The genetics revolution and the assault on rheumatoid arthritis.
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Arthritis, Rheumatoid↗
Biomedical subjects
C I Amos
Publications and source records attributed to C I Amos.
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↗
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↗
A genome-wide search for susceptibility genes linked to alcohol dependence.
We performed two-point linkage analysis during a genome-wide search for susceptibility genes that predispose to alcohol dependence with the Collaborative Study on the Genetics on Alcoholism (COGA) data made available for the Genetic Analysis Workshop 11 (GAW11). For chromosomes 1 and 4 our findings supported results reported by Reich et al. [1998] based on the same data. We found similarity between our findings in regions on chromosomes 8 and 10 and reported results for schizophrenia linkage studies. Differences between our results with COGA data and those obtained by Reich et al. [1998] are due to our use of a lod score method versus their use of the affected relative pair (sib pair) method.
Alcoholism↗
Is there a genetic basis for lung cancer susceptibility?
The major risk factor for lung cancer is exposure to tobacco smoke. Exposure to radon, heavy metals used in smelting, and asbestos also greatly increase risks for lung cancer. However, only about 11% of tobacco smokers ultimately develop lung cancer, suggesting that genetic factors may influence the risk for lung cancer among those who are exposed to carcinogens. Further support for this hypothesis is provided by several epidemiological studies and also from molecular epidemiological studies. Epidemiological studies show approximately 14-fold increased risks for lung cancer among average tobacco smokers and approximately 2.5-fold increased risks attributable to a family history of lung cancer after controlling for tobacco smoke. Segregation analyses suggest that a rare autosomal dominant gene may explain susceptibility to early-onset lung cancer, but these results explain a minority of lung cancer cases, which include a family history. Therefore, more common genetic variants or polymorphisms are hypothesized to affect lung cancer risk. Environmental carcinogenesis resulting from tobacco smoke exposure is a complex process that can involve activation of procarcinogens that lead to adduct formation and subsequent failure of DNA repair, which should normally remove these adducts. Studies comparing DNA repair capacity among newly diagnosed lung cancer patients and age-matched controls indicate significant differences between the two groups. On culturing with bleomycin lymphocytes from lung cancer patients and age- and ethnicity-matched controls, the lymphocytes from lung cancer cases have been consistently observed to show higher levels of chromatid breaks than the control lymphocytes. A similar assay has been developed using benzo-[alpha]pyrene diol-epoxide (BPDE), a reactive substrate that is derived by in vitro processes from benzo[alpha]pyrene, a major carcinogen in tobacco smoke. Results from this assay show an even more significantly higher level of damaged chromatids in lung cancer patients than in controls. Poor DNA repair is independent of tobacco smoking status. The cellular processes involved in DNA repair of bleomycin and BPDE have not yet been fully elaborated. However, the consistency of findings with these two carcinogens indicates that DNA repair capacity influences risk for lung cancer among individuals.
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
Associations among telomerase activity, p53 protein overexpression, and genetic instability in lung cancer.
Genomic instability is a driving force for tumorigenesis. p53 and telomerase play central roles in maintaining genomic integrity. The purpose of this study was to assess the associations among p53 protein overexpression, telomerase activity and genetic instability in lung cancer. We found that telomerase activity was detectable in 80% of 100 lung tumours, but only 7.7% of 91 paired adjacent normal tissues. p53 protein was overexpressed in 63% of the tumours but only 2% of the normal tissues. p53 was overexpressed in 56 of the 80 (70%) tumour tissues with telomerase activity but only seven of the 20 (35%) without telomerase activity. p53 protein overexpression carried a 6.7-fold (95% confidence interval, 1.7-27.7) increased risk for positive telomerase activity after adjustment by age, sex, ethnicity, smoking status and family history of lung cancer. The mean in vitro bleomycin-induced breaks per cell (a marker of cancer susceptibility) was significantly higher (0.92) for patients who overexpressed p53 in lung tumour tissue than that for patients with no detectable p53 expression in lung tumour tissue (0.65). Our data suggest that p53 protein overexpression may be common in individuals genetically susceptible to carcinogen exposure. p53 status may be related to telomerase expression.
Adult↗
Genetic analysis of multiplex rheumatoid arthritis families.
To examine the genetic contribution of HLA and non-HLA genes in the etiopathogenesis of rheumatoid arthritis (RA), 60 Caucasian multiplex families were identified and DNA analyzed for over 52 markers including DRB1, DQA1 and DQB1 alleles. Many of the markers were chosen because of close proximity to candidate genes suggested by previous studies or models of pathogenesis. Sibling pair analysis (SIBPAL), relative pair analysis (RELPAL) and linkage studies using two different models of inheritance suggested linkage for the MHC and two additional chromosomal regions: chromosome 2 (D2S443 near CD8 and IGk; 2p13-2p11.1), and chromosome 15 (CYP19-estrogen synthase; 15q15). No support was found for two chromosomal regions, 1p36 and 3q13, recently suggested by other studies. We used transmission disequilibrium testing (TDT), conditional logistic regression, and segregation analysis to study the contributions that the shared epitope and TNF-c have in contributing to risk for RA. These studies provide additional evidence that the association of HLA alleles in RA patients from multiplex families is similar to that observed in sporadic disease, suggest candidate regions for further analysis and find additional support for an association of TNF-c alleles with RA susceptibility.
Adult↗
Comparison of linkage-disequilibrium methods for localization of genes influencing quantitative traits in humans.
Linkage disequilibrium has been used to help in the identification of genes predisposing to certain qualitative diseases. Although several linkage-disequilibrium tests have been developed for localization of genes influencing quantitative traits, these tests have not been thoroughly compared with one another. In this report we compare, under a variety of conditions, several different linkage-disequilibrium tests for identification of loci affecting quantitative traits. These tests use either single individuals or parent-child trios. When we compared tests with equal samples, we found that the truncated measured allele (TMA) test was the most powerful. The trait allele frequencies, the stringency of sample ascertainment, the number of marker alleles, and the linked genetic variance affected the power, but the presence of polygenes did not. When there were more than two trait alleles at a locus in the population, power to detect disequilibrium was greatly diminished. The presence of unlinked disequilibrium (D'*) increased the false-positive error rates of disequilibrium tests involving single individuals but did not affect the error rates of tests using family trios. The increase in error rates was affected by the stringency of selection, the trait allele frequency, and the linked genetic variance but not by polygenic factors. In an equilibrium population, the TMA test is most powerful, but, when adjusted for the presence of admixture, Allison test 3 becomes the most powerful whenever D'*>.15.
Alleles↗
Testing the robustness of the likelihood-ratio test in a variance-component quantitative-trait loci-mapping procedure.
Detection of linkage to genes for quantitative traits remains a challenging task. Recently, variance components (VC) techniques have emerged as among the more powerful of available methods. As often implemented, such techniques require assumptions about the phenotypic distribution. Usually, multivariate normality is assumed. However, several factors may lead to markedly nonnormal phenotypic data, including (a) the presence of a major gene (not necessarily linked to the markers under study), (b) some types of gene x environment interaction, (c) use of a dichotomous phenotype (i.e., affected vs. unaffected), (d) nonnormality of the population within-genotype (residual) distribution, and (e) selective (extreme) sampling. Using simulation, we have investigated, for sib-pair studies, the robustness of the likelihood-ratio test for a VC quantitative-trait locus-detection procedure to violations of normality that are due to these factors. Results showed (a) that some types of nonnormality, such as leptokurtosis, produced type I error rates in excess of the nominal, or alpha, levels whereas others did not; and (b) that the degree of type I error-rate inflation appears to be directly related to the residual sibling correlation. Potential solutions to this problem are discussed. Investigators contemplating use of this VC procedure are encouraged to provide evidence that their trait data are normally distributed, to employ a procedure that allows for nonnormal data, or to consider implementation of permutation tests.
Analysis of Variance↗
Testing for linkage under robust genetic models.
Robust genetic models are used to assess linkage between a quantitative trait and genetic variation at a specific locus using allele-sharing data. Little is known about the relative performance of different possible significance tests under these models. Under the robust variance components model approach there are several alternatives: standard Wald and likelihood ratio tests, a quasilikelihood Wald test, and a Monte Carlo test. This paper reports on the relative performance (significance level and power) of the robust sibling pair test and the different alternatives under the robust variance components model. Simulations show that (1) for a fixed sample size of nuclear families, the variance components model approach is more powerful than the robust sibling pair approach; (2) when the number of nuclear families is at least approximately 100 and heritability at the trait locus is moderate to high (>0.20) all tests based on the variance components model are equally effective; (3) when the number of nuclear families is less than approximately 100 or heritability at the trait locus is low (<0. 20), on balance, the Monte Carlo test provides the best power and is the most valid. The different testing procedures are applied to determine which are able to detect the known association between low density lipoprotein cholesterol and the common genotypes at the locus encoding apolipoprotein E. Results from this application show that the robust sibling pair method may be more effective in practice than that indicated by simulations.
Alleles↗
Intention to learn results of genetic testing for hereditary colon cancer.
INTRODUCTION: This report investigates the correlates of intention to find out genetic test results in colorectal cancer patients undergoing genetic counseling and testing for hereditary nonpolyposis colon cancer. Specifically, we investigated whether intention to learn genetic test results was associated with sociodemographic factors, medical history, psychosocial factors, attitudes, beliefs, and decisional considerations related to genetic testing. MATERIALS AND METHODS: Among 342 colorectal cancer patients who went through an informed consent process and gave blood for genetic testing and who were eligible for a psychosocial questionnaire study, 269 cases completed a baseline interview. Patients were contacted in person during a routine clinic visit or by letter and follow-up telephone call and were interviewed either in person or by telephone. RESULTS: In univariate analysis, intention to learn test results was positively associated with income, quality of life, a belief that being tested will help family members prevent cancer, being worried about carrying an altered gene, and a belief that one has the ability to cope with test results. It was negatively associated with a belief that genetic counseling is too much trouble relative to the benefits. Intention also was positively associated with scales measuring the pros of learning test results and the pros of informing relatives about test results; it was negatively associated with the cons of learning test results. In multivariable analysis, the belief that testing would help family members prevent cancer, being worried about carrying an altered gene, and the pros of learning test results remained statistically associated with intention when other variables were included in the model. CONCLUSIONS: Our findings showed that the positive aspects of genetic testing were more strongly associated with intention than were the negative aspects. They also showed that persons who stated an intention to learn their genetic test results were more likely than persons who did not to affirm both the benefits and the importance of such testing. These results are consistent with the literature on psychosocial aspects of genetic testing for breast cancer.
Adaptation, Psychological↗
Chromosome 5 aberrations and genetic predisposition to lung cancer.
In this study, we aimed to confirm the finding that chromosome 5 aberrations are predisposing factors for lung cancer. The study population consisted of 118 previously untreated lung cancer patients and 101 healthy controls. Lymphocytes were treated with bleomycin for 5 hr and then allowed to recover in a drug-free medium for 48 hr. The mean number of cells with chromosome 5 abnormalities among 100 cells examined was significantly higher in patients (9.12) than in controls (4.69) (p < 0.001). The most frequent aberration was a 5q deletion and the breakpoints clustered at the 5q13-5q31 region. We then dichotomized the number of induced chromosome 5 abnormalities in peripheral blood lymphocytes by the 75th percentile in that of the controls. 103 (87.3%), of the 118 patients, but only 31 (30.7%) of the 101 controls, exhibited induced breaks above this point. After adjustment for age, sex, ethnicity and smoking status, we found that the sensitive group was at 14.4-fold increased risk for lung cancer. There was also a significant (p < 0.01) gradient of increased risk for lung cancer with an increasing number of chromosome 5 lesions. Therefore, chromosome 5 lesions, especially those at 5q, may be a molecular target of carcinogens in the development of lung cancer.
Aged↗
Benzo[a]pyrene diol epoxide and bleomycin sensitivity and susceptibility to cancer of upper aerodigestive tract.
BACKGROUND: Tobacco smoking is an established risk factor for cancers of the upper aerodigestive tract, and measurement of chromosomal aberrations, i.e., chromatid breaks, induced in lymphocytes in vitro by bleomycin has been shown to be a predictor of risk for these cancers. In a case-control study, we recruited case subjects who were previously treated with surgery and/or radiotherapy for stage I or stage II squamous cell carcinoma of the head and neck to test the hypothesis that lymphocytic chromatid breaks induced by benzo[a]pyrene diol epoxide (BPDE), a tobacco mutagen, may also be associated with risk of developing cancers of the upper aerodigestive tract. METHODS: Case subjects were matched to control subjects on the basis of age, sex, ethnicity, and smoking status. Primary lymphocytes from 67 case subjects and 81 control subjects were treated with 2 microM BPDE for 24 hours, and the frequency of induced chromatid breaks was determined. All statistical tests were two-sided. RESULTS: Lymphocytes from case subjects compared with lymphocytes from control subjects showed significantly more breaks per cell induced by BPDE (mean+/-standard deviation, 0.77+/-0.38 versus 0.49+/-0.25; P<.001). Lymphocytes from 64.2% of case subjects were sensitive to BPDE (using a cutoff value of > or =0.60 break per cell). Subjects in the highest quartile of chromatid breaks had an approximately 20-fold increased risk of cancer compared with those in the lowest quartile after adjustment for age, sex, ethnicity, and smoking status. The association between BPDE sensitivity and cancer risk was higher in former smokers than in current smokers and higher in younger patients than in older patients. Subjects with sensitivity to both BPDE and bleomycin were at a 19.2-fold increased risk of cancer compared with those who were not sensitive to either agent. CONCLUSIONS: Mutagen sensitivity assays may aid in identifying individuals at risk of cancer, and use of parallel assays with two mutagens may improve risk predictability.
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
A parallel study of in vitro sensitivity to benzo[a]pyrene diol epoxide and bleomycin in lung carcinoma cases and controls.
BACKGROUND: Because only a fraction of smokers develop neoplastic lesions, host factors may affect their susceptibility to the carcinogenic effects of tobacco smoke. Benzo[a]pyrene diol epoxide (BPDE) is the metabolic product of benzo[a]pyrene (B[a]P), a constituent of tobacco smoke. Therefore, BPDE sensitivity may shed some light on smoking-related carcinogenesis. METHODS: First, differential BPDE sensitivity was tested in five lymphoblastoid cell lines. Then sensitivity to BPDE and bleomycin (an excellent lung carcinoma risk predictor) was tested in parallel in the lymphocytes of 57 lung carcinoma cases and 82 controls. RESULTS: The optimal BPDE treatment duration was 24 hours. The xeroderma pigmentosum cell line was the most sensitive, followed by head and neck cancer, ataxia telangiectasia, and normal cells. The mean breaks per cell for cases and controls were 0.78 and 0.46, respectively (P < 0.0001). BPDE sensitivity was significantly associated with lung carcinoma, with an odds ratio (OR) of 7.26, compared with an OR of 4.56 for bleomycin sensitivity. There was also a dose-response correlation between the quartiles of BPDE-induced breaks and lung carcinoma risk, with ORs of 2.39, 3.12, and 15.03. It is noteworthy that individuals who were sensitive to both BPDE and bleomycin had a significantly increased OR of 38.36. CONCLUSIONS: BPDE sensitivity may be a biologic marker to identify individuals who are susceptible to the carcinogenic effects of tobacco smoke. BPDE and bleomycin sensitivity might represent different repair or sensitivity pathways; however, when these assays are used in parallel, they might refine our ability to identify high risk individuals.
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
Segregation analysis of idiopathic talipes equinovarus in a Texan population.
"Idiopathic" talipes equinovarus (ITEV) is a nonsyndromal congenital anomaly of one or both feet. Casting and surgery are often necessary to obtain correct foot alignment. In spite of treatment, residual deformities of the feet occur and calf muscles may be hypoplastic. The cause of ITEV is unknown but genetic factors have been postulated. Complex segregation analysis was performed on 173 ITEV families including 93 Caucasian and 48 Hispanic families. The recessive mixed model was the best fitting model and no differences were found based on ethnicity. These results confirm previous studies suggesting that there is a genetic component to the development of ITEV.
Clubfoot↗
Variation in the region of the angiotensin-converting enzyme gene influences interindividual differences in blood pressure levels in young white males.
BACKGROUND: The renin-angiotensin system regulates blood pressure through its effects on vascular tone, renal hemodynamics, and renal sodium and fluid balance. METHODS AND RESULTS: Using data from a large population-based sample of 1488 siblings having a mean age of 14.8 years and belonging to the youngest generation of 583 randomly ascertained three-generation pedigrees from Rochester, Minn, we carried out variance components-based linkage analyses to evaluate the contribution of variation in four renin-angiotensin system gene regions (angiotensinogen, renin, angiotensin I-converting enzyme, and angiotensin II receptor type 1) to interindividual variation in systolic, diastolic, and mean arterial pressure. We rejected the null hypothesis that allelic variation in the region of the angiotensin-converting enzyme (ACE) gene does not contribute to interindividual blood pressure variability. After conditioning on measured covariates, variation in this region accounted for 0%, 13% (P=0.04), and 16% (P=0.04) of the interindividual variance in systolic, diastolic, and mean arterial pressures, respectively. These estimates were even greater in a subset of subjects with a positive family history of hypertension (0%, 29% [P=0.005], and 32% [P<0.005], respectively). In sex-specific analyses, genetic variation in the region of the ACE gene significantly influenced interindividual blood pressure variation in males (37% for SBP [P=0.03], 38% for DBP [P=0.04], and 53% for MAP [P<0.005]) but not in females. CONCLUSIONS: Although it is possible that variation in a gene near the ACE gene may explain the observed results, knowledge about the physiological involvement of ACE in blood pressure regulation supports the proposition that the ACE gene itself influences blood pressure variability in a sex-specific manner.
Adolescent↗
Case-control study of the D2 dopamine receptor gene and smoking status in lung cancer patients.
BACKGROUND: Interindividual differences in the structure and expression of the dopamine receptor genes affect dopamine availability and may be the genetic basis for variation in vulnerability to tobacco smoking. In this study, prevalences of polymorphisms in the TaqIA allele (A1 and A2) and the TaqIB allele (B1 and B2) of the D2 dopamine receptor gene in 157 lung cancer case patients and 126 control subjects were determined to assess whether individuals homozygous or heterozygous for the less common A1 and B1 alleles are more vulnerable to nicotine addiction. METHODS: Case and control subjects were accrued from an ongoing epidemiologic study. Blood samples were collected from them and subjected to molecular genetic analyses. Subjects were interviewed to obtain relevant information. Current and former smokers were administered a questionnaire to quantify their addiction to nicotine. RESULTS: The combined B1B2 genotypes appeared to be more prevalent in ever smokers than in never smokers among case patients (30.3% versus 13.3%; two-sided P = .233) and among control subjects (30.9% and 0%; two-sided P = .02); statistically significant differences were not observed among those with A1 genotypes. Statistically significant correlations between the presence of the A1 and B1 alleles were observed (r = .73 for case subjects and r = .76 for control subjects; two-sided P<.001). Individuals with rarer genotypes reported having been substantially younger at the time of smoking initiation (statistically significant for both A1 and B1) and having attempted to quit smoking fewer times (statistically significant for only A1). CONCLUSION: Variant alleles of the D2 dopamine receptor gene may play a role in determining nicotine addiction, although the associations between the at-risk genotypes and measures of nicotine addiction were not entirely consistent.
Aged↗
Exclusion of a p53 germline mutation in a classic Li-Fraumeni syndrome family.
Li-Fraumeni syndrome (LFS) is characterized by a high risk of sarcomas, early onset of breast cancer, and a diversity of other cancers occurring as multiple primary tumors in multiple family members. In many families with LFS, germline mutations within the tumor-suppressor gene p53 have been identified. However, mutations in p53 have not been detected in approximately 30% of LFS families. To address the possibility either that p53 mutations were being missed or that another predisposing gene is altered in LFS, we used a variety of methods to accurately determine the p53 status in a large LFS kindred. A transcriptional activation assay on exons 4-10 of p53 excluded a mutation within the DNA-binding domain of p53. Single-stranded conformational-polymorphism analysis, using intronic primers and sequencing of all the coding exons and intron/exon junctions, also yielded no mutations. Finally, linkage analysis excluded potential mutations in the noncoding regions of p53. Our findings exclude the presence of a p53 germline mutation in a classic LFS family.
Adult↗