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M de Andrade

Publications and source records attributed to M de Andrade.

At least 19 recordsLinked to original sources
PubMed2001

Gamma-radiation sensitivity and risk of glioma.

BACKGROUND: About 9% of human cancers are brain tumors, of which 90% are gliomas. gamma-Radiation has been identified as a risk factor for brain tumors. In a previous pilot study, we found that lymphocytes from patients with glioma were more sensitive to gamma-radiation than were lymphocytes from matched control subjects. In this larger case-control study, we compared the gamma-radiation sensitivity of lymphocytes from glioma patients with those from control subjects and investigated the association between mutagen sensitivity and the risk for developing glioma. METHODS: We used a mutagen sensitivity assay (an indirect measure of DNA repair activity) to assess chromosomal damage. We gamma-irradiated (1.5 Gy) short-term lymphocyte cultures from 219 case patients with glioma and from 238 healthy control subjects frequency matched by age and sex. After irradiation, cells were cultured for 4 hours, and then Colcemid was added for 1 hour to arrest cells in mitosis. Fifty metaphases were randomly selected for each sample and scored for chromatid breaks. All statistical tests were two-sided. RESULTS: We observed a statistically significantly higher frequency of chromatid breaks per cell from case patients with glioma (mean = 0.55; 95% confidence interval [CI] = 0.50 to 0.59) than from control subjects (mean = 0.44; 95% CI = 0.41 to 0.48) (P<.001). Using 0.40 (the median number of chromatid breaks per cell in control subjects) as the cut point for defining mutagen sensitivity and adjusting for age, sex, and smoking status, we found that mutagen sensitivity was statistically significantly associated with an increased risk for glioma (odds ratio = 2.09; 95% CI = 1.43 to 3.06). When the data were divided into tertiles, the relative risk for glioma increased from the lowest tertile to the highest tertile (trend test, P<.001). CONCLUSION: gamma-Radiation-induced mutagen sensitivity of lymphocytes may be associated with an increased risk for glioma, a result that supports our earlier preliminary findings.

Adult↗
PubMed2001

alpha-Synuclein gene haplotypes are associated with Parkinson's disease.

We report haplotype analysis of the alpha-synuclein gene in Parkinson's disease (PD), extending earlier reports of an association with a polymorphism within the gene promoter. This analysis showed significant differences in haplotypes between PD cases and controls. Our analyses demonstrate that genetic variability in the alpha-synuclein gene is a risk factor for the development of PD. These genetic findings are analogous to the tau haplotype over-represented in progressive supranuclear palsy and further extend the similarity in the etiologies and pathogeneses of the synucleinopathies and tauopathies.

Adult↗
PubMed2001

Risk assessment for developing gliomas: a comparison of two cytogenetic approaches.

Chromosome instability (CIN) measured as chromosome aberrations has long been suggested as a cancer susceptibility biomarker. Conventional cytogenetic end-points are now being improved by combining molecular methods, which increases the sensitivity, specificity, and precision of the assay. In this study we examined both spontaneous and gamma-ray induced CIN in lymphocyte cultures from 51 previously untreated glioma patients and 51 age-, sex- and ethnicity-matched controls. CIN was assessed using two parallel methods: (1) the mutagen sensitivity (MS) assay and (2) the multicolor fluorescence in situ hybridization (FISH) assay. The frequency of spontaneous breaks was significantly higher in glioma patients (mean+/-S.D., 2.12+/-1.07) than in controls (1.24+/-0.86, P<0.001) when using the FISH assay but not the MS assay (0.019+/-0.02 and 0.019+/-0.01, respectively; P=0.915). Similarly, the frequency of induced chromatid breaks was significantly higher using the FISH assay (3.39+/-1.72) but not the MS assay (0.42+/-0.16) in the patients versus controls (2.08+/-1.18 and 0.37+/-0.15, respectively; P<0.001 and P=0.10, respectively). By using the median number of breaks in the controls as the cutoff value, we observed an odds ratio (ORs) of 5.13 (95% CI=2.23-12.1) for spontaneous and 4.86 (95% CI=2.08-11.4) for induced CIN using the FISH assay, whereas the ORs were 1.32 (95% CI=0.49-3.58) and 1.28 (95% CI=0.59-2.80) for spontaneous and induced CIN using the MS assay. There was also a significant increase in the frequency of hyperdiploid cells in the glioma cases which could only be detected using the FISH assay (OR=4.0, 95% CL=0.9-17.0). By combining both methods an estimated risk of 7.0 (95% CI=1.7-25.6) was observed. There was no correlation between the breaks detected by the two methods suggesting that each method is a measure of a different event. The results indicate that using the multicolor FISH assay for detection of CIN in peripheral blood lymphocytes in glioma patients is a more useful marker for risk assessment.

Adult↗
PubMed2001

Segregation analysis of cancer in families of glioma patients.

A small proportion of brain tumors are attributed to a genetic predisposition; however, the hereditary proportion is undetermined. This study evaluates the degree of familial aggregation of cancer in a large series of brain tumor patients. Our study included 5,088 relatives of 639 probands (3,810 first- and 1,278 second-degree), diagnosed with a glioma between June 1992 and June 1995 at The University of Texas M. D. Anderson Cancer Center, Houston, Texas, with diagnosis under age 65 years, and residents of the United States or Canada. We conducted an in-person or telephone interview with patients and/or their next-of-kin, and obtained family histories for the probands' first-degree (parents, siblings, offspring) and selected second-degree relatives (aunts, uncles, grandparents) using a sequential sampling strategy. Reported cancers were documented by medical records and/or death certificates (if the relative was deceased and medical records were unavailable). We conducted segregation analysis using the Pedigree Analysis Program (PAP). The analyses were divided into two categories: (1) all 639 families, and (2) a subset of families whose gliomas stained positive on p53 immunohistochemistry analysis. We demonstrated that a multifactorial Mendelian model was favored, while a model postulating a purely environmental cause of brain cancer was rejected. This study indicates that familial cancer in relatives of glioma patients are probably a result of multigenic action, and familial clustering of cancer among relatives of glioma patients may involve unknown environmental exposures.

Adolescent↗
PubMed2001

A comparison of software packages that assess linkage using a variance components approach.

We report single-point and multipoint results from three statistical genetics software packages using a variance components approach for quantitative traits. When possible, we have shown the effects of covariates. Results from GENEHUNTER, SOLAR, and ACT software packages are compared for the quantitative trait immunoglobulin E (IgE) using chromosome 5 asthma familial data from Oxfordshire (England), Perth (Australia), and Freiburg (Germany), and using the genome-wide German data. Although few differences among variance components results for GENEHUNTER, SOLAR, and ACT were detected on a limited region of chromosome 5, these packages showed larger disagreement in the German data for chromosomes 1, 9, and 14.

Adult↗
PubMed2001

Practical application of residuals from survival models in quantitative trait linkage analysis.

A number of familial diseases have an age-of-onset component, which can be considered as a censored quantitative trait. However, few software resources are available for the use of time-to-event endpoints in linkage analysis. The purpose of this analysis was to examine the use of martingale residuals from Cox survival models as quantitative traits for familial diseases with variable age at onset. We used these residuals as quantitative traits in variance components linkage scans for the 50 replicates of the general population simulated data for chromosomes 6 and 7. The region on chromosome 6 containing markers D06G034 and D06G035 demonstrated evidence for linkage, consistent with the underlying genetic model. This analysis demonstrates the applicability of using martingale residuals as a quantitative trait in linkage analyses of diseases that depend on age of onset.

Adult↗
PubMed2001

Comparison of multivariate tests for genetic linkage.

OBJECTIVES: Multivariate tests for linkage can provide improved power over univariate tests but the type I error rates and comparative power of commonly used methods have not previously been compared. Here we studied the behavior of bivariate formulations of the variance component (VC) and Haseman-Elston (H-E) approaches. METHODS: We compared through simulation studies the bivariate H-E test with the unconstrained bivariate VC approach and with a VC approach in which the major-gene correlation is constrained to +/-1. We also compared these methods to univariate methods. RESULTS: Bivariate approaches are more powerful than univariate analyses unless the traits are very highly positively correlated. The power of the bivariate H-E test was less than the VC procedures. The constrained test was often less powerful than the unconstrained test. The empirical distributions of the bivariate H-E test and the unconstrained bivariate VC test conformed with asymptotic distributions for samples of 100 or more sibships of size 4. CONCLUSIONS: The unconstrained VC test is valuable for testing for preliminary linkages using multivariate phenotypes. The bivariate H-E test was less powerful than the bivariate VC tests.

Computer Simulation↗
PubMed2001

Genetic linkage methods for quantitative traits.

We discuss methods for detecting genetic linkage for quantitative data. The usual LOD score method uses a pseudolikelihood formulation and has optimal power provided all parameters are correctly specified, but can lead to erroneous estimates of the location for the locus influencing a trait under misspecification of parameters describing the variance of the trait. Alternative methods, in which attention focuses upon modelling covariation among relatives as a function of genetic marker, similarity lead to unbiased estimates of the location and major gene heritability of the trait influencing locus. The Haseman-Elston approach uses a regression method to perform linkage analysis and its properties have been widely studied. This method is generally less powerful than variance components procedures, but the maximum likelihood-based variance components procedures require normality of the trait to ensure robustness of the genetic linkage tests (i.e. a correct false positive rate). When samples are non-randomly selected an ascertainment correction is generally required in order to obtain unbiased parameter estimates when applying variance components methods. For quantitative traits, ascertainment corrections usually condition either on the proband exceeding a threshold, or on the trait value of the proband. We summarize simulations that show that both approaches lead to similar efficiencies for estimating genetic effects. Finally, we discuss methods for analysing diseases that include time-to-onset information. A variety of methods are available for the linkage analysis of quantitative traits. Here, we have reviewed the most commonly used methods.

Biometry↗
PubMed2001

The impact of population admixture on traditional linkage analysis.

INTRODUCTION: Families of admixed ancestry are routinely excluded from traditional (Log of the Odds [LOD] score) linkage analysis or are analyzed as being derived from a homogeneous population using the proband's ethnicity. Using traditional linkage analysis with these families can cause complications due to the mixing of different disease rates and allele frequencies that occurs. The presence of admixture violates the key assumptions of Hardy-Weinberg Equilibrium (HWE) and Linkage Equilibrium (LE) invoked in the current methods of linkage analysis. If one or more of these assumptions are violated, incorrect inference for linkage could result. DESIGN AND METHODS: Through simulation, we investigated the effect of admixture of two populations on the LOD score under various conditions, using prostate cancer as our underlying disease model. Four-generation homogeneous and admixed families were simulated with 27 markers and two linked, bi-allelic disease loci. Two different types of admixture were tested: admixture within a family unit and a mixture of homogeneous families within a data set. All mixing was done at the founder level in three different proportions: 30/70, 50/50 and 70/30. RESULTS AND CONCLUSIONS: We observed that the LOD scores under both models of admixture were closest to the homogeneous family scores of the population having the highest mixing proportion. Random sampling of families or ascertainment of families with disease affection status did not affect this observation, nor did the mode of inheritance (dominant/recessive) or sample size. Thus, the presence of families of mixed population ancestry impacts linkage analysis in terms of the LOD score and the estimate of the recombination fraction.

Alleles↗
PubMed2000

Analysis of aromatic DNA adducts and 7,8-dihydro-8-oxo- 2'-deoxyguanosine in lymphocyte DNA from a case-control study of lung cancer involving minority populations.

The purpose of this study was to examine the level of smoking-related aromatic DNA adducts and oxidative DNA damage in current smokers from a lung cancer case-control study in African Americans and Mexican Americans. In addition, mutagen sensitivity (bleomycin-induced chromatid breaks), a marker of genetic susceptibility, was assessed in these patients and correlated with the level of DNA damage. Lymphocyte DNA from cases and age-, sex-, and ethnicity-matched controls was analyzed for aromatic DNA adducts (43 cases and 47 controls) and the level of 7, 8-dihydro-8-oxo-2'-deoxyguanosine (8-oxo-dG) was determined in 46 cases and 48 controls using (32)P-postlabeling. Overall, lung cancer cases had significantly (P < 0.05) higher levels of aromatic DNA adducts and 8-oxo-dG (mean+/-SEM; 6.03+/-1.16/10(8) nucleotides and 5.82+/-0.77/10(5) nucleotides, respectively) compared to the controls (2.80+/-0.36/10(8) nucleotides and 3.65+/-0.56/10(5) nucleotides, respectively). The case-control differences for these two biomarkers were especially evident in current smokers. Both male and female lung cancer cases had higher levels of aromatic DNA adducts compared to the corresponding controls but only in men was the difference statistically significant (P=0.002). Cases who started smoking at earliest age had highest levels of aromatic DNA adducts and 8-oxo-dG. The level of aromatic DNA adducts in lung cancer cases, but not controls, was positively correlated with bleomycin-induced chromatid breaks (P=0.011). In contrast, the level of 8-oxo-dG was not correlated with mutagen sensitivity in either cases or controls or with the level of aromatic DNA adducts. The data suggest that levels of both aromatic DNA adducts and 8-oxo-dG may be useful in predicting risk of lung cancer in these minority populations. The correlation between aromatic DNA adducts and mutagen sensitivity in lung cancer cases and the trend for higher levels of DNA damage in cancer cases who started smoking earliest are particularly interesting and merit further study.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2000

Ascertainment issues in variance components models.

One of the main concerns in the family studies of complex diseases is the effect that ascertainment and correction for it may have on test procedures and estimators. Elston and Sobel [1979] and Hopper and Mathews [1982] proposed two ways to correct for ascertainment in the study of quantitative trait data. For single ascertainment, using a variance components approach, we present results of simulation studies comparing estimates from these two methods for different selection criteria. We also show results from simulations when ascertained families are analyzed either at random or by correcting for ascertainment. For discordant sibpairs, we compare a variance components model that incorporates ascertainment correction with the extreme discordant sib pairs (EDSP) design proposed by Risch and Zhang [1995]. Our results show that there is minimal difference between the two methods of ascertainment correction. In the presence of effects from a large genetic background and the segregation of a rare gene, both ascertainment affected the polygenic and environmental components of variance but had rather little impact on the estimate of the linked major gene component of variance. The results also show the EDSP is slightly more powerful the variance components procedures for common alleles, and the variance components procedure is much more powerful than using EDSP when there is a rare allele segregating in the population.

Family Health↗
PubMed2000

Gender difference in smoking effect on chromosome sensitivity to gamma radiation in a healthy population.

In the general population, there is variation in radiosensitivity associated with cancer risk. However, data on the role of epigenetic factors in the variation of radiosensitivity are scarce. Thus we investigated the effects of smoking and age on the radiosensitivity of human lymphocytes by measuring the frequency of chromosome aberrations after in vitro exposure to gamma rays in peripheral lymphocytes from 441 healthy subjects (18-95 years old). We analyzed the frequency of both spontaneous (baseline) and in vitro gamma-ray-induced (1.5 Gy) chromatid breaks in 50 well-spread metaphases per subject. The overall mean frequencies of spontaneous and induced breaks were 0.02 and 0.45 per cell, respectively. The mean frequency of induced breaks was significantly higher in men than in women (P = 0.03) but did not differ by age or ethnicity. Donors who had ever smoked showed a small but significantly increased frequency of induced breaks (mean = 0.47) compared to nonsmokers (mean = 0.41; P = 0.005). Further stratification and multivariate analyses revealed that the smoking effect was more pronounced in men than in women. These findings support a smoking effect on radiosensitivity in a healthy population, particularly in men. Therefore, when evaluating the association between radiosensitivity and susceptibility to smoking-related cancers, the effect of smoking should be taken into account.

Adult↗
PubMed2000

Statistical models for analysis of cytogenetic biomarkers.

BACKGROUND: Bleomycin-induced chromosomal breaks (CB) and sister chromatid exchange (SCE) in peripheral blood lymphocytes have been shown to be sensitive cytological markers for susceptibility to DNA damage in patients with various types of cancer and in healthy controls. Factors such as age, sex, smoking, and alcohol consumption could affect the values of some of these biomarkers and should be considered as covariates when analyzing cytogenetic biomarkers because these factors can affect the frequency of CB and SCE. METHODS: We propose a statistical method using negative binomial (NB) distribution to evaluate the numbers of CB and SCE. In order to determine the best model to represent the frequency of CB and SCE, we compared the NB model with the widely used Poisson model and log-transformed normal model by using generalized linear models. To demonstrate the better fit of the NB model, we analyzed three different data sets from studies conducted at The University of Texas M.D. Anderson Cancer Center. The first set was a case-control study of lung cancer in a population of African Americans and Mexican Americans (286 cases and 156 controls), the second set consisted of 311 head and neck cancer patients, and the third set consisted of 105 Hodgkin's disease patients. RESULTS: For CB; the estimates of the variability for Hodgkin's disease, head and neck, and lung cancers were 487.24, 502.82, and 520.15, respectively. For SCE, the estimates of the variability for Hodgkin's disease was 9777.01. For CB, the dispersion estimates under the three models (Poisson, NB, and Normal) for Hodgkin's disease, head and neck, and lung cancers were: 12.30, 1.20, 0.85; 8.94, 1.05, 0.22; and 10.10, 1.05, 0.25, respectively. For SCE (Hodgkin's disease only), the dispersion estimates under the three models (Poisson, NB, and Normal) were 30.91, 1.11, 0.10, respectively. CONCLUSIONS: Our results demonstrate that the NB model provides a better interpretation and fit for the frequency of CB and SCE in different cancer types. Therefore, we recommend it as a model for the analysis of cytogenetic biomarkers.

Biomarkers↗
PubMed2000

Dietary intake of isothiocyanates: evidence of a joint effect with glutathione S-transferase polymorphisms in lung cancer risk.

Isothiocyanates (ITCs) are nonnutrient compounds in cruciferous vegetables with anticarcinogenic properties. One proposed mechanism for their protective action is through down-regulation of cytochrome P-450 biotransformation enzyme levels and induction of phase II detoxifying enzymes. Because ITCs also serve as a substrate for GSTs, we evaluated dietary intake of ITCs and GSTM1 and GSTT1 genotype information in a lung cancer case-control study. There were 503 newly diagnosed lung cancer cases (264 men and 239 women) identified from The University of Texas M. D. Anderson Cancer Center and 465 controls (252 men and 213 women) recruited from enrollees in a local managed care organization. Subjects had an in-person interview including a semiquantitative food frequency questionnaire, and blood samples were obtained for genotyping. Cases reported significantly lower ITC intake per day compared with controls (P = 0.009). There was no main effect associated with the GSTM1 null genotype [odds ratio (OR) = 1.09]. However, there was a statistically significant OR of 1.41 associated with the GSTT1 null genotype. On stratified analysis, low ITC intake and the GSTM1 null genotype were associated with increased lung cancer risk in current smokers, with an OR of 2.22 [confidence interval (CI) = 1.20-4.10). For current smokers with the GSTT1 null genotype, the OR with low ITC intake was 3.19 (CI = 1.54-6.62). The comparable OR in the presence of both null genotypes was 5.45 (CI = 1.72-17.22). These effects were not demonstrable for former smokers by GSTM1 genotype, although the risk for low ITC intake and GSTT1 null genotype was 1.79 (CI = 0.95-3.37). Thus, current smokers who are homozygous null for the GST null genotype and who consume less carcinogenic blocking compounds are at higher lung cancer risk. Some of the inconsistencies reported in the role of GST genotypes in lung cancer risk could be due to unexpected confounding from dietary factors.

Aged↗
PubMed1999

Methods to estimate genetic components of variance for quantitative traits in family studies.

The aim of this paper was to compare several methods of estimating the genetic components of a quantitative trait in familial data. The Expectation and Maximization (E-M) algorithm, the Newton-Raphson method, and the scoring method were compared for estimating polygenic and environmental effects on nuclear families. We also compared scoring and quasilikelihood (QL) methods when a linked genetic marker was available to estimate effects from a major gene. Generally, all procedures performed similarly in estimating polygenic and environmental variance components. The E-M algorithm yielded more precise estimators when heritability was low. The scoring method was much faster than the other methods and yielded slightly more precise estimates of mean effects but slightly less precise estimates of the variance components. Estimates of major gene effects were not affected by the number of alleles at the trait locus. For these relatively large sample sizes, QL and scoring had similar precision, but QL took 32 times longer than scoring. Finally, we compared the results of applying these methods to data from the Bogalusa Heart Study. Results showed larger imprecision when the QL method was applied, consistent with earlier studies that showed decreased precision of quasilikelihood compared with maximum likelihood in moderately small sample sizes.

Algorithms↗
PubMed1999

Assessing linkage of monoamine oxidase B in a genome-wide scan using a univariate variance components approach.

We report results when one alcoholism related quantitative trait, monoamine oxidase B (MAOB), is analyzed by the variance components approach for linkage [Amos, 1994; Amos et al., 1996] using the Collaborative Study on the Genetics of Alcoholism data set provided for the Genetic Analysis Workshop 11. We used two different covariate models, one with age at interview, sex, ethnicity, and smoking status and the other with age at interview, sex, and ethnicity. The univariate analysis showed 24 markers on four different chromosomes (1, 4, 9, and 12) to have evidence for linkage with the quantitative trait (single-point and multipoint linkage). However, when outliers for MAOB were removed, the significant evidence for linkage disappeared.

Chromosomes, Human, Pair 1↗
PubMed1999

Genome scans for genetic predisposition to alcoholism by use of transmission disequilibrium test analyses.

We report the results of the analysis of three measures of alcoholism and six associated symptoms using transmission disequilibrium (TDT) analysis on data from the Collaborative Study on the Genetics of Alcoholism data set. Implementation of identity-by-state (IBS) routines for error checking revealed 10 reported full siblings that were rejected as a full sibling to all of their purported full siblings with p < 0.05. TDT analysis revealed two loci with significant transmission disequilibrium (p < 0.001) on chromosomes 1 and 7. Analysis by parental origin found alleles at three loci displaying significant disequilibrium in the transmission of the paternal alleles for at least three of the nine tested traits. These loci are on chromosomes 6, 9, and 13. Analyses of Caucasian families alone and the use of a single affected individual from each family also yielded significant results for the loci on chromosomes 6, 9, and 13.

Alcoholism↗