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PubMed2001

High-throughput multiplex SNP genotyping with MALDI-TOF mass spectrometry: practice, problems and promise.

Single nucleotide polymorphisms (SNPs) are currently being identified and mapped at a remarkable pace, providing a rich genetic resource with vast potential for disease gene discovery, pharmacogenetics, and understanding the origins of modern humans. High-throughput, cost effective genotyping methods are essential in order to make the most advantageous and immediate use of these SNP data. We have incorporated the use of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF) in our laboratory as a tool for differentiating genotypes based on the mass of the variant DNA sequence, and have utilized this method for production scale SNP genotyping. We have combined a 4 microl PCR amplification reaction using 3 ng of genomic DNA with a secondary enzymatic reaction (mini-sequencing) containing oligonucleotide primers that anneal immediately upstream of the polymorphic site, dideoxynucleotides, and a thermostable polymerase used to extend the PCR product by a single base pair. Mass spectrometry (MS) analysis of mini-sequencing reactions was performed using a MALDI-TOF instrument (Voyager-DE, Perseptive Biosystems, Framingham, MA). We performed both single and multiplex PCR and mini-sequencing reactions, and genotyped seven different variant sites in a random sample of 989 individuals. Genotypes generated with MS methods were compared with genotypes produced using a 5' exonuclease fluorescence-based assay (Taqman, Applied Biosystems, Foster City, CA) and a gel-based genotyping protocol. Because multiple polymorphisms can be detected in a single reaction, the MS technique provides a cost-effective and efficient method for high-throughput genotyping.

Alleles↗

PubMed2004

Glutathione S-transferase M3 (A/A) genotype as a risk factor for oral cancer and leukoplakia among Indian tobacco smokers.

Polymorphism in glutathione S-transferase (GST) genes, causing variations in enzyme activities, may influence susceptibility to oral cancer and leukoplakia in smokers and/or smokeless tobacco users. In this case-control study consisting of 109 leukoplakia and 256 oral cancer patients and 259 controls, genotype frequencies at GSTM1, GSTT1, GSTM3 and GSTP1 loci were determined by polymerase chain reaction-restriction fragment length polymorphism methods and analyzed by multiple logistic regression to determine the risks of the diseases. There were no significant differences in the distributions of GSTM1, GSTM3 and GSTT1 genotypes in patients and controls when all individuals were compared. In contrast, frequencies of ile/ile genotype at codon 105 and variant val-ala haplotype of GSTP1 was significantly higher (OR = 1.5; 95% CI = 1.0-2.0) and lower (OR = 1.4; 95% CI = 1.0-1.9) in oral cancer patients compare to controls, respectively. The impacts of all genotypes on risks of oral cancer and leukoplakia were also analyzed in patients with different tobacco habits and doses. Increased risks of cancer and leukoplakia were observed in tobacco smokers with GSTM3 (A/A) genotype (OR = 2.0, 95% CI = 1.0-4.0; OR = 2.0, 95% CI = 1.0-4.4, respectively). So, GSTM3 (A/A) genotype could become one of the markers to know which of the leukoplakia would be transformed into cancer. Heavy tobacco chewing (> 124 chewing-year) increased the risk of cancer in individuals with GSTT1 homozygous null genotype (OR = 3.0; 95% CI = 1.0-9.8). Furthermore, increased lifetime exposure to tobacco smoking (> 11.5 pack-year) increased the risk of leukoplakia in individuals with GSTM1 homozygous null genotype (OR = 2.4; 95% CI = 1.0-5.7). It may be suggested that polymorphisms in GSTP1, GSTM1, GSTM3 and GSTT1 genes regulate risk of cancer and leukoplakia differentially among different tobacco habituals.

Adult↗

PubMed2002

Viral genotypes and response to interferon in patients with acute prolonged hepatitis B virus infection of adulthood in Japan.

Acute hepatitis B virus (HBV) infection was diagnosed in 57 adults admitted to Toranomon Hospital in Tokyo, Japan. Genotypes of HBV were determined by a serological method and compared to those in 1,077 patients with chronic hepatitis B. The distribution of genotypes were: genotype A (acute, 22.8% vs. chronic, 1.9%; P < 0.00001); B (14.0% vs. 9.4%); C (43.9% vs. 87.7%, P = 0.004); D (1.8% vs. 0.2%); F (1.8% vs. 0.2%); and unable to be typed (15.8% vs. 0.6%, P = 0.001). The infection persisted in seven (12%) of them. They included six (86%) of the seven patients who received prednisolone or glycyrrhizin during an acute phase of illness and one of the 41 (2%) who did not (P = 0.01). Interferon was given to the seven patients with acute prolonged HBV infection, and four of them responded by clearing hepatitis B e antigen (HBeAg) and surface antigen (HBsAg) from serum. Of the four responders, one was infected with HBV genotype B and three with genotype C. HBsAg persisted in the remaining three patients all of whom were infected with HBV genotype A, and HBeAg stayed positive in one of them. These results indicate that HBV genotype A prevails in Japanese patients with acute hepatitis B, and suggest a high efficacy of interferon in the adult patients with acute prolonged HBV infection, except in those infected with HBV genotype A.

Acute Disease↗

PubMed2003

Genotyping of herpes simplex virus type 1 strains isolated from ocular materials of patients with herpetic keratitis.

Herpes simplex virus type 1 (HSV-1) is the etiological agent of herpetic keratitis. The epithelial form ("epithelial keratitis") is attributed mainly to destruction of the epithelium through active viral replication within the epithelium. The stromal form ("stromal keratitis") is associated with immune reactions within the stroma and is the common cause of human blindness. In the present study, 29 HSV-1 strains isolated from human ocular materials of herpetic keratitis were classified into 14 genotypes on the basis of DNA polymorphisms. Twenty-one of 29 (72%) strains from eyes examined in the present study were of genotypes that were shown previously to be present in strains from non-ocular lesions (including genital herpes). Five of nine (56%) strains from eyes related to stromal keratitis were of the F1 genotype, while four of twenty (20%) strains from eyes not related to stromal keratitis were of the F1 genotype. Thus, the proportion of F1 genotype was assumed to be larger in the group of strains related to stromal keratitis than in that not so related, suggesting an association of the F1 genotype with stromal keratitis. A connection of F1 genotype with recurrence was proposed previously; hence, F1 genotype seems to be associated to both stromal keratitis and the recurrence, thereby supporting the relationship between stromal keratitis and recurrence.

Adolescent↗

PubMed2001

HCV genotype and "silent" HBV coinfection: two main risk factors for a more severe liver disease.

To evaluate whether HCV genotype and a "silent" HBV infection may be related to a more severe clinical presentation of liver disease, 205 anti-HCV/HCV-RNA positive, HBsAg/anti-HBs negative patients with chronic hepatitis (113 males and 92 females; median age 55 years, range 18-77), were studied on presentation at the Liver Unit from January 1993 to December 1997. Presence of serum anti-HBc, in the absence of HBsAg and anti-HBs, was considered a marker of "silent" HBV infection. Of the 205 patients, 134 had undergone percutaneous liver biopsy. Two main diagnosis groups were established: the mild liver disease group (76 patients), and the severe liver disease group (109 patients); 20 patients who had refused to undergo liver biopsy were not included in the clinical and virological evaluation because the diagnosis was uncertain. The prevalence of severe liver disease was similar in the genotype 1 and non-1 groups (61.3% of 98 patients with genotype 1 and 52.9% of 70 patients with a non-1 genotype). Instead, the 88 patients with "silent" HBV infection showed a higher percentage of severe liver disease than the 97 anti-HBc negative patients (72.7% vs. 46.4%, respectively: P < 0.0005). Of the 88 anti-HBc positive patients, the prevalence of those with severe liver disease was similar in the 32 cases with serum HBV-DNA as detected by PCR and in the 56 HBV-DNA negative (81.2% vs. 67.8%, P = 0.4). The relation between "silent" HBV infection and severe liver disease was observed both in genotype 1 and non-1 infected patients. Nevertheless, the anti-HBc negative patients infected by genotype 1 showed a severe liver disease more frequently than those infected by a non-1 genotype, with a difference that is significant to the statistical analysis (P < 0.05). The findings suggest that "silent" HBV infection in anti-HCV positive chronic hepatitis enhances the severity of the liver disease. Evidence was also found that in patients without "silent" HBV infection there is a correlation between the presence of HCV genotype 1 and the severity of liver disease.

Adolescent↗

PubMed2001

Predominance of genotype A HBV in an HBV-HIV-1 dually positive population compared with an HIV-1-negative counterpart in Japan.

Hepatitis B virus (HBV) has seven genotypes, A to G. Previous studies have shown that genotype C is the most prevalent strain in chronic HBV carriers in East Asia. This study was undertaken to investigate the epidemiology of HBV genotypes among Japanese patients who are coinfected with human immunodeficiency virus type 1 (HIV-1). The sequences of the complete hepatitis B surface antifen (HBsAg) genes were obtained from 18 coinfected Japanese patients. Among the 18 patients, 12 of 13 men who had sex with men (MSM) had genotype A (92%), whereas only one of five heterosexual or hemophiliac patients had genotype A. The predominance of genotype A HBV in MSM showed a striking contrast to the current genotype prevalence in the Japanese population. Owing to the recent decrease in the rate of vertical transmission in Japan, the role of sexual behavior in the transmission of HBV cannot be overestimated. Thus, the relative proportion of genotype A may gradually increase in Japan.

Adult↗

PubMed1994

Hepatitis C virus and its genotypes in patients suffering from chronic hepatitis C with or without a cryoglobulinemia-related syndrome.

Recently, evidence has been presented for a possible association between hepatitis C virus (HCV) infection and essential mixed cryoglobulinemia (EMC). Eleven consecutive patients with EMC and two with cryoglobulinemia type I were examined for the presence of markers of HCV infection. Eleven of 13 patients (10 with EMC and 1 with type I cryoglobulinemia) had anti-HCV antibodies (as determined by a second generation anti-HCV assay) and HCV-RNA in plasma or serum. HCV-RNA was also detected in liver biopsies of five patients. Genotyping showed that HCV genotype 1 was found in 10 of 11 patients with HCV-RNA (9 genotype 1b and 1 genotype 1a) and only one patient had HCV genotype 2. However, a similar high prevalence of genotype 1b (100%) was found in a group of 14 consecutive patients with chronic hepatitis C, who had no clinical evidence of cryoglobulinemia. Concomitant infection was present in three patients with genotypes 2, 3 and 4, respectively. These findings stress the high prevalence of HCV infection in patients with EMC and further study shows that a difference in genotype prevalence was not found between HCV-related EMC and chronic hepatitis C without clinical manifestations of EMC.

Adult↗

PubMed1995

Clinical characteristics and antibody profiles of chronic hepatitis C patients: relation to hepatitis C virus genotypes.

Genotyping of 179 consecutive Japanese chronic hepatitis C patients was carried out based on the variation in the hepatitis C virus (HCV) core gene. The results were correlated with clinical features and antibody responses toward specific HCV proteins deduced from the nucleotide sequence of genotype I/1a. Genotypes II/1b, III/2a, and IV/2b were identified in 138 (77%), 24 (13%), and 12 (7%) patients, respectively. Five patients had double infections. Genotype dependence was observed only for antibody response toward the NS4 (5-1-1) protein, which was infrequent in genotype III/2a patients (33%) compared with genotype II/1b (81%; P < 0.01) and genotype IV/2b (75%; P < 0.05). Following interferon-alpha therapy, sustained amniotransferase normalisation was achieved by 89% (eight of nine) patients without antibody to the 5-1-1 protein and 33% (17 of 51) with it (P < 0.01). These findings indicate that absence of antibody response to the 5-1-1 protein is frequent in genotype III/2a HCV carriers and may serve to predict responses to interferon therapy.

Adult↗

PubMed1995

Seroprevalence of hepatitis C virus infection and its genotype in Lanzhou, western China.

The seroprevalence of hepatitis C virus (HCV) infection in Lanzhou, Western China was studied. HCV genotypes in 20 patients with HCV infection was determined by genotype-specific primer for polymerase chain reaction (PCR) based on HCV core region and compared with the genotype assigned by sequence comparison and molecular evolutionary analysis based on the same region. Antibody to HCV (anti-HCV) was present in 2.5% of volunteer blood donors and in 35.0% of paid blood donors (P < 0.01). HCV infection is uncommon in patients with liver disease who attended liver clinics in this locality; 4.0% with acute hepatitis and 4.0% with chronic hepatitis, 10.0% with liver cirrhosis, and none with hepatocellular carcinoma were seropositive for anti-HCV. Genotype 1b and 2a were both found to be prevalent. Together, they accounted for 19 of 20 (95%) patients with HCV infection. Sequencing of the HCV core region from two patients showed that the assignment of HCV genotype by genotype-specific primers for PCR matched well with the genotyping results based on sequence comparison and molecular evolutionary analysis. These data showed that HCV is present in Western China, HCV infection is more common in paid blood donors, and HCV genotypes 1b and 2a are both prevalent in Western China.

Amino Acid Sequence↗

PubMed2004

Hepatitis B virus genotype D strains from Estonia share sequence similarity with strains from Siberia and may specify ayw4.

The genotypes and subtypes of 205 HBV isolates collected during 1989-2002 in Estonia and 14 other regions of the former USSR were determined by sequencing and phylogenetic analysis of the S gene. The in Europe prevailing genotypes, A and D, were also circulating in the whole territory of the former USSR including Estonia and accounted for 18.5 and 81% of the strains, respectively. All genotype A strains specified adw2, and a single genotype C strain specified adrq+. Most genotype D strains specified ayw3 and ayw2, although, three strains from Estonia and Siberia specified ayw4. Due to unique substitutions, Ser122 and Ala127, four strains could not be classified according to the subtype. One strain specifying ayw3 encoded Leu143 and Ala145 and was possibly an immune "escape" mutant. At phylogenetic analysis 93% of the Estonian genotype D strains belonged to a cluster specifying mainly ayw3 and were more similar to isolates from Siberia and the Far-East of Russia than to isolates originating from Central Russia which belonged to another cluster of strains specifying mainly ayw2. This pattern might be explained by part of the Estonian population, has roots east of European Russia, based on linguistic evidence. Eight dominant HBV strains represented by identical S gene sequences were identified, one within genotype A and seven within genotype D, three of which included isolates from Estonia and Siberia. Some of these strains were collected over a period of at least 13 years indicating there are genetically stable variants of HBV that remain conserved over decades.

Estonia↗

PubMed2005

Human papillomavirus genotypes and their association with cervical neoplasia in a cohort of Western Australian women.

Human papillomavirus (HPV) is known to be the cause of almost all cervical cancers. The genotypes have been classified into high and low risk types according to their oncogenic potential. However, data for many of the genotypes are limited and some (HPV-26, 53, and 66) have no agreed status. A study was undertaken to determine the HPV genotype distribution in women of Western Australia and the association with cervical neoplasia. Liquid based cervical samples from a cohort of 282 Western Australian women were tested for HPV DNA by PCR followed by DNA sequencing to determine HPV genotypes. HPV-53 and HPV-16 were the most common genotypes found in this population. In addition 86 archived liquid based cervical samples from women with cervical intraepithelial neoplasia grades 1-3 (CIN 1-3) were tested for HPV DNA. Also 32 archived paraffin biopsy samples from women with squamous cell carcinoma were also tested. HPV-16 was the most common genotype found in these samples. Of the cohort of Western Australian women tested, 27% were found to contain HPV and approximately half of these contained known high-risk HPV genotypes, but only 30% of these were types 16 or 18. The data from this study indicate that HPV-53 is not oncogenic based on an R value and odds ratio (OR) of zero. The data also suggest that HPV-73 may be oncogenic, while HPV-66 is unlikely to be. Two high-risk HPV genotypes that are associated with the Asian region (HPV-52 and HPV-58) were found in Western Australian women suggesting a possible epidemiological link between women in these countries.

Australia↗

PubMed2006

A previously unrecognized sixth genotype of GB virus C revealed by analysis of 5'-untranslated region sequences.

GB virus C (GBV-C) is a positive-strand RNA virus that infects a large proportion of the world's human population. It has been classified tentatively as a member of the Flaviviridae family and has been shown to exist as a group of five closely related genotypes. Recently, we reported the first full-length genome sequence of a genotype 5 isolate from South Africa. As part of the analysis of that sequence, a phylogenetic tree was elucidated from the 5'-untranslated region (UTR) that showed excellent congruence to the tree produced by analysis of complete open reading frame sequences. When 5'-UTR analysis was broadened subsequently to include additional isolates from around the globe, a heretofore unrecognized GBV-C genotype was discovered in Indonesia. When first reported in 2000, these isolates were described as constituting a novel fifth genotype. However, comparison to isolates from the then-known fourth and fifth genotypes (from Myanmar/Vietnam and South Africa, respectively) was not performed. A dataset of 121 GBV-C 5'-UTR sequences was complied and included representatives of the fourth and fifth genotypes as well as the "novel" Indonesian sequences and demonstrated, with strong support via bootstrap analysis, the existence of a sixth GBV-C genotype among infected individuals in Indonesia. The discovery of this sixth genotype emphasizes the diverse nature of GBV-C isolates and may have important implications for the interpretation of studies involving GBV-C/HIV co-infected individuals.

5' Untranslated Regions↗

PubMed2006

Analysis of the full-length genome of genotype 4 hepatitis E virus isolates from patients with fulminant or acute self-limited hepatitis E.

It was suggested that hepatitis E virus (HEV) genotype 4 is associated more closely with the severity of hepatitis E than genotype 3, although the virological basis remains unknown. The aim of this study was to examine whether genomic differences among genotype 4 HEVs are responsible for the development of fulminant hepatitis. Full-length sequences of genotype 4 HEVs from three patients with fulminant hepatitis and six patients with acute self-limited hepatitis were determined. The sequences were analyzed with those of 13 genotype 4 HEV isolates whose entire nucleotide sequence is known. Analysis of 22 full-length sequences (fulminant hepatitis, 5; acute hepatitis, 17) revealed that C at nt 1816 and U at nt 3148 (U3148), both of which do not change the amino acid sequences, were significantly associated with fulminant hepatitis (P = 0.0489, respectively). When partial nucleotide sequences containing nt 1816 or nt 3148 were determined in 16 additional HEV isolates of genotype 4, a closer association between U3148 and fulminant hepatitis (P = 0.0018) was observed. The comparison of 86 HEV isolates of all four genotypes showed that U3148 had a stronger association with fulminant hepatitis than other nucleotides at nt 3148 (P = 0.0006). Patients infected with HEV with U3148 had a significantly lower value of the lowest prothrombin activity (P = 0.0293). Nt 3148 is located within the RNA helicase domain, and 22-nt sequence including nt 3148 was well conserved among all genotypes. A silent substitution of U3148 in HEV may be associated with the development of fulminant hepatitis. Further studies are needed to clarify the underlying mechanism.

Acute Disease↗

PubMed2002

HPV16/18 prevalence in cervical lesions/cancers and p53 genotypes in cervical cancer patients from India.

OBJECTIVES: The HPV16/18 code for an oncoprotein-E6, which binds to p53 tumor suppressor protein and degrades the protein via ubiquitination. A common polymorphism of p53 in exon 4 codon 72, resulting in either proline (Pro) or arginine (Arg), affects HPV16/18 E6-mediated degradation of p53 protein in vivo. Hence, in the current study we investigated the prevalence of HPV16/18 in cervical lesions and the distribution of p53 genotypes in cervical cancers and normal healthy women. METHODS: DNA from 337 Indian women with invasive cervical cancers, 164 women with clinically normal cervix, 64 women with low-grade squamous intraepithelial lesions (LSIL), and 5 women with high-grade squamous intraepithelial lesions (HSIL) was examined for the presence of HPV16/18 using consensus primers in a polymerase chain reaction (PCR), and the specific HPV type was identified by Southern hybridization of the PCR product using HPV16/18 type-specific nucleotide sequences as probes. Further, 134 women with cervical cancers and 131 healthy women were used to determine the frequency of p53 genotypes, Pro/Pro, Arg/Arg, and Pro/Arg, using peripheral blood cell DNA to indicate the constitutional genotypes and allele-specific primers, in a PCR-based assay. RESULTS: We observed a prevalence of HPV16/18 in 77% (258/337) of cervical cancer patients, 38% (24/64) of LSILs, 4 of 5 HSILs, and 15.2% (25/164) of normal healthy women. The frequency of distribution of the three genotypes of p53 codon 72 in a subgroup of the HPV16/18-positive cervical cancer patients was Pro/Pro 0.18 and Arg/Arg 0.26, with the heterozygous Pro/Arg 0.56, differing significantly from the genotype frequency in the normal healthy women (chi(2) = 6.928, df = 2, P < 0.05). CONCLUSIONS: A high prevalence of HPV16/18 was observed in the cervical cancers. The prevalence in LSILs confirms HPV16/18 infection as an early event and further indicates a role in progression of lesions. The p53 genotype distribution indicated that women homozygous for Arg genotype were at a 2.4-fold higher risk for developing HPV16/18-associated cervical carcinomas, compared to those showing heterozygous Pro/Arg genotype (odds ratio 2.4, 95% confidence interval 1.89 to 3.04).

Arginine↗

PubMed1997

Geographic distribution and genetic variability of hepatitis delta virus genotype I.

Three genotypes of hepatitis delta virus (HDV) have been identified, each with different geographic distributions and disease associations. To better define the geographic distribution and genetic variability of HDV genotype I, and to evaluate the extent of genome variability in populations with different patterns of HDV infection, we have analyzed the sequence of HDV RNA in the sera of 72 patients from different areas. Patients were primarily residents of the United States and areas in and around Greece, including Archangelos, Rhodes. All sequences obtained belonged to HDV genotype I, confirming the wide geographic distribution of this genotype and its predominance in Europe and the United States. In contrast to previous studies, phylogenetic analysis of this large and diverse group of sequences, along with all available previously published HDV sequences, showed no well-defined subtypes within genotype I. Low sequence diversity was found for isolates from the United States, Archangelos, Turkey, and Albania, suggesting that HDV was introduced more recently and/or from fewer sources into these areas as compared to mainland Greece, Italy, and north Africa, where sequence diversity is much greater. The low sequence diversity among isolates from Archangelos is particularly interesting in light of the unusually mild pattern of HDV disease found in this community. Comparison of nucleic acid and amino acid sequences within and among genotypes indicated both highly conserved regions as well as genotype-specific sequences that could be related to functional differences. The most distinctive of the latter was that corresponding to the C-terminal 19-20 amino acids of the long form of hepatitis delta antigen, which is highly conserved within each genotype but considerably diverged among them.

Amino Acid Sequence↗

PubMed1999

Hepatitis C virus: an infectious molecular clone of a second major genotype (2a) and lack of viability of intertypic 1a and 2a chimeras.

Of the six major genotypes of hepatitis C virus (HCV), infectious cDNA clones of only genotype 1 have been reported. Here, we report the construction of an infectious cDNA clone representing a second major HCV genotype, genotype 2. This infectious clone (pJ6CF) encodes the consensus polyprotein of strain HC-J6(CH), genotype 2a. Its encoded polyprotein differs from those of the infectious clones of genotypes 1a and 1b by approximately 30%. Intertypic chimeric cDNA clones constructed from infectious clones of genotypes 1a and 2a of HCV were not infectious. RNA transcripts of four chimeras containing the 2a structural genes (C, E1, and E2) in the backbone of an infectious genotype 1a clone (pCV-H77C) were not viable in a chimpanzee regardless of whether p7 was from the 1a or 2a clone. However, the chimpanzee was subsequently infected with RNA transcripts of each of the two infectious parent clones, indicating that the inability of the chimeras to replicate was intrinsic to the clones and not the result of preexisting protective immune responses.

3' Untranslated Regions↗

PubMed1996

Steady-state plasma levels of nortriptyline and its 10-hydroxy metabolite: relationship to the CYP2D6 genotype.

The relationship between the CYP2D6 genotype and the steady state plasma levels of nortriptyline (NT), its main active metabolite 10-hydroxynortriptyline (10-OH-NT) and the NT/10-OH-NT ratio were studied in 21 Caucasian depressed patients treated with 100-150 mg NT daily. The patients had participated in a previously published study investigating the role of NT and 10-OH-NT for the therapeutic effect of NT, and the plasma level data were from that study. In the present follow-up study, the patients were genotyped with respect to the polymorphic CYP2D6 by allele-specific PCR amplification and EcoRI RFLP. One poor metabolizer (PM) was identified and she had the highest plasma concentration of NT. Among the 20 extensive metabolizers (EM), the genotype (homozygous versus heterozygous EM) alone was not found to explain the variance in dose-corrected NT concentrations, but contributed significantly when gender was also taken into account. Together, these factors accounted for 59% of the variability in NT levels. Female patients had higher plasma levels of NT than male patients. 10-OH-NT levels were influenced by genotype, and NT/10-OH-NT ratio by genotype and gender. The present follow-up study confirms a relationship between the CYP2D6 genotype and the plasma levels of NT and its active metabolite. Identification of PM by genotyping should be of value for the prediction of the plasma levels and, consequently, the lower than average dose of NT required for optimal therapy. Also among EM, the genotype contributes to the variability in NT and 10-OH-NT levels but alone is of limited practical value for the prediction of optimal dosage.

Adult↗

PubMed2002

Endothelial nitric oxide synthase genotype modulates the improvement of coronary blood flow by pravastatin: a placebo-controlled PET study.

The objective was to study whether coronary blood flow or its response to pravastatin are affected by genetic variation in the endothelial nitric oxide synthase (eNOS) gene. Vascular endothelial nitric oxide maintains endothelium-dependent vasodilatation and also mediates antithrombotic actions. Its formation is catalyzed by eNOS, a constitutive enzyme, which has a polymorphic site in intron 4 (4a/b). Some clinical studies have suggested an association of the rare a-allele of eNOS with coronary artery disease and myocardial infarction. We carried out a double-blind placebo-controlled study involving 43 men (aged 35+/-4 years), who were randomized to receive either 40 mg/day pravastatin ( n=21) or placebo ( n=22) for 6 months. Myocardial blood flow was measured by positron emission tomography (PET) using (15)O-labeled water. PET was performed at rest and after stimulation by adenosine infusion. PET and lipid analyses were carried out at baseline and after 6 months. eNOS genotyping was done by PCR. At baseline there were no differences in basal or adenosine-stimulated coronary blood flow between subjects with either eNOS bb or ba genotypes. At the end of the study genotypes reacted differently between pravastatin and placebo groups with respect to the change in adenosine-stimulated flow (ANCOVA P=0.008). More specifically, after pravastatin treatment the adenosine-stimulated flow increased by 54.5% in men with the eNOS ba genotype, whereas in the men with the bb genotype no significant change in flow was observed ( P=0.002 for ba versus bb). In the placebo group there were no significant changes in blood flow from the baseline values ( P=0.916 for ba versus bb). After pravastatin treatment both genotype groups showed a similar decrease in serum total cholesterol and low-density lipoprotein cholesterol ( P<0.00001 for both). Our results suggest that adenosine-stimulated myocardial perfusion improves after treatment with pravastatin in subjects with the eNOS ba genotype but not in those with the bb genotype. This effect is not dependent on the decrease of serum cholesterol.

Adult↗