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PubMed1997

Apolipoprotein E genotyping in patients with neurodegenerative diseases.

OBJECTIVES: There is a growing demand to perform apolipoprotein E (Apo-E) genotyping on neuropathologic archive material. Due to the extremely long fixation time, this material is unsuitable for routinely used Apo-E genotyping methods. We present an investigation into the applicability of a new method. DESIGN AND METHODS: An Apo-E genotyping method was tested for use on formalin-fixed paraffin-embedded brain tissue, using semi-nested PCR followed by hybridization with biotin-labeled allele-specific oligonucleotides, and chemiluminescent detection. The method was applied to 88 archive samples of different neurologic disorders. RESULTS: With this technique 76% (67/88) of the samples could be genotyped. The crucial step is the semi-nested PCR. All the samples from which a PCR product could be obtained, the Apo-E gene could be genotyped without interpretation problems. Seventy-six percent of the samples that could not be genotyped, were fixed in unbuffered formalin. CONCLUSIONS: This technique offers a good Apo-E genotyping method applicable on neuropathological archive material in order to support in retrospect clinical studies.

Alzheimer Disease↗
PubMed1995

Familial sinistrality: the utility of calculating exact genotype probabilities for individuals.

Measures of familial sinistrality are frequently used in neuropsychological research. However they suffer from the problem that they are essentially a global measure of phenotypes in the family, whereas they are interpreted as an indicator of the genotype of the individual concerned. In this paper it is shown how to calculate a precise probabilistic estimate of a proband's genotype, given a particular genetic model of handedness, using all of the information available in a family tree. Example calculations are provided for a range of families with one or two sinistral relatives. Genotype probabilities are also calculated for a large population data set (the National Childhood Encephalopathy Study) and it is shown that familial sinistrality does not account for all of the variability present in the genotype probabilities, and that genotype probabilities provide an additional prediction of individual sinistrality after taking familial sinistrality into account, whereas all of the information in familial sinistrality is accounted for by the genotype probabilities. Finally it is shown how genotype probabilities can be used to assess whether there is heterozygote advantage for a characteristic, and using this method it is suggested that there is no support for heterozygotes having higher intellectual ability than homozygotes.

Family↗
PubMed2001

Apoprotein E genotype and the response of serum cholesterol to dietary fat, cholesterol and cafestol.

Previous studies on the effect of apoprotein E (APOE) polymorphism on the response of serum lipids to diet showed inconsistent results. We therefore studied the effect of apoprotein E polymorphism on responses of serum cholesterol and lipoproteins to various dietary treatments. We combined data on responses of serum cholesterol and lipoproteins to saturated fat, to trans-fat, to dietary cholesterol, and to the coffee diterpene cafestol with newly obtained data on the apoprotein E polymorphism in 395 mostly normolipidemic subjects. The responses of low-density lipoprotein (LDL-) cholesterol to saturated fat were 0.08 mmol/l larger in subjects with the APOE3/4 or E4/4 genotype than in those with the APOE3/3 genotype (95% confidence interval: -0.01-0.18 mmol/l). In contrast, responses of LDL-cholesterol to cafestol were 0.11 mmol/l smaller in subjects with the APOE3/4 or E4/4 genotype than in those with the APOE3/3 genotype (95% confidence interval: -0.29-0.07 mmol/l). Responses to dietary cholesterol and trans-fat did not differ between subjects with the various APOE genotypes. In conclusion, the APOE genotype may affect the response of serum cholesterol to dietary saturated fat and cafestol in opposite directions. However, the effects are small. Therefore, knowledge of the APOE genotype by itself may be of little use in the identification of subjects who respond to diet.

Adult↗
PubMed2001

Effect of glutathione S-transferase M1 genotype on progression of atherosclerosis in lifelong male smokers.

We hypothesize that smokers with the null genotype for GSTM1 (GSTM1-0), who thus lack the detoxification enzyme glutathione S-transferase mu-1, develop atherosclerosis at an increased rate compared to smokers with the positive genotype (GSTM1-1). We used data from a 2-year randomized placebo-controlled trial on the effect of vitamin E on atherosclerosis among 189 male smokers. Progression of atherosclerosis was measured by 2-year change of the common carotid intima media thickness (CCA-IMT) as measured by B-mode ultrasonography. The frequency of GSTM1-0 genotype was 0.5 in both the placebo and the vitamin E group. Smokers with GSTM1-0 genotype had a tendency to higher baseline CCA-IMT values than those with GSTM1-1 (0.97 versus 0.92 mm, P=0.09). Within the placebo group, more CCA-IMT progression was found for smokers with the GSTM1-0 than for smokers with the GSTM1-1 genotype after adjustment for baseline IMT and major CVD risk factors (0.050 versus -0.002 mm, P=0.046). In the vitamin E group no effect of GSTM1 genotype on atherosclerosis progression was found. Overall, smokers with GSTM1-0 genotype had a higher mean 2-year progression compared to those with GSTM1-1 as shown by a difference in increase of 0.042 mm (95% CI 0.006; 0.078, P=0.02). In conclusion, our data suggest that smokers lacking the detoxifying enzyme GST mu-1 develop progression of atherosclerosis at an increased rate.

Arteriosclerosis↗
PubMed1998

Association between angiotensin I-converting enzyme genotypes, extracranial artery stenosis, and stroke.

The insertion(I)/deletion(D) polymorphism of the angiotensin-converting-enzyme (ACE) gene has been associated with an increased risk of myocardial infarction, lacunar stroke, and with an increased intimal-medial thickness in several populations. The aim of this study was to evaluate whether the ACE I/D genotype is associated with stenosis of extracranial arteries and stroke in middle-aged and aged men and women. We studied 388 patients (247 male, 141 female) using Doppler and Duplex ultrasound of the extracranial arteries. Patients' history was obtained by standard questionnaire and by the hospital case records. Genomic DNA was analyzed by polymerase chain reaction (PCR) to identify the I/D polymorphism, with a second insertion specific PCR in samples classified as homozygous DD genotypes to prevent mistyping. The ACE genotype groups (DD 132, ID 164, II 92) were well matched for the basic characteristics. The DD genotype was more common in patients with extracranial artery stenosis > or = 50%, compared with patients without stenosis (59/147 versus 73/241, odds ratio 1.54, 95%-CI 1.01-2.37), but was not associated with a history of stroke (30/91 versus 102/297, odds ratio 0.94, 95%-CI 0.57-1.54). The association of the DD genotype with extracranial artery stenosis was also present in hypertensive subjects (n = 206, odds ratio 1.76, 95%-CI 0.99-3.17). In the whole group multiple logistic regression analysis revealed that the association of the DD genotype with extracranial artery stenosis was independent of age, gender, hypertension, hyperlipidemia, and diabetes. In conclusion, the ACE DD genotype is a weak risk factor for hemodynamically relevant stenosis of extracranial arteries, but not for stroke.

Adult↗
PubMed1999

The genotype interactions of methylenetetrahydrofolate reductase and renin-angiotensin system genes are associated with myocardial infarction.

We analyzed the evolution with age of the frequencies of the I/D polymorphism of the angiotensin I-converting enzyme (ACE), a1166c of the angiotensin II AT1 receptor (AT1R), M235T of the angiotensinogen (AGT) and A225V of their methylenetetrahydrofolate reductase (MTHFR) gene in a healthy (H) population and the subsequent comparison to age- and sex-matched groups of myocardial infarction (MI) subjects. A total of 472 H subjects were divided into three groups < 30, 30-55 and > 55 years old and 277 individuals with MI into two groups 30-55 and > 55 years old. The evolution with age showed that the AGT M allele (P < 0.001) and the MTHFR V allele (P < 0.05) frequency decreased with age in H men. The comparison between healthy and MI groups showed that the MM genotype frequency increased in MI men > 55 years (OR =4.16; 95% CI; 1.72-10.1) The cc genotype showed a similar behaviour (OR = 3.96; 95% CI; 1.21-12.9). In men, all the combinations with MM genotype presented a high risk, with OR values between 1.10 and 7.22. In women, the cc genotype increased in the MI > 55 group (OR = 6.66; 95% CI; 2.02-21.9). All the combinations with the cc genotype showed OR values between 1.71 and 13.3. The MM genotype in men and cc genotype in men and women, are independent risk factors for MI. We propose that the study of the allele frequency evolution in an H population at different ages is essential to determine risk factors for MI in case-control studies, since data from isolated age-matched groups can be misinterpreted.

Adult↗
PubMed1999

Prevalence of mixed infection by different hepatitis C virus genotypes in patients with hepatitis C virus-related chronic liver disease.

Multiple infection by different hepatitis C virus (HCV) genotypes may be of great clinico-pathologic interest. In this study we determined the effective prevalence of coinfections by two or more HCV genotypes in 213 subjects with HCV-positive chronic hepatitis by using genotype-specific polymerase chain reaction (PCR), genotype-specific probe hybridization, and direct sequencing. The most prevalent genotype was HCV-1b (54%). HCV-2 (a/c) was also prevalent (27%), and types 1a and 3a were found in 5% and 3% of patients, respectively. A mixed infection was detected in 23 patients (10.8%): 4 out of 23 were coinfected by types 1a + 1b, while the remaining 19 patients had a b + 2 (a/c) mixed infection. Further analysis based on restriction fragment length polymorphism (RFLP) on type-specific PCR products was used to verify genotyping results. Only four coinfections (1a + 1b in 2 patients and 1b + 2 (a/c) in the remaining 2 patients, respectively) were confirmed by enzyme cleavage. All patients with true coinfection had long-lasting infection and liver cirrhosis. Both true and false mixed infections resulting from RFLP analysis were confirmed by direct sequencing of type-specific amplification products. We also determined a recurrent C/T transversion at position 618 in all sequenced samples. In 4 cases another point mutation (G/A at position 626) was found, reducing the number of mismatches between HCV-2 and HCV-1b from 4 to 3 (or 2). Interestingly, all HCV-2 isolates sequenced showed the highest degree of nucleotide homology with HCV-2 subtype c, confirming the relatively high prevalence of this subtype in Italy. In conclusion, we showed the possibility of multiple infection by different HCV types in the general population of chronically infected patients without particular risk factors, even if in a low percentage of cases. Further studies are needed to assess the clinical relevance of chronic HCV infection with multiple genotypes.

Adult↗
PubMed1998

Prenatal diagnosis of the fetal Rhc genotype from peripheral maternal blood.

OBJECTIVE: To determine the fetal Rhc genotype by using the polymerase chain reaction (PCR) amplification procedure and maternal blood at the different steps of the fetal cell enrichment process. METHODS: Maternal peripheral venous blood samples were obtained from 11 pregnant women homozygous for the C antigen before amniocentesis. Three were not alloimmunized and eight were alloimmunized. The fathers were known to be heterozygous or homozygous for the c antigen by serologic testing. The mononuclear cell layer was isolated from maternal blood and flow sorted using monoclonal antibodies to CD36 or CD71 and glycophorin A. This was followed by PCR of the blood, mononuclear cells, and the sorted cells with allele-specific primers to RhCc genes. Gel electrophoresis was performed to predict fetal Rhc genotype. The fetal RhCc genotype was confirmed by serologic and DNA testing. RESULTS: All infants were positive for the Rhc gene. The positive fetal Rhc genotype was determined correctly in three of the 11 maternal blood samples without enrichment, in six of the nine mononuclear cell samples, and in seven of the eight sorted cell samples. The fetal genotype from one sorted sample was predicted to be homozygous C. One infant was determined by serology on cord blood to be negative for the c antigen, but repeated infant DNA amplification was consistent with the c genotype. CONCLUSION: Noninvasive fetal Rhc genotyping can be determined by PCR amplification of the rare fetal cells in maternal blood. These data reaffirm that enrichment of maternal blood for fetal cells is necessary to improve the sensitivity of the test.

Blood Grouping and Crossmatching↗
PubMedDate not supplied

Plasmodium falciparum: PCR detection and genotyping of isolates from peripheral, placental, and cord blood of pregnant Malawian women and their infants.

Polymerase chain reaction (PCR) is both a sensitive means of detecting malaria parasitaemia, and a simple tool for identifying genetic differences in parasites infecting human subjects. We compared PCR to microscopy in detection of Plasmodium falciparum infection in peripheral, placental and cord blood samples collected from 131 pregnant Malawian women and their infants in 1997-99. Infections detected by species-specific PCR were genotyped at the merozoite surface protein 1 and 2 loci, and minimum numbers of infecting genotypes determined. PCR was of similar sensitivity to microscopy in detecting peripheral and placental infection, and placental blood PCR was 100% specific compared to placental histology. Cord blood parasitaemia was more frequently detected by PCR than microscopy, 20% versus 6%. Genotype numbers in peripheral blood (mean 2.36; range 1-5), placental blood (mean 2.41; range 1-6) and cord (mean 2.14; range 1-4) were similar. The frequency of detection of each allelic family did not differ between sites. Genotypes from different sites in each patient were compared. In 69% of women, genotypes were detected in peripheral blood and not placenta, or vice versa, suggesting possible differential sequestration of different parasite populations. Cord blood genotypes were usually a subset of those in peripheral and placental blood, but, in some cases, genotypes were found in cord blood that were absent from the mother. Transplacental infection before term, and clearance of maternal infection, is postulated.

Adult↗
PubMed2003

Strong association between the GSTM1-null genotype and lung cancer in a Turkish population.

Glutathione S-transferases are possibly related to the detoxification of many xenobiotics involved in the etiology of cancer. To investigate the role of the glutathione S-transferase M1 deletion (GSTM1-null) in lung cancer, the polymerase chain reaction was used to determine the GSTM1 genotypes of lung cancer patients (n=101) and hospital (n=206) in a Turkish population. The prevalence of the GSTM1-null genotype in the case group was 48%, compared to 18% in the control group, giving an odds ratio (OR) of 4.14 (95% confidence interval [CI]=2.36-7.27). The analysis of patients by histologic type of lung cancer (10% adenocarcinoma, 43% squamous cell carcinoma, 26% small cell carcinoma, and 11% large cell carcinoma) showed no association between histopathologic type of lung cancer and GSTM1-null genotype. When the interaction between the GSTM1-null genotype and smoking status was analyzed, among the 67 smokers, the GSTM1-null genotype was found in 37 (55%) with an OR of 2.58 (95% CI=1.00-6.73) indicating a significant association. However, no association was found between smoking exposure (<30 and > or =30 packs/year) and GSTM1-null genotype. We conclude that, in this study the null GSTM1 genotype is an independent risk factor for the development of lung cancer for Turkish population.

Adult↗
PubMed1998

Genotyping of hepatitis B virus by restriction pattern analysis of a pre-S amplicon.

A method is described for genotyping of hepatitis B virus (HBV), based on the restriction fragment length polymorphism (RFLP) created by Ava2 and Dpn2 action on an amplified segment of the pre-S region. Analysing 51 database sequences by phylogenetic tree construction and RFLP prediction, the method was shown to be capable of detecting all known genotypes (A-F). The method was applied to 99 serum samples from hepatitis B e antigen (HBeAg)-positive chronic carriers, comparing observed agarose gel patterns with the RFLP predicted from the database sequences. In 95 typable samples the following genotypes were observed; 23 A, 20 B, 20 C, 22 D, 5 E and 5 F. Phylogenetic grouping of the 51 database sequences and RFLP genotyping of the 99 patient samples were compared with typing based on S gene analysis, showing disagreement in only one case, a database sequence of ayw subtype which was classified as genotype D by pre-S region and genotype A by S region analysis. This method should be useful for epidemiological investigations and for studying the potential influence of genotype on the course of infection.

Genotype↗
PubMed2002

Steatosis accelerates fibrosis development over time in hepatitis C virus genotype 3 infected patients.

BACKGROUND/AIMS: Steatosis is common in patients with hepatitis C virus (HCV) infection. Its influence on disease progression is only partially understood. The aim of this study was to evaluate the impact of steatosis on fibrosis progression over time in relation to HCV genotype. METHODS: We retrospectively analyzed 98 patients who underwent dual liver biopsies prior to antiviral treatment. The median follow-up time was 5.8 years. Biopsy specimens were assessed for necroinflammatory activity, fibrosis and steatosis. RESULTS: The prevalence and grade of steatosis were strongly associated with HCV genotype 3, independent of sex, age, body mass index and alcohol consumption. Progressive fibrosis was more prevalent in patients whose initial biopsy showed steatosis, an effect seen mainly in genotype 3 infected patients. Low-grade steatosis was observed in overweight patients, but high-grade steatosis was associated with genotype 3, independent of body mass index. CONCLUSIONS: Our data confirm the association between HCV genotype 3 and steatosis. Furthermore, we showed that steatosis in genotype 3 infected patients is a risk factor for progression of fibrosis. Therefore, patients with genotype 3 and steatosis ought to be recommended for early therapeutic intervention.

Adult↗
PubMed2003

The influence of hepatitis B virus genotype on the development of lamivudine resistance during long-term treatment.

BACKGROUND/AIMS: Genotype-dependent development of lamivudine resistance in hepatitis B virus (HBV) has not been reported. METHODS: We determined the cumulative rate of emergence of YMDD motif mutant in 213 Japanese patients with chronic hepatitis B infected with genotype A, B, or C and treated with lamivudine for more than 1 year. RESULTS: The emergence rate of lamivudine resistance was independent of the genotype (A, B, and C). In contrast, the emergence rate was significantly higher in the Ba ("a" stands for Asia) subgroup of HBV than in Bj ("j" for Japan) subgroup (P<0.05). For genotype C (HBV/C), the emergence rate in hepatitis B e antigen (HBeAg)-positive was significantly higher than in HBV/C-HBeAg-negative (P<0.05), but the rate in HBV/B-HBeAg-positive was similar to HBV/B-HBeAg-negative. Only four patients with HBV/C developed severe acute exacerbation of hepatitis accompanied by emergence of YMDD mutant, but none of the patients with other genotypes developed such complication. CONCLUSIONS: Our results suggest that lamivudine resistance in HBV does not seem to depend on the genotype but rather on the subgroup of HBV/B. The results also suggest that lamivudine resistance according to HBeAg state might be different between HBV/B and HBV/C. Large-scale prospective studies of each genotype should be conducted in the future to confirm these findings.

Adult↗
PubMed1996

Hepatitis C virus genotypes and subtypes in patients with hepatitis C, with and without cryoglobulinemia.

BACKGROUND/AIMS: Recent reports have shown a high frequency of anti-hepatitis C virus antibodies in patients with cryoglobulinemia. The factors involved in the production of cryoglobulins in hepatitis C virus-infected patients are unknown. To assess the role of hepatitis C virus genotypes in the pathogenesis of mixed cryoglobulinemia, we analyzed their prevalence in a group of 118 hepatitis C virus-infected patients according to the presence or absence of cryoglobulins. METHODS: The hepatitis C virus genome was typed using the Line Probe Assay (LiPA, Innogenetics), for the most common genotypes (1a, 1b, 2a, 2b, 3, 4 or 5). RESULTS: Cryoglobulinemia was diagnosed in 60 (51%) patients, 33 (55%) of whom had type II and 27 (45%) type III cryoglobulins. Forty-four (37%) patients had no cryoglobulinemia and 14 (12%) patients had transient cryoglobulins. Cryoglobulins were significantly less prevalent in patients infected by genotype 1a. We found no statistical link between the hepatitis C virus genotype and the presence of symptomatic cryoglobulinemia, or the hepatitis C virus genotype and the type (II or III) of cryoglobulin. Interestingly, all six patients infected by hepatitis C virus genotype 4 or 5 had cryoglobulins. CONCLUSIONS: In patients with hepatitis C virus infection, cryoglobulinemia is not strongly associated with a particular HCV genotype or subtype. The mechanism by which cryoglobulins are produced remains to be elucidated.

Adult↗
PubMed1998

Correlation between virus genotype and chronicity rate in acute hepatitis C.

BACKGROUND/AIMS: Forty-two patients with the diagnosis of acute hepatitis C virus hepatitis were studied to investigate the relationship between hepatitis C virus genotype and progression to chronic infection. METHODS: The patients were followed for more than 1 year (mean age 29 years, male/female ratio 2.5). Intravenous drug use was documented in 15 cases, blood transfusion in four, surgical intervention, dental therapy or other parenteral exposure in 15, and unknown factors in the remaining eight. The evolution to chronicity was diagnosed on the basis of a persistent increase in transaminase levels, the presence of HCV-RNA and the histological pattern of chronic hepatitis. RESULTS: The majority of cases presented hepatitis C virus infection of subtype 1a (38.1%) or 1b (33.9%). Six cases showed the presence of genotype 3a (14.3%). Subtype 2c was observed in three out of four cases infected with genotype 2. No significant association was demonstrated with documented risk factors. The overall chronicity rate was 59.5%. This value increased to 92% in individuals infected with genotype 1b. By multivariate analysis the age-adjusted odds ratio for infection with genotype 1b as compared with all other genotypes was 14.4 (95% confidence interval; 1.52-137). Moreover, significant differences (p= 0.0002) were present in this group for histological activity index (8.7 as compared with 5-7). CONCLUSIONS: The results of this prospective study are consistent with an independent association between hepatitis C virus genotype 1b and a poor prognosis.

Acute Disease↗
PubMed2002

HLA DQA1-DQB1 genotypes in Bedouin families with celiac disease.

Celiac disease (CD) has a strong genetic association with human leukocyte antigens (HLA). The primary susceptibility for CD is HLA-DQA1*05 DQB1*02 (also known as DQ2), with the remainder of cases primarily HLA-DQA1*03 DQB1*03 (also known as DQ8). In a set of nine Bedouin multiplex celiac disease families and one simplex, we genotyped DNA samples at HLA DQA1 and DQB1. Nineteen celiac disease patients had at least one DQA1*05 DQB1*02 genotype (= DQ2), 4 affecteds had the second most common genotype of DQA1*03 DQB1*0302 (= DQ8), 9 were DQ2 and DQ8, and 4 had at least one copy of DQB1*02 without the DQA1*05 genotype. Using transmission disequilibrium testing, we observed a significant over-representation in affecteds of the DQA1*05 DQB1*02 genotype (p = 0.0089), as well as over-representation of the DQA1*03 DQB1*0302 genotype (p = 0.078). The HLA DQA1 DQB1 high-risk genotypes associated with celiac disease are similar in these Bedouin families with CD to what is observed in Northern and Southern Europeans.

Alleles↗
PubMed1997

The genotype 2/2 of the presenilin-1 polymorphism is decreased in Spanish early-onset Alzheimer's disease.

We have found a significantly lower frequency of the presenilin-1 (PS-1) intronic polymorphism 2/2 genotype in early-onset Alzheimer's disease (AD) patients without APOE epsilon4 alleles (2/2 = 0.054; P = 0.009) as compared to age matched non-epsilon4 controls (2/2 = 0.227). Moreover the average age of onset in AD patients with the PS-1 2/2 genotype is older than that in AD patients with a 1/2 genotype or with a 1/1 genotype. This data suggest a protective effect of the 2/2 genotype which would delay the age of onset in AD. Our results do not support an association between the 1/1 genotype and AD. However, a non-significant increase of the 1/1 genotype is found in non-epsilon4 AD patients (P = 0.20).

Age of Onset↗
PubMed1997

Human identification by genotyping of personal articles.

In cases of personal identification of unknown skeletal remains, forensic scientists normally analyze an individual's genotype or phenotype by comparison with those of other family members such as patients. However, such genotyping does not necessarily provide conclusive proof of identity. In this study, we attempted personal identification by comparison of several short tandem repeat (STR) loci in samples from three corpses in various stages of decomposition with samples from personal articles of the respective individuals. The first victim had been found dead in a burned car. Almost 100% of his body was charred. The genotypes of the iliac bone from the burned body with regard to several STR loci were compared with those from a single hair recovered from the vacuum cleaner from the candidate's home. The second victim was found in a forest after more than 5 years. Several STR loci genotypes of skeletal bone were compared with those of the candidate's mummified umbilical cord kept in his parent's house. In the last case the victim was found in the sea after more than 7 months. The genotypes of the loci in the pubic bone of the corpse were compared with those of a menstrual bloodstain on the candidate's underwear left in the washing machine at her home. We succeeded in identification of the three cases by comparison of several VNTR and STR loci in the corpses with those in personal articles. In conclusion, personal identification can sometimes be performed more precisely by genotyping of personal articles than by comparison with the genotypes of relatives.

Adult↗