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PubMed2006

Histopathology of chronic hepatitis C in relation to virus genotype.

BACKGROUND/AIM: The natural history of hepatitis C virus (HCV) infection is variable and the factors determining the course of the illness are unclear. There are geographical variations in the distribution of different HCV genotypes, and some of them are related to the specific infection routes. Regarding our country, the dominant genotype is genotype 1b. It is unclear and still remains a question whether the distinct histopathological manifestations are related to the particular genotypes of HCV. Thus, the aim of this study was to determine whether the distinct histopathological manifestations of HCV infection might be in relation to the individual virus genotype. METHODS: In this study we examined 126 patients with chronic HCV infection regarding the histopathological features, demographic data, and virus genotype. The observed groups of patients were predominantly infected with HCV genotypes 1b and 3a. RESULTS: In this study we found that the patients infected with HCV genotype 1b had more frequently moderate or severe necroinflammatory activity of the disease, significantly higher grading score as compared with other genotypes (p < 0.0001). A higher degree of fibrosis was, also, more common in the patients infected with genotype 1b of HCV as compared with other genotypes (p < 0.05). There were no significant correlations between the necroinflammatory activity of the disease and the stage of fibrosis in 1b, 4 and mixed genotypes. CONCLUSION: The present data support the hypothesis that distinct genotypes of HCV are associated with the particular histopathological manifestation of the disease.

Adolescent↗
PubMed1997

Hepatitis C virus genotypes in Korea and their relationship to clinical outcome in type C chronic liver diseases.

OBJECTIVES: The relationship between HCV genotype and the development of more serious liver disease has not been clearly established. This study was to investigate the distribution pattern of HCV genotypes in Korea and their relationship to the viremic level and to progression of chronic liver disease. METHODS: Study population was 217 patients with type C chronic liver disease. They were divided into 4 groups; 83 patients with near-normal ALT (group 1), 64 patients with elevated ALT (group 2), 20 patients with decompensated liver cirrhosis (group 3) and 50 patients with hepatocellular carcinoma (group 4). HCV genotypes were determined by reverse transcription polymerase chain reaction (RT-PCR) using mixed primer sets, and then the fidelity of genotyping was confirmed by cloning and sequencing. HCV RNA concentration was measured by quantitative competitive RT-PCR for 23 patients in group 2. RESULTS: The genotypes could be determined in 166 (76%) out of 217 patients. Type 1b and type 2a were predominantly occurring over the other types in somewhat similar frequency (45% and 51%, respectively). The genotype distribution of type 1b and 2a among four different groups showed 42% and 54% in group 1, 49% and 45% in group 2, 53% and 47% in group 3 and 41% and 57% in group 4; thus there was no significant difference in genotype distribution among 4 different disease groups. However, the viremia levels in patients with genotype 1b infection were significantly higher than those with genotype 2a. CONCLUSION: Genotype 2a infection is as prevalent as genotype 1b in Korea, and genotype 2a infection may pose no less risk for progression of disease despite lower replication level than genotype lb infection.

Adolescent↗
PubMedDate not supplied

Interferon treatment for patients with chronic hepatitis C infected with high viral load of genotype 2 virus.

BACKGROUND/AIMS: Interferon treatment is more effective in patients with chronic hepatitis C infected with genotype 2a virus than those with genotype 1b virus. We analyzed patients with chronic hepatitis C treated by interferon in our clinics to develop a more effective regimen of interferon treatment for patients with genotype 2 virus infection. METHODOLOGY: We retrospectively analyzed the virological response of 36 patients with chronic hepatitis C with a high viral load, including 28 cases infected with the genotype 2a virus and 8 cases with the genotype 2b virus. The serum viral load of these patients were 6.0 log copies/mL and higher by the competitive polymerase chain reaction assay method. All patients could be treated with interferon-alpha or -beta for 6 months. Eleven patients were administered 6 million units of interferon-beta once daily for 6 weeks and then thrice weekly (group A). Twelve patients were administered 6 million units of interferon-alpha daily initially for 2 weeks and then thrice weekly (group B), and 10 patients were treated with the same dose of interferon-alpha thrice weekly from the first administration (group C). We decided the criteria of complete remission as the absence of serum HCV-RNA at both points of the end of interferon treatment and 6 months later. RESULTS: For all patients with genotype 2a virus infection, the complete remission, transient response and no response rates were 46.4%, 39.3% and 14.3%, respectively. The complete remission rates in group A, B and C were 100%, 41.7% and 20%, respectively. The transient remission rates in group B and C were 41.7% and 60%, respectively. The no response rates in group B and C were 16.7% and 20%, respectively. All patients with a high viral load of genotype 2a virus showed eradicated serum HCV-RNA virus in group A. The eradication rate of serum HCV-RNA in patients infected with the genotype 2a virus in group A was significantly higher than that of group B (p < 0.02) or group C (p < 0.01). For all patients with genotype 2b virus infection, complete remission, transient remission and no response rates were 12.5%, 50.0% and 37.5%, respectively. The complete remission rate of patients with the genotype 2b virus in group A and group B plus C was 0% and 25.0%, respectively. The eradication rate of patients with the genotype 2a virus in group A was significantly higher than that of patients with the genotype 2b virus (p < 0.01). CONCLUSIONS: These findings suggest that the initial sufficient dose of interferon administration is effective to eradicate serum HCV-RNA in patients with a high viral load of genotype 2a virus in chronic hepatitis C.

Adult↗
PubMed2002

[Distribution of hepatitis B virus genotype in Hunan Province and its clinical significance].

OBJECTIVE: To study the distribution of hepatitis B virus genotype in Hunan Provine and its clinical significance. METHODS: HBV genotype was determined by the restriction fragment length polymorphism analysis in 185 PCR positive patients, including 42 asymptomatic HBV carriers (ASC), 38 chronic mild or moderate hepatitis (CH), 80 fulminant hepatic failure (FHF), and 25 hepatocellular carcinoma (HCC) patients in Hunan Province. RESULTS: Of the 185 patients, 136 (73.5%) were genotype B, and 49 (26.5%) were genotype C. There was a statistical significance in the distribution of genotype B between FHF and ASC, and between HCC and ASC (83.7% vs. 57.1%, 76% vs. 57.1%, P < 0.01, respectively). Vertical transmission and HBeAg positivity were higher in genotype C than in genotype B (38.8% vs. 13.2%, 57.1% vs. 30.9%, respectively, P < 0.001). The ALT value was significantly higher in genotype B than in genotype C (P < 0.001). CONCLUSION: Genotypes B and C exist in Hunan. Genotypes B is the major genotype in this area and associated with the development of severe liver diseases. Genotype C is associated with vertical transmission.

Adolescent↗
PubMed2002

[Nucleotide sequence analysis of new genotype of hepatitis G virus in population at high risk for HCV infection in Guangxi].

OBJECTIVE: To examine the prevalence and the sequence of the genes of new genotypes of hepatitis G virus (HGV) in Guangxi, China. METHODS: Serum samples were collected from 85 intravenous drug abusers (IVDAs), 80 patients with liver diseases (PLDs) and 50 blood donors (BDs). All sera (n=215) were tested by using EIA for HBsAg, anti-HCV and anti-HIV, and by using nested PCR for HGV RNA. In 62 subjects positive for HGV, HGV RNA was sequenced, and a phylogenetic tree was constructed for analyzing genotypes of HGV. RESULTS: HGV RNA was detected in 85 of 215 serum samples (39.53%). The positivity rates for HBsAg, anti-HCV and anti-HIV were 39.07%, 42.79% and 0, respectively. First, 11 nucleotide sequences were determined and the isolates were grouped into three clusters with HGV. 5 of 11 HGV isolates clustered in a distinct phylogenetic branch (genotype Asia) which was different from the described GBV-C and HGV sequences, suggesting the presence of a new genotype of HGV in this locality. Second, 51 nucleotide sequences were determined and analyzed for their genotypes of HGV, and showed genotype GBV-C (3.23%), genotype HGV 30-65% and new genotype (genotype Asia) 64.51%, respectively. CONCLUSIONS: There were subgenotypes in 3 genotypes of HGV; The predominant genotypes of HGV were genotype Asia and genotype HGV among IVDAs, PLDs, and BDs patients in Guangxi, China.

Adult↗
PubMed2005

[Genotyping of hepatitis E virus by PCR combining with single restriction endonuclease analysis].

OBJECTIVE: To develop a simple method for genotyping of hepatitis E virus (HEV) and to investigate HEV genotype distribution in Nanjing area. METHODS: Twenty-seven full HEV sequences currently-available in GenBank were analyzed with MegAlign and MapDraw programs of DNA STAR software. Degenerate primers were designed and applied to amplify a fragment in HEV ORF1 region. HEV genotypes were determined by the size of the PCR products and by single restriction endonuclease analysis. RESULTS: The PCR products of HEV genotype 1 and 2 were 275 bp and 269 bp in size. Distinctively, the PCR products of genotype 3 and 4 were 317 bp and 314 bp in size. Moreover, the PCR products of genotype 1 could be digested by Nae 1, but the products of genotype 2 could not. Distinctively, the PCR products of HEV genotype 3 could be digested by Not 1, but the products of genotype 4 could not. Six HEV reference strains standing for different HEV genotypes were clustered into their own types as predicted. Within 43 HEV IgM-positive clinical specimens collected in Nanjing, 19 were HEV PCR-positive and identified as genotype 4. CONCLUSION: A simple method of PCR combined with single restriction endonuclease analysis is developed for HEV genotyping. This assay allows rapid identification of a large number of HEV isolates directly from clinical specimens. Among patients with hepatitis E in Nanjing, most were infected with HEV genotype 4.

DNA Restriction Enzymes↗
PubMed2004

Clinical and virological differences between hepatitis B virus genotypes B and C: a case-control study.

OBJECTIVE: The pathogenic significance of hepatitis B virus (HBV) genotypes is undefined. The aim of this study was to elucidate the differences in clinical and virologicalfeatures between HBV genotypes B and C by conducting a case-control study in Thai patients who were chronically infected with the virus. PATIENTS AND METHOD: HBV genotyping was assessed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) method in stored sera of 470 patients with chronic hepatitis B. Among these, 65 patients with HBV genotype B were enrolled and matched individually to those with HBV genotype C according to sex, age, and distribution of liver disease which included asymptomatic carrier, chronic hepatitis, cirrhosis and hepatocellular carcinoma. RESULTS: Serum alanine aminotransferase (ALT) was significantly higher in patients with genotype C than those with genotype B. Hepatitis B e antigen (HBeAg) was significantly more frequent in genotype C than genotype B patients (50.8 and 30.8%, respectively, p=0.03), but the levels of HBV DNA were comparable between them. Among patients who were positive for HBeAg, the mean age of genotype C patients tended to be older than genotype B patients. CONCLUSION: The present study demonstrated that patients with HBV genotype C had a significantly higher rate of HBeAg, experienced delayed HBeAg seroconversion and exhibited more severe liver disease compared to those with genotype B.

Adult↗
PubMed2005

[Distribution and clinical significance of hepatitis B virus (HBV) genotypes and subtypes in HBV-infected patients].

OBJECTIVE: To study hepatitis B virus (HBV) genotype and subtype distribution and its clinical significance in HBV-infected patients. METHODS: We used type/subtype-specific primers and PCR to detect HBV genotype and subtype of 445 HBV-infected patients from Beijing, Changchun, Hanchuan Shenzhen, Qingyuan and Nanjing, including 7 acute hepatitis (AH), 36 asymptomatic HBV carriers (ASC), 352 chronic hepatitis (CH), 28 liver cirrhosis (LC), and 22 hepatocellular carcinoma (HCC) cases. Genotyping results were confirmed by PCR product sequencing. RESULTS: Among 445 HBV-infected patients, the proportions of genotype B, C, and B/C were 32.6% (145/445), 53.7% (239/445), and 13.7% (61/445), respectively. In genotype C, 13 (5.4%) were subtype C1, 135 (56.5%) were subtype C2, and the remaining 91 (38.1%) were neither C1 nor C2. In genotype B, 100 (69.0%) were subtype Ba, 25 (17.2%) subtype Bj, and the other 20 (13.8%) were neither Ba nor Bj. In genotype B/C, 15 (24.6%) were Ba/C2, 8 (13.1%) Bj/C2, 6 (9.8%) Ba/C1, 3 (4.9%) Bj/C1, 11 (18.0%) Ba/neither C1 nor C2, 7 (11.5%) Bj/neither C1 nor C2, and 6 (9.8%) neither Ba nor Bj/neither C1 nor C2, 2 (3.3%) neither Ba nor Bj/C1, 3 (4.9%) neither Ba nor Bj/C2. The HBV genotype and subtype distribution we found exhibited significant differences in the various clinical types of HBV infection tested, and showed that genotype C was predominant among patients with liver cirrhosis (78.6%) and hepatocellular carcinoma (86.4%) while genotype B was predominant in asymptomatic carriers (72.2%). In addition, genotype and subtype distribution showed no significant differences between male and female patients, but genotype and subtype distribution showed significant differences in patients positive or negative with HBeAg. CONCLUSION: Subtypes Ba and C2 are predominant in patients with hepatitis B from these 6 cities, and genotype C may be associated with the development of liver cirrhosis and hepatocellular carcinoma.

Genotype↗
PubMed2006

[Hepatitis E virus of different genotypes contains multiple-type antigenic epitopes].

Monoclonal antibodies (McAbs) were prepared against a recombinant protein p166Us derived from US-1 strain of hepatitis E virus (HEV). The immune reactivity of the McAbs to seven p166s derived from different genotypes and subtypes of HEV, which included p166Bur (genotype I a), p166Pak (genotype I b), p166Mor (genotype I c), p166Mex (genotype II), p166Us (genotype III), p166Nz (swine HEV, genotype III) and p166Chn (genotype IV), was tested by an indirect enzyme-linked immunosorbent assay (ELISA) and a Western blotting assay. The immunological relationship between the McAbs and native HEV particles or anti-HEV positive serum samples was analyzed by an antigen-competitive or antibody-competitive ELISA. Totally, six McAb-producible hybridoma cell lines, designated by the name of 4D3, 2E3, 11E11, 12H5, 3A3 and 1F1 respectively, were cloned and obtained in this study. The McAb of 4D3 could react to all of the seven p166 recombinant proteins. This kind of reaction could be inhibited by each of 4 genotypes of native HEV particles or anti-HEV positive serum samples. The McAbs produced by 2E3, 11E11 and 12H5 reacted to p166Us, p166Nz and p166Chn, but did not react to p166Bur, p166Pak, p166Mor and p166Mex. The reaction of McAb of 2E3, as an example of the McAbs of 2E3, 11E11 and 12H5, could be only inhibited by genotype III and IV HEV or anti-HEV positive serum. The McAb of 3A3 could bind to p166Us as well as p166Nz. The McAb produced by 1F1 was reactive to the p166Us only. However, neither of I , II , IV genotype HEV particles or antisera could inhibit both of their reactions to p166Us. The data as mentioned above suggested that there are multiple-type antigenic epitopes such as genotype I, II, III and IV common, III and IV common, and III specific epitopes within HEV ORF2 encoded p166 proteins of different genotypes and subtypes of HEV. Moreover, the antigenic epitopes on recombinant protein p166s and these on native HEV particles possess identical immunological characteristics.

Animals↗
PubMed2007

Genotype and variations in core promoter and pre-core regions are related to progression of disease in HBV-infected patients from Northern Vietnam.

Vietnam is one of the countries with a high rate of hepatitis B virus (HBV) infection, but there are only a few reports about relation of HBV genotypes and mutations to clinical course in Northern Vietnam. The characteristics of HBV and its relationship to clinical outcome in patients from Northern Vietnam were analyzed. Serum samples were collected from 183 HBV-infected Vietnamese patients. They were clinically categorized into 4 groups: hepatocellular carcinoma (HCC), liver cirrhosis (LC), chronic hepatitis (CH), and asymptomatic carriers (ASC). HBV serology, alpha-fetoprotein, HBV genotypes, HBV-DNA level and mutations in the core promoter and pre-core regions of HBV-DNA were examined. The majority of sera contained HBV genotype B (67.8%) and C (27.9%). The median age was matched between genotype B and C (38.2 vs. 42.9 years). The rates of HBeAg seroconversion and G1896A for genotype B were significantly higher than those for genotype C (P<0.05). Genotype C had a higher HBV-DNA level than genotype B. C1858 was frequent, especially in genotype C (62.7%). The most prevalent genotype in ASC and CH was genotype B. The presence of the mutation A1762T/G1764A correlated with disease progression. The triple mutation T1753C/A1762T/ G1764A was quite common and was more prevalent in LC and HCC than in CH and ASC. In Northern Vietnamese, HBV genotypes B and C were prevalent. Genotype C and mutations in the core promoter region were associated with progressive, severe liver diseases.

Adolescent↗
PubMedDate not supplied

Kinetic characterization of acetylator genotype-dependent and -independent N-acetyltransferase isozymes in homozygous rapid and slow acetylator inbred hamster liver cytosol.

Acetyl-coenzyme A (AcCoA)-dependent arylamine N-acetyltransferase (NAT) activity (EC 2.3.1.5) was examined in liver cytosol derived from homozygous rapid acetylator (Bio. 87.20) and homozygous slow acetylator (Bio. 82.73/H) Syrian inbred hamsters. Expression of NAT activity toward p-aminobenzoic acid (PABA), 2-aminofluorene (AF), and 4-aminobiphenyl (ABP) was acetylator genotype-dependent, whereas N-acetyltransferase activity toward isoniazid was acetylator genotype-independent. Two isozymes of NAT activity were partially purified by anion exchange fast protein liquid chromatography from the hepatic cytosol of both homozygous rapid and homozygous slow acetylator hamsters. The first eluting NAT isozyme exhibited a polymorphic expression toward AF, ABP, and PABA although the second eluting NAT isozyme exhibited a monomorphic expression across acetylator genotypes toward the same substrates. Determination of Michaelis-Menten kinetic constants in hepatic cytosol of homozygous rapid and slow acetylator hamsters suggests that PABA, AF, and ABP NAT activities were acetylator genotype-dependent because of catalysis by polymorphic NAT isozyme that is both an apparent Km and Vmax variant, whereas, the acetylator genotype-independent expression of isoniazid NAT activity appeared to result from catalysis via a common monomorphic NAT isozyme in both acetylator genotypes. Additional kinetic studies on the partially purified NAT isozymes of homozygous rapid and slow acetylator hamster liver confirmed that the polymorphic NAT isozyme exhibited a substantially higher apparent maximum velocity in homozygous rapid acetylators than slow acetylators toward PABA, AF, and ABP as well as acetylator genotype-related differences in the apparent Km toward each of these substrates. In contrast, the monomorphic NAT isozyme of both acetylator genotypes showed apparent Vmax levels of NAT activity that did not vary with acetylator genotype. Furthermore, the monomorphic NAT isozyme did not show acetylator genotype-related variations in apparent Km toward the arylamine carcinogens AF and ABP, although differences were noted for PABA and AcCoA. These results suggest that the acetylator genotype-dependent expression of AcCoA-dependent NAT activity in hamster hepatic cytosol toward arylamines is primarily accountable by structural variants (allozymes) of polymorphic NAT under the genetic regulation of the acetylator gene locus. The acetylator genotype-independent expression of isoniazid NAT activity is attributable to a common monomorphic NAT isozyme in both acetylator genotypes.

4-Aminobenzoic Acid↗
PubMed1998

Distribution of hepatitis C virus genotypes among intravenous drug users. A ten-year study in Palermo, Sicily.

A cross-sectional study was carried out on the sera of 88 active intravenous drug users (IVDU) collected between 1985 and 1986 to evaluate the circulation of HCV genotypes in Western Sicily. The patients were grouped by age and classified by their HIV status. Genotype 3a (48.8% of all cases) was most frequently detected, followed by genotype 1a (20.4%) and type 1b (17.0%). No significant differences in HCV genotype distribution were observed between HIV positive and negative individuals. Next, the HCV genotype distribution found in sera samples of IDVUs drawn between 1985 and 1986 was studied and divided into three age groups. The genotype distribution in the younger group was then compared with samples collected ten years later, between 1995 and 1996, from young HIV negative IVDU individuals. A different distribution between HCV genotypes 3a and 1a was found with a relative, though not significant, increase in the detection of genotype 1a (38%). Finally, sera from six IVDUs obtained at three different times over a ten-year period were genotyped for HCV. None of the subjects showed any change in the genotype found at the first sampling throughout the ten years. The results suggest that a) genotype 1a and 3a are the most common among IVDUs in Western Sicily, b) concurrent HIV infection does not seem to influence HCV genotype and c) infected IVDUs harbor almost exclusively one genotype.

Adolescent↗
PubMed1998

[Prevalence of hepatitis C virus genotypes: epidemiology and histologic characteristics].

OBJECTIVE: To analyse the prevalence of HCV genotypes among patients from Gran Canaria and the relation with the routes of viral transmission, date of primoinfection and severity of hepatic lesion. PATIENTS AND METHODS: 179 patients were studied. In 61 patients the date of exposure was determinate. Liver biopsies were obtained in 139 patients. Genotypes were determinate by reverse hybridisation using InnoLiPA genotyping kit (Innogenetics). RESULTS: The distribution of genotypes was: 1b, 114 (63.7%), 1a, 30 (16.7%); 1, 17 (9.5%); 3a, 7 (3.9%); 4c/4d, 6 (3.3%); 2, 1 (0.5%); 2a/2c, 2 (1.1%), 3, 1 (0.5%) and 4f, 1 (0.5%). We did not find any case of coinfection with a second genotype. In univariable analysis, we found statistically differences in sex (78.9% of women infected with genotype 1b compared with 55.1% of men, p < 0.01 and 31.6% of men infected with 1a, 3a and 4c/4d compared with 15.7% of women, p < 0.01) and age (median age in genotype 1b 45 +/- 12 years vs 36 +/- 9 years in the other genotypes, p < 0.01). HCV subtypes 1a and 3a were predominant in patients IVDA (47.6% and 23.85% respectively) and 1b in blood transfusion receptors (71.2%) (p < 0.01). In 40.2% of the patients, the sources of infection were unknown. In the multivariable logistical regression analysis we found the only factor influencing the genotypes distribution was the transmission mechanism (p < 0.001) and sex and age are relationated with the transmission mode. The media infection duration in patients infected with 1b was 22 +/- 11 years vs 9 +/- 6 years in the other genotypes. We found differences in the liver histologic findings and the age of the patient, but not in the different genotypes. CONCLUSIONS: Our study reflects the higher frequency of HCV subtype 1b in our area and a different prevalence of genotypes in relation to mode of transmission. Our results suggest that in our media the liver damage seems to be directly influenced by the age of the patient, but not influenced by HCV genotype.

Adult↗
PubMed2003

Carriers for type II 3beta-hydroxysteroid dehydrogenase (HSD3B2) deficiency can only be identified by HSD3B2 genotype study and not by hormone test.

OBJECTIVE: We investigated adrenal steroidogenic function relevant to 3beta-hydroxysteroid dehydrogenase (HSD3B2) activity in vivo and HSD3B2 genotype in clinically normal family members of patients with HSD3B2 genotype-proven HSD3B2 deficiency congenital adrenal hyperplasia (CAH) to determine whether genotype-proven carriers for HSD3B2 deficiency exhibit decreased enzyme activity analogous to the mildly decreased adrenal 21-hydroxylase activity in the carriers of CYP21 gene mutation. DESIGN/PATIENTS: Nineteen adult family members (ages median/range: 37/19-56 years) including 13 females and six males of six unrelated patients with HSD3B2 genotype-proven HSD3B2 deficiency were studied. MEASUREMENTS: All family members had HSD3B2 DNA analysis and an ACTH stimulation test (Cortrosyn 0.25 mg IV bolus) for determination of adrenal HSD3B activity. RESULTS: Ten of 13 females and five of six males were carriers of a proven or predictably deleterious mutation in one allele of the HSD3B2 gene, which was identified in the probands. ACTH-stimulated levels of 17-hydroxypregnenolone (delta5-17P), 17-hydroxyprogesterone (17-OHP), cortisol (F), dehydroepiandrosterone (DHEA) and androstenedione (delta4-A) and ratios of delta5-17P to 17-OHP, delta5-17P to F and DHEA to delta4-A, as well as increments of delta5-17P and DHEA values (ACTH-stimulated - baseline) in the genotype-proven female carriers (age, mean +/- SD: 36 +/- 6.7 years) and male carriers (age, mean +/- SD: 37 +/- 6.7 years) did not differ significantly from age-matched normal females (35 +/- 5.4 years, n = 20) and normal males (35 +/- 6 years, n = 10), respectively. There were no significant differences in any of the ACTH-stimulated hormonal levels or ratios between the female carriers with a seriously deleterious genotype (n = 5) and the female carriers with mildly deleterious genotypes (n = 5). These hormonal levels and ratios in three genotype-normal females and one genotype-normal male overlapped with those of the carriers. CONCLUSION: These data suggest that normal adrenal HSD3B2 activity is maintained in the genotype-proven carriers because heterodimers of mutant and wild-type HSD3B2 enzymes may be stable and exhibit similar activity compared to homodimers of wild-type enzymes, possibly by a relatively rate-unlimited effect of haplo-wild-type enzyme activity. However, we cannot preclude entirely the possibility of a limited expression of another HSD3B activity under ACTH stimulation contributing to the normal adrenal HSD3B activity in vivo in the HSD3B2 genotype-proven heterozygotes. Which mechanism plays a role in maintaining normal enzyme activity in the heterozygotes remains to be elucidated. The hormone findings in the genotypic-proven carriers for HSD3B2 deficiency also indicate that carriers for this disorder cannot be detected by a hormone test and can only be detected by HSD3B2 genotype study.

3-Hydroxysteroid Dehydrogenases↗
PubMed1997

Evidence that the apolipoprotein E-genotype effects on lipid levels can change with age in males: a longitudinal analysis.

We previously reported that change, with age, in plasma levels of total cholesterol (TC) and LDL cholesterol (LDL-C) differed between apolipoprotein E (APOE) genotypes epsilon 3 epsilon 3 and epsilon 3 epsilon 4, in a sample of 77 older, unrelated males. By use of a larger sample from that cohort, followed longitudinally during 1969-87, the change in TC and in LDL-C, between the epsilon 3 epsilon 3 and epsilon 3 epsilon 4 APOE genotypes, over three exams, was reanalyzed. Additionally, the change in triglycerides (TG) and in HDL-cholesterol (HDL-C), between the epsilon 3 epsilon 3 and epsilon 3 epsilon 4 APOE genotypes-as well as the differences between the epsilon 3 epsilon 3 and epsilon 3 epsilon 2 genotypes, for TC, LDL-C, TG, and HDL-C-were contrasted over the three exams. At exam 1 TG was higher in the epsilon 3 epsilon 4 group than in the epsilon 3 epsilon 3 group (mean age 48 years), and at exams 2 and exam 3 (mean ages 58 and 63 years, respectively) it was similar (P = .009 for the exam-by-genotype-interaction effect in the repeated-measures analysis). A similar trend was seen for TC (P = .03), yet previously detected LDL-C effects were not apparent (P = .46). Those with the epsilon 3 epsilon 2 genotype had higher TG and lower LDL-C and TC at each exam than were seen in those with the epsilon 3 epsilon 3 genotype, although the differences in the values were not always statistically significant. Differences in TC, LDL-C, and TG, between the epsilon 3 epsilon 2-genotype and epsilon 3 epsilon 3-genotype groups, did not significantly change over the three exams. HDL-C levels were relatively stable over the exams; however, the exam-by-genotype interaction was significant for the epsilon 3 epsilon 2 genotype versus the epsilon 3 epsilon 3 genotype (P = .02). The epsilon 4 allele effects on TG and TC changed between longitudinal exams and may be age dependent. Changes, with age, in the effect of the epsilon 3 epsilon 4 genotype on lipids may impact the risk of developing atherosclerotic disease.

Aged↗
PubMed1997

Immune responses to the hepatitis C virus NS4A protein are profoundly influenced by the combination of the viral genotype and the host major histocompatibility complex.

The interaction between the host major histocompatibility complex (MHC) and the genotype of the hepatitis C virus (HCV) was analysed using synthetic full-length non-structural (NS) 4A proteins, residues 1658-1712, of genotypes 1b, 2b, 3a, 4a and 5a. Human and murine antibodies specific for the five NS4A genotypes analysed focused on residues 1688-1707. In immunized B10 H-2 congenic mice, the H-2d, H-2f and H-2s haplotypes were good responders to NS4A, irrespective of the viral genotype. In contrast, the H-2k haplotype was a low or non-responder to all NS4A genotypes, except for genotype 2b. Also, H-2f- and H-2s-restricted NS4A genotype 1b-specific T-cells focused on residues 1670-1679 and 1683-1692, respectively, whereas H-2k-restricted NS4A genotype 2b-specific T-cells focused on the carboxy terminus. Interestingly, H-2f-restricted genotype 1b-specific T-cells did not cross-react with T-cell site analogues of seven other genotypes, whereas the H-2s-restricted, genotype 1b-specific T-cells cross-reacted with genotypes 1a, 4a and 5a. Thus the combination of viral genotype and host MHC profoundly influences the ability to mount an HCV NS4A-specific immune response.

Amino Acid Sequence↗
PubMed1997

Hepatitis C virus replicative levels and efficiency of genotyping by specific PCR and antibody assay.

We studied factors which influence the detection of hepatitis C virus genotypes by the group-specific PCR of the sequence within the core region gene and by the newly developed genotype-specific NS4 antibody assay. Genotyping was performed on 75 hepatitis C virus carriers in Japan, where patients with hepatitis C viremia are exclusively infected with genotype 1b, 2a, and 2b. PCR failed to identify genotypes in 8 (11%) patients, whereas 12 (16%) patients, including the 8 patients mentioned above, could not be genotyped by the serological assay. Serological genotypes showed almost complete agreement with those found by the PCR except that double infection was revealed in only two of the eight patients serologically judged to be coinfected with genotypes 1 and 2. In each assay, disease activity and levels of viremia assessed by a competitive reverse transcription PCR assay were significantly lower in patients infected with untypeable isolates than in those infected with typeable ones (P < 0.01). The PCR could identify the genotypes of isolates from all 64 patients with levels of viremia of > or = 10(6) copies/ml, and the genotype-specific antibody responses were found in 60 (94%) patients. In contrast, isolates from only 3 (27%) of 11 patients with low levels of viremia (< 10(6) copies/ml) could be genotyped by the PCR (P < 0.00001), and these patients showed the genotype-specific antibody responses (P < 0.00001). These findings suggest that low levels of hepatitis C virus replication may reduce the efficiency of genotyping by serological assay as well as by PCR.

Adult↗
PubMed2005

Detection of genotyping errors and pseudo-SNPs via deviations from Hardy-Weinberg equilibrium.

Genotype error can greatly reduce the power of a genetic study. For family data, genotype error can be assessed by examining marker data for non-Mendelian inconsistencies, closely linked markers for double recombination events, and consistency of duplicate genotypes. For case-control data, duplicate samples are genotyped, and controls are tested for deviations from Hardy-Weinberg equilibrium (HWE). Duplicate samples can provide accurate estimates of genotyping error rates, unless systematic genotyping errors have occurred. Although genotyping errors can cause deviations from HWE, these deviations are usually small, and the power to detect them is low except for high rates of genotyping error and/or large sample sizes. An additional problem is that even when deviations from HWE are detected for marker loci, without additional experimentation it is not possible to unequivocally implicate genotyping error as the cause. The power and sample sizes necessary to detect deviations from HWE for single-nucleotide polymorphism (SNP) data are examined for a variety of genotyping error and pseudo-SNP models. For the majority of genotyping models examined, the power is poor to detect deviations from HWE. For example, for 1,000 controls, if an allele with a frequency of 0.1 fails to amplify for 28% of the heterozygous genotypes producing a sample error rate of 0.05, the power is 0.51 to detect a deviation from HWE at an alpha level of 0.05. On the other hand, the detection of deviations from HWE for pseudo-SNPs (paralogous and ectopic sequence variants) for the majority of models examined produces a power of >0.8 for sample sizes as small as 50 individuals.

Gene Frequency↗