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At least 541 records · Page 30Linked to original sources
PubMed2001

Distribution of HIV-1 resistance-conferring polymorphic alleles SDF-1-3'A, CCR2-64I and CCR5-Delta32 in diverse populations of Andhra Pradesh, South India.

Polymorphic allelic variants of chemokine receptors CCR2 and CCR5, as well as of stromal-derived factor-1 SDF-1, the ligand for the chemokine receptor CXCR4, are known to have protective effects against HIV-1 infection and to be involved with delay in disease progression. We have studied the DNA polymorphisms at the loci that encode these proteins in 525 healthy individuals without any history of HIV-1 infection from 11 diverse populations of Andhra Pradesh, South India. The two protective alleles SDF-1-3'A and CCR2-64I at the SDF-1 and CCR2 loci, respectively, are present in all populations studied, although their frequencies differ considerably across populations (from 17% to 35% for the SDF-1-3'A allele, and from 3% to 17% for CCR2-64I). In contrast the CCR5-Delta32 allele is observed only in three populations (Yamani, Pathan and Kamma), all in low frequencies (i.e. 1% to 3%). The mean number of mutant alleles (for the three loci together) carried by each individual varies from 0.475 (in Vizag Brahmins) to 0.959 (in Bohra Muslims). The estimated relative hazard values for the populations, computed from the three-locus genotype data, are comparable to those from Africa and Southeast Asia, where AIDS is known to be widespread.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Correlation between N-acetyltransferase activity and NAT2 genotype in Chinese males.

Eighty-four healthy Chinese male control subjects derived from an occupation-based case-control study of bladder cancer were evaluated for hepatic N-acetyltransferase activity by dapsone and for NAT2 genotype using allele-specific amplification of peripheral leukocyte DNA by the polymerase chain reaction. Fifty-nine percent of the overall variation in acetylation activity was explained by genotype (p < 0.0001). The remaining variation in acetylation was not associated with dapsone N-hydroxylation activity, age, current smoking status, or weight in the study population, or within any genotype subgroup. Although acetylation activity in the homozygous mutant group did not overlap with the other genotype categories, there was moderate overlap in acetylation between the heterozygous mutant and wildtype groups, and substantial variation in acetylation within them. Considering all subjects with the identical NAT2 genotype as phenotypically similar and all subjects with differing NAT2 genotypes as phenotypically distinct may result in misclassification of metabolic risk factors in epidemiological investigations. As such, it would seem prudent, where possible, to collect both acetylation phenotype and NAT2 genotype data, since the advantages and limitations of these two sources of information complement, and serve to assess the accuracy of each other.

Aged↗
PubMed2002

Flow cytometric immunophenotyping in posttransplant lymphoproliferative disorders.

We studied the flow cytometric immunophenotyping (FCI) and genotypic data of 11 specimens from 10 transplant recipients and categorized them based on a scheme for posttransplant lymphoproliferative disorders (PTLDs). Specimens had been analyzed by polymerase chain reaction and/or Southern blot for T-cell and B-cell (immunoglobulin heavy chain and light chain genes) gene rearrangements (BGR). The categories for PTLDs were as follows: 1, 1; 2, 6; and 3, 4. The plasmacytic and polymorphic B-cell hyperplasias (PBCHs) revealed no monoclonal/aberrant cells by FCI or genotypic studies (GS). Three of 4 polymorphic B-cell lymphomas (PBCLs) revealed monoclonal or aberrant (no surface light chain) B cells by FCI; 1 of 3 revealed a BGR. However, the 1 case with no monoclonal/aberrant B cells by FCI revealed a BGR. Both immunoblastic lymphomas revealed monoclonal or aberrant B cells by FCI; 1 revealed a BGR. Both multiple myelomas revealed monoclonal plasma cells by FCI; 1 revealed a BGR. In the 4 PTLDs with monoclonal/aberrant B cells by FCI and no clonality detected by GS, the GS were performed on fresh and paraffin-embedded tissue samples. FCI of the plasmacytic and PBCHs supported no clonal process by GS. FCI defined a clonal process in 2 PBCLs, I immunoblastic lymphoma, and 1 multiple myeloma that were negative by GS. However, 1 PBCL that was polyclonal by FCI was monoclonal by GS. Thus, FCI is useful for identifying a clonal process in PTLDs with negative results by GS; FCI and GS should be performed routinely in PTLDs to detect a clonal process.

Adult↗
PubMed1994

Multilocus DNA fingerprinting: the independence problem in quantitative paternity testing.

A simulation study was performed in order to determine whether or not the assumption of independence, made in the quantitative analysis of multilocus DNA fingerprints, represents an inadmissible over-simplification. A total of 10,000 cases of true and false paternity, respectively, were simulated in twenty replicas of various genetic models. Log-likelihood ratios (paternity vs. non-paternity; LR) were calculated using published likelihood formulae and assuming position-wise independence. The resulting LR distributions were compared to (i) the results of a classical analysis of the underlying genotype data, and (ii) the distributions expected from the likelihood model employed in the LR calculations. Although considerable discrepancies were observed between these distributions, decision making about paternity appeared to be only marginally affected, especially when only a fraction of each multilocus DNA fingerprint was analyzed.

Chromosome Mapping↗
PubMed2004

Defining the phenotype in human genetic studies: forward genetics and reverse phenotyping.

The definition of phenotypes for genetic study is a challenging endeavor. Just as we apply strict quality standards to genotype data, we should expect that phenotypes meet consistently high standards of reproducibility and validity. The methods for achieving accurate phenotype assignment in the research setting--the 'research diagnosis'--are different from the methods used in clinical diagnosis in the patient care setting. We evaluate some of the main challenges of phenotype definition in human genetics, and begin to outline a set of standards to which phenotypes used in genetics studies may aspire with the goal of increasing the quality and reproducibility of linkage and association studies. Revisiting the traditional phenotype definitions through a focus on familial components and heritable endophenotypes is a time-honored approach. Reverse phenotyping, where phenotypes are refined based on genetic marker data, may be a promising new approach. The stakes are high, since the success of gene mapping in genetically complex disorders hinges on the ability to delineate the target phenotype with accuracy and precision.

Chromosome Mapping↗
PubMed2006

A whole genome long-range haplotype (WGLRH) test for detecting imprints of positive selection in human populations.

MOTIVATION: The identification of signatures of positive selection can provide important insights into recent evolutionary history in human populations. Current methods mostly rely on allele frequency determination or focus on one or a small number of candidate chromosomal regions per study. With the availability of large-scale genotype data, efficient approaches for an unbiased whole genome scan are becoming necessary. METHODS: We have developed a new method, the whole genome long-range haplotype test (WGLRH), which uses genome-wide distributions to test for recent positive selection. Adapted from the long-range haplotype (LRH) test, the WGLRH test uses patterns of linkage disequilibrium (LD) to identify regions with extremely low historic recombination. Common haplotypes with significantly longer than expected ranges of LD given their frequencies are identified as putative signatures of recent positive selection. In addition, we have also determined the ancestral alleles of SNPs by genotyping chimpanzee and gorilla DNA, and have identified SNPs where the non-ancestral alleles have risen to extremely high frequencies in human populations, termed 'flipped SNPs'. Combining the haplotype test and the flipped SNPs determination, the WGLRH test serves as an unbiased genome-wide screen for regions under putative selection, and is potentially applicable to the study of other human populations. RESULTS: Using WGLRH and high-density oligonucleotide arrays interrogating 116 204 SNPs, we rapidly identified putative regions of positive selection in three populations (Asian, Caucasian, African-American), and extended these observations to a fourth population, Yoruba, with data obtained from the International HapMap consortium. We mapped significant regions to annotated genes. While some regions overlap with genes previously suggested to be under positive selection, many of the genes have not been previously implicated in natural selection and offer intriguing possibilities for further study. AVAILABILITY: the programs for the WGLRH algorithm are freely available and can be downloaded at http://www.affymetrix.com/support/supplement/WGLRH_program.zip.

Algorithms↗
PubMed2004

Graphical modeling of the joint distribution of alleles at associated loci.

Pairwise linkage disequilibrium, haplotype blocks, and recombination hotspots provide only a partial description of the patterns of dependences and independences between the allelic states at proximal loci. On the gross scale, where recombination and spatial relationships dominate, the associations can be reasonably described in these terms. However, on the fine scale of current high-density maps, the mutation process is also important and creates associations between loci that are independent of the physical ordering and that can not be summarized with pairwise measures of association. Graphical modeling provides a standard statistical framework for characterizing precisely these sorts of complex stochastic data. Although graphical models are often used in situations in which assumptions lead naturally to specific models, it is less well known that estimation of graphical models is also a developed field. We show how decomposable graphical models can be fitted to dense genetic data. The objective function is the maximized log likelihood for the model penalized by a multiple of the model's degrees of freedom. We also describe how this can be modified to incorporate prior information of locus position. Simulated annealing is used to find good solutions. Part of the appeal of this approach is that categorical phenotypes can be included in the same analysis and association with polymorphisms can be assessed jointly with the interlocus associations. We illustrate our method with genotypic data from 25 loci in the ELAC2 gene. The results contain third- and fourth-order locus interactions and show that, at this density of markers, linkage disequilibrium is not a simple function of physical distance. Graphical models provide more flexibility to express these features of the joint distribution of alleles than do monotonic functions connecting physical and genetic maps.

Alleles↗
PubMed2003

Prevalence of genotypic drug resistance among a cohort of HIV-infected newborns.

A retrospective, blinded study was conducted to examine the prevalence of antiretroviral drug resistance among a cohort of HIV-infected infants born in 1998 and 1999 in New York State. The earliest available HIV-positive specimen was tested. Most samples were from infants younger than 60 days of age. Genotype data were generated for the protease and reverse transcriptase genes of HIV-1 proviral DNA from 91 infected infants. Eleven infants (12.1%) had provirus with mutations associated with drug resistance, with all three classes of antiretroviral drugs represented. Two infants (2.2%) had mutations associated with resistance to two classes of antiretrovirals. Perinatal antiretroviral drug exposure was examined; it was not found to be significantly associated with the presence of resistance mutations. However, for those infants who had perinatal antiretroviral exposure and genotypic evidence of drug resistance to HIV, the mutations that were detected correlated with at least one antiretroviral from the perinatal period. The prevalence of genotypic drug resistance among this infant cohort is comparable with that found among recently infected adults. These results suggest that resistance testing should be strongly considered for perinatally infected infants, at the earliest possible time point, to avoid use of antiretroviral drugs to which the infant has preexisting resistance.

Anti-HIV Agents↗
PubMed2005

TAU haplotype and the Saitohin Q7R gene polymorphism do not influence CSF Tau in Alzheimer's disease and are not associated with frontotemporal dementia or Parkinson's disease.

BACKGROUND: Recent studies have described Saitohin(STH), a gene located in the human TAU gene. The corresponding protein shows a similar tissue expression to tau, which is involved in many neurodegenerative disorders including Alzheimer's disease (AD), frontotemporal dementia (FTD) and Parkinson's disease (PD). A single nucleotide polymorphism in the STH gene has been suggested to be involved in sporadic AD and is in complete linkage disequilibrium with the TAU haplotype H1. OBJECTIVE: A case-control study was performed to further explore the possible involvement of the STH Q7R polymorphism and the extended TAU haplotype in AD, FTD or PD. METHODS: Patients with AD (n = 398), FTD (n = 96) and PD (n = 105), and controls (n = 186) were genotyped for the STH polymorphism and/or the TAU haplotype. Genotype data were related to levels of total-tau, phospho-tau and Abeta(1-42) in cerebral spinal fluid (CSF) in more than 300 AD patients and to an amount of senile plaques and neurofibrillary tangles in the frontal cortex and hippocampus in patients with autopsy-confirmed AD. RESULTS: The STH Q7R polymorphism and the TAU haplotype were in complete linkage disequilibrium in all patients (AD and FTD) and controls investigated for both genes. There were no significant differences in genotype or allele distributions in AD, FTD or PD cases compared to controls. Neither TAU haplotype nor STH influenced CSF levels of total-tau, phospho-tau and Abeta(1-42) significantly. In AD patients with neuropathological scores of plaque and tangles, no associations with TAU haplotype and STH were found. CONCLUSION: We found no evidence that could support a major pathogenic role of STH and TAU haplotype in AD, FTD or PD.

Aged↗
PubMed2005

Genetic linkage map of medaka with polymerase chain reaction length polymorphisms.

With recent improvements in genetic and genomic infrastructures, great interest has been taken in genetic dissection of multi-factorial traits. A genetic map consisting of markers that are highly polymorphic and rapidly genotyped is essential for the genetic mapping of such a complex trait. Medaka, Oryzias latipes, is an excellent model system for genetic studies. To promote genetic mapping of complex traits in medaka we developed the first high-throughput and genome-wide marker set in the organism by using its genomic information and the bioinformatic techniques. We tested 545 primer pairs and obtained 265 co-dominant markers between two inbred strains, HNI and Hd-rR. Our map, consisting of 231 uniquely mapped markers, covers 1257.3 centimorgan (cM) of the medaka genome with an average interval distance of 5.4 cM. Furthermore, the newly designed markers were examined for polymorphisms among six medaka inbred strains: HNI, Hd-rR and four additional strains. Most of our markers are simple sequence length polymorphisms (SSLPs) and can be rapidly genotyped by an automated system under a single polymerase chain reaction (PCR) condition. Together with the genotyping data of six medaka inbred strains, our new marker set provides a powerful tool for genome-wide analysis of complex biological phenomena found widely in medaka populations.

Animals↗
PubMed1999

Hepatitis C virus infection in four haemodialysis units of southern Italy: epidemiological report.

UNLABELLED: The haemodialysis patients are an high risk population for hepatitis viral infections. While the incidence of HBV has decreased worldwide, HCV is now the major cause of viral infection in these patients. The aim of our study was to define a complete map of patients undergoing routine replacement therapy by haemodialysis in the province of Foggia, Southern Italy, who were HCV Ab positive, the presence of viraemia and their genotypes; moreover, we investigated the probable factors involved in determining the infection as well as the means of prevention. MATERIALS AND METHODS: We enrolled 330 patients treated in four haemodialysis centres (DC) and six secondary units; mean age was 57 years and mean duration of dialysis 76 months. Samples were drawn to determine cytolysis indexes and the HCV Ab status; in HCV positive patients, we also looked for viraemia and HCV genotypes. Data were analysed by a transversal cross-section study. RESULTS AND CONCLUSIONS: Prevalence of HCV infection was 0.43 (males 0.45, females 0.42). The risk of contracting the infection was shown to be significantly different in the various DCs and did not seem to be related to the severity of the preventive measures. There was no significant difference between the various DCs in the comparison between the odds of HCV-RNA+ and HCV-RNA- patients. No significant prevalence of a given genotype emerged from a cross-sectional study related to the comparison between different genotypes. Moreover, transfusions of blood products seemed to have no significant relation to HCV infection. Finally, patients treated with haemodialysis for more than 36 months run a seven time greater risk of contracting HCV infection.

Adolescent↗
PubMed1988

An embryogenic model to explain cytogenetic inconsistencies observed in chorionic villus versus fetal tissue.

While the fetus and placenta have a common ancestry, chorionic villus tissue does not always reflect fetal genotype. Data are presented from 15 CVS subjects in whom cytogenetic inconsistencies were observed when comparing (1) cultured chorionic villi, (2) direct chromosome preparations of intact villi, and (3) cultured fetal tissue. Embryogenic models are presented to explain these discrepancies. Mosaicism confined to direct chromosome preparations was the most commonly observed inconsistency. This can be explained by postzygotic non-disjunction limited to cytotrophoblast. In all but one instance, the abnormal cell line was limited to the placenta, with the normal cell line reflecting fetal genotype. Analysis of direct chromosome preparations from multiple individually processed villus fragments may be helpful in recognizing mosaicism confined to the placenta. While both direct chromosome preparations and villus cultures can be misleading, the latter are more likely to reflect fetal genetic status since they are derived from the extraembryonic mesoderm.

Chorionic Villi↗
PubMed1998

Sensitivity of the Western blot detection of prion protein PrPres in natural sheep scrapie.

The sensitivity of Western blot detection of PrPres using two different extraction procedures on brain material of 30 scrapie-affected sheep was compared. Whereas PrPres could be detected in all sheep after extraction with the first method, 30% did not give any signal after extraction with the second method. However, the second method, when positive, permitted the detection of PrPres from smaller amounts of infected brain tissue. When used with the ruminant specific monoclonal antibody p4, the second method gave positive signals corresponding to less than 12.5 microg of scrapie-infected brain, that, up to now, is the highest sensitivity described for PrPres detection from naturally infected ruminant brains. The overall results showed highly variable levels of PrPres between sheep and are presented in relation to breed, survival time and animal genotype data. Further progress can thus be expected for PrPres detection in prion diseases, if more efficient extraction procedures and more sensitive immunological reagents are used. Such technical improvements could contribute to more accurate diagnosis in animals affected naturally.

Animals↗
PubMed2006

Computation of haplotypes on SNPs subsets: advantage of the "global method".

BACKGROUND: Genetic association studies aim at finding correlations between a disease state and genetic variations such as SNPs or combinations of SNPs, termed haplotypes. Some haplotypes have a particular biological meaning such as the ones derived from SNPs located in the promoters, or the ones derived from non synonymous SNPs. All these haplotypes are "subhaplotypes" because they refer only to a part of the SNPs found in the gene. Until now, subhaplotypes were directly computed from the very SNPs chosen to constitute them, without taking into account the rest of the information corresponding to the other SNPs located in the gene. In the present work, we describe an alternative approach, called the "global method", which takes into account all the SNPs known in the region and compare the efficacy of the two "direct" and "global" methods. RESULTS: We used empirical haplotypes data sets from the GH1 promoter and the APOE gene, and 10 simulated datasets, and randomly introduced in them missing information (from 0% up to 20%) to compare the 2 methods. For each method, we used the PHASE haplotyping software since it was described to be the best. We showed that the use of the "global method" for subhaplotyping leads always to a better error rate than the classical direct haplotyping. The advantage provided by this alternative method increases with the percentage of missing genotyping data (diminution of the average error rate from 25% to less than 10%). We applied the global method software on the GRIV cohort for AIDS genetic associations and some associations previously identified through direct subhaplotyping were found to be erroneous. CONCLUSION: The global method for subhaplotyping can reduce, sometimes dramatically, the error rate on patient resolutions and haplotypes frequencies. One should thus use this method in order to minimise the risk of a false interpretation in genetic studies involving subhaplotypes. In practice the global method is always more efficient than the direct method, but a combination method taking into account the level of missing information in each subject appears to be even more interesting when the level of missing information becomes larger (>10%).

Apolipoproteins E↗
PubMed2003

WebQTL: web-based complex trait analysis.

WebQTL is a website that combines databases of complex traits with fast software for mapping quantitative trait loci (QTLs) and for searching for correlations among traits. WebQTL also includes well-curated genotype data for five sets of mouse recombinant inbred (RI) lines. Thus, to identify QTLs, users need provide only quantitative trait data from one of the supported populations. The WebQTL databases include both biological traits--neuroanatomical, pharmacological, and behavioral traits--and microarray-based gene expression data from BXD RI lines. A search function finds correlations between RNA expression and biological traits, and mapping functions find QTLs for either type of trait. The WebQTL service is available at http://www.webqtl.org/.

Animals↗
PubMed1996

Association of the epsilon 4 allele of apolipoprotein E with poor performance on a dementia screen in African Americans.

In a community-based study of Alzheimer's disease in African Americans age 65 and over, subjects were classified into three levels of performance based on their scores as measured by the Community Screening Instrument for Dementia (CSI"D"), consisting of cognitive and functioning components. In a subset of 268 subjects with apolipoprotein E (APOE) genotype data, we found that the epsilon 4 allele of APOE was associated with intermediate/poor performance (single copy epsilon 4 odds ratio 1.51, 95% CI 1.18 to 1.92; double copy epsilon 4 odds ratio 3.42, 95% CI 2.18 to 5.43). From these data, we believe it would be possible to conduct population screening for the effects of possession of the APOE-epsilon 4 allele using information derived from the CSI"D".

Aged↗
PubMed1997

Evidence for genetic heterogeneity in familial Wilms' tumor.

Wilms' tumor (WT), a childhood kidney cancer, occurs both sporadically and, less frequently, in a familial context. Genetic linkage studies of several large WT families have excluded the one cloned WT gene, WT1, as the locus responsible for familial predisposition. These data demonstrate the existence of a familial predisposition gene distinct from WT1 and, more broadly, imply that the genetic etiology of WT is heterogenous. However, it has been unknown whether the predisposition observed in large WT families is also heterogenous or perhaps is due to mutations at a single locus. Recently, examination of a large French-Canadian WT family has demonstrated genetic linkage to 17q12-q21. We report here the results from a genetic linkage study of six WT pedigrees. Analyses of genotype data from eight loci within the 17q12-q21 region in these families resulted in cumulative lod scores of <-4.0 through the region, thereby excluding linkage. The ability to rule out the 17q region as the site of a predisposition gene in several of these pedigrees individually demonstrates the existence of more than one gene that predisposes to WT in large pedigrees and again emphasizes that the etiology of WT is genetically heterogenous.

Adult↗
PubMed2005

Temperature gradient capillary electrophoresis (TGCE)--a tool for the high-throughput discovery and mapping of SNPs and IDPs.

Temperature gradient capillary electrophoresis (TGCE) can be used to distinguish heteroduplex from homoduplex DNA molecules and can thus be applied to the detection of various types of DNA polymorphisms. Unlike most single nucleotide polymorphism (SNP) detection technologies, TGCE can be used even in the absence of prior knowledge of the sequences of the underlying polymorphisms. TGCE is both sensitive and reliable in detecting SNPs, small InDel (insertion/deletion) polymorphisms (IDPs) and simple sequence repeats, and using this technique it is possible to detect a single SNP in amplicons of over 800 bp and 1-bp IDPs in amplicons of approximately 500 bp. Genotyping data obtained via TGCE are consistent with data obtained via gel-based detection technologies. For genetic mapping experiments, TGCE has a number of advantages over alternative heteroduplex-detection technologies such as celery endonuclease (CELI) and denaturing high-performance liquid chromatography (dHPLC). Multiplexing can increase TGCE's throughput to 12 markers on 94 recombinant inbreds per day. Given its ability to efficiently and reliably detect a variety of subtle DNA polymorphisms that occur at high frequency in genes, TGCE shows great promise for discovering polymorphisms and conducting genetic mapping and genotyping experiments.

Chromosome Mapping↗