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PubMed1999

The TP53 genotype but not immunohistochemical result is predictive of response to cisplatin-based neoadjuvant therapy in stage III non-small cell lung cancer.

BACKGROUND: The cytotoxic effects of cisplatin and anthracyclins have been attributed to apoptosis induction, which has been recognized as a major function of the TP53 gene. The TP53 gene appears to be mutated in about 50% of cases of non-small cell lung cancer. A possible dependence of chemotherapy response on TP53 genotype was evaluated retrospectively in a group of patients with advanced non-small cell lung cancer and induction treatment. METHODS: Patients with complete or partial remission were compared with those with stable or progressive disease with respect to TP53 genotype and overall survival. Mutations in the TP53 gene were detected by complete direct sequencing (exons 2-11). RESULTS: A normal TP53 genotype proved to be significantly associated with major response to chemotherapy (P <.001). Overall, no association was found between p53 protein expression and TP53 genotype. A normal TP53 genotype was found to be highly sensitive in predicting response to treatment, whereas a mutant genotype was revealed to be specific in predicting lack of response. The difference in overall length of survival was significant between patients exhibiting a normal TP53 genotype (corresponding to those whose disease responded to chemotherapy) and patients showing mutant TP53 genotype (corresponding to those who had disease resistant to chemotherapy, P =.027). CONCLUSIONS: In a small cohort of patients with advanced non-small cell lung cancer we found a direct link between normal TP53 genotype and response to cisplatin-based induction treatment and also between mutant genotype and resistance to treatment, whereas p53 immunohistochemical result was predictive of neither.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Close association of predominant genotype of herpes simplex virus type 1 with eczema herpeticum analyzed using restriction fragment length polymorphism of polymerase chain reaction.

Herpes simplex virus type 1 (HSV-1) strains belonging to the same genotype can possibly share biological properties and clinical manifestations common to the genotype. We classified previously 66 HSV-1 strains into 35 genotypes (F1-F35) using restriction fragment length polymorphism (RFLP) and F1 and F35 genotypes were revealed to be predominant [Arch. Virol. 13 (1993) 29]. It was found later that the F35 genotype seemed to be closely associated with eczema herpeticum [J. Med. Virol. 49 (1996) 329]. In the present study, a convenient method was developed for classification of two predominant genotypes by RFLP of polymerase chain reaction (RFLP-PCR). Using this method, genotypes of 21 strains isolated from eczema herpeticum were analyzed; seven of 21 strains (33.3%) were of F1 and five of 21 (23.8%) were of F35. Genotypes of 19 strains isolated from facial herpes other than eczema herpeticum were as follows; six of 19 (31.6%) strains were of F1 and one of 19 (5.3%) were of F35. Thus, strains belonging to F35 were appear to have been isolated more frequently from eczema herpeticum (5/21) than from facial herpes (1/19). These ratios showed a statistically significant difference. These results support the hypothesis that F35 strains is clearly associated with eczema herpeticum, in agreement with previous study. This is the first report of PCR-based approach for classification of HSV-1 strains into genotypes seeking an association of a genotype with clinical manifestation.

Dermatitis, Atopic↗
PubMed2003

Frequent coinfection with hepatitis B virus strains of distinct genotypes detected by hybridization with type-specific probes immobilized on a solid-phase support.

A genotype-specific probes assay (GSPA) was developed for distinguishing the seven genotypes (A-G) of hepatitis B virus (HBV). Nucleotide (nt) sequences corresponding to preS1 region were amplified by PCR with a primer labeled with biotin, and delivered to eight wells on which complementary sequences specific to one or other genotype had been immobilized. Thereafter, hybridization of HBV DNA sequences amplified from the test serum was detected by colorimetry. When 256 sera from HBV carriers in Bangladesh, Cameroon, Japan, South Africa, USA and Uzbekistan were subjected to GSPA, genotypes were concordant with those of ELISA with monoclonal antibodies to epitopes on preS2-region products in 242 (94.6%) of them; 8 sera (3.1%) were not genotypeable by either method. Cloning analysis confirmed the presence of two distinct HBV genotypes in the seven selected sera with coinfection. There were 7 (2.7%) sera with discordant genotyping results between GSPA and ELISA. When HBV DNA clones propagated from these sera were sequenced and analyzed phylogenetically, the genotypes determined by GSPA were verified. Coinfection with HBV strains of two distinct genotypes was identified by GSPA in 28 (10.9%) sera, while it was suggested by ELISA in only 2 (0.8%) sera. The GSPA method would be particularly useful for detecting the coinfection with distinct HBV genotypes of any clinical relevance, which seems to be more frequent than reported previously.

Biotin↗
PubMed2001

Relationship between allozyme genotype and sensitivity to stressors in the western mosquitofish Gambusia affinis detected for elevated temperature but not mercury.

Previous studies with Gambusia holbrooki have found associations of allozyme genotype with tolerance to metals, pesticides, heat, and salinity. To examine the generality of these relationships, we looked for similar associations of mercury and heat tolerance with allozyme genotype at the GPI-2, MDH-1 and MDH-2 loci in its sister species Gambusia affinis. This was done to assess if the loci themselves or closely linked loci were associated with mercury tolerance, because weaker linkage associations would be unlikely to persist across species boundaries. Moreover, the use of two very different types of stress allowed us to determine if the higher tolerance of particular allozyme genotypes is specific to a certain stress or reflects a higher tolerance to stress in general. Associations between genotype and tolerance to mercury and heat were determined in laboratory exposures of about 875 fish in each of two exposures where tolerance was measured as time-to-death, followed by electrophoresis on cellulose acetate gels. For none of the three loci did we find an association of genotype with tolerance to mercury. This contrasts with reports of such an association for GPI-2 and MDH-1 in G. holbrooki, so our results do not support the hypothesis that observed associations between allozyme genotypes and mercury tolerance are due to the allozymes or closely linked loci. However, our comparison was weakened by a scarcity of the GPI-2 genotypes reported to be mercury sensitive in G. holbrooki. Furthermore, rapid mortality in our mercury exposure may have affected the ability to detect genotypic differences in survival. The MDH-1 heterozygote showed higher tolerance to heat stress compared to homozygotes, although this difference was only significant for the most common homozygous genotype. No such relationship between MDH-1 and heat stress has been reported in G. holbrooki. We found no evidence that associations between allozyme genotype and tolerance are similar for different types of stresses, which could be an advantage for using allozymes as an indicator of exposure history to a stressor. Our study also showed that G. affinis sex and weight influence tolerance to mercury and heat.

Aldose-Ketose Isomerases↗
PubMed1997

Unexpected high prevalence of hepatitis C virus genotype 4 in Southern Spain.

BACKGROUND/AIMS: A unusually high rate of HCV-infected individuals in whom the HCV genotype cannot be ascertained by means of single PCR and LIPA procedures has recently been reported in our area. The aim of the present study was to investigate the epidemiological, clinical and molecular characteristics of these patients. METHODS: Cross-sectional study. Eighty anti-HCV-positive patients with chronic liver disease, 45 (56.25%) of them intravenous drug users, were included. HCV genotyping was carried out in all patients using commercial single PCR and LIPA procedures. Samples where no HCV RNA amplification and/or indeterminate HCV genotype were found were also tested by means of a nested PCR. HCV viral load was measured in all patients. RESULTS: HCV genotyping was not achieved in 23 (28.75%) individuals. No amplification of HCV RNA was found in 19 of them, and in four other cases the LIPA procedure did not allow identification of a distinct HCV genotype. After the use of nested PCR+LIPA, it was found that the HCV genotype 4 was found in 11 of those 23 individuals (47.82%). Ten of these 11 HCV genotype 4-harboring individuals were intravenous drug users. The HCV viral load was lower in HCV genotype 4-harboring individuals than in those whom the genotypes 1, 2 or 3 were found (p<0.001). CONCLUSIONS: A high rate of HCV genotype 4-harboring cases has been found among HCV-infected individuals in Southern Spain. Had only single PCR been used, these individuals could have been wrongly regarded as non-viremic.

Chronic Disease↗
PubMed1998

Hepatitis delta genotypes in chronic delta infection in the northeast of Spain (Catalonia).

BACKGROUND/AIMS: Based on genetic analysis of variants obtained around the world, three genotypes of the hepatitis delta virus have been defined. Hepatitis delta virus variants have been associated with different disease patterns and geographic distributions. To determine the prevalence of hepatitis delta virus genotypes in the northeast of Spain (Catalonia) and the correlation with transmission routes and clinical disease, we studied the nucleotide divergence of the consensus sequence of HDV RNA obtained from 33 patients with chronic delta hepatitis (24 were intravenous drug users and nine had no risk factors), and four patients with acute self-limited delta infection. METHODS: Serum HDV RNA was amplified by the polymerase chain reaction technique and a fragment of 350 nucleotides (nt 910 to 1259) was directly sequenced. RESULTS: Genetic analysis of the nucleotide consensus sequence obtained showed a high degree of conservation among sequences (93% of mean). Comparison of these sequences with those derived from different geographic areas and pertaining to genotypes I, II and III, showed a mean sequence identity of 92% with genotype I, 73% with genotype II and 61% with genotype III. At the amino acid level (aa 115 to 214), the mean identity was 87% with genotype I, 63% with genotype II and 56% with genotype III. Conserved regions included the RNA editing domain, the carboxyl terminal 19 amino acids of the hepatitis delta antigen and the polyadenylation signal of the viral mRNA. CONCLUSIONS: Hepatitis delta virus isolates in the northeast of Spain are exclusively genotype I, independently of the transmission route and the type of infection. No hepatitis delta virus subgenotypes were found, suggesting that the origin of hepatitis delta virus infection in our geographical area is homogeneous.

Adolescent↗
PubMed2001

Relationship between the angiotensin-converting enzyme genotype and the forearm vasodilator response to estrogen replacement therapy in postmenopausal women.

OBJECTIVES: We sought to evaluate the relationship between the angiotensin-converting enzyme (ACE) genotype and the change in forearm vasoreactivity in response to a three-month course of oral estrogen in postmenopausal women. BACKGROUND: The ACE genotype is a known predictor of the response to an ACE inhibitor drug; however, it is not clear whether it can modify the effect of estrogen replacement therapy (ERT) on endothelial function in postmenopausal women. METHODS: Fifty-five postmenopausal women received 0.625 mg of conjugated equine estrogen daily for three months. Forearm blood flow (FBF) was measured by strain-gauge plethysmography. RESULTS: Twenty-one, 25 and 9 patients had the insertion/deletion (ID), II and DD genotypes, respectively. Plasma ACE activity was significantly higher at baseline in patients with either the DD or ID genotype than in those with the II genotype (p < 0.05). A significant decrease in plasma ACE activity with ERT was seen in the ID and II genotypes (p < 0.05), but not in the DD genotype. There were no significant differences in the FBF responses to reactive hyperemia at baseline between the three groups. Estrogen replacement therapy did not alter the FBF response to reactive hyperemia in the DD genotype (4.0 +/- 1.3%), although ERT significantly increased the FBF response in the ID and II genotypes (32.6 +/- 7.5% and 30.6 +/- 6.5%, respectively; p < 0.05). Forearm blood flow after administration of sublingual nitroglycerin did not change over three months in any of the three groups. CONCLUSIONS: These findings suggest that the effect of ERT in postmenopausal women on forearm endothelial function may be determined in part by the genotype of the ACE gene.

Administration, Oral↗
PubMed1998

High prevalence of hepatitis C virus genotype 6 among certain risk groups in Hong Kong.

The genotype of hepatitis C virus (HCV) of 172 HCV-RNA positive serum specimens taken from patients with chronic liver diseases, thalassaemia major, chronic renal failure (CRF), haemophilia and intravenous drug abusers (IVDA) was determined by analysis of the amplified 5'UTR region by genotype-specific oligonucleotide probes and restriction fragment length polymorphism (RFLP). Six different genotypes and subtypes (1a, lb, 2, 3, 4 and 6) were found. Genotype lb was the predominant genotype among patients with chronic liver diseases (69.6%), followed by genotype 6 (18.8%), which was similar to that reported for blood donors in earlier studies. Pronounced differences in the distribution of genotypes were seen between the four risk groups. Patients with CRF had a similar distribution to those with chronic liver diseases, whilst the greatest diversity of genotypes was seen in patients with haemophilia, which was expected since they were given factor VIII manufactured overseas. Genotype 6 was particularly prominent in patients with thalassaemia major (50%) and IVDA (62.5%). It is possible that clonal spread of HCV genotype 6 has taken place among a closed subset of the population in Hong Kong through intravenous drug abuse.

Female↗
PubMed2001

Effects of genotype, nutrient availability, and defoliation on aspen phytochemistry and insect performance.

Genetic and environmental variability, and their interactions, influence phytochemical composition and, in turn, herbivore performance. We evaluated the independent and interactive effects of plant genotype, nutrient availability, and defoliation on the foliar chemistry of quaking aspen (Populus tremuloides) and consequences for performance of gypsy moths (Lymantria dispar). Saplings of four genotypes were grown under two conditions of nutrient availability and subjected to three levels of artificial defoliation. Concentrations of all secondary and primary metabolites evaluated responded to at least one or more of the experimental treatments. Of the secondary metabolites, phenolic glycosides were affected strongly by genotype, less so by nutrient availability, and not induced by defoliation. Condensed tannins were strongly dependent upon genotype, soil nutrient availability, and their interaction, and, in contrast to phenolic glycosides, were induced by artificial defoliation. Of the primary metabolites, foliar nitrogen was affected by genotype and soil nutrient availability. Starch concentrations were affected by genotype, nutrient availability, defoliation and interactions among these factors. Foliar water content responded to genotype, nutrient availability, and defoliation, and the effect of nutrient availability depended on genotype. Herbivore performance on these plants was strongly influenced by plant genotype and soil nutrient availability, but much less so by defoliation. Although several of the compound types (condensed tannins, starch, and water) responded to defoliation, quantitative variation in these compounds did not contribute to substantive changes in herbivore performance. Rather, the primary source of variation in insect performance was due to plant genotype (phenolic glycoside levels), while nutrient availability (foliar nitrogen levels) was of secondary importance. These results suggest that genetic variation in aspen plays a major role in determining patterns of insect performance, whereas environmental variation, such as was tested, here is of negligible importance.

Animals↗
PubMed2006

Identification of probable genotyping errors by consideration of haplotypes.

Undetected genotyping errors pose a problem in genetic epidemiological studies, as they may invalidate statistical analysis or reduce its power. Haplotype analysis requires an improved standard of the data, because a haplotype can be inferred correctly only if the genotypes of all its markers are correct. Here, we present a method that identifies probable genotyping errors in trio samples with the help of the estimated haplotype frequency distribution of the sample. If the likelihood of the most likely haplotype explanation depends strongly on just one genotype, in the sense that setting the genotype to be missing leads to a much more likely haplotype explanation, this genotype is considered as a potential genotyping error. We describe a method that systematically searches the whole data set for such potential errors. Based on the haplotype distribution of a real data set, we carry out a simulation study to estimate the sensitivity and specificity of the method. In addition, we apply our approach to the real data set itself. Potentially erroneous genotypes are re-determined via sequencing. The results of both the simulation study and of the application to the real data set show that a considerable proportion of true genotyping errors is detected and that the number of false-positive signals is acceptable. We conclude that it is indeed possible to identify probable genotyping errors by considering haplotypes. The method described here will be part of the next release of our FAMHAP software.

Computer Simulation↗
PubMed2001

Prevalence and genotype distribution of TT virus in various specimen types from thalassaemic patients.

Peripheral blood mononuclear cells (PBMC), plasma, saliva and urine samples were collected from 50 thalassaemic patients for TT virus (TTV) detection by two sets of PCR. The set B nested PCR was more sensitive than the widely used NG hemi-nested PCR with TTV positive rates approximately PBMC: 98% vs. 70%; plasma: 92% vs. 66%; saliva: 62% vs. 22%; urine: 22% vs. 6%. All 50 patients had TTV detected in one or more specimens, with 16% of patients being positive in all four specimen types: 40% positive in PBMC, plasma and saliva; 30% positive in PBMC and plasma. In 82 NG hemi-nested PCR-positive samples TTV genotype was identified, 68.3% had a single genotype, 25.6% had multiple genotypes and 6.1% were uncharacterized. The positive rates for genotypes by specimen were: G1 (36/82), G2 (49/82), G3 (2/82), G4 (7/82), G5 (1/82) and G6 (3/82). Among the 42 patients for whom the genotype was examined, 42.9% had single-type infection, 45.2% had co-infections and 11.9% had uncharacterized genotypes. Sixteen of them had TTV detected both in PBMC and plasma with seven having identical genotypes in both samples. Eight patients had TTV detected in PBMC, plasma and saliva; two of them harboured identical genotypes in all three samples. The results indicate that, apart from hepatocytes, PBMC is a major cell type for TTV infection occurs. Shedding of TTV in urine and saliva is common and may have a significant role in nonblood-borne transmission among the general population. TTV-infected patients often harbour multiple genotypes suggesting infection with one genotype does not necessarily confer protection against the others. No correlation between TTV infection and liver dysfunction was observed.

DNA Virus Infections↗
PubMed2002

Methylenetetrahydrofolate reductase genotype, vitamin B12, and folate influence plasma homocysteine in hemodialysis patients.

Hyperhomocysteinemia, a well-recognized cardiovascular risk factor, is frequent in hemodialysis (HD) patients. A common polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, C-->T substitution at nucleotide 677, is associated with homocysteine (Hcy) level elevation. We examined whether three factors involved in the methionine cycle could influence plasma Hcy concentrations in HD patients: MTHFR polymorphism; vitamin B12, an essential cofactor; and folate, the substrate. In a cross-sectional study, serum vitamin B12, folate, and plasma Hcy were measured and MTHFR genotyping was performed in 534 HD patients. Effects of MTHFR genotypes, vitamin B12, and folate on plasma Hcy levels were examined in 450 HD patients not administered vitamin B12 or folate. To examine the effect of vitamin B12 on plasma Hcy concentrations, we compared plasma Hcy concentrations in HD patients with and without vitamin B12 supplementation. To examine whether functional vitamin B12 deficiency exists even in HD patients with normal vitamin B12 concentrations, 15 HD patients (serum vitamin B12 concentrations, 250 to 2,100 pg/mL) were treated with vitamin B12 (mecobalamin, 1.5 mg/d) for 8 weeks. Serum concentrations of methylmalonic acid (MMA) and vitamin B12 were measured. Hcy levels were higher and folate levels were lower in patients with the TT and CT genotypes compared with patients with the CC genotype. Analysis of covariance to determine independent predictors of high Hcy levels identified low serum vitamin B12 and folate levels and high albumin (Alb) levels in CC-genotype patients, low folate levels and high Alb levels in CT-genotype patients, and low folate levels in TT-genotype patients. Plasma Hcy levels were lower in CC- and CT-genotype patients with vitamin B12 supplementation than in those without supplementation. Vitamin B12 supplementation for 8 weeks significantly reduced MMA concentrations in HD patients with normal serum vitamin B12 concentrations. These results indicate that MTHFR genotype influences the correlation of Hcy level with vitamin B12 and folate levels in HD patients. Functional vitamin B12 deficiency may exist, even in HD patients with normal vitamin B12 concentrations. The efficacy of vitamin B12 and folate supplementation on plasma Hcy levels may depend on MTHFR genotype.

Cross-Sectional Studies↗
PubMed2006

Hepatitis C virus genotypes and viral concentrations in participants of a general population survey in the United States.

BACKGROUND & AIMS: Estimates of the long-term benefits of antiviral therapies for chronic hepatitis C are influenced by the frequency of characteristics that affect response in the population treated. This study determined hepatitis C virus (HCV) genotypes and RNA titers among HCV-infected persons in the general population of the United States. METHODS: Genotypes were determined from the NS5b region, and HCV RNA was quantified by using Amplicor Monitor (Roche Diagnostic Systems, Inc, Branchburg, NJ) from 275 HCV RNA-positive participants in the Third National Health and Nutrition Examination Survey conducted during 1988 to 1994. RESULTS: The HCV genotypes identified included 1a (n = 142), 1b (n = 73), 2a (n = 8), 2b (n = 27), 3a (n = 17), 4 (n = 3), and 6 (n = 5). Based on weighted analysis of persons infected with genotypes 1, 2, and 3, genotype 1 predominated in all age groups (75.3%). By racial/ethnic group, genotype 1 was found in 90.9% of non-Hispanic blacks, 69.6% of non-Hispanic whites, and 71.2% of Mexican Americans. After adjusting for age and gender, only non-Hispanic black race/ethnicity was independently associated with genotype 1 infection (adjusted odds ratio 4.9; 95% confidence interval, 1.9-12.8). The overall geometric mean concentration of HCV RNA was 2.1 x 10(6) IU/mL; concentrations > 2 million IU/mL were found in 53.0% overall and 50.3% of persons with genotype 1. CONCLUSIONS: Persons with chronic hepatitis C in the United States who may require treatment in the foreseeable future are predominantly infected with genotype 1, including a disproportionate number of non-Hispanic blacks. These features emphasize the need for improved therapies that reduce or eliminate complications from genotype 1 infections.

Adolescent↗
PubMed2000

Immunohistochemical differentiation of hepatitis D virus genotypes.

Determination of hepatitis D virus (HDV) genotypes is epidemiologically and clinically important. Phylogenic analysis based on sequencing analysis of multiple HDV strains isolated from sera of patients is not convenient for mass screening in routine laboratories. This study was designed to develop genotype-specific antibodies against hepatitis delta antigen (HDAg) and to apply these antibodies for immunohistochemical differentiation of HDV genotypes in formalin-fixed, paraffin-embedded liver biopsies of patients. Divergence in the carboxyl-terminal 19 amino acids of the large HDAg between genotypes I and II is more than 70%. Peptides covering these residues were conjugated to keyhole limpet hemocyanin and were used for immunization. The generated antibodies were confirmed for their specificity by binding to type-specific HDAgs expressed in DNA-transfected Huh-7 hepatoma cells. Liver biopsies from 6 patients who had dominant genotype I HDV and 33 patients who had dominant genotype II HDV in sera were stained with these antibodies. The accuracy for these antibodies was 94.9%, and the agreement between dominant HDV genotypes in serum and dominant hepatic HDV genotypes based on HDAg staining was nearly perfect (kappa = 0.83). In summary, the carboxyl-terminal 19 amino acids of the large HDAg can be used as immunogens to generate genotype-specific antibodies. These antibodies were proven to be useful in immunohistochemical differentiation of HDV genotypes in liver biopsies.

Amino Acid Sequence↗
PubMed2001

Screening for acetaldehyde dehydrogenase 2 genotype in alcohol-induced asthma by using the ethanol patch test.

BACKGROUND: We have previously reported that alcohol-induced asthma in Japanese patients is caused by increased blood acetaldehyde concentration resulting from abnormalities of acetaldehyde dehydrogenase 2 (ALDH2) enzyme activity on the basis of ALDH2 genotype differences. OBJECTIVES: The purpose of the present study was to determine whether the ethanol patch test could predict the ALDH2 genotype in Japanese asthmatic subjects. METHODS: An ethanol patch test on the upper arm and a questionnaire survey addressing the past history of alcohol-induced asthma were administered to 148 adult Japanese asthmatic subjects. The ALDH2 genotypes in these 148 subjects were also determined by means of PCR. RESULTS: The genotype distribution of ALDH2 determined by PCR in 68 subjects with positive ethanol patch test results was 4 (5.9%), 56 (82.4%), and 8 (11.8%) for genotypes NN (normal homozygote), NM (mutant heterozygote), and MM (mutant homozygote). The ALDH2 genotype in 80 subjects with a negative test result was only NN. The distribution of ALDH2 genotype in 78 (52.7%) subjects who had experienced alcohol-induced asthma symptoms on the basis of the questionnaire was 27 (34.6%), 44 (56.4%), and 7 (9.0%) for genotypes NN, NM, and MM, respectively. On the other hand, 70 subjects had never experienced alcohol-induced asthma symptoms. In these subjects the ALDH2 genotype was NN in 51 (72.9%), NM in 18 (25.7%), and MM in 1 (1.4%). CONCLUSIONS: Our results indicate that the results of ethanol patch testing correlate well with ALDH2 genotype, as determined by means of PCR, suggesting that the ethanol patch test is useful for the screening of alcohol-induced asthma.

Adult↗
PubMed2002

Effect of cytochrome P4502C19 genotypic differences on cure rates for gastroesophageal reflux disease by lansoprazole.

BACKGROUND AND OBJECTIVES: The acid-inhibitory effect of lansoprazole depends on differences in cytochrome P450 (CYP) 2C19 genotypes. We assessed whether therapeutic effects of lansoprazole on gastroesophageal reflux disease (GERD) depended on the CYP2C19 genotype status in relation to the grade of GERD. METHODS: A total of 65 patients with GERD (grades A-D) completed treatment with lansoprazole, by taking 30 mg orally once a day for 8 weeks. The CYP2C19 genotype status of patients was determined by polymerase chain reaction-restriction fragment length polymorphism analysis. Before and after treatment, esophageal endoscopy was performed. GERD was considered to be cured on the basis of endoscopic findings at the end of treatment. Plasma lansoprazole levels could be determined at 3 hours after the last 30-mg dose of lansoprazole in the 27 genotyped patients. RESULTS: Cure rates for GERD depended significantly on the CYP2C19 genotype status, as well as the grade of GERD before treatment. Cure rates in the homozygous extensive, heterozygous extensive, and poor metabolizer groups were 45.8%, 67.9%, and 84.6%, respectively. Cure rates in the groups with GERD grade A, grade B, and grade C or D were 85.0%, 60.0%, and 45.0%, respectively. The cure rate in patients with the homozygous extensive metabolizer genotype of CYP2C19 with a GERD grade of C or D was very low (16.7%). Plasma lansoprazole levels in patients with the homozygous extensive metabolizer genotype were the lowest of the 3 groups. CONCLUSIONS: CYP2C19 genotype status, as well as the grade of GERD before treatment, is one of the determinants for the success or failure of treatment of GERD with lansoprazole. The low cure rate in patients with the homozygous extensive metabolizer genotype appeared to be a result of these patients having the lowest plasma lansoprazole levels among the 3 genotype groups.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2002

Proposed criteria for classification of new genotypes of mumps virus.

The nucleotide sequences of a 300 bp segment carrying the small hydrophobic (SH) protein gene of a large number of virus strains, belonging to 10 different mumps virus genotypes denoted A-J, were compared. When virus strains belonging to the same genotype were compared intra-genotypically, a variation in the range 2-4% was recorded. The level of inter-genotypical variation was higher (8-18%). A consistent finding was the more pronounced variation found when the A genotype was compared to the B-J genotypes than when the B-J genotypes were compared among themselves. A similar relatively more pronounced genetic variation between the A and B-D genotypes has also been found previously with the hemagglutinin-neuraminidase and fusion protein genes. It is concluded that the establishment of a new genotype should be founded on a nucleotide variation of the SH gene of > or = 6% in relation to previously described genotypes.

Classification↗
PubMed2000

The use of case-parent triads to study joint effects of genotype and exposure.

Most noninfectious disease is caused by low-penetrance alleles interacting with other genes and environmental factors. Consider the simple setting where a diallelic autosomal candidate gene and a binary exposure together affect disease susceptibility. Suppose that one has genotyped affected probands and their parents and has determined each proband's exposure status. One proposed method for assessment of etiologic interaction of genotype and exposure, an extension of the transmission/disequilibrium test, tests for differences in transmission of the variant allele from heterozygous parents to exposed versus unexposed probands. We show that this test is not generally valid. An alternative approach compares the conditional genotype distribution of unexposed cases, given parental genotypes, versus that of exposed cases. This approach provides maximum-likelihood estimators for genetic relative-risk parameters and genotype-exposure-interaction parameters, as well as a likelihood-ratio test (LRT) of the no-interaction null hypothesis. We show how to apply this approach, using log-linear models. When a genotype-exposure association arises solely through incomplete mixing of subpopulations that differ in both exposure prevalence and allele frequency, the LRT remains valid. The LRT becomes invalid, however, if offspring genotypes do not follow Mendelian proportions in each parental mating type-for example, because of genotypic differences in survival-or if a genotype-exposure association reflects an influence of genotype on propensity for exposure-for example, through behavioral mechanisms. Because the needed assumptions likely hold in many situations, the likelihood-based approach should be broadly applicable for diseases in which probands commonly have living parents.

Disease Susceptibility↗