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PubMed1998

MICA gene polymorphism in Takayasu's arteritis and Buerger's disease.

To further clarify the HLA-linked genes susceptible to arterio-vasculitis of unknown etiology, Takayasu's arteritis and Buerger's disease, polymorphism in the MICA gene, a newly identified gene near the HLA-B gene and expressed in epithelial cell lineage, was investigated. Polymerase chain reaction (PCR)-DNA conformation polymorphism (DCP) analysis and subsequent sequencing of the MICA gene have revealed that there are 5 MICA alleles which are different in the number of a GCT repeat in exon 5: MICA alleles MICA-1.1, -1.2, -1.3 and -1.4 have 9, 6, 5 and 4 GCT repeats, respectively, and MICA-1.5 has 5 GCT repeats with a 1 bp frameshift insertion in the repeat. MICA genotyping data in 81 Japanese patients with Takayasu's arteritis, 38 Japanese patients with Buerger's disease, and 160 healthy Japanese controls showed that MICA-1.2 and -1.4 were significantly associated with Takayasu's arteritis and Buerger's disease, respectively. Because MICA-1.2 and -1.4 were in strong linkage disequilibria with HLA-B52 and -B54 in the Japanese populations, respectively, we have compared the odds ratio (OR) of the risk to the diseases for individuals having both or each of the disease-associated MICA and HLA-B alleles. It was found that MICA-1.2 gave a significantly high OR of risk to Takayasu's arteritis in the absence of HLA-B52, suggesting that the HLA-linked gene susceptible to Takayasu's arteritis is mapped near the MICA gene. In contrast, MICA-1.4 gave a significantly high OR of risk to Buerger's disease only in the presence of HLA-B54, suggesting that the HLA-linked gene susceptible to Buerger's disease is linked to the HLA-B54-MICA-1.4 haplotype, and may be differently mapped from that to Takayasu's arteritis.

Amino Acid Sequence↗

PubMed2001

Linkage disequilibrium and haplotype analysis among four novel single-nucleotide polymorphisms in the human leukemia inhibitory factor (LIF) gene.

Leukemia inhibitory factor (LIF) is a pleiotropic cytokine implicated in various pathological conditions, such as rheumatoid arthritis and osteoporosis. Despite the possible importance of LIF as a therapeutic target, little is known about the bioregulation of the human LIF gene. We here sequenced the entire structure of the LIF gene of 48 alleles in the Japanese population. These experiments identified four single-nucleotide polymorphisms (SNPs) and determined their allelic frequencies from a 48-allele sequence in the Japanese population. All four SNPs found in the LIFgene were located within exon 3, that is, a C/T at nucleotide (nt) position 3951, a C/G at nt position 4376, an A/C at nt position 4442, and a G/A at nt position 5961 (nucleotide numbering starts from the ATG start codon). Based on the genotypic data, we constructed four major haplotypes in the tested population. Two-way comparisons of SNPs revealed complete linkage disequilibrium between SNPs at positions 3951, 4376, and 4442. These results may prove to be useful as genetic markers for population-based disease-association studies in osteoporosis.

Alleles↗

PubMed2000

Initial results of genomic scans for ovulation rate in a cattle population selected for increased twinning rate.

Genomic scans were conducted with 273 markers on 181 sires from a cattle population selected for increased twinning rate to identify chromosomal regions containing genes that influence ovulation rate. Criteria used for selecting markers were number of alleles, ease of scoring, and relative position within linkage group. Markers were multiplexed or multiple-loaded on the gels to reduce the costs and labor required to obtain genotypic data. This approach reduced the number of gels by 45% when compared with running each marker independently. Male animals selected for the genomic scan sired the majority of the population. A modified interval analysis was used in a granddaughter design to compare effects of each allele within sire for 10 different sire families. The midparent deviation of the son's estimated breeding value for ovulation rate was used as the phenotype. Forty-one potential peaks were identified with a nominal significance level < or = 0.05. The 10 peaks with the highest significance levels (P < 0.02) were selected for further analysis. Markers were genotyped across daughters of the sire where nominal significance was found for each of the 10 peaks. One peak (BTA5, relative position 40 cM) was found to be nominally significant in the daughters. The nominal significance levels were P = 0.01 for the sons (n = 32) and P = 0.02 for the daughters (n = 94) of sire 784403. A combined genomewide significance value (P = 0.07) was calculated that accounted for the 10 analyses with sons and the 10 analyses with daughters. These results strongly suggest that this region contains a gene(s) that is involved in the follicular recruitment and development process.

Animals↗

PubMed2003

Molecular monitoring in malaria vaccine trials.

Molecular techniques offer new approaches for malaria field trials, particularly PCR techniques, which facilitate accurate diagnosis of Plasmodium infections and increase the power of estimates of vaccine effects on malaria prevalence or incidence. Molecular methods also help to assess selective effects of vaccines. Longitudinal genotyping data can be used to initiate novel analyses of parasite dynamics, including estimates of incidence of infection with individual parasite clones and duration of infections. In addition, high-throughput methods can be used to apply these techniques routinely in randomized controlled trials, as well as programme-based evaluations of malaria control.

Animals↗

PubMed2000

The M34T allele variant of connexin 26.

GJB2 encodes the protein Connexin 26, one of the building blocks of gap junctions. Each Connexin 26 molecule can oligomerize with five other connexins to form a connexon; two connexons, in turn, can form a gap junction. Because mutations in GJB2 are the most common cause of congenital severe-to-profound autosomal recessive nonsyndromic hearing loss, the effect of the Connexin 26 allele variants on this dynamic 'construction' process and the function of any gap junctions that do form is particularly germane. One of the more controversial allele variants, M34T, has been hypothesized to cause autosomal dominant nonsyndromic hearing loss. In this paper, we present clinical and genotypic data that refutes this hypothesis and suggests that the effect of the M34T allele variant may be dependent on the mutations segregating in the opposing allele.

Alleles↗

PubMed2003

Quality control trial for human immunodeficiency virus type 1 drug resistance testing using clinical samples reveals problems with detecting minority species and interpretation of test results.

Between January and March 2000, a quality control panel for human immunodeficiency virus (HIV) drug resistance testing was analyzed by 20 laboratories in five countries. The panel consisted of three clinical samples with different drug resistance genotypes and phenotypes and one HIV-negative plasma. Participants were asked to report the methods used for amplification and sequencing, a list of drug resistance-associated mutations that were detected in the protease and reverse transcriptase of each sample, and an interpretation concerning the susceptibility or resistance to 14 antiretroviral drugs. A total of 22 genotypic data sets were generated, which showed an overall good technical quality except for three participants, who failed to report key mutations for drug resistance. Problems were encountered in three respects: (i). resistant minorities of L90M in the protease, which were determined to about 12% by real-time amplification, were only detected by one-fourth of the participants; (ii). newly described resistance mutations were frequently not reported; and (iii). interpretations of drug resistance-associated mutations varied widely, in particular for protease inhibitors. In some cases, different interpretations were caused by differences in the detection of resistant minorities, but even for the same genotypic profile, interpretations varied considerably. Similar discrepancies were revealed if current Web-based interpretation systems were used to predict drug resistance for samples of the proficiency panel. This indicates that a consensus for the interpretation of drug resistance-associated mutations is urgently needed.

Antiviral Agents↗

PubMed2007

Comparison of clinical and environmental isolates of Legionella pneumophila obtained in the UK over 19 years.

Between January 1980 and December 1998, 3458 cases of Legionnaires' disease were reported to the national surveillance scheme in England and Wales. Of these, 463 (13.4%) were reported as proven by culture and isolation of Legionella spp., with 96.3% being Legionella pneumophila. Serogroup (Sgp), monoclonal antibody (mAb) subgrouping and restriction fragment length polymorphism (RFLP) analysis data were obtained for 321 (69.3%) of these, of which 284 were classified as being unrelated to any other isolate in the study. Typing data were also available for 117 unrelated environmental isolates of L. pneumophila obtained from England and Wales, giving a total of 401 unrelated isolates in the study. Of the clinical isolates, 88.0% were Sgp1, compared with only 42.7% of environmental isolates (p <0.001); 79.6% of clinical isolates were subgrouped as mAb2+, compared with only 12.8% of environmental isolates (p <0.001). RFLP typing identified 67 types among the 401 isolates, with clinical isolates showing significantly less diversity than environmental isolates (index of diversity (IOD) 0.944 vs. 0.958; p <0.05), with three RFLP types (1, 5 and 14) accounting for 40.0% of all clinical isolates. Combining the phenotypic and genotypic data resulted in 173 distinct phenons, with clinical isolates showing significantly less diversity than environmental isolates (IOD 0.964 vs. 0.996; p <0.01). Three phenons accounted for 30% of all clinical isolates. These data strongly suggest that some strains of L. pneumophila are more likely to cause human infection than would be expected from their distribution in the environment.

Disease Outbreaks↗

PubMed2005

Spatial genetic structure of northern pike (Esox lucius) in the Baltic Sea.

The genetic relationships among 337 northern pike (Esox lucius) collected from the coastal zone of the central Baltic region and the Finnish islands of Aland were analysed using five microsatellite loci. Spatial structure was delineated using both traditional F-statistics and individually based approaches including spatial autocorrelation analysis. Our results indicate that the observed genotypic distribution is incompatible with that of a single, panmictic population. Isolation by distance appears important for shaping the genetic structure of pike in this region resulting in a largely continuous genetic change over the study area. Spatial autocorrelation analysis (Moran's I) of individual pairwise genotypic data show significant positive genetic correlation among pike collected within geographical distances of less than c. 100-150 km (genetic patch size). We suggest that the genetic patch size may be used as a preliminary basis for identifying management units for pike in the Baltic Sea.

Animals↗

PubMed2004

Genotypic and developmental evidence for the role of plasmodesmatal regulation in cotton fiber elongation mediated by callose turnover.

Cotton fibers are single-celled hairs that elongate to several centimeters long from the seed coat epidermis of the tetraploid species (Gossypium hirsutum and Gossypium barbadense). Thus, cotton fiber is a unique system to study the mechanisms of rapid cell expansion. Previous work has shown a transient closure of plasmodesmata during fiber elongation (Y.-L. Ruan, D.J. Llewellyn, R.T. Furbank [2001] Plant Cell 13: 47-60). To examine the importance of this closure in fiber elongation, we compared the duration of the plasmodesmata closure among different cotton genotypes differing in fiber length. Confocal imaging of the membrane-impermeant fluorescent molecule carboxyfluorescein revealed a genotypic difference in the duration of the plasmodesmata closure that positively correlates with fiber length among three tetraploid genotypes and two diploid progenitors. In all cases, the closure occurred at the rapid phase of elongation. Aniline blue staining and immunolocalization studies showed that callose deposition and degradation at the fiber base correlates with the timing of plasmodesmata closure and reopening, respectively. Northern analyses showed that the expression of a fiber-specific beta-1,3-glucanase gene, GhGluc1, was undetectable when callose was deposited at the fiber base but became evident at the time of callose degradation. Genotypically, the level of GhGluc1 expression was high in the short fiber genotype and weak in the intermediate and long fiber genotypes. The data provide genotypic and developmental evidence that (1) plasmodesmata closure appears to play an important role in elongating cotton fibers, (2) callose deposition and degradation may be involved in the plasmodesmata closure and reopening, respectively, and (3) the expression of GhGluc1 could play a role in this process by degrading callose, thus opening the plasmodesmata.

Cell Enlargement↗

PubMed2003

On the power to detect SNP/phenotype association in candidate quantitative trait loci genomic regions: a simulation study.

We use coalescent methods to investigate the ability of linked neutral "markers" to reveal in simulated population samples the presence of one or more single nucleotide polymorphisms that is contributing to a trait having a complex genetic basis (QTN: quantitative trait nucleotide). Realistic mutation and recombination rates in our simulations allow us to generate SNP data appropriate for analyzing human variation across short chromosomal intervals corresponding to approximately 100 kilobases. We investigate the performance of both single marker and multiple-marker (haplotype) data for several ad hoc procedures. Our results with single SNP markers indicate that (1) the density of SNP markers need not be much higher than 10% in order to achieve near-maximal detection of a QTN; (2) a higher density of markers does not improve much on the ability to localize a QTN within an interval unless the recombination rate is high. Haplotype-based tests were investigated for the case in which more than one QTN is present in the studied interval. Larger sample sizes improve both the probability of detecting the haplotype with the largest number of QTNs, as well as the ability to infer correct haplotypes from genotypic data. Testing a series of short haplotypes across a longer interval can also be beneficial. The rate of false positives (i.e., when the most significant haplotype does not contain the greatest number of QTNs in the sample) can be very high when the contribution of individual QTNs to a trait is small. The elimination of low-frequency haplotypes does not substantially reduce the probability of detecting the haplotype with the largest number of QTNs but it can reduce the rate of false positives.

Computational Biology↗

PubMed2005

Campylobacter jejuni isolated from retail poultry meat, bovine feces and bile, and human diarrheal samples in Japan: comparison of serotypes and genotypes.

To determine the significance of poultry and bovine as infectious sources of Campylobacter jejuni in Japan, the serotype distribution and pulsed-field gel electrophoresis (PFGE) patterns of poultry and bovine isolates were compared with those of isolates from patients with diarrhea in Akita (Japan). Serotypes O:2 and O:4-complex were common in human, poultry, and bovine isolates, and serotype O:23,36,53 was common in human and bovine isolates. SmaI PFGE patterns of isolates belonging to these serotypes were generated. Eight PFGE patterns were shared by poultry and human isolates and three patterns were shared by human and bovine isolates. Further analysis of the isolates having the same SmaI PFGE pattern by KpnI PFGE confirmed that four patterns and two patterns were still shared by poultry and human isolates, and bovine and human isolates, respectively. Thus, serotypic and genotypic data indicated a possible link between sporadic human campylobacteriosis and C. jejuni from retail poultry and bovine bile and feces, suggesting that bovine serves as an infectious source of C. jejuni in Japan, as is observed in other countries.

Animals↗

PubMed2004

Standardizing a composite measure of linkage disequilibrium.

The maximum and minimum are obtained for a composite measure of linkage disequilibrium used with genotypic data when the phase of double heterozygotes cannot be determined. These bounds are used to standardize the composite measure in the same way used for D', the standardized gametic measure of linkage disequilibrium. Standardization produces a measure which lies between -1 and 1, and allows comparison of linkage disequilibrium between populations. The method is illustrated using two loci in the CASR gene.

Gene Frequency↗

PubMed2003

Endothelial nitric oxide synthase polymorphism in preeclampsia.

OBJECTIVE: We wished to determine whether genetic variability in the gene encoding endothelial nitric oxide synthase (eNOS) modifies individual susceptibility to the development of preeclampsia. METHODS: The study involved 132 preeclamptic and 113 healthy control pregnant women who were genotyped for the Glu298Asp polymorphism in the eNOS gene. Chi(2) analysis was used to assess genotype and allele frequency differences between preeclamptic women and controls. RESULTS: A statistically similar allelic distribution of eNOS Glu298Asp polymorphism was observed in the two groups, with the frequency of the variant G allele being 74.6% in the preeclampsia group and 67.7% in the control group (P = .091; odds ratio 1.40, 95% confidence interval 0.95, 2.01). Accordingly, the genotype distribution of the NOS polymorphism in the preeclamptic and control groups was found to be similar (P = .233). CONCLUSION: These genotype data in subjects from eastern Finland were not suggestive of an important contribution of the Glu298Asp polymorphism in the NOS gene on preeclampsia across populations. However, the observed association between the G allele and disease risk, of borderline significance, may imply that other polymorphism(s) in the gene may modify disease risk.

Adult↗

PubMed2026

Influence of IFNG rs2069709 on the severity of varicella in children.

OBJECTIVE: Aim: To assess the association between IFNG rs2069709 genotypes (CC, AC), as well as demographic factors such as sex and age, with the risk of complicated varicella in children. PATIENTS AND METHODS: Materials and Methods: The study included 132 children with confirmed varicella. Genotyping was performed using PCR with the TaqMan Genotyping Assay. Statistical analysis comprised the χ2 test, allele frequency evaluation, and logistic regression to determine the effects of genotype, sex, and age on disease severity. RESULTS: Results: The AC genotype was detected in 67.2% of children, while the CC genotype accounted for 20.3%; samples lacking genotype data (12.5%) were excluded from analysis. The C allele predominated in the uncomplicated group (64.2%), whereas the A allele was more frequent among children with complicated varicella (41.3%). Logistic regression demonstrated a tendency toward increased risk of complicated disease in AC carriers (OR=2.05; p=0.10). Sex and age showed no significant association with disease severity (p>0.05). Although statistical significance was not reached, the findings indicate that variability in the IFNG locus may influence individual immune responses to varicella-zoster virus. CONCLUSION: Conclusions: The IFNG rs2069709 C allele may act as a protective factor against severe varicella, while the A allele may increase susceptibility to complications. The observed trend for the AC genotype highlights the potential role of genetic markers in predicting disease course. Larger studies are required to confirm these associations and clarify their underlying mechanisms.

Humans↗

PubMed2026

Anthropometric and cardio-metabolic trait variation and genetic associations in sub-Saharan Africa.

The genetics of complex traits in Africa has been historically understudied, which can contribute to healthcare inequalities. Here, we present observations of 27 anthropometric, cardiovascular, and blood biomarker measurements across 2,124 individuals from sub-Saharan Africa for whom we also have dense genotype data. First, we identified trait values that differ significantly across populations and subsistence lifestyles (e.g., hemoglobin levels and height). We then identified traits with high degrees of sexual dimorphism (e.g., weight and grip strength). ADMIXTURE analyses revealed substantial population structure in our dataset, and many of the phenotypes studied here are correlated with genetic ancestry components, particularly skin color and body size traits. A variance partitioning approach further revealed traits in which much of the SNP heritability is due to polymorphisms that also contribute to differences between ancestry components. Following genomic imputation, we performed genome-wide association studies (GWASs) for all 27 traits and identified >100 independent autosomal SNPs with genome-wide significant associations for at least one trait (p < 5 × 10-8). Many of these trait-associated variants are rare outside of Africa (minor-allele frequency [MAF] < 1%). We found that 100 kb windows surrounding the top GWAS hits from our African-ancestry cohort were enriched for trait associations in an identically sized European cohort and vice versa. We performed a more detailed analysis of height prediction from genetic data, finding that genome-wide admixture proportions predict height in Africans better than polygenic predictors based on large-scale European height GWASs.

Female↗

PubMed2005

TNF-alpha promoter polymorphisms and susceptibility to human papillomavirus 16-associated cervical cancer.

BACKGROUND: Polymorphisms in the TNF-alpha promoter region have recently been shown to be associated with susceptibility to cervical cancer. Some polymorphisms have been reported to influence transcription for this cytokine. Altered local levels in the cervix may influence an individual's immune response, thereby affecting persistence of human papillomavirus (HPV) 16 infection, a primary etiological factor for cervical cancer. METHODS AND RESULTS: The association of 11 TNF-alpha single-nucleotide polymorphisms (SNPs) with susceptibility to HPV16-associated cervical cancer was investigated. Sequencing of the TNF-alpha promoter region confirmed 10 SNPs, and 1 previously unreported SNP (161 bp upstream of the transcriptional start site) was discovered. Microsphere-array flow cytometry-based genotyping was performed on 787 samples from Hispanic and non-Hispanic white women (241 from randomly selected control subjects, 205 from HPV16-positive control subjects, and 341 from HPV16-positive subjects with cervical cancer). The genotype distribution of 3 SNPs (-572, -857, and -863) was significantly different between case subjects and control subjects. Analysis of haplotypes, which were computationally inferred from genotype data, also revealed statistically significant differences in haplotype distribution between case subjects and control subjects. CONCLUSIONS: We report new associations between several TNF-alpha SNPs and susceptibility to cervical cancer that support the involvement of the TNF- alpha promoter region in development of cervical cancer.

Adolescent↗

PubMed2006

Investigation of a new diagnosis of multidrug-resistant, dual-tropic HIV-1 infection--New York City, 2005.

In December 2004, infection with a strain of multidrug-resistant (MDR), dual-tropic human immunodeficiency virus (HIV)-1 was newly diagnosed in a man aged 46 years in New York City (NYC). The man (i.e., the index patient) had no history of antiretroviral treatment and reported having sex with multiple named and anonymous male partners, using crystal methamphetamine, and engaging in unprotected insertive and receptive anal intercourse. He had rapid progression to acquired immunodeficiency syndrome (AIDS) after experiencing signs and symptoms of acute HIV infection. The case was reported to the New York City Department of Health and Mental Hygiene (NYCDOH) in late January 2005 and has been described previously. This report describes the public health investigation of the index patient's reported contacts and a review of viral genetic sequencing (genotype) results from other HIV-infected patients in the NYC region to estimate the prevalence of this strain of HIV. The investigation, conducted by NYCDOH, Connecticut Department of Public Health, Aaron Diamond AIDS Research Center, New York State Department of Health, and CDC, identified three other patients with similar risk factors who engaged in high-risk sexual activity at the same time and in the same venues as the index patient and who were infected with a genotypically homologous strain of HIV. The findings demonstrate the usefulness of population-based reporting of HIV genotyping data to identify exact matches of new HIV mutations associated with drug resistance and to determine their characteristics and public health importance. The findings also demonstrate the continued risk for HIV transmission among men who have sex with men (MSM) through high-risk behaviors and the need to find effective methods to prevent HIV transmission in this population.

Anti-HIV Agents↗

PubMed2002

Single nucleotide polymorphism array analysis of flow-sorted epithelial cells from frozen versus fixed tissues for whole genome analysis of allelic loss in breast cancer.

Analysis of allelic loss in archival tumor specimens is constrained by quality and quantity of tissue and by technical limitations on the number of chromosomal sites that can be efficiently evaluated in conventional analyses using polymorphic microsatellite markers. Newly developed array-based assays have the potential to yield genome-wide data from small amounts of tissue but have not been validated for use with routinely processed specimens. We used the Affymetrix HuSNP assay, composed of 1494 single nucleotide polymorphism sites, to compare allelic loss results obtained from both formalin-fixed and frozen breast tissue samples. Tumor cells were separated from normal epithelia and nonepithelial cells by dissection and bivariate cytokeratin/DNA flow sorting; normal breast cells from the same patient served as constitutive normal. Allele results from the HuSNP array averaged 96% reproducibility between duplicates and were concordant between the fixed and frozen normal samples. We also analyzed DNA from the same samples after whole-genome amplification (primer extension preamplification). Although overall signal intensities were lower, the genotype data from the primer extension preamplification material was concordant with genomic DNA data from the same samples. Results from genomic normal tissue DNA averaged informative single nucleotide polymorphism at 379 (25%) loci genome-wide. Although data points were clustered and some segments of chromosomes were not informative, our data indicated that the Affymetrix HuSNP assay could provide an efficient and valid genome-wide analysis of allelic imbalance in routinely processed and whole genome-amplified pathology specimens.

Breast Neoplasms↗