions.

Adiponectin↗

PubMed1990

Beta-globin gene cluster haplotypes in Hb C heterozygotes.

Previous work has suggested that the beta C mutation arose on a relatively rare beta A chromosome with a unique haplotype, and these data have been used to postulate a single origin of the beta C allele. Most characteristic of this haplotype has been the absence of a Hpa I recognition site 3' to the beta-globin gene. We studied 40 patients with Hb SC, 11 with Hb AC, and one with Hb CC. Complete haplotyping was possible on 44 beta C alleles and 3' haplotyping was possible on an additional four beta C alleles. Our results support the predominence of a unique beta C haplotype which is characterized by the absence of the Hpa I site. However, one patient who was homozygous for Hb C had one beta C allele with an atypical haplotype which contained the Hpa I site. It is unclear at this time whether or not this represents a second origin of the beta C mutation.

Anemia, Sickle Cell↗