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Biomedical subjects

C I Amos

Publications and source records attributed to C I Amos.

At least 73 records · Page 4Linked to original sources
PubMed1998

Familial clustering of rheumatoid arthritis with other autoimmune diseases.

Previous studies have shown that rheumatoid arthritis aggregates within families. However, no formal genetic analysis of rheumatoid arthritis in pedigrees together with other autoimmune diseases has been reported. We hypothesized that there are genetic factors in common in rheumatoid arthritis and other autoimmune diseases. Results of odds-ratio regression and complex segregation analysis in a sample of 43 Caucasian pedigrees ascertained through a rheumatoid arthritis proband or matched control proband, revealed a very strong genetic influence on the occurrence of both rheumatoid arthritis and other autoimmune diseases. In an analysis of rheumatoid arthritis alone, only one inter-class measure, parent-sibling, resulted in positive evidence of aggregation. However, three inter-class measures (parent-sibling, sibling-offspring, and parent-offspring pairs) showed significant evidence of familial aggregation with odds-ratio regression analysis of rheumatoid arthritis together with all other autoimmune diseases. Segregation analysis of rheumatoid arthritis alone revealed that the mixed model, including both polygenic and major gene components, was the most parsimonious. Similarly, segregation analysis of rheumatoid arthritis together with other autoimmune diseases revealed that a mixed model fitted the data significantly better than either major gene or polygenic models. These results were consistent with a previous study which concluded that several genes, including one with a major effect, is responsible for rheumatoid arthritis in families. Our data showed that this conclusion also held when the phenotype was defined as rheumatoid arthritis and/or other autoimmune diseases, suggesting that several major autoimmune diseases result from pleiotropic effects of a single major gene on a polygenic background.

Adult↗
PubMed1998

Segregation analysis of squamous cell carcinoma of the head and neck: evidence for a major gene determining risk.

We and others have shown that a family history of squamous cell carcinoma of the head and neck (SCCHN) is a risk factor for this disease. We performed a segregation analysis on a dataset comprised of 1429 first-degree relatives of 242 unselected cases of SCCHN and 934 first-degree relatives of 156 spouse controls. Using the SAGE software, we demonstrated that a Mendelian model was favored and a model postulating a purely environmental cause of SCCHN was rejected. The model suggests that 18% of the population who smoke and drink are susceptible. The lifetime risk for non-smokers and non-drinkers who are heterozygotes for the susceptible allele is close to zero, but for those heterozygotes who smoke and drink the risk is 14% by age 70. These findings suggest that specific genetic factors account for a significant fraction of the risk of SCCHN associated with a family history of SCCHN.

Alcohol Drinking↗
PubMed1998

Genetic linkage analysis using lognormal variance components.

Typically genetic studies of continuous traits such as cholesterol levels or blood pressure assume that interindividual variability follows a normal distribution. Here we develop methods to analyze positively skewed data by assuming a lognormal distribution. We develop a variance components approach for identifying such effects from a major gene, residual polygenic factors and nongenetic factors. We compare by a simulation study results from fitting this lognormal model with either applying the log transformation or not transforming the data. We found that the lognormal model provided more precise estimates and more powerful tests than a simple log transformation when analyzing lognormally distributed data. Power varied with sibship size. For the same total number of nonindependent sibpairs, larger sibships were less powerful. However, larger sibships are more economical because they require a smaller sample size to obtain a specified power. To illustrate the application of this lognormal model to real data, we studied evidence for linkage between triglycerides and the lipoprotein lipase gene.

Genetic Linkage↗
PubMed1998

The quantitative LOD score: test statistic and sample size for exclusion and linkage of quantitative traits in human sibships.

We present a test statistic, the quantitative LOD (QLOD) score, for the testing of both linkage and exclusion of quantitative-trait loci in randomly selected human sibships. As with the traditional LOD score, the boundary values of 3, for linkage, and -2, for exclusion, can be used for the QLOD score. We investigated the sample sizes required for inferring exclusion and linkage, for various combinations of linked genetic variance, total heritability, recombination distance, and sibship size, using fixed-size sampling. The sample sizes required for both linkage and exclusion were not qualitatively different and depended on the percentage of variance being linked or excluded and on the total genetic variance. Information regarding linkage and exclusion in sibships larger than size 2 increased as approximately all possible pairs n(n-1)/2 up to sibships of size 6. Increasing the recombination (theta) distance between the marker and the trait loci reduced empirically the power for both linkage and exclusion, as a function of approximately (1-2theta)4.

Chromosome Mapping↗
PubMed1998

Linkage of familial Hibernian fever to chromosome 12p13.

Autosomal dominant periodic fevers are characterized by intermittent febrile attacks of unknown etiology and by recurrent abdominal pains. The biochemical and molecular bases of all autosomal dominant periodic fevers are unknown, and only familial Hibernian fever (FHF) has been described as a distinct clinical entity. FHF has been reported in three families-the original Irish-Scottish family and two Irish families with similar clinical features. We have undertaken a genomewide search in these families and report significant multipoint LOD scores between the disease and markers on chromosome 12p13. Cumulative multipoint linkage analyses indicate that an FHF gene is likely to be located in an 8-cM interval between D12S77 and D12S356, with a maximum LOD score (Z max) of 3.79. The two-point Z max was 3.11, for D12S77. There was no evidence of genetic heterogeneity in these three families; it is proposed that these markers should be tested in other families, of different background, that have autosomal dominant periodic fever, as a prelude to identification of the FHF-susceptibility gene.

Chromosome Mapping↗
PubMed1998

Deletion in poly(ADP-ribose)polymerase pseudogene and lung cancer risk.

The poly(ADP-ribose)polymerase (PADPRP) gene has been implicated in carcinogenesis through its role in DNA repair, replication and recombination. A two-allele polymorphism in the chromosome 13 PADPRP pseudogene has been studied in several racial groups. It has been suggested that the B allele, which results from a 193-bp deletion in the gene, predisposes to myeloma in Blacks. We assessed the association between chromosome 13 PADPRP pseudogene genotype, mutagen sensitivity (a marker reflecting host DNA repair capability), cigarette smoking, and lung cancer risk in a minority lung cancer case-control study. The chromosome 13 PADPRP pseudogene polymorphism was detected by polymerase chain reaction-based analysis. Mutagen sensitivity was measured by an in vitro assay that quantified bleomycin-induced chromatid breaks in peripheral blood lymphocyte cultures. We examined 121 cases (80 African-Americans and 41 Mexican-Americans) with previously untreated lung cancer and 171 matched controls. Our results suggested that the distribution of the PADPRP pseudogene genotype frequencies was significantly different among African-American and Mexican-American controls (P < 0.001). The susceptibility genotype (i.e. at least one B allele) was found in 82.5% of African-American cases, 79.4% of African-American controls, 53.7% of Mexican-American cases, and 32.4% of Mexican-American controls. The odds ratios (OR) and 95% confidence intervals for the PADPRP susceptibility genotypes were 2.3 (95% CI = 0.7-8.0) and 3.2 (95% CI = 1.0-10.3) for African-Americans and Mexican-Americans respectively, after adjustment by age, sex, pack-years and mutagen sensitivity. Patients with the susceptibility genotype appeared to have more mutagen-induced breaks than did patients with the other genotype. Only adenocarcinoma was significantly associated with the PADPRP susceptibility genotype (OR = 3.8). Mutagen sensitivity (> or = 1 break/cell) was significantly associated with lung cancer risk for both ethnic groups with increased ORs of above three-fold. On stratified analysis, synergistic interactions were noted for the PADPRP susceptibility genotype, mutagen sensitivity and smoking status. In Mexican-Americans, the ORs for PADPRP susceptibility genotype, mutagen sensitivity and both risk factors combined were 1.3, 2.7 and 17.1 respectively. The combined OR for the PADPRP susceptibility genotype and smoking status was 15.6. Therefore, this polymorphism appears to be associated with lung cancer risk. However, it is likely that no single genotype is sufficiently predictive of risk and that a panel of susceptibility markers is needed to define the high-risk subgroup.

Black People↗
PubMed1998

The role of germline polymorphisms in the T-cell receptor in susceptibility to ankylosing spondylitis.

The role of germline polymorphisms of the T-cell receptor A/D and B loci in susceptibility to ankylosing spondylitis was investigated by linkage studies using microsatellite markers in 215 affected sibling pairs. The presence of a significant susceptibility gene (lambda > or = 1.6) at the TCRA/D locus was excluded (LOD score < -2.0). At the TCRB locus, there was weak evidence of the presence of a susceptibility gene (P = 0.01, LOD score 1.1). Further family studies will be required to determine whether this is a true or false-positive finding. It is unlikely that either the TCRA/D or TCRB loci contain genes responsible for more than a moderate proportion of the non-MHC genetic susceptibility to ankylosing spondylitis.

Family Health↗
PubMed1998

Chromosome breaks and sister chromatid exchange as predictors of second cancers in Hodgkin's disease.

Hodgkin's disease (HD) survivors face an increased risk of developing second cancers. We evaluated baseline cytogenetic biomarkers, sister chromatid exchange (SCE) and chromosome breaks [spontaneous (SCB) and bleomycin-induced (BIB)], as predictors of second cancer risk in a cohort of 105 adult HD patients. During follow-up, seven second cancers occurred. SCBs and BIBs showed no association with risk of second primaries. Multivariate Cox regression revealed that high levels of SCEs (relative risk (RR)=11.3, p=0.02) and age (RR=1.08, p=0.02) predicted second cancer risk. Histology, stage, and treatment were not associated with elevated risk. In conclusion, baseline SCE frequencies may be a useful biomarker for identifying HD patients at increased risk of developing second cancers. These results need to be verified in a larger cohort with a longer follow-up time.

Adolescent↗
PubMed1998

Cytochrome P450 2E1 DraI polymorphisms in lung cancer in minority populations.

Cytochrome P4502E1 (CYP2E1) is involved in the metabolic activation of carcinogenic N-nitrosamines. This study was performed to examine whether CYP2E1 DraI polymorphisms in intron 6 are related to susceptibility to lung cancer and are associated with carcinogenetic exposure. We therefore genotyped CYP2E1 by PCR amplification of peripheral WBC DNA from 126 patients with previously untreated lung cancer (85 African Americans and 41 Mexican Americans) and 193 controls (104 African Americans and 89 Mexican Americans). Mutagen sensitivity was measured with an in vitro assay quantitating bleomycin-induced chromatid breaks in peripheral blood lymphocyte cultures. The CYP2E1 DraI DD genotype was found in 86.5% of all cases and in 74.6% of all controls (P = 0.03), in 78.1% of 41 Mexican-American cases and in 69.6% of their controls (P = 0.70), and in 90.6% of African American cases and in 78.8% of their controls (P = 0.05). The DD genotype was found to be associated with a significantly higher risk of lung cancer overall with an odds ratio (OR) of 2.4 [95% confidence interval (CI), 1.1-5.3]. This risk was significantly elevated for men and for those who had ever smoked [ORs of 3.4 (95% CI, 1.3-8.7) and 2.6 (95% CI, 1.1-6.0), respectively], but not for women and nonsmokers [ORs of 0.7 (95% CI, 0.1-3.8) and 0.9 (95% CI, 0.1-10.6), respectively]. Stratified analysis showed an interaction that seemed greater than multiplicative between cigarette smoking and the CYP2E1 DraI DD genotype. The ORs for the CYP2E1 DraI DD genotype, cigarette smoking, and both risk factors combined were 1.5, 8.5, and 22.7, respectively. The CYP2E1 DraI polymorphism and the CYP2E1 PstI polymorphism in the upstream flanking regions were significantly associated in Mexican Americans but not in African Americans. We therefore conclude that the CYP2E1 DraI polymorphism seems to be associated with lung carcinogenesis. However, a larger study is warranted to evaluate the interactions among CYP2E1 DraI DD genotype, mutagen sensitivity, and cigarette smoking.

Aged↗
PubMed1997

Identification of quantitative trait loci controlling levels of radiation-induced thymocyte apoptosis in mice.

Thymocyte apoptosis levels are higher in C57BL/6J mice than in C3Hf/Kam mice. Low-dose irradiation increases the numbers of thymocytes undergoing apoptosis, but the strain difference persists. We mapped three loci controlling radiation-induced thymocyte apoptosis levels in F2 intercross progeny of these strains. The strongest association of a genomic region with an apoptosis level occurred in a region of chromosome 11 known to harbor a locus (or loci) important in the pathogenesis of several rodent models of autoimmune disease. Additional loci influencing radiation-induced thymocyte apoptosis were identified on chromosomes 9 and 16. The genetic polymorphisms underlying these loci may have an evolutionary role in fine-tuning the apoptotic response in T cells and may be important in the etiology of lymphoproliferative disorders and autoimmunity.

Animals↗
PubMed1997

Estimating the strength of genetic effects: a comparison of maximum likelihood and transmission disequilibrium methods in the study of ankylosing spondylitis.

Here we compare several methods for evaluating associations in the analysis of family data. We applied the transmission disequilibrium test (TDT), and logistic regression, familial aggregation, and segregation analyses for the study of Ankylosing Spondylitis. All methods detected effects from B27 upon susceptibility for Ankylosing Spondylitis. However, the TDT was unable to detect effects from B40 and also could not include sex as a covariate during the analysis. Conditioning or not conditioning the data for the ascertainment event led to little difference in the estimated covariate effects, although the genetic model for residual effects not due to the covariates did change. Results from these studies provide further characterization of the relationship between HLA B27, B40, and sex upon risk for developing Ankylosing Spondylitis. We also identified potential effects from further genetic susceptibility.

Adolescent↗
PubMed1997

Fine mapping of a genetic locus for Peutz-Jeghers syndrome on chromosome 19p.

Peutz-Jeghers syndrome (PJS) was recently mapped in a single report to the telomeric region of chromosome 19p (A. Hemminki et al., Nat. Genet., 15: 87-90, 1997). Our studies confirm this location and provide further localization of the PJS locus. In the five families examined, there were no recombinants with the marker D19S886. The multipoint log odds score at D19S886 is 7.52, and we found no evidence for genetic heterogeneity. We also found that all carriers expressed the PJS phenotype and no noncarriers displayed PJS sequellae, indicating complete penetrance with no sporadic cases.

Chromosome Mapping↗
PubMed1997

Evidence for genetic heterogeneity in familial Wilms' tumor.

Wilms' tumor (WT), a childhood kidney cancer, occurs both sporadically and, less frequently, in a familial context. Genetic linkage studies of several large WT families have excluded the one cloned WT gene, WT1, as the locus responsible for familial predisposition. These data demonstrate the existence of a familial predisposition gene distinct from WT1 and, more broadly, imply that the genetic etiology of WT is heterogenous. However, it has been unknown whether the predisposition observed in large WT families is also heterogenous or perhaps is due to mutations at a single locus. Recently, examination of a large French-Canadian WT family has demonstrated genetic linkage to 17q12-q21. We report here the results from a genetic linkage study of six WT pedigrees. Analyses of genotype data from eight loci within the 17q12-q21 region in these families resulted in cumulative lod scores of <-4.0 through the region, thereby excluding linkage. The ability to rule out the 17q region as the site of a predisposition gene in several of these pedigrees individually demonstrates the existence of more than one gene that predisposes to WT in large pedigrees and again emphasizes that the etiology of WT is genetically heterogenous.

Adult↗
PubMed1997

Genetic analysis of simulated oligogenic traits in nuclear and extended pedigrees: summary of GAW10 contributions.

Participants of GAW10 had available simulated data on phenotypic and marker data for 200 replicates of each of two different collections of pedigrees. The simulated phenotype was multivariate and oligogenic, and included a number of complexities. Participants took widely different approaches to analysis. We compare their results to identify analysis approaches and use of the data that had the greatest impact on the conclusions, accuracy of estimates, and power to identify genetic factors.

Computer Simulation↗
PubMed1997

Comparison of model-free linkage mapping strategies for the study of a complex trait.

We compared several strategies for identifying and estimating effects from a genetic locus in the etiology of a complex trait. For our analyses we used data from simulated trait 1 and chromosome 5. Results from analysis of the first 20 replicates showed that a components of variance test provided considerably better power for identifying linkage than tests that consider pair differences. We also compared the power from constructing tests with a single marker, an approximate method using five markers jointly, or a multipoint analysis using all 25 markers on chromosome 5 jointly. Results from this analysis showed substantially better power when all markers were jointly used in the analysis. Results from considering all replicates showed that all methods of estimation provided maximal test statistics at the correct marker position, but the components of variance procedure provided more power to detect the correct position than other methods.

Analysis of Variance↗
PubMed1997

Assessing linkage on chromosome 5 using components of variance approach: univariate versus multivariate.

We report results when one disease related quantitative trait (Q1) is analyzed versus multiple related quantitative traits using a components of variance approach [Amos, 1994; de Andrade and Amos, 1996]. In both cases, we used age, sex and environmental factor (EF) as covariates. Analysis with ascertainment correction of samples selected through probands with extremely high trait values was also performed and is presented. Testing procedures to detect linkage using the components of variance approach are discussed. The univariate and multivariate analyses showed effects of locus 15 on chromosome 5 only for Q1. This result was confirmed when using ascertainment correction.

Analysis of Variance↗
PubMed1997

Correlates of psychologic distress in colorectal cancer patients undergoing genetic testing for hereditary colon cancer.

In this article the authors describe the demographic and psychosocial correlates of 2 measures of psychologic distress among 200 colorectal cancer patients undergoing genetic testing for hereditary nonpolyposis colon cancer. The prevalence of symptoms of depression on the Center for Epidemiologic Studies Depression (CES-D) Scale was 24%. In multivariate analysis, female sex, less formal education, fewer sources of social contacts, and less satisfaction with them were associated with high scores on the CES-D Scale. Characteristics associated with high scores on the State-Trait Anxiety Inventory were younger age, less formal education, non-White race, local-regional stage of disease, fewer social contacts, and less satisfaction with them. Information on psychosocial correlates of psychologic distress may prove useful in guiding genetic counseling sessions, in identifying subgroups that need more intensive follow-up, and in developing interventions to facilitate adjustment to genetic test results.

Adaptation, Psychological↗