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C I Amos

Publications and source records attributed to C I Amos.

At least 19 recordsLinked to original sources
PubMed2006

High-density SNP analysis of 642 Caucasian families with rheumatoid arthritis identifies two new linkage regions on 11p12 and 2q33.

We have completed a genome wide linkage scan using >5700 informative single-nucleotide polymorphism (SNP) markers (Illumina IV SNP linkage panel) in 642 Caucasian families containing affected sibling pairs with rheumatoid arthritis (RA), ascertained by the North American Rheumatoid Arthritis Consortium. The results show striking new evidence of linkage at chromosomes 2q33 and 11p12 with logarithm of odds (LOD) scores of 3.52 and 3.09, respectively. In addition to a strong and broad linkage interval surrounding the major histocompatibility complex (LOD>16), regions with LOD>2.5 were observed on chromosomes 5 and 10. Additional linkage evidence (LOD scores between 1.46 and 2.35) was also observed on chromosomes 4, 7, 12, 16 and 18. This new evidence for multiple regions of genetic linkage is partly explained by the significantly increased information content of the Illumina IV SNP linkage panel (75.6%) compared with a standard microsatellite linkage panel utilized previously (mean 52.6%). Stratified analyses according to whether or not the sibling pair members showed elevated anticyclic citrullinated peptide titers indicates significant variation in evidence for linkage among strata on chromosomes 4, 5, 6 and 7. Overall, these new linkage data should reinvigorate efforts to utilize positional information to identify susceptibility genes for RA.

Arthritis, Rheumatoid↗
PubMed2004

A major lung cancer susceptibility locus maps to chromosome 6q23-25.

Lung cancer is a major cause of death in the United States and other countries. The risk of lung cancer is greatly increased by cigarette smoking and by certain occupational exposures, but familial factors also clearly play a major role. To identify susceptibility genes for familial lung cancer, we conducted a genomewide linkage analysis of 52 extended pedigrees ascertained through probands with lung cancer who had several first-degree relatives with the same disease. Multipoint linkage analysis, under a simple autosomal dominant model, of all 52 families with three or more individuals affected by lung, throat, or laryngeal cancer, yielded a maximum heterogeneity LOD score (HLOD) of 2.79 at 155 cM on chromosome 6q (marker D6S2436). A subset of 38 pedigrees with four or more affected individuals yielded a multipoint HLOD of 3.47 at 155 cM. Analysis of a further subset of 23 multigenerational pedigrees with five or more affected individuals yielded a multipoint HLOD score of 4.26 at the same position. The 14 families with only three affected relatives yielded negative LOD scores in this region. A predivided samples test for heterogeneity comparing the LOD scores from the 23 multigenerational families with those from the remaining families was significant (P=.007). The 1-HLOD multipoint support interval from the multigenerational families extends from C6S1848 at 146 cM to 164 cM near D6S1035, overlapping a genomic region that is deleted in sporadic lung cancers as well as numerous other cancer types. Parametric linkage and variance-components analysis that incorporated effects of age and personal smoking also supported linkage in this region, but with somewhat diminished support. These results localize a major susceptibility locus influencing lung cancer risk to 6q23-25.

Chromosome Mapping↗
PubMed2004

Genotype-phenotype correlations in Peutz-Jeghers syndrome.

BACKGROUND AND AIMS: Peutz-Jeghers syndrome (PJS) is a dominantly inherited disorder often caused by mutations in STK11. Time to onset of symptoms was characterised for a large collection of individuals with PJS who had been tested for STK11 mutations and genotype-phenotype correlations were evaluated. METHODS: We characterised mutations in 42 independent probands and also used a historical cohort design to study 51 individuals with Peutz-Jeghers syndrome who had completed self-administered questionnaires. RESULTS: Mutations were detected in 22/32 (69%) probands with PJS and 0/10 probands referred to rule out PJS. Real-time PCR analysis to quantitate DNA failed to detect any large deletions in PJS participants without STK11 mutations. The median time to onset for gastrointestinal symptoms or polypectomy was 13 years of age but showed a wide variability. Gastric polyps were frequent in PJS participants, with a median age at onset of 16 years. Individuals with missense mutations had a significantly later time to onset of first polypectomy (p = 0.04) and of other symptoms compared with those participants either with truncating mutations or no detectable mutation. CONCLUSION: STK11 mutation analysis should be restricted to individuals who meet PJS criteria or their close relatives. Direct sequencing of STK11 yields a high rate of point mutations in individuals who meet phenotypic PJS criteria. Individuals with missense mutations of STK11 typically had a later time to onset for PJS symptoms. The common occurrence of gastric polyps may facilitate chemopreventive studies for this disorder.

AMP-Activated Protein Kinase Kinases↗
PubMed2003

Effect of Box-Cox transformation on power of Haseman-Elston and maximum-likelihood variance components tests to detect quantitative trait Loci.

Non-normality of the phenotypic distribution can affect power to detect quantitative trait loci in sib pair studies. Previously, we observed that Winsorizing the sib pair phenotypes increased the power of quantitative trait locus (QTL) detection for both Haseman-Elston (HE) least-squares tests [Hum Hered 2002;53:59-67] and maximum likelihood-based variance components (MLVC) analysis [Behav Genet (in press)]. Winsorizing the phenotypes led to a slight increase in type 1 error in H-E tests and a slight decrease in type I error for MLVC analysis. Herein, we considered transforming the sib pair phenotypes using the Box-Cox family of transformations. Data were simulated for normal and non-normal (skewed and kurtic) distributions. Phenotypic values were replaced by Box-Cox transformed values. Twenty thousand replications were performed for three H-E tests of linkage and the likelihood ratio test (LRT), the Wald test and other robust versions based on the MLVC method. We calculated the relative nominal inflation rate as the ratio of observed empirical type 1 error divided by the set alpha level (5, 1 and 0.1% alpha levels). MLVC tests applied to non-normal data had inflated type I errors (rate ratio greater than 1.0), which were controlled best by Box-Cox transformation and to a lesser degree by Winsorizing. For example, for non-transformed, skewed phenotypes (derived from a chi2 distribution with 2 degrees of freedom), the rates of empirical type 1 error with respect to set alpha level=0.01 were 0.80, 4.35 and 7.33 for the original H-E test, LRT and Wald test, respectively. For the same alpha level=0.01, these rates were 1.12, 3.095 and 4.088 after Winsorizing and 0.723, 1.195 and 1.905 after Box-Cox transformation. Winsorizing reduced inflated error rates for the leptokurtic distribution (derived from a Laplace distribution with mean 0 and variance 8). Further, power (adjusted for empirical type 1 error) at the 0.01 alpha level ranged from 4.7 to 17.3% across all tests using the non-transformed, skewed phenotypes, from 7.5 to 20.1% after Winsorizing and from 12.6 to 33.2% after Box-Cox transformation. Likewise, power (adjusted for empirical type 1 error) using leptokurtic phenotypes at the 0.01 alpha level ranged from 4.4 to 12.5% across all tests with no transformation, from 7 to 19.2% after Winsorizing and from 4.5 to 13.8% after Box-Cox transformation. Thus the Box-Cox transformation apparently provided the best type 1 error control and maximal power among the procedures we considered for analyzing a non-normal, skewed distribution (chi2) while Winzorizing worked best for the non-normal, kurtic distribution (Laplace). We repeated the same simulations using a larger sample size (200 sib pairs) and found similar results.

Chromosome Mapping↗
PubMed2002

Power of a simplified multivariate test for genetic linkage.

In this paper we compare the power of the multivariate Haseman-Elston (MHE) test proposed earlier by Amos et al. (1990) and a computationally rapid new version of the multivariate Haseman-Elston test (NMHE) (Elston et al. 2000). We show that the power of NMHE was, for different simulation setups, identical or higher than that of MHE. In the bivariate case, the power of the NMHE method was somewhat less than that of the computationally intensive maximum likelihood variance components method (Amos et al. 2001). We present comparisons of the empirical distributions of the NMHE test to its limiting distributions for a range of numbers of traits. The distribution of the NMHE test appeared to conform satisfactorily to its limiting asymptotic distribution in large samples. Otherwise, empirical critical values for NMHE are somewhat higher than predicted, i.e. the test proposed by Elston et al. (2000) is non-conservative. The use of empirical critical values is therefore recommended for limited sample sizes (less than several hundred families). We also present the results of a linkage analysis performed by the NMHE method on a set of 4 body size-related traits. The method identified meaningful combinations of traits that showed significant linkage on chromosome 2 and suggestive linkage to regions on chromosomes 16 and 17.

Body Constitution↗
PubMed2001

Contrasting molecular pathology of colorectal carcinoma in Egyptian and Western patients.

Colorectal carcinoma is uncommon in Egypt, but a high proportion of cases occurs before age 40 years and in the rectum. We compared the molecular pathology of 59 representative Egyptian patients aged 10-72 to Western patients with sporadic, young-onset, or hereditary non-polyposis colorectal cancer syndrome (HNPCC)-associated carcinoma and found significant differences. Most Egyptian cancers were rectal (51%) and poorly differentiated (58%). High levels of microsatellite instability (MSI-H) were frequent (37%) and attributable in some cases (36%) to methylation of the promoter of the hMLH1 mismatch repair gene, but no MSI-H cancer had loss of hMSH2 mismatch repair gene product of the type seen with germline hMSH2 mutation in HNPCC. K-ras mutation was uncommon (11%). In subset analyses, high frequencies of MSI-H in rectal carcinomas (36%) and p53 gene product overexpression in MSI-H cancers (50%) were found. MSI-H and K-ras mutation in Egyptians under age 40 were unusual (17% and 0%, respectively), and schistosomiasis was associated with MSI and K-ras mutation. Cluster analysis identified 2 groups: predominantly young men with poorly differentiated mucinous and signet-ring cell colorectal carcinoma lacking K-ras mutation; older patients who had well- or moderately differentiated adenocarcinoma often with MSI-H, K-ras mutation and schistosomiasis. Our findings show that the molecular pathology of colorectal cancer in older as well as younger Egyptians has unique differences from Western patients, and schistosomiasis influences the molecular pathogenesis of some tumours.

Adolescent↗
PubMed2001

A genomewide screen in multiplex rheumatoid arthritis families suggests genetic overlap with other autoimmune diseases.

Rheumatoid arthritis (RA) is an autoimmune/inflammatory disorder with a complex genetic component. We report the first major genomewide screen of multiplex families with RA gathered in the United States. The North American Rheumatoid Arthritis Consortium, using well-defined clinical criteria, has collected 257 families containing 301 affected sibling pairs with RA. A genome screen for allele sharing was performed, using 379 microsatellite markers. A nonparametric analysis using SIBPAL confirmed linkage of the HLA locus to RA (P < .00005), with lambdaHLA = 1.79. However, the analysis also revealed a number of non-HLA loci on chromosomes 1 (D1S235), 4 (D4S1647), 12 (D12S373), 16 (D16S403), and 17 (D17S1301), with evidence for linkage at a significance level of P<.005. Analysis of X-linked markers using the MLOD method from ASPEX also suggests linkage to the telomeric marker DXS6807. Stratifying the families into white or seropositive subgroups revealed some additional markers that showed improvement in significance over the full data set. Several of the regions that showed evidence for nominal significance (P < .05) in our data set had previously been implicated in RA (D16S516 and D17S1301) or in other diseases of an autoimmune nature, including systemic lupus erythematosus (D1S235), inflammatory bowel disease (D4S1647, D5S1462, and D16S516), multiple sclerosis (D12S1052), and ankylosing spondylitis (D16S516). Therefore, genes in the HLA complex play a major role in RA susceptibility, but several other regions also contribute significantly to overall genetic risk.

Alleles↗
PubMed2001

A chromosome 15 quantitative trait locus controls levels of radiation-induced jejunal crypt cell apoptosis in mice.

Jejunal crypt cells undergo apoptosis in response to ionizing radiation exposure. In mice the number of cells deleted by apoptosis is determined by several factors including the dose of radiation, the time of day the apoptosis level is quantified, and the strain of mouse irradiated. We previously found that the difference in radiation-induced apoptosis levels between C57BL/6J (B6) and C3Hf/Kam (C3H) mice is controlled by multiple genes, and this set of genes is distinct from that controlling thymocyte apoptosis levels in the same strain combination. Here, we report that a new quantitative trait locus on chromosome 15, Rapop5, partly accounts for the murine strain difference in susceptibility to radiation-induced jejunal crypt cell apoptosis. In addition, we show sexual dimorphism in the extent of radiation-induced jejunal crypt cell apoptosis, with female mice having higher levels.

Animals↗
PubMed2001

Age-associated risk of cancer among individuals with N-acetyltransferase 2 (NAT2) mutations and mutations in DNA mismatch repair genes.

Mutations in N-acetyltransferase 2 (NAT2), a highly polymorphic enzyme involved in the metabolism of xenobiotics and carcinogens, may affect risk for colorectal cancer (CRC), especially among individuals with germ-line mutations in DNA mismatch repair genes. We determined the NAT2 genotypes and allele frequencies for 86 individuals with CRC who had mutations in hMLH1, hMSH2, or hPMS1. No significant difference in time to onset was observed between rapid (NAT2*4) and slow (NAT2*5, NAT2*6, and NAT2*7) acetylators. However, when individuals were stratified separately by NAT2 polymorphism (NAT2*5, NAT2*6, and NAT2*7), those who were heterozygous at the mutant locus NAT2*7 after adjustment for the NAT2 mutant loci NAT2*5 and NAT2*6 had a significantly higher risk of CRC (hazard ratio, 2.96; P = 0.012) and all of the cancers (hazard ratio, 3.37; P = 0.00004) than individuals homozygous for wild type at the NAT2*7 allele. These findings suggest that NAT2 genotype may be an important factor in tumorigenesis of CRC and cancers related to hereditary nonpolyposis CRC among individuals with mismatch repair defects.

Acetylation↗
PubMed2001

Modulation of nucleotide excision repair capacity by XPD polymorphisms in lung cancer patients.

Sequence variations have been identified in a number of DNA repair genes, including XPD, but the effect of these polymorphisms on DNA repair capacity (DRC) is uncertain. We therefore examined XPD polymorphisms at Lys751Gln and Asp312Asn in 341 white lung cancer cases and 360 age-, sex-, ethnicity-, and smoking-matched controls accrued in a hospital-based molecular epidemiological study of susceptibility markers for lung cancer. As previously reported, DRC was statistically significantly lower in the cases than in the controls (7.8% versus 9.5%; P < 0.001), which represents an average 18% reduction among the cases. The variant Lys751Gln and Asp312Asn allele frequencies were 0.36 and 0.29, respectively, for the cases and 0.33 and 0.27, respectively, for the controls. For subjects homozygous for the variant genotype at either locus, the adjusted odds ratio [95% confidence interval (CI)] was 1.84 (1.11-3.04; P = 0.018, for trend). Both cases and controls with the wild-type genotypes exhibited the most proficient DRC. The risk (95% CI) for suboptimal DRC (defined as less than the median DRC value among the controls) was 1.57 (0.74-3.35) for those with the Gln/Gln751 genotype. For cases with the Asn/Asn312 genotype, the risk (95% CI) was 3.50 (1.06-11.59). For cases who were homozygous at either locus, the risk was 2.29 (1.03-5.12; P = 0.048, for trend). The pattern was less evident among the controls, although there was a nonsignificant 41% increase in the risk of suboptimal DRC for controls who were homozygous at either locus. These results suggest that the two XPD polymorphisms have a modulating effect on DRC, especially in the cases.

Case-Control Studies↗
PubMed2001

Leptin and prostate cancer.

BACKGROUND: Higher prostate cancer mortality rates among US immigrants from countries with lower rates suggest environmental influences on prostate carcinogenesis (e.g., diet, body composition). METHODS: In a study identifying determinants of clinically relevant prostate cancer, we compared plasma concentrations of leptin, an adiposity-related hormone, in 48 men with tumors </= 0.5 cc measured after radical prostatectomy and 151 men with tumors > 0.5 cc in volume or with histologic evidence of extraprostatic extension but without metastases ("high-volume disease"), matched by age (+/- 5 years) and year at diagnosis (+/- 1 year). RESULTS: Men with high-volume disease exhibited higher leptin concentrations overall and after stratification by age, testosterone level, height, and body mass index (BMI). Analysis revealed that men with elevated leptin concentrations had an increased risk of diagnosis with high-volume disease (odds ratio (OR) = 2.35, 95% confidence interval (CI) = 1.01-5.44), as did men with high leptin and high testosterone (OR = 9.73, 95% CI = 2.05-46.24) and men >/=5'8" with high leptin (OR = 3.67, 95% CI = 1.40-9.63). CONCLUSIONS: Leptin may affect the risk of clinically relevant prostate cancer through testosterone and factors related to stature and obesity.

Aged↗
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

International Genetic Epidemiology Society: commentary on Darkness in El Dorado by Patrick Tierney.

The International Genetic Epidemiology Society (IGES) has examined the charges against James V. Neel and his colleagues contained in the recently published book by Patrick Tierney entitled Darkness in El Dorado: How Scientists and Journalists Devastated the Amazon (W.W. Norton, 2000). The book implicates Neel in causing or promoting an epidemic of measles among the Yanomamö Indians of Venezuela in 1968 leading to "hundreds if not thousands" of deaths by using a "dinosaur" vaccine (Edmonston B) as a deliberate "experiment" to test his "eugenic" theories. Tierney also attempts to link this research, funded by the Atomic Energy Commission (AEC), with a broader tapestry of human radiation experiments. To investigate these serious charges, the IGES undertook a thorough examination of most source documents referenced in Tierney's book, Neel's field logs, notes, first-hand reports, contemporary writings, film sound tracks, etc., and conducted interviews with many relevant persons. The IGES finds that these allegations are false. Neel was not a eugenicist and was in fact highly critical of both the scientific basis of eugenics and its coercive social policies. In this regard, Tierney has grossly misrepresented Neel's views on a wide range of social implications of modern civilization for the long-term health of the gene pool. Far from causing an epidemic of measles, Neel did his utmost to protect the Yanomamö from the ravages of the impending epidemic by a vaccination program using a vaccine that was widely used at the time and administered in an appropriate manner. There was nothing experimental about the vaccination program, which in fact severely hindered the primary scientific objectives of the expedition. Although the research was funded in large part by the AEC, there was no element of radiation research and the work had no connection with the ethical abuses that have been reported from AEC-sponsored radiation research, such as studies of heavy isotopes. Neel's seminal contributions to a broad range of topics in human genetics have been extensively chronicled elsewhere. His research on the Yanomamö in particular has provided unique insights into the evolutionary biology of our species, the role of sociocultural practices, such as kinship relationships and selective pressures in shaping the genetic diversity of primitive population isolates, as well as the general picture of health in such populations. The IGES decries the damage done to the reputation of one of its founders and its first President and the misperception this book may have caused about the conduct of research in genetic epidemiology. Ethical issues about scientific research in primitive populations deserve serious and wide discussion, but the IGES condemns the gross misrepresentation of the facts and demonization of the principal characters in this book.

Bioethics↗
PubMed2001

Variance components analysis for genetic linkage of time to onset for disease.

We compared two variance components methods for detecting genes that influence time to onset for a complex disease using simulated data. We first divided the extended families into nuclear families. The first method fitted variance components to the martingale residuals, which were obtained from first fitting a proportional hazards model to the time to onset data for the trait, allowing for the quantitative traits Q1-Q5, sex, age, and the environmental factor. The second method treated time to onset among the affected individuals as a quantitative trait adjusting for the same factors as in the first method. Power of these analyses were similar for either approach. However, we found an excess of false-positive results when fitting the martingale residual model or the affected-only model to identify genetic factors linked to chromosome 6. Applying a power transformation to the martingale residuals decreased the type I error rate and increased the power of tests for genetic linkage. We also found that robust variance correction lead to test with a slightly lower type I error rate, perhaps because the robust variance correction adjusts for the fact that we did not specifically model the effects of the mitochondrial factor in our analysis.

Analysis of Variance↗
PubMed2001

Modeling age x major gene interaction by a variance component approach.

The variance component method has become popular for linkage analysis due to its computational simplicity and generally high power. In this paper we model phenotypic variability of an individual as a mixed effects model in which both the major gene as well as the polygene effects interact with age. We applied the proposed model to the simulated data of Genetic Analysis Workshop 12. We considered the quantitative trait, Q4, in the outbred population. Two major genes influence this trait, each interacting with age independently. Consequently, trait variability is a function of age and also there is interaction of major gene effects with age. By using our model we were able to detect interaction between the major gene effects and age for this trait.

Adolescent↗
PubMed2001

Adaptations of linkage and association methods for the study of asthma, a complex trait.

Early studies that found significant linkage between markers on 5q and asthma and IgE have not been reproduced. In an attempt to improve the power of these studies we performed a variance components linkage analysis and transmission-disequilibrium tests (TDT) with haplotypes using markers on 5q, using the Southampton and Perth data sets supplied by GAW. The linkage analysis with covariates revealed a maximum lod of 1.57 in the Perth families. The addition of age and RAST significantly improved the fit of the null models but did not improve the lod scores. The TDT tests showed a marginally significant association with D5S393 and D5S399 and with three markers together (IL9, IL4, D5S393). We conclude that further studies are needed to delineate the environmental contribution to this disease so that the genetic factors can be more easily identified. In addition, haplotype analysis may help to identify specific genetic effects.

Adolescent↗
PubMed2001

Cost of linkage versus association methods.

Identifying genetic factors that influence disease risk is a major goal in genetic epidemiology. In the past, for disease with relatively simple etiology, genetic linkage methods have been highly effective for this purpose. However, as we begin to study more complex diseases and disorders for which each specific genetic factor may play a minor role in causation, the relative values of genetic linkage methods that do not require linkage disequilibrium versus association-based methods that do require linkage disequilibrium must be evaluated. Here, we compare the cost-effectiveness of linkage and association methods for identifying genetic factors for a quantitative trait locus that explains 10% of interindividual variability. We find that the choice of analytical scheme depends upon the degree of disequilibrium in the population. Because this parameter has not been adequately assessed, planning association studies is currently difficult.

Analysis of Variance↗