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Biomedical subjects

A K Daly

Publications and source records attributed to A K Daly.

At least 19 recordsLinked to original sources
PubMed1998

Heterozygosity for hereditary hemochromatosis is associated with more fibrosis in chronic hepatitis C.

Hepatic iron has been associated with more aggressive liver disease in chronic viral hepatitis. We evaluated whether the recently described C282Y mutation of the hemochromatosis gene, designated HFE (responsible for at least 83% of hereditary hemochromatosis), was associated with more advanced liver disease in chronic hepatitis C. One hundred thirty-seven patients with biopsy-proven chronic hepatitis C were studied and liver biopsies scored for necroinflammation (grade 0-18) and fibrosis (stage 0-6). Genomic DNA was amplified by polymerase chain reaction and the C282Y mutation identified by restriction with RsaI and electrophoretic separation of restriction fragments. Ten (7.3%) patients had the C282Y mutation. No C282Y homozygous patients were identified. Age, sex distribution, and estimated weekly alcohol consumption were not significantly different between those with and without the mutation. Serum ferritin was higher in the heterozygotes (mean, 339 microg/L) compared with homozygous wild types (153 microg/L; P = .0005). In the majority of patients, liver iron was graded 0 out of 4, but hepatocyte iron staining was more commonly present in heterozygotes compared with homozygous normals (30% compared with 4% [P = .02]). Liver disease was more advanced in those with the mutant allele (mean fibrosis stage: 3.6, compared with wild type: 1.5 [P = .01]). Cirrhosis was found more often in those with the mutation (40%) compared with those without (8.7%) (P = .01; odds ratio: 7.6 [1.9-31.2]). There was no significant difference in inflammation scores between heterozygotes and wild type (mean, 5.4 compared with 4.1). Hepatitis C virus (HCV)-RNA titers were measured by branched DNA assay (HCV RNA 2.0-Chiron), and there was no difference between heterozygous and homozygous normal patients. Thus, despite relatively minor increases in iron stores, individuals who are heterozygous for hemochromatosis appear to develop more fibrosis in chronic hepatitis C. Venesection may be useful therapy in this subgroup.

Adult↗
PubMed1998

Tumour necrosis factor-alpha gene promoter polymorphism and decreased insulin resistance.

Insulin resistance is a feature of non-diabetic relatives of non-insulin-dependent diabetic (NIDDM) families. Tumour necrosis factor-alpha (TNF alpha) expression is linked with insulin resistance, and is under strong genetic control. We examined the relationship between insulin resistance and two polymorphisms of the TNF alpha promoter region (positions -238 and -308). Non-diabetic relatives (n = 123) of NIDDM families and control subjects (n = 126) with no family history of diabetes were studied. Insulin resistance was determined by homeostasis model assessment (HOMA) and short insulin tolerance test (ITT), and genotyping was by restriction digest. The -238 polymorphism (TNFA-A allele) was carried by 14 relatives and 11 control subjects, and all were heterozygotes. To examine the relationship between the -238 polymorphism and insulin resistance independent of potentially confounding factors, the relatives with the TNFA-A allele were individually pair-matched for age, sex, waist-hip ratio, body mass index, and glucose tolerance with relatives homozygous for the wild-type allele. Relatives with the TNFA-A allele had decreased insulin resistance (HOMA index: 2.0, 3.6 +/- 2.1 [means +/- SD of differences], p = 0.03), and this was true for comparable pair-matched control subjects (HOMA index: 1.1, 1.9 +/- 0.8, p = 0.01). Combining relative (n = 7) and control (n = 4) pairs that had undergone an ITT, subjects with the TNFA-A allele had an increased K(ITT) (3.8, 3.0 +/- 1.0%/min, p = 0.04) similarly indicating decreased insulin resistance. There was no significant relationship between the -308 polymorphism and insulin resistance. We conclude that the TNFA-A allele is associated with decreased insulin resistance as assessed by two independent methods, and may protect against the future development of NIDDM in susceptible individuals.

Adult↗
PubMed1998

No evidence for involvement of the interleukin-10 -592 promoter polymorphism in genetic susceptibility to primary biliary cirrhosis.

BACKGROUND/AIMS: Primary biliary cirrhosis is a chronic cholestatic liver disease with an autoimmune aetiology. Family studies, which have shown a significantly increased incidence of primary biliary cirrhosis in the close relatives of patients, suggest that genetic factors play a significant role in determining disease susceptibility. Several studies have previously identified loci which appear to play a role in determining this susceptibility, including the MHC class II allele HLA DR8, and the class III encoded C4A null allele (C4AQ0). Here, we have studied another candidate susceptibility locus in primary biliary cirrhosis, an apparently functional biallelic polymorphism at position -592 in the promoter region of the gene encoding the immuno-modulatory cytokine interleukin-10. Interleukin-10 plays an important role in the functional control, in vivo, of autoreactive Th-1 type CD4+ T-cells, with experimental manipulation of interleukin-10 leading to significant modulation of disease development in animal models of autoimmunity. METHODS: Interleukin-10 -592 genotypes were studied by polymerase chain reaction in 171 well-characterised, histologically-staged, primary biliary cirrhosis patients and 141 locally matched controls. RESULTS: Of 171 primary biliary cirrhosis patients, 99 were homozygous for the commoner allele (C/C), 68/171 (40%) were heterozygotes (A/C), whilst 4/171 (2%) were homozygous for the rarer allele (A/A). These genotype frequencies were not significantly different from those seen in controls (p=0.49, odds ratio 1.2 [0.8-1.91). CONCLUSIONS: These findings, in the first study of IL-10 as a candidate locus in a human autoimmune disease, suggest that IL-10 -592 is not a susceptibility locus in primary biliary cirrhosis.

Autoimmune Diseases↗
PubMed1998

The RsaI polymorphism of CYP2E1 and susceptibility to alcoholic liver disease in Caucasians: effect on age of presentation and dependence on alcohol dehydrogenase genotype.

Twin studies in Caucasians suggest that susceptibility to alcoholic liver disease is, in part, genetically determined. Because most of the deleterious effects of alcohol are caused by its metabolism, attention has focused upon genes encoding ethanol metabolizing enzymes. Caucasians are polymorphic at only two of these gene loci--cytochrome P450 2E1 (CYP2E1) and alcohol dehydrogenase 3 (ADH3). We examined the frequency of the RsaI polymorphism of CYP2E1 and ADH3 genotype in 264 patients with alcoholic liver disease and 121 local control individuals. There was a non-significant excess of the rare c2 CYP2E1 allele in patients with advanced liver disease compared with control individuals/patients with steatosis only (0.029 versus 0.017/0.00). However, patients with the c2 allele presented at a younger age compared with those with the wild type c1 allele only (42.3 +/- 1.6 years versus 49.0 +/- 0.6 years; P = 0.001) with at least as advanced histology (93% cirrhotic versus 74%). Male patients had a higher frequency of the ADH3*2/*2 genotype (which encodes the less active gamma2 subunit) than control individuals [odds ratio (OR) 2.04 (1.11-3.76)], however, ADH3 genotype did not differ with histological stage or with age of presentation. Patients with advanced disease possessing the c2 allele had a significantly higher frequency of the ADH3*2/*2 genotype compared with c1 homozygotes [OR 3.71 (1.24-11.09)]. This study demonstrates that, although rare in Caucasians, possession of the mutant c2 allele of CYP2E1 increases the risk of alcoholic liver disease at a given level of cumulative alcohol consumption. This risk appears to be particularly manifest in individuals carrying the ADH3*2 allele, presumably reflecting increased metabolism of ethanol by CYP2E1. In the absence of the c2 allele, ADH3 genotype does not influence the risk of advanced alcoholic liver disease but, in males at least, may influence the risk of alcoholism.

Age Distribution↗
PubMed1997

CYP2E1 genetic polymorphisms and risk of nasopharyngeal carcinoma in Taiwan.

BACKGROUND: Nasopharyngeal carcinoma occurs disproportionately among individuals of Chinese descent. The cytochrome P450 2E1 enzyme (CYP2E1) is known to activate nitrosamines and other carcinogens that are possibly involved in the development of this disease. Certain alleles of the CYP2E1 gene are thought to be more highly expressed than others, and their distribution varies between Asian and Caucasian populations. We conducted a case-control study to investigate whether such variations affect the risk of developing nasopharyngeal cancer. METHODS: Three hundred sixty-four patients with nasopharyngeal carcinoma (96% of 378 eligible patients) and 320 control subjects (86% of 374 eligible subjects) were studied. A risk factor questionnaire was administered to participants to assess factors postulated to be linked to nasopharyngeal carcinoma. Peripheral blood was obtained from all subjects and DNA was purified from nucleated cells. A polymerase chain reaction-based restriction fragment length polymorphism assay that used the restriction enzymes Rsa I and Dra I was used to detect wild-type and variant forms of the CYP2E1 gene. RESULTS: Individuals homozygous for an allele of the CYP2E1 gene that is detected by Rsa I digestion (c2 allele) were found to have an increased risk of nasopharyngeal carcinoma (relative risk [RR] = 2.6; 95% confidence interval [CI] = 1.2-5.7); this effect was limited to nonsmokers (RR = 9.3; 95% CI = 2.7-32) and was not affected by alcohol consumption. CONCLUSIONS: Our findings suggest that the CYP2E1 genotype is a determinant of nasopharyngeal carcinoma risk.

Adult↗
PubMed1997

Association of a tumor necrosis factor promoter polymorphism with susceptibility to alcoholic steatohepatitis.

Twin concordance studies suggest that genetic factors play a role in determining why only a minority of heavy drinkers develop hepatitis and cirrhosis. Tumor necrosis factor alpha (TNF-alpha) has emerged as the "final common pathway" in the pathogenesis of alcohol-related hepatic necro-inflammation. We have examined the frequency of the two recently described polymorphisms of the TNF-alpha promoter in 150 patients with biopsy-proven alcoholic liver disease and 145 healthy volunteers. There was a significant excess of the rare allele (TNFA-A; G(-238) --> A) at position -238 in patients with steatohepatitis compared with controls or patients without this lesion. This is consistent with previous suggestions that the TNFA-A allele, which falls within a putative Y regulation box of the TNF-alpha promoter, is associated with increased TNF-alpha expression. No differences were observed for the polymorphism at position -308.

Age Factors↗
PubMed1997

Genetic polymorphism of CYP2D6 and lung cancer risk in African-Americans and Caucasians in Los Angeles County.

The well described genetic polymorphism of the CYP2D6 gene influences response to a wide variety of therapeutic agents metabolized by the CYP2D6 enzyme product. CYP2D6 also appears to play a role, along with other cytochrome P450 enzymes, in the metabolic activation of the tobacco specific nitrosamine, NNK, as well as metabolism of nicotine to cotinine. While impaired activity of CYP2D6 was strongly protective against lung cancer in some studies, primarily based on phenotyping, the literature is conflicting. The molecular basis of CYP2D6 deficiency is now well understood, enabling the use of genotyping to classify individuals. We therefore examined whether lung cancer risk is reduced by the presence of four CYP2D6 alleles associated with impaired activity due to an inactivating mutation--CYP2D6*4, CYP2D6*3, CYP2D6*5 and CYP2D6*16--among 341 incident cases of lung cancer and 710 population controls of Caucasian or African-American ethnicity in Los Angeles County, California. We did not confirm a strong association between the presence of these inactivating alleles and lung cancer risk [odds ratio (OR) = 0.90, 95% confidence interval (CI) 0.60-1.35 for Caucasians], although there was a small decreased risk among the African-Americans (OR = 0.66, 95% CI 0.38-1.14). Among smokers, when the data are stratified according to lifetime smoking history, there is a suggestion of an association limited to Caucasian smokers of <35 pack-years, the median for all smokers in these data (OR = 0.49, 95% CI 0.23-1.04). However, among African-American smokers, who smoke less than Caucasians, the association did not differ between smoking categories. We also examined the possible role of additional copies of the CYP2D6 gene, which lead to enhanced CYP2D6 activity, in increasing lung cancer risk. Among controls the prevalence of having more than two copies of the CYP2D6 gene and no inactivating alleles was 4.3% for Caucasians and 4.9% for African-Americans. Relative to subjects with an inactivating allele, those with an additional copy of the CYP2D6 gene and no inactivating alleles may be at increased risk of lung cancer, particularly for adenocarcinoma (OR = 3.61, 95% CI 1.08-11.7 for African-Americans and OR = 2.20, 95% CI 0.69-6.0 for Caucasians). Our data suggest that the CYP2D6 genetic polymorphism is not the strong risk factor for lung cancer suggested by some studies of phenotype, but may play a minor role.

Adult↗
PubMed1997

Relationship between acetylator status, smoking, and diet and colorectal cancer risk in the north-east of England.

Some previous studies have suggested that the fast phenotype of the N-acetyltransferase NAT2 may confer susceptibility to colorectal cancer because of greater activation of dietary heterocyclic amines, particularly in individuals who also consume well-done red meat, but other studies have not supported this. We describe a large case-control study examining the interaction between dietary, smoking and drinking habits, and acetylation genotype in relation to susceptibility to colorectal cancer. One-hundred-and-seventy-four incident cases and 174 matched controls were recruited. Genotyping for polymorphisms in NAT2 was performed using a method that detects >95% of slow alleles and data on personal habits were collected using a standardized questionnaire. We found no difference in the frequency of the fast acetylator genotype between cases and controls [odds ratio = 0.95 (95% CI 0.61-1.49)], and analysis by sex, age and site also revealed no difference in acetylator genotype. There was, however, considerable heterogeneity in dietary risk factors between fast and slow acetylators. Analysis by acetylator type shows that recent smoking was more frequent in slow acetylator cases than matched controls [OR = 2.31 (1.16-4.6)] and that heavy alcohol consumption was also more frequent in the slow acetylator cases than controls [OR = 2.5 (1.02-7.29)]. In contrast, frequent fried meat intake was seen more frequently in fast acetylator cases than matched controls [OR = 6.0 (1.34-55)]. The odds ratio for the combination of fast acetylator status and frequent fried meat consumption in cases was 6.04 (1.6-26). Our study suggests that there may be different risk factors for colorectal cancer in slow and fast acetylators, and reveals a new observation that slow acetylators may be at risk of colon cancer from smoking. In our community, the overall effect of acetylator status on colorectal cancer risk is neutral.

Acetylation↗
PubMed1997

Antipsychotic drug-induced movement disorders in schizophrenics in relation to CYP2D6 genotype.

BACKGROUND: Approximately 5-10% of Caucasians (poor metabolisers) show impaired metabolism of at least 20 therapeutically important drugs, including a number of commonly used antipsychotic agents, because they lack the cytochrome p450 enzyme CYP2D6. The molecular basis of this defect is now well understood and simple genotyping tests using the polymerase chain reaction (PCR) have been developed. METHOD: To determine whether poor metabolisers are more susceptible to acute dystonic reactions and chronic movement disorders associated with the administration of antipsychotic drugs, we determined CYP2D6 genotypes in a group of 76 schizophrenics using previously described methods involving PCR and restriction fragment length polymorphism analysis. RESULTS: There was no difference in genotype frequencies between the schizophrenics and a normal control population, suggesting that CYP2D6 genotype was not a factor in determining susceptibility to the disease. However, four of the five poor metabolisers compared with 44% of the remaining subjects were suffering from a movement disorder at the time of the study, although because of the small number of poor metabolisers in the group the difference was not statistically significant. Poor metabolisers were not more likely to suffer an acute dystonic reaction. CONCLUSIONS: CYP2D6 genotype is not a determinant of susceptibility to acute dystonic reactions but may be a contributory factor in antipsychotic drug-induced movement disorders including tardive dyskinesia.

Antipsychotic Agents↗
PubMed1996

Ultrarapid metabolizers of debrisoquine: characterization and PCR-based detection of alleles with duplication of the CYP2D6 gene.

Up to 7% of Caucasians may demonstrate ultrarapid metabolism of debrisoquine due to inheritance of alleles with duplicated functional CYP2D6 genes. Here we describe the genomic organization of the duplicated CYP2D6 genes in the 42 kb XbaI allele. We postulate that this duplication originates from a homologous, unequal cross-over event which involved two 29 kb XbaI wild-type alleles, and had break points within a 2.8 kb direct repeat (CYP-REP) flanking the CYP2D6 gene. Moreover, we have designed two different PCR assays for detection of alleles with duplicated CYP2D6 genes. Both assays correctly identified 29 out of 29 subjects positive for the 42 kb XbaI allele. No false negative or false positive reactions were observed.

Alleles↗
PubMed1996

Stereoselective cardiotoxic effects of terodiline.

OBJECTIVE: To study the cardiovascular and electrocardiographic (ECG) effects of the R(+)- and S(-)- enantiomers of terodiline. The racemic drug was previously used to treat detrusor instability but was withdrawn after it caused serious ventricular arrhythmias associated with prolongation of the QT interval. METHODS: A double-blind, placebo-controlled, randomized crossover study was performed that involved nine healthy volunteers who were given single oral doses of racemic terodiline hydrochloride (200 mg), R(+)-terodiline hydrochloride (100 mg), S(-)-terodiline tartrate (100 mg), or placebo. Plasma concentrations of each enantiomer and cardiovascular and ECG effects, including QT intervals and QT dispersion, were measured over 14 days after each treatment. RESULTS: Both racemic and R(+)-terodiline significantly increased QT interval, corrected QT interval (QTc), and QRS duration (all p < 0.05), without affecting QT dispersion. S(-)-Terodiline tartrate (100 mg) did not affect QTc. Peak effects occurred 8 hours after dosing when increases in QTc from baseline (95% confidence intervals) were -3 (-20, 13) for placebo, 23 (8, 37) for racemic terodiline, 19 (6, 33) for R(+)-terodiline, and 0 (-10, 9) ms1/2 for S(-)-terodiline. Although differences were observed between the pharmacokinetics of the two enantiomers, these were not sufficient to account for the differences in ECG effects, and elimination half-lives were similar. Elimination of terodiline enantiomers was not significantly delayed in two genotypic poor metabolizers of debrisoquin (CYP2D6). CONCLUSIONS: QT prolongation associated with racemic terodiline is caused exclusively by the R(+)-enantiomer, which therefore appears to be responsible for the ventricular arrhythmias caused by the drug.

Adolescent↗
PubMed1996

Lung cancer risk in relation to the CYP2E1 Rsa I genetic polymorphism among African-Americans and Caucasians in Los Angeles County.

Genetic polymorphisms in the activation or detoxication of carcinogens, such as those in tobacco smoke, may produce differences in individual susceptibility to lung cancer. The cytochrome P450 CYP2E1 is an enzyme involved in the metabolism of nitrosamines in tobacco smoke. A polymorphism of CYP2E1 detectable by the restriction enzyme Rsa I may be functionally important because it is located in a putative binding site for the transcription factor HNF-1 and has been associated with higher levels of CYP2E1 transcription. It is conceivable that this CYP2E1 Rsa I polymorphism might contribute to differences in susceptibility to lung cancer. We conducted a case-control study of patients with incident lung cancer and population controls in Los Angeles County to examine the association between the CYP2E1 Rsa I polymorphism and lung cancer risk among African-Americans and Caucasians. Samples of white blood cell DNA sufficient for determination of the CYP2E1 Rsa I genotype by a polymerase chain reaction-based assay were obtained from 341 cases and 706 controls with data on lifetime smoking history. No subjects were homozygous for the CYP2E1 Rsa I rare c2 allele. The rare c2 allele was not associated with an increased risk of lung cancer (adjusted odds ratio, OR 0.72; 95% confidence interval, CI = 0.35-1.46). Among the population controls the percentage of subjects carrying the rare c2 allele was lower (p = 0.002) among African-Americans (2%) compared with Caucasians (8%). However, the association between the CYP2E1 Rsa I genotype and lung cancer risk did not differ between ethnic groups. There was no important association between the CYP2E1 Rsa I genotype and lung cancer risk in analyses stratified by cell-type, smoking history, gender, occupational asbestos exposure, and dietary intake of antioxidants vitamin C, vitamin E or beta carotene. Due to the low frequency of the c2 allele in these populations, larger studies would be necessary to rule out a modest association between the CYP2E1 Rsa I polymorphism and lung cancer risk.

Adult↗
PubMed1996

Nomenclature for human CYP2D6 alleles.

To standardize CYP2D6 allele nomenclature, and to conform with international human gene nomenclature guidelines, an alternative to the current arbitrary system is described. Based on recommendations for human genome nomenclature, we propose that alleles be designated by CYP2D6 followed by an asterisk and a combination of roman letters and arabic numerals distinct for each allele with the number specifying the key mutation and, where appropriate, a letter specifying additional mutations. Criteria for classification as a separate allele and protein nomenclature are also presented.

Alleles↗
PubMed1996

Characterization and PCR-based detection of two different hybrid CYP2D7P/CYP2D6 alleles associated with the poor metabolizer phenotype.

The majority of humans deficient in the cytochrome P450 CYP2D6 enzyme, so-called poor metabolizers (PMs), can now be identified by genotyping for several different PM-associated mutations. However, additional null alleles remain to be identified as demonstrated by subjects with the PM phenotype in the absence of a corresponding genotype. The rare 11 kb band on Xba I RFLP analysis, which is distinct from the 13 kb CYP2D6D (CYP2D6*5) allele, has been proposed to constitute such a unique non-functional allele. Here we demonstrate that the 11 kb band represents at least two different nine exon CYP2D7P/CYP2D6 hybrids generated by large deletions in the CYP2D gene cluster due to unequal cross-over or looping-out mechanisms. The total allele frequency was approximately 0.001-0.01 in European and North American Caucasians. The most common variant (CYP2D6*16) had breakpoints lying between the end of exon 7 and the start of exon 9 of the respective genes. The "CYP2D7-like' part of the gene was most homologous to the previously described CYP2D7AP and CYP2D7 (44/11.5) sequences. The other chimeric allele consisted of exon 1 of CYP2D7 and exons 2-9 from CYP2D6, and may be similar to a hybrid gene termed CYP2D6*13 recently described in a French individual. Two different routine PCR assays were developed for rapid and sensitive detection of these alleles, namely amplification of a 8 kb fragment from both CYP2D6*13 and CYP2D6*16, together with a CYP2D6*16-specific method which gave a 1.4 kb PCR product. The 8 kb assay for the CYP2D6*13 and CYP2D6*16 alleles also produced a 9.5 kb fragment in samples positive for the 13 kb CYP2D6*5 allele. Therefore, it is now possible to screen for the large CYP2D gene deletions by a single long PCR method.

Alleles↗