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PubMed2000

Galactose breath testing distinguishes variant and severe galactose-1-phosphate uridyltransferase genotypes.

A galactose breath test that quantitates [1-(13)C]galactose conversion to 13CO2 provides information on the whole body galactose oxidative capacity. As there is little information on the relationship between whole body oxidation and the genotype in patients with galactosemia, we measured the 13CO2 excretion for 2 h after administration of [1-(13)C]galactose in 37 patients (3-48 y old) with galactose-1-phosphate uridyltransferase (GALT) deficiency and 20 control subjects (3-37 y old). Eleven patients with the common Q188R/Q188R genotype and no detectable erythrocyte GALT activity eliminated <2% of a bolus of [1-(13)C]galactose as 13CO2 compared with 8.47 to 28.23% in controls. This defines a severe metabolic phenotype. Seven patients with one Q188R allele and a second mutant allele such as L195P, E308K, V151A, M142K, or Q344K and one patient with a K285N/unknown genotype also released <2% as 13CO2 in 2 h. The presence of N314D or S135L as the second mutant allele does not impair total body galactose oxidation, as individuals with the GALT genotype of Q188R/N314D, K285N/N314D, and Q188R/S135L had normal 2-h galactose breath tests. Subjects with S135L/S135L, N314D/N314D, S135L/deltaT2359 as well as other rarer genotypes such as R258C/Y209C, E203K/IVSC-N314D, K285N/T138M, Q188R/D113N, S135L/F171S, R148W/N314D, and IVSC-N314D/N314D oxidized galactose comparable to controls. The dissociation of residual erythrocyte GALT activity and whole body galactose oxidative capacity is exemplified by blacks with a S135L/S135L genotype and absent erythrocyte GALT activity. An oral 2-h [1-(13)C]galactose breath test distinguishes severe and variant GALT genotypes and enables delineation of the extent of impaired galactose metabolism in an array of patients who possess diverse GALT mutations. It may prove to be useful in establishing whether a patient is capable of manifesting disease similar to patients with a Q188R/Q188R genotype.

Adolescent↗

PubMed2005

Population genotyping of hepatitis C virus by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analysis of short DNA fragments.

BACKGROUND: Identifying hepatitis C virus (HCV) genotypes has become increasingly important for determining clinical course and the outcome of antiviral therapy. Here we describe the development of restriction fragment mass polymorphism (RFMP) analysis, a novel matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) assay suitable for high-throughput, sensitive, specific genotyping of multiple HCV species. METHODS: The assay is based on PCR amplification and mass measurement of oligonucleotides containing genotype-specific motifs in the 5' untranslated region, into which a type IIS restriction endonuclease recognition was introduced by PCR amplification. Enzymatic cleavage of the products led to excision of multiple oligonucleotide fragments representing variable regions whose masses were determined by MALDI-TOF MS. RESULTS: The RFMP assay identified viral genotypes present at concentrations as low as 0.5% and reliably determined their relative abundance. When sera from 318 patients were analyzed, the RFMP assay exhibited 100% concordance with results obtained by clonal sequencing and identified mixed-genotype infections in 22% of the samples, in addition to several subtype variants. CONCLUSIONS: The RFMP assay has practical advantages over existing methods, including better quantitative detection of mixed populations and detection of genotype variants without need for population-based cloning, enabling reliable viral genotyping in laboratories and efficient study of the relationship between viral genotypes and clinical outcome.

5' Untranslated Regions↗

PubMed2000

Susceptibility to hepatocellular carcinoma associated with null genotypes of GSTM1 and GSTT1.

AIM:In order to study the association between the null genotypes of GSTM1 and GSTT1 and the genetic susceptibility to hepatocellular carcinoma (HCC).METHODS:The genotypes of GSTM1 and GSTT1 of 63 cases of HCC and 88 controls were detected with the multiple PCR technique.RESULTS:The frequency of GSTM1 null genotype was 57.1% among the cases, and 42.0% among the controls, the difference being statistically significant (X(2) = 3.35, P = 0.067), but X(2) value approaching the significance level. The odds ratio was 1.84 (95% CI = 0.91-3.37). The frequency of GSTT1 non-null genotype was 87.3% among the cases and 62.5% among the controls, the difference being statistically significant (X(2) = 11.42, P = 0.0007274). The odds ratio was 4.13 (95% CI = 1.64-10.70).According to the cross analysis, the GSTT1 non null genotype was more closely associated with HCC than GSTM1 null genotype, and these two factors play an approximate additive interaction in the occurrence of HCC.CONCLUSION:The persons with GSTM1 null genotype and GSTT1 non-null genotype have the increased risk to HCC.

Journal Article↗

PubMedDate not supplied

[Occurrence of markers, distribution of genotypes and risk factors for viral hepatitis C among some groups of the population in the Novosibirsk region].

The occurrence of markers, genotypic variability of isolates and risk factors for viral hepatitis C (HCV) were studied in 4 groups of residents of the Novosibirsk region (altogether 2,000 persons). Anti-HCV IgG were detected within the range from 4.6% among medical personnel to 48% among the patients of the drug-abuse clinic. The detection rate of HCV RNA in seropositive samples varied from 79.3% to 86.3%. The determination of genotype was carried out for 388 isolates: 1b--50.3%, 2a--4.4%, 2c--0.3%, 3a--44.8%. The highest risk indices with respect to HCV among the residents of the region were linked with the drug use (OR=77.5; p<0.05) as well as with risky behavior and low social status. The elevated numbers of seropositive persons were detected among unemployed (OR=16.3), alcohol abusers (OR=3.9), persons having more than 4 sex partners in their lifetime (OR=4.3) and persons having homosexual contacts (OR=6.6). In some groups blood transfusions also played a definite role in the transmission of HCV. In the analysis, carried out separately for two different genotypes the intravenous use of drugs was perceptibly stronger linked with VHC of genotype 3 (OR=85.5) in comparison with HCV of genotype 1 (OR=49.3) and genotype 2 (OR=41.1). Genotype 1 prevailed in the older age group and genotype 3, among young people.

Adolescent↗

PubMed1997

Influence of GSTM1 and NAT2 genotypes on placental DNA adducts in an environmentally exposed population.

The placenta bulky DNA adducts have been studied in relation to metabolic genotypes for glutathione S-transferase M1 (GSTM1) and N-acetyl transferase 2 (NAT2) in 158 mothers (113 nonsmokers and 45 smokers) living in two regions with different annual average air pollution levels of sulphur dioxide, nitrogen oxides, particulate matter < 10 microns, and polycyclic aromatic hydrocarbons. One region was the district of Teplice as the polluted industrial region with mines and brown coal power plants, and the other was the district of Prachatice, an agricultural region without heavy industry. DNA adduct levels were determined by using a butanol extraction enrichment procedure of 32P-postlabeling. GSTM1 and NAT2 genotypes were studied by using polymerase chain reaction. The total DNA adduct levels included a diagonal radioactive zone (DRZ) and one distinct spot outside DRZ (termed X), which was detected in almost all placenta samples and correlated with DRZ (r = .682; P < .001). We found the total DNA adduct levels 2.12 +/- 1.46 (0.04-7.70) and 1.48 +/- 1.09 (0.11-4.98) adducts per 10(8) nucleotides for Teplice and Prachatice districts, respectively, indicating significant differences between both regions studied (P = .004). Elevated DNA adduct levels were found in smoking mothers (10 or more cigarettes per day) by comparison with nonsmoking mothers (3.21 +/- 1.39 versus 1.32 +/- 0.88 adducts per 10(8) nucleotides; P < .001). Placental DNA adduct levels in smokers correlated with cotinine measured in plasma (r = .432; P = .003). This relation indicates that cigarette smoking could be predominantly responsible for DNA adduct formation in placentas of smoking mothers. DNA adduct levels were evaluated separately for non-smokers (1.50 +/- 1.00 vs. 1.09 +/- 0.66 adducts/10(8) nucleotides for the Teplice and Prachatice districts, respectively; P = .046) and smokers (3.35 +/- 1.47 vs. 2.91 +/- 1.20 adducts/10(8) nucleotides for Teplice and Prachatice districts, respectively; P = .384) to exclude the effect of active cigarette smoking on the district variation. These findings indicate that the effect of the environmental pollution in cigarette smokers is practically overlapped by tobacco exposure. No seasonal variation was observed for DNA adduct levels in the overall population studied and no relation between total DNA adduct levels in placenta and levels of vitamins A, C, and E in venous and cord blood was found. A positive GSTM1 genotype was detected in 78 subjects, while negative GSTM1 genotype was found in 80 subjects. Higher DNA adduct levels were detected in the group with GSTM1-negative genotype by comparison with GSTM1-positive genotype (2.05 +/- 1.30 vs. 1.66 +/- 1.39 adducts/10(8) nucleotides; P = .018). This finding is more pronounced in the Teplice district (2.33 +/- 1.36 vs. 1.88 +/- 1.56 adducts/10(8) nucleotides; P = .053) than for the Prachatice district (1.61 +/- 1.09 vs. 1.36 +/- 1.10 adducts/10(8) nucleotides; P = .248) and for nonsmokers (1.45 +/- 0.82 vs. 1.18 +/- 0.93 adducts/10(8) nucleotides; P = .029) more than for smokers (3.45 +/- 1.14 vs. 2.95 +/- 1.62 adducts/10(8) nucleotides; P = .085). Significant district and seasonal differences were found in subgroups with GSTM1-negative genotype. DNA adduct levels in placentas of the GSTM1-negative subgroup were higher in mothers living in the polluted district of Teplice than in Prachatice (P = .012). The adduct levels in placentas sampled in the summer period were higher than in the winter period in the GSTM1-negative population (P = .006). No effect of the NAT2 genotype on DNA adduct levels was observed.

Adolescent↗

PubMed2025

Development and application of a novel beta-tubulin genotyping tool reveals host-specific transmission cluster in Balantioides coli.

Balantioides coli is a zoonotic ciliated protozoan that infects humans and other mammals. Conventional and ITS-based genotyping approaches have limitations that hinder precise molecular epidemiological investigations. The objective of this study was to develop a new β-tubulin gene-based approach to enhance the detection and genotyping of B. coli. We performed single-cell isolation and whole-genome sequencing on two B. coli isolates from pigs and two from guinea pigs. We then used the β-tubulin gene sequences to design PCR primers for the new genotyping assay. We validated the assay using 56 ITS-confirmed B. coli-positive fecal DNA samples from pigs, cattle, sheep, and guinea pigs. Phylogenetic analyses were conducted using both β-tubulin and ITS sequences. The β-tubulin-based nested PCR assay exhibited 100% detection efficiency and greater specificity than ITS-based methods. Phylogenetic analysis of the β-tubulin gene sequences classified B. coli into three genotypes (I-III). Genotype III appears to be specific to guinea pigs. Genotypes I and II were found across multiple hosts, indicating potential cross-species transmission. Of the five full-length B. coli β-tubulin sequences obtained in this study, 264 polymorphic sites (19.8%) were identified, including both synonymous and non-synonymous mutations. Frequent recombination events within the β-tubulin locus were detected, indicating substantial genetic diversity. Therefore, the β-tubulin gene is a robust marker for genotyping and epidemiological studies of B. coli. The novel nested PCR assay overcomes the limitations of ITS-based methods and has produced data revealing previously unrecognized genetic diversity and host specificity patterns of B. coli.

Tubulin↗

PubMed1996

Apolipoprotein E genotype determines survival in the oldest old (85 years or older) who have good cognition.

OBJECTIVE: To quantify the influence of apolipoprotein E (APOE) polymorphism on cognition and survival in a population sample aged 75 years or older. DESIGN: The Kungsholmen Project established a cohort of 1810 residents in a district in Stockholm, Sweden, aged 75 years or older in 1987. Information on cognition at cohort inception is available for all subjects. Subjects were followed up for mortality to January 1, 1995. SUBJECTS: Included in this study are 1077 subjects (of 1124 genotyped for APOE) with the common epsilon 2/3, epsilon 3/3, and epsilon 3/4 APOE genotypes. RESULTS: The odds of cognitive impairment for the epsilon 3/4 vs epsilon 3/3 genotype declined with age: 4.8 for age 75 through 79 years; 1.7 for age 80 through 84 years; and 1.0 (i.e., no association) for age 85 years or older. Despite this association, APOE polymorphism did not significantly predict survival in subjects younger than 85 years, nor did it predict survival in subjects 85 years or older who were cognitively impaired. Instead, survival varied fourfold with respect to APOE polymorphism in those 85 years or older who had good cognition: Mortality in subjects with the epsilon 2/3 genotype was half that in those who carried the epsilon 3/3 genotype (hazard ratio, 0.5; 95% confidence interval, 0.2 to 0.9), and mortality in subjects with the epsilon 3/4 genotype was twice that in those who carried the epsilon 3/3 genotype (hazard ratio, 2.0; 95% confidence interval, 1.1 to 3.5). This fourfold variation resulted in 2-year differences in survival. CONCLUSIONS: The minor sequence variation in the apolipoprotein E isoforms resulted in a fourfold difference in the risk of death among the oldest old (age > or = 85 years) with good cognition. The observed variation in mortality was unlikely to have been caused by cognitive impairment, as APOE polymorphism was not a risk factor for cognitive impairment in this age group.

Age Factors↗

PubMed1998

Apolipoprotein E genotype and deposits of Abeta40 and Abeta42 in Alzheimer disease.

OBJECTIVE: To examine the differential deposition of amyloid beta (Abeta) peptide isoforms Abeta40 and Abeta42 in the Alzheimer disease (AD) brain in relation to the apolipoprotein E (APOE) genotype. BACKGROUND: The APOE epsilon4 genotype is an inherited risk factor for AD and is associated with increased deposition of Abeta protein in the cerebral cortex. Previous data from familial AD due to mutations in presenilin 1 and presenilin 2 genes and the amyloid precursor protein suggest that the long form of Abeta peptide, Abeta42, is selectively increased in these circumstances. Herein, we examine whether APOE genotype influenced the species of Abeta peptide deposited. DESIGN AND METHODS: The amount of Abeta40, Abeta42, and total Abeta deposited in immunostained temporal lobe tissue of 28 cases of AD of known APOE genotype was determined. RESULTS: Individuals with the APOE epsilon4 genotype (APOE epsilon4/4) were associated with both increased Abeta40 (P<.05) and Abeta42 (P<.05) compared with individuals without the APOE epsilon4/4 genotype. CONCLUSION: Our results differ from the data from AD due to mutations in presenilin 1 and presenilin 2 genes and the amyloid precursor protein and suggest that the APOE epsilon4 genotype mediates increased Abeta deposition by a mechanism that differs from that found in other genetic causes of AD.

Aged↗

PubMed1994

K-ras-2 topographic genotyping of pancreatic adenocarcinoma.

OBJECTIVE: To determine the frequency distribution of K-ras-2 point mutation genotypes in pancreatic adenocarcinoma and to evaluate the effectiveness of K-ras-2 genotyping as a means to predict localized disease and potential long-term survival. DESIGN: Topographic genotyping from archival formalin-fixed, paraffin-embedded large- and biopsy-sized tissue specimens as well as cytologic fluid using polymerase chain reaction products and direct sequencing together with clinicopathologic and statistical analysis. SETTING: Tertiary care medical center with molecular diagnostics pathology laboratory. PATIENTS: Patients treated between 1988 and 1993 at Rhode Island Hospital, Providence, yielding 55 primary and 56 metastatic specimens of pancreatic adenocarcinoma. RESULTS: Each primary pancreatic adenocarcinoma was found to contain one of eight specific genotypes that was maintained in all metastatic deposits of that individual tumor. Primary adenocarcinomas confined to the pancreatic bed at diagnosis were predominantly of a normal genotype (56% [14/25]). Pancreatic adenocarcinomas progressing to distant hematogenous metastasis were almost exclusively mutated (88% [7/8]; P < .005). Patients undergoing pancreatic resection (Whipple's operation) and having a normal K-ras-2-genotype (58% [11/19]) had a significantly longer survival (21.3 months) than similar patients with mutated tumors (8.2 months). CONCLUSIONS: The findings support the feasibility of K-ras-2 topographic genotyping to identify potentially indolent disease and suggest a potentially useful role in the preoperative evaluation of pancreatic adenocarcinoma.

Adenocarcinoma↗

PubMed2026

Management and Consequences of Genotype-Positive Familial Hypercholesterolemia.

IMPORTANCE: Familial hypercholesterolemia (FH) is a common genetic condition that causes hypercholesterolemia and increased risk for premature atherosclerotic cardiovascular disease (ASCVD). The prevalence, management, and consequences of genetically confirmed FH across the US are poorly understood. OBJECTIVE: To identify genotype-positive FH in a national US cohort and describe its prevalence, consequences, and lipid-lowering management. DESIGN, SETTING, AND PARTICIPANTS: In the All of Us (AoU) cohort study, whole-genome sequencing and phenotypic data from US adult participants enrolled between May 2018 and July 2022 were analyzed to identify and study genotype-positive FH. Data were analyzed between May 2024 and May 2025. EXPOSURE: FH variants (pathogenic or likely pathogenic) in LDLR, APOB, and PCSK9 genes were manually classified with standard criteria. MAIN OUTCOMES AND MEASURES: The primary outcomes were demographic characteristics, lipid measurements, ASCVD, and prevalence of FH and noncarriers in AoU. Lipid management was then characterized among individuals with FH through lipid-lowering therapy (LLT) documentation and guideline-based low-density lipoprotein cholesterol (LDL-C) targets. RESULTS: A total of 245 388 participants were included, with mean (SD) age of 56.5 (16.9) years and 145 563 female participants (59.3%). Genotype-positive FH was identified in 865 participants (prevalence, 0.35%; 95% CI, 0.33%-0.38%; 1 in 287 participants). Among individuals with genotype-positive FH, 349 (40%) were prescribed statins, and 332 (38.4%) had LDL-C measured. Coronary artery disease, peripheral artery disease, and transient ischemic attack or stroke were significantly more common in genotype-positive FH carriers compared to noncarriers (coronary artery disease: odds ratio [OR], 2.91; 95% CI, 2.34-3.58; peripheral artery disease: OR, 1.51; 95% CI, 1.16-1.96; and transient ischemic attack or stroke: OR, 1.54; 95% CI, 1.11-2.09). Only 30.1% of participants positive for FH variants had LDL-C less than 100 mg/dL at their most recent result compared to 48.2% of noncarriers (P < .001). Of the total participants with ASCVD and LLT prescription, significantly fewer individuals with FH met the secondary prevention LDL-C target (<70 mg/dL; 19.33% vs 43.12%; P < .001) compared to noncarriers. CONCLUSIONS AND RELEVANCE: This cohort study finds a prevalence of genotype-positive FH in All of Us participants of 0.35% (95% CI, 0.33%-0.38%), with state-level variation. A minority of individuals with genotype-positive FH met guideline-recommended LDL-C targets and had increased rates of ASCVD.

Humans↗

PubMed1996

Characterization of a new genotype II hepatitis delta virus from Taiwan.

Three genotypes of HDV, which may be associated with different clinical pictures and epidemiological patterns, have been identified. In contrast to Type I and Type III HDV, both of which have multiple isolates, Type II HDV so far includes only a single isolate (Japan-1) from a low prevalence area (Japan). Recently, Type II has been reported to be the predominant genotype in Taiwan, which is also a low prevalence area, and is associated with less aggresive disease than Type I. However, the sequence and structure of these viruses have not been characterized. The complete characterization of a second member (Taiwan-3 isolate) of the Type II HDV from Taiwan is reported. These two Type II HDV isolates (Taiwan-3 and Japan-1) have 93.8% nucleotide homology and 89.3% amino acid homology, respectively. These shared sequences establish the common characteristics of Type II viruses. Sequence comparisons of various HDV genotypes show that the autocatalytic region of the RNA is relatively conserved between Type I and Type II (88.5-95.6% homology) but is significantly divergent in Type III (76.8-80.3% homology). The hypervariable region (nucleotides 1602-658) of RNA, however, is heterogeneous (64.9-73.0%) among all three genotypes. The delta antigen sequence is also very heterogeneous (64.9-73.0%). Most strikingly, the C-terminal sequence (19 amino acids) of the large delta antigen is almost completely different in each of the three genotypes. The heterogeneity in this region of three HDV genotypes may be a basis for their different biological properties, and the nucleotide sequences of this region can be used to differentiate the different genotypes of HDV. The consensus sequence in the four previously identified conserved domains of HDV RNA is defined more precisely.

Adult↗

PubMed1996

Discrepancy of hepatitis C virus genotypes as determined by phylogenetic analysis of partial NS5 and core sequences.

The use of phylogenetic analyses of partial NS5 and core regions for hepatitis C virus (HCV) genotyping was evaluated by analysing seven Honduran and 24 European HCV strains. Core primers were designed with which HCV genotypes 1, 2, and 3 were readily amplified. The reliability of phylogenetic analysis of a 111-bp core sequence was verified by comparing the typing results with those obtained using the whole core gene of 52 reference strains. Accordant genotypes (1a, 1b, 2b, and 3a) were obtained when phylogenetic analyses were undertaken on both the partial core and a 222-bp NS5 sequence in all of the European HCV strains. Genotypes 1a, 1b, and 3a were identified among the Honduran strains by phylogenetic analysis of the partial NS5 sequence. Interestingly, two of three Honduran type 3a strains, as determined by the NS5 sequence analysis, turned out to be type 1a by core sequence analysis. These two strains were also classified as type 1a, but not 3a, by a core type-specific PCR. Furthermore, the E2/NS1 regions were similar to HCV-PT, a representative strain of genotype 1a. The results indicate that chimeral HCV strains exist, although in most cases a good concordance is found when phylogenetic analysis of partial core and NS5 sequences are used for genotyping. This finding should be taken into account when HCV is genotyped by phylogenetic analysis of a partial HCV sequence from a single genomic region.

Amino Acid Sequence↗

PubMed1996

Genotypes of hepatitis C virus in Nigeria.

A pilot survey of hepatitis C virus (HCV) infection in Nigeria was carried out on healthy adult blood donors and children of preschool age. Sixteen of 200 (8%) donors were positive for antibodies using a second generation enzyme-linked immunosorbent assay (ELISA) but all of the children were negative. Supplementary testing of the ELISA-positives using a recombinant immunoblot assay (RIBA-2) confirmed the presence of antibody in four and two others were indeterminate. Four of the anti-HCV-positive sera and one found positive by ELISA but which was negative by RIBA-2 were found to be positive for HCV RNA using reverse transcriptase-polymerase chain reaction (RT-PCR) and primers specific for the 5' untranslated region (5'UTR) of the HCV genome. The NS5 and core regions also were amplified and the PCR products from all three regions were sequenced. Sequences from the 5'UTR could be divided into two groups: one group comprised three isolates with greater than 95% sequence identity with published sequences of genotype 1 and the other comprised two isolates with greater than 93% sequence identity with genotype 4. Analysis of three sequences amplified from the NS5 region confirmed this assignment to genotypes 1 and 4. Pairwise comparisons of the NS5 region sequences with representatives of 1a, 1b, 1c (for the first group) and 4a-4h (for the second group) show the first group to include subtypes classifiable as 1a and a novel sequence and the second group to include a novel sequence within genotype 4. Sequence analysis of the core region was consistent with this interpretation. These data confirm the presence of at least two major HCV genotypes in Nigeria (genotypes 1 and 4) and we report two novel sequences which have been designated provisionally as genotypes 1d and 4i.

Adult↗

PubMed1997

Mutations in the NS5A gene of hepatitis C virus in North American patients infected with HCV genotype 1a or 1b.

Previous studies from Japan have described an association between a conserved sequence within the hepatitis C virus (HCV) genome and resistance to interferon (IFN) therapy for patients infected with HCV genotype 1b [Enomoto et al. (1995): Journal of Clinical Investigation 96: 224-230; Enomoto et al. (1996): New England Journal of Medicine 334:77-81]. The present study examines amino acid sequences surrounding the putative Interferon Sensitivity Determining Region (ISDR) of the NS5A gene of HCV in 21 North American patients with genotype 1a or 1b infection receiving recombinant IFN therapy. The ISDR consensus or intermediate pattern was observed in 13 of 14 NS5A clones from North American patients infected with genotype 1b. However, we found no evidence of the consensus ISDR sequence in any NS5A clones isolated from 15 patients with genotype 1a infection. In select cases, gel shift analysis showed no significant changes in the clonal frequency of the putative ISDR domain of HCV genotype 1a or 1b infected patients who were either nonresponsive to IFN therapy, or relapsed following withdrawal of IFN therapy. These results suggest that a conserved ISDR domain is neither associated with, nor responsible for, IFN resistance in North American patients infected with HCV genotype 1a, and demonstrate a need for further investigation into the reported association between ISDR consensus sequences and IFN resistance in genotype 1b clones.

Amino Acid Sequence↗

PubMed1999

Hepatitis delta virus genotype IIb predominates in an endemic area, Okinawa, Japan.

Hepatitis delta virus (HDV) infection is relatively common in the Miyako Islands, Okinawa, Japan, where the infection has been reported to be associated with low pathogenicity. HDV RNA extracted from each of 6 patients with HDV-related chronic liver disease living in the islands was amplified by reverse transcription-polymerase chain reaction and examined genetically to determine the HDV genotype. All isolates from the 6 patients were classified as genotype II by the neighbor-joining method. However, these isolates had relatively low homology (75-81%) to the HDV genotype II isolate reported from Japan, and showed relatively high identity (83-95%) to the novel genotype II isolate (HDV genotype IIb) recently reported from Taiwan. Phylogenetic analysis showed that the 6 isolates form a novel group within HDV genotype II. Furthermore, there was notable variation in sequence among the 6 isolates compared with the relatively close clustering of HDV isolates within limited areas (e.g., United States, Archangelos, Turkey, Albania, Peru). HDV genotype II in the Miyako Islands is therefore unique, and HDV infection may have been introduced at a relatively early time in this area.

Adult↗

PubMed1999

Anti-HCV RIBA/LiaTek reactivity and HCV genotype in EIA-negative patients with viremia.

Individuals infected with hepatitis C virus (HCV) usually produce anti-HCV antibodies detectable by enzyme immunoassay (EIA); however, in certain viremic cases this antibody does not appear. To investigate whether anti-HCV in these cases is detectable by Western blot (WB), 38 HCV RNA positive/anti-HCV EIA-negative sera were tested by RIBA 3.0 or LiaTek III. The HCV genotypes (INNO-LiPA) were analyzed to determine whether the variance in these genotypes can be the reason for the late, weak antibody production or its absence. As the control group, 282 EIA-positive/HCV RNA-positive patients were examined. A single band reactivity of various intensities by RIBA or LiaTek was observed in 16/38 EIA negative sera. Positive results with NS3 were detected in 4 sera and weak positive (+/-) with core, NS3, and NS5 in 5, 6, and 1 sera, respectively. In 3 cases with anti-NS3, the seroreversion was observed in follow-up. The distribution of genotypes in anti-HCV-negative versus anti-HCV-positive groups was: 1b alone, 50.0% vs. 78.0%; 3a alone, 13.2% vs. 15.6%; and mixed (1b+3a), 36.8% vs. 5.0%, respectively. The follow-up studies showed that viremia was lost spontaneously in 12/35 patients. In some patients infected with two genotypes, the spontaneous loss of the 3a genotype was observed. The study showed that WB tests are useful for serological confirmation of HCV infection in some EIA negative/HCV RNA-positive patients but, because seroreversion may occur, sequential sera samples should be tested. No unusual HCV genotype was detected in anti-HCV-negative/HCV RNA-positive cases, but the frequency of mixed infection with the 1b+3a genotypes in this group was found to be higher than that in anti-HCV-positive hepatitis patients.

Blotting, Western↗

PubMed1999

Glutathione S-transferase T1 and M1 genotypes in normal mucosa, transitional mucosa and colorectal adenocarcinoma.

Gene codings for glutathione S-transferase T1 (GSTT1) and M1 (GSTM1) are polymorphic in humans with null genotypes present in approximately 20 and 50%, respectively. A significant excess of homozygous null GSTT1 and GSTM1 genotypes has been demonstrated among individuals with certain types of cancers. This finding suggests that GSTT1 and GSTM1 may play a role in tumour susceptibility. However, reports concerning colorectal cancer susceptibility are controversial. In the present study, we used a multiplex polymerase chain reaction (PCR) approach to identify and analyze simultaneously the genotypes of both the genes in 99 patients with colorectal cancer and 109 healthy controls. Compared with the control group, a significant excess of homozygous null genotypes for GSTT1 was found in normal mucosa among the cancer patients, but not for GSTM1. Both genes were more frequently deleted in tumours than in corresponding normal mucosa. Furthermore, GSTT1 null genotype in tumour tissue, was significantly related to old age and to poor differentiation of tumours. GSTM1 null genotype in tumour was more frequent in the rectal tumours compared with tumours of left colon and right colon. Our results suggest that individuals with GSTT1 null genotype may be genetically predisposed for an increased risk of developing colorectal cancer. Allele loss in tumour tissue, which reflects genetic instability, may be considered as a marker for evaluating clinico-pathological characteristics of the cancer patients.

Aged↗

PubMed2002

Association between asbestos exposure, cigarette smoking, myeloperoxidase (MPO) genotypes, and lung cancer risk.

BACKGROUND: As observed in tobacco-associated carcinogenesis, genetic factors such as the polymorphic metabolic/oxidative enzyme myeloperoxidase (MPO) could modulate individual susceptibility to asbestos-associated carcinogenesis. METHODS: RFLP-PCR analysis identified the MPO genotypes in 375 Caucasian lung cancer cases and 378 matched controls. An epidemiological interview elicited detailed information regarding smoking history and occupational history and exposures. RESULTS: Asbestos exposure was associated with a significantly elevated risk estimate (OR = 1.45; 95% CI 1.04-2.02). On stratified analysis, we found the MPO genotypes modified the effect of asbestos exposure on lung cancer risk. Specifically, G/G carriers who were exposed to asbestos had an odds ratio (OR) of 1.72 (95% CI; 1.09-2.66), while A-allele carriers (G/A + A/A) exposed to asbestos exhibited a reduced OR of 0.89 (95% CI; 0.56-1.44). The OR was further reduced to 0.73 (0.49-1.06) for A-allele carriers not exposed to asbestos. A similar trend was observed for the joint effects between the MPO genotypes and pack-years smoking. Next, all three risk factors (MPO genotypes, asbestos exposure, and smoking) were analyzed simultaneously for joint effects. Heavy smokers with the G/G genotype and a history of asbestos exposure demonstrated a statistically significant elevated risk estimate (OR = 2.19; 95% CI 1.16-4.11), while the A-allele carriers with the same exposure profile were at a lower risk for lung cancer (OR = 1.18; 95% CI 0.58-2.38). The A-allele genotypes demonstrated similar protective effects for the other three exposure profiles. CONCLUSIONS: For a similar level of exposure to established carcinogens, individuals with the MPO A-allele genotypes appear to have a reduced risk of lung cancer.

Aged↗