Biomedical subjects

Christopher I Amos

Publications and source records attributed to Christopher I Amos.

At least 37 records · Page 2Linked to original sources

PubMed2006

Rheumatoid arthritis association with the FCRL3 -169C polymorphism is restricted to PTPN22 1858T-homozygous individuals in a Canadian population.

OBJECTIVE: Variants in genes encoding the Fc receptor-like 3 (FcRL-3) and the class II major histocompatibility complex (MHC) transactivator proteins have been associated with an increased risk of rheumatoid arthritis (RA) in Japanese and Nordic populations, respectively. The aim of this study was to investigate these associations in a Canadian Caucasian cohort of RA cases and healthy controls. METHODS: A total of 1,187 RA patients and 462 healthy controls were genotyped for FCRL3 and MHC2TA gene variants associated with RA. Epistasis between the FCRL3 -169C and the PTPN22 1858T variants was also examined. RESULTS: An association was detected between RA and both the FCRL3 -169C allele (OR 1.19, P = 0.023) and the homozygous genotype (OR 1.41, P = 0.027), but association of the MHC2TA promoter region variant (-168G) with RA was not replicated. Stratification of the RA cohort by PTPN22 genotypes revealed the FCRL3 risk variant and RA association was stronger in the patient subgroup lacking PTPN22 1858T variants (P = 0.004) and was not detectable in the subgroup with PTPN22 1858T variants (P = 0.52). The PTPN22 association with RA was greater in the absence than in the presence of the FCRL3 -169C allele (P = 0.0008 versus P = 0.001). The PTPN22 1858T variant also increased the risk of autoimmune thyroid disease (AITD) in the RA patients, whereas the FCRL3 risk variant was protective against AITD. CONCLUSION: Our findings support an association of RA with an FCRL3 functional polymorphism and reveal that this association is stronger in the absence of PTPN22 risk genotypes. These findings support a genetic heterogeneity across RA populations, suggesting that both the FCRL3 and PTPN22 genes play roles in RA susceptibility, but in different individuals.

Adult↗

PubMed2006

DLG5 variants contribute to Crohn disease risk in a Canadian population.

Variants in the gene encoding the DLG5 scaffolding protein have been reported to be associated with increased risk of inflammatory bowel disease (IBD) and particularly Crohn's disease (Crohn disease; CD). These findings have not been uniformly replicated in follow-up studies. In this study we genotyped a cohort of 402 Canadian CD and 179 ulcerative colitis (UC) patients and 537 healthy controls for three IBD/CD-associated DLG5 variants. Our data reveal that the common DLG5 haplotype (A), which was previously considered protective for IBD, is associated with modest increases in risk for IBD (P=0.02) and CD (P=0.04). The effects of haplotype copy number on risk for IBD were minor, with the odds ratio (ORs) being 1.37 for the heterozygous risk genotype and 1.7 for the homozygous risk genotype. While we were unable to replicate the proposed association between the DLG5 c.113G>A variant and IBD, an association of IBD (P=0.02) and CD (P=0.04) with the rarer c.4136C>A variant was replicated in this cohort. These associations were restricted to the non-Jewish subjects in this cohort and were not detected in the Ashkenazi Jewish population studied here. Within the non-Jewish group, no associations were detected between the DLG5 variants and specific phenotypic features, such as site of disease, and there was no evidence of epistasis between DLG5 and any of the CD-associated CARD15 or SLC22A4/A5 gene variants. Together, the results indicate a role for DLG5 variants in IBD susceptibility and suggest that further studies are warranted to evaluate this role in different IBD populations and to determine the functional pathways that couple DLG5 variants to IBD.

Adult↗

PubMed2006

Stochastic search gene suggestion: a Bayesian hierarchical model for gene mapping.

Mapping the genes for a complex disease, such as diabetes or rheumatoid arthritis (RA), involves finding multiple genetic loci that may contribute to the onset of the disease. Pairwise testing of the loci leads to the problem of multiple testing. Looking at haplotypes, or linear sets of loci, avoids multiple tests but results in a contingency table with sparse counts, especially when using marker loci with multiple alleles. We propose a hierarchical Bayesian model for case-parent triad data that uses a conditional logistic regression likelihood to model the probability of transmission to a diseased child. We define hierarchical prior distributions on the allele main effects to model the genetic dependencies present in the human leukocyte antigen (HLA) region of chromosome 6. First, we add a hierarchical level for model selection that accounts for both locus and allele selection. This allows us to cast the problem of identifying genetic loci relevant to the disease into a problem of Bayesian variable selection. Second, we attempt to include linkage disequilibrium as a covariance structure in the prior for model coefficients. We evaluate the performance of the procedure with some simulated examples and then apply our procedure to identifying genetic markers in the HLA region that influence risk for RA. Our software is available on the website http://www.epigenetic.org/Linkage/ssgs-public/.

Alleles↗

PubMed2006

DNMT3b polymorphism and hereditary nonpolyposis colorectal cancer age of onset.

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant syndrome of familial malignancies resulting from germ-line mutations in DNA mismatch repair genes. Colorectal and endometrial cancers are most frequently observed. A polymorphic C-to-T change in the promoter region of the DNMT3b gene, -149 bp from the transcription start site, is reported to greatly increase promoter activity and is associated with increased risk for lung cancer and decreased postsurgical survival in patients with small cell carcinoma of the head and neck. We studied the influence of this DNMT3b polymorphism on HNPCC age of onset. We determined the DNMT3b genotype of 146 mismatch repair mutation carriers from 72 families. Of these, 74 participants had colorectal cancer. The participants were genotyped by single-strand conformational polymorphism analysis and DNA sequencing. We tested the association between age of onset and DNMT3b genotypes by comparing Kaplan-Meier survival curves, evaluating the homogeneity of the curves using the log-rank test, Wilcoxon's test, and Fleming-Harrington test and estimating the strength and direction of the association using the Cox proportional hazards regression model adjusting for potential demographic and genetic confounding factors. HNPCC patients carrying one or two copies of the DNMT3b variant T allele developed their colorectal cancer significantly earlier than HNPCC patients who were homozygous for the wild-type DNMT3b allele. Combining knowledge of an individual's DNMT3b genotype with information on other genetic and environmental risk factors may improve risk estimates and help to identify individuals who are genetically susceptible to developing HNPCC at an earlier age.

Adult↗

PubMed2005

Examining the effect of linkage disequilibrium on multipoint linkage analysis.

Most linkage programs assume linkage equilibrium among multiple linked markers. This assumption may lead to bias for tightly linked markers where strong linkage disequilibrium (LD) exists. We used simulated data from Genetic Analysis Workshop 14 to examine the possible effect of LD on multipoint linkage analysis. Single-nucleotide polymorphism packets from a non-disease-related region that was generated with LD were used for both model-free and parametric linkage analyses. Results showed that high LD among markers can induce false-positive evidence of linkage for affected sib-pair analysis when parental data are missing. Bias can be eliminated with parental data and can be reduced when additional markers not in LD are included in the analyses.

Genetic Markers↗

PubMed2005

In vitro sensitivity to ultraviolet B light and skin cancer risk: a case-control analysis.

BACKGROUND: Mutagen sensitivity, measured as mutagen-induced chromatid breaks per cell in primary lymphocytes in vitro, has been used to study susceptibility to various epithelial cancers. Patients with xeroderma pigmentosum are highly sensitive to ultraviolet (UV) light due to inherited defects in DNA repair and have a 1000-fold higher risk of UV-induced skin cancer than the general population. However, an association between UV-induced chromosomal aberrations and risk of skin cancer in the general population has not been established. METHODS: We assessed in vitro UVB-induced chromatid breaks in a hospital-based case-control study. The study included 469 patients with skin cancer (231 with nonmelanoma skin cancer [NMSC] and 238 with cutaneous malignant melanoma [CMM]) and 329 cancer-free control subjects. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). All statistical tests were two-sided. RESULTS: Compared with the frequency of UVB-induced chromatid breaks per cell in control subjects (mean = 0.28 breaks per cell, 95% CI = 0.27 to 0.30), that in NMSC patients (basal cell carcinoma [BCC], n = 143, mean = 0.36 breaks per cell, 95% CI = 0.33 to 0.39 and squamous cell carcinoma [SCC], n = 88, mean = 0.35 breaks per cell, 95% CI = 0.32 to 0.38) was higher (P = .001 and P < .001, respectively), but that in CMM case patients (mean = 0.30 breaks per cell, 95% CI = 0.28 to 0.33) was not (P = .22). A frequency of chromatid breaks per cell above the median of control subjects was associated with nearly threefold increased risks for BCC (OR = 2.78, 95% CI = 1.79 to 4.30) and SCC (OR = 2.62, 95% CI = 1.50 to 4.60), but not with an increased risk of CMM. A dose-response relationship was evident between mutagen sensitivity and risk for both BCC (Ptrend < .001) and SCC (Ptrend < .001). Multiplicative interactions between mutagen sensitivity and sun exposure variables on risk, particularly for sunburn in BCC and hair color, tanning ability, and family history of skin cancer in SCC, were seen for NMSC but not CMM. CONCLUSIONS: UVB-induced mutagen sensitivity may play a role in susceptibility to NMSC but not to CMM.

Adult↗

PubMed2005

Mutation of Lkb1 and p53 genes exert a cooperative effect on tumorigenesis.

Peutz-Jeghers syndrome (PJS) is a dominantly inherited disorder characterized by gastrointestinal hamartomatous polyps and mucocutaneous melanin pigmentation. Germ line mutations in LKB1 cause PJS. We have generated mice carrying an Lkb1 exon 2 to 8 deletion by gene targeting in embryonic stem cells. Heterozygotes develop gastric hamartomas that are histologically similar to those found in humans with PJS. LKB1 is also reportedly a mediator of p53-dependent apoptosis. To explore the potential combined effects of p53 and Lkb1 alterations on tumorigenesis, we carried out a series of matings with Lkb1(+/-) and p53 null mice to generate Lkb1(+/-)/p53(+/-) and Lkb1(+/-)/p53(-/-) mice. Similar to the Lkb1(+/-) mice, gastrointestinal hamartomas have also been detected in the mice with these two genotypes. The Lkb1(+/-)/p53(+/-) mice displayed a dramatically reduced life span and increased tumor incidence compared to the mice with either Lkb1 or p53 single gene knockout. The time to onset of polyposis in Lkb1(+/-)/p53(-/-) mice is approximately 2 months earlier than Lkb1(+/-)/p53(+/-) and Lkb1(+/-) mice, whereas the latter two show a similar time to onset which is at approximately 6 months of age. These results strongly suggested that mutations of p53 and Lkb1 gene cooperate in the acceleration of tumorigenesis.

AMP-Activated Protein Kinases↗

PubMed2005

Differing DNA methylation patterns and gene mutation frequencies in colorectal carcinomas from Middle Eastern countries.

PURPOSE: The epidemiology of colorectal carcinoma is well known to differ among countries but the molecular characteristics are usually assumed to be similar. International differences in molecular pathology have not been studied extensively but have implications for the management of patients in different countries and of immigrant patients. EXPERIMENTAL DESIGN: We evaluated the CpG island methylator phenotype pathway characterized by concordant methylation of gene promoters that often silences transcription of the genes, the microsatellite instability pathway, and K-ras and p53 gene status in 247 colorectal carcinomas from the three selected Middle Eastern countries of Egypt, Jordan, and Turkey. RESULTS: Colorectal carcinoma from Egypt had the lowest frequencies of methylation. In multinomial logistic regression analysis, Jordanian colorectal carcinoma more frequently had methylation involving the p16 tumor suppressor gene (odds ratio, 3.5; 95% confidence interval, 1.2-10.6; P = 0.023) and MINT31 locus (odds ratio, 2.3; 95% confidence interval, 1.0-5.1; P = 0.041). The K-ras proto-oncogene was more frequently mutated in colorectal carcinoma from Turkey (odds ratio, 2.9; 95% confidence interval, 1.2-6.7; P = 0.016), but p53 overexpression was more common in both Jordanian and Turkish colorectal carcinoma than in Egyptian cases (odds ratio, 2.5; 95% confidence interval, 1.2-5.5; P = 0.019; and odds ratio, 3.6; 95% confidence interval, 1.8-7.1; P = 0.0003, respectively). The findings in Turkish colorectal carcinoma were most similar to those reported for Western cases. CONCLUSIONS: Colorectal carcinoma from Middle Eastern countries have differing gene methylation patterns and mutation frequencies that indicate dissimilar molecular pathogenesis, probably reflecting different environmental exposures. These molecular differences could affect prevention strategies, therapeutic efficacy, and transferability of clinical trial results.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Empirical bayes method for incorporating data from multiple genome scans.

Individual genome scans tend to have low power and can produce markedly biased estimates of QTL effects. Further, the confidence interval for their location is often prohibitively large for subsequent fine mapping and positional cloning. Given that a large number of genome scans have been conducted, not to mention the large number of variables and subsets tested, it is difficult to confidently rule out type 1 error as an explanation for significant effects even when there is apparent replication in a separate data set. We adapted Empirical Bayes (EB) methods [1] to analyze data from multiple genome scans simultaneously and alleviate each of these problems while still allowing for different QTL population effects across studies. We investigated the effects of using the EB method to include data from background studies to update the results of a single study of interest via simulation and demonstrated that it has a stable confidence level over a wide range of parameters defining the background studies and increased the power to detect linkage, even when some of the background studies were null or had QTL effect at other markers. This EB method for incorporating data from multiple studies into genome scan analyses seems promising.

Alzheimer Disease↗

PubMed2005

PTPN22 genetic variation: evidence for multiple variants associated with rheumatoid arthritis.

The minor allele of the R620W missense single-nucleotide polymorphism (SNP) (rs2476601) in the hematopoietic-specific protein tyrosine phosphatase gene, PTPN22, has been associated with multiple autoimmune diseases, including rheumatoid arthritis (RA). These genetic data, combined with biochemical evidence that this SNP affects PTPN22 function, suggest that this phosphatase is a key regulator of autoimmunity. To determine whether other genetic variants in PTPN22 contribute to the development of RA, we sequenced the coding regions of this gene in 48 white North American patients with RA and identified 15 previously unreported SNPs, including 2 coding SNPs in the catalytic domain. We then genotyped 37 SNPs in or near PTPN22 in 475 patients with RA and 475 individually matched controls (sample set 1) and selected a subset of markers for replication in an additional 661 patients with RA and 1,322 individually matched controls (sample set 2). Analyses of these results predict 10 common (frequency >1%) PTPN22 haplotypes in white North Americans. The sole haplotype found to carry the previously identified W620 risk allele was strongly associated with disease in both sample sets, whereas another haplotype, identical at all other SNPs but carrying the R620 allele, showed no association. R620W, however, does not fully explain the association between PTPN22 and RA, since significant differences between cases and controls persisted in both sample sets after the haplotype data were stratified by R620W. Additional analyses identified two SNPs on a single common haplotype that are associated with RA independent of R620W, suggesting that R620W and at least one additional variant in the PTPN22 gene region influence RA susceptibility.

Arthritis, Rheumatoid↗

PubMed2005

Psychological impact of genetic testing for hereditary nonpolyposis colorectal cancer.

PURPOSE: This study examines the impact of hereditary nonpolyposis colorectal cancer (HNPCC) genetic test results on psychological outcomes among cancer-affected and -unaffected participants up to 1 year after results disclosure. PATIENTS AND METHODS: A total of 155 persons completed study measures before HNPCC genetic testing, and at 2 weeks and 6 and 12 months after disclosure of test results. RESULTS: Mean scores on all outcome measures remained stable and within normal limits for cancer-affected participants, regardless of mutation status. Among unaffected carriers of HNPCC-predisposing mutations, mean depression, state anxiety, and cancer worries scores increased from baseline to 2 weeks postdisclosure and decreased from 2 weeks to 6 months postdisclosure. Among unaffected noncarriers, mean depression and anxiety scores did not differ, but cancer worries scores decreased during the same time period. Affected and unaffected carriers had higher mean test-specific distress scores at 2 weeks postdisclosure compared with noncarriers in their respective groups; scores decreased for affected carriers and all unaffected participants from 2 weeks to 12 months postdisclosure. Classification of participants into high- versus low-distress clusters using mean scores on baseline psychological measures predicted significantly higher or lower follow-up scores, respectively, on depression, state anxiety, quality of life, and test-specific distress measures, regardless of mutation status. CONCLUSION: Although HNPCC genetic testing does not result in long-term adverse psychological outcomes, unaffected mutation carriers may experience increased distress during the immediate postdisclosure time period. Furthermore, those with higher levels of baseline mood disturbance, lower quality of life, and lower social support may be at risk for both short- and long-term increased distress.

Colorectal Neoplasms, Hereditary Nonpolyposis↗

PubMed2005

Genetic mapping of a third Li-Fraumeni syndrome predisposition locus to human chromosome 1q23.

Li-Fraumeni syndrome (LFS) is a clinically and genetically heterogeneous inherited cancer syndrome. Most cases ( approximately 70%) identified and characterized to date are associated with dominantly inherited germ line mutations in the tumor suppressor gene TP53 (p53) in chromosome 17p13.1. In a subset of non-p53 patients with LFS, CHEK2 in chromosome 22q11 has been identified as another predisposing locus. Studying a series of non-p53 LFS kindred, we have shown that there is additional genetic heterogeneity in LFS kindred with inherited predisposition at loci other than p53 or CHEK2. Using a genome-wide scan for linkage with complementing parametric and nonparametric analysis methods, we identified linkage to a region of approximately 4 cM in chromosome 1q23, a genomic region not previously implicated in this disease. Identification ofa third predisposing gene and its underlying mutation(s) should provide insight into other genetic events that predispose to the genesis of the diverse tumor types associated with LFS and its variants.

Checkpoint Kinase 2↗

PubMed2005

Possible genomic imprinting of three human obesity-related genetic loci.

To detect potentially imprinted, obesity-related genetic loci, we performed genomewide parent-of-origin linkage analyses under an allele-sharing model for discrete traits and under a family regression model for obesity-related quantitative traits, using a European American sample of 1,297 individuals from 260 families, with 391 microsatellite markers. We also used two smaller, independent samples for replication (a sample of 370 German individuals from 89 families and a sample of 277 African American individuals from 52 families). For discrete-trait analysis, we found evidence for a maternal effect in chromosome region 10p12 across the three samples, with LOD scores of 5.69 (single-point) and 4.52 (multipoint) for the pooled sample. For quantitative-trait analysis, we found the strongest evidence for a maternal effect (single-point LOD of 2.85; multipoint LOD of 4.01 for body mass index [BMI] and 3.69 for waist circumference) in region 12q24 and for a paternal effect (single-point LOD of 4.79; multipoint LOD of 3.72 for BMI) in region 13q32, in the European American sample. The results suggest that parent-of-origin effects, perhaps including genomic imprinting, may play a role in human obesity.

Adipose Tissue↗

PubMed2005

SLC22A4 polymorphisms implicated in rheumatoid arthritis and Crohn's disease are not associated with rheumatoid arthritis in a Canadian Caucasian population.

OBJECTIVE: Single-nucleotide polymorphisms (SNPs) in the SLC22A4 gene encoding the organic cation transporter OCTN1 have been associated with rheumatoid arthritis (RA) in the Japanese population and with Crohn's disease in a Canadian cohort. The RA-associated and Crohn's disease-associated SNPs include, respectively, an intronic variant (slc2F2) and an exonic variant (1672T). We used a case-control approach to investigate the prevalence of these variants in a Canadian RA cohort and to determine whether RA and Crohn's disease share SLC22A4 susceptibility alleles. METHODS: Nine hundred eighteen unrelated patients with RA, 507 patients with Crohn's disease, and 623 healthy controls were genotyped for the putatively RA-associated slc2F1 and slc2F2 variants and the Crohn's disease-associated SLC22A4 1672T variant. RESULTS: Neither slc2F1 nor slc2F2 showed evidence for association with RA, the allele frequencies of these variants being significantly different in the Canadian population compared with those reported in the Japanese population, but not significantly different between patients with RA and controls. In addition, associations between the 1672T Crohn's disease risk allele and RA or between the slc2F1-A and slc2F2-T risk alleles and Crohn's disease were not detected in this study cohort, and the latter 2 alleles were not in linkage disequilibrium with the 1672T variant. CONCLUSION: These observations do not support roles for any of the previously identified SLC22A4 disease risk alleles in RA susceptibility in the Canadian population. The slc2F1/slc2F2 risk alleles were not associated with Crohn's disease nor in linkage disequilibrium with the Crohn's disease-associated 1672T variant, and accordingly, also appear to be irrelevant to Crohn's disease susceptibility in the population under study.

Adult↗

PubMed2005

Association of the lymphoid tyrosine phosphatase R620W variant with rheumatoid arthritis, but not Crohn's disease, in Canadian populations.

OBJECTIVE: A single-nucleotide polymorphism in the PTPN22 gene encoding the lymphoid protein tyrosine phosphatase (Lyp) has recently been identified as a functional variant associated with susceptibility to rheumatoid arthritis (RA), type 1 diabetes, and systemic lupus erythematosus. To determine whether association of this variant (PTPN22 1858T) with RA is reproducible and is also observed in another autoimmune condition, Crohn's disease, we investigated the association between the PTPN22 1858T allele and RA and Crohn's disease in a Canadian population. METHODS: Two RA case-control cohorts representing a total of 1,234 patients and 791 healthy controls as well as a cohort of 455 patients with Crohn's disease and 190 controls were genotyped for the PTPN22 C1858T polymorphism, and genotype frequencies were compared between patients and controls. RESULTS: Significant association of the PTPN22 1858T allele with RA was detected in both the Toronto-based RA cohort (P = 1.6 x 10(-6), odds ratio [OR] 1.8) and the Halifax-based RA cohort (P = 9.4 x 10(-4), OR 1.94). Association of the risk allele with RA was not affected by sex, age at disease onset, or the presence of either rheumatoid factor or rheumatoid nodules. No association between the PTPN22 risk allele and Crohn's disease was detected. CONCLUSION: These observations confirm the association of RA susceptibility with the PTPN22 1858T allele. However, the data also reveal a lack of association between this variant and Crohn's disease, suggesting that the PTPN22 1858T allele is a risk allele for multiple, but not all, autoimmune diseases.

Arthritis, Rheumatoid↗

PubMed2005

Refining the complex rheumatoid arthritis phenotype based on specificity of the HLA-DRB1 shared epitope for antibodies to citrullinated proteins.

OBJECTIVE: The main genetic risk factor for rheumatoid arthritis (RA), the HLA region, has been known for 25 years. Previous research has demonstrated, within the RA population, an association between HLA-DRB1 alleles carrying the shared epitope (SE) and antibodies directed against cyclic citrullinated peptides (anti-CCP antibodies). We undertook this study to make the first comparison of SE allele frequencies in the healthy population with those in RA patients who do or do not harbor anti-CCP antibodies. METHODS: HLA-DRB1 typing was performed in 408 RA patients from the Leiden Early Arthritis Clinic (the Leiden EAC; a Dutch population-based inception cohort in which disease course was followed up over time), in 423 healthy Dutch controls, and in 720 affected members of 341 US multiplex (sibpair) families of Caucasian origin from the North American RA Consortium (NARAC) with well-established disease and fulfilling the American College of Rheumatology classification criteria for RA. The presence of anti-CCP antibodies was determined by enzyme-linked immunosorbent assay. RESULTS: For the Leiden EAC, the odds ratio (OR) describing the association of 2 copies of the SE allele with anti-CCP positivity (using no copies of the SE allele in the healthy control group as the referent) was 11.79 (P < 0.0001), while the OR for 1 SE allele was 4.37 (P < 0.0001). No association with the SE was observed in the Dutch anti-CCP-negative RA patients. For the NARAC families, linkage and association analysis revealed the SE to be associated only with anti-CCP-positive disease and not with anti-CCP-negative disease. Stratified analyses indicated that anti-CCP antibodies primarily mediated association of the SE with joint damage or disease persistence. CONCLUSION: HLA-DRB1 alleles encoding the SE are specific for disease characterized by antibodies to citrullinated peptides, indicating that these alleles do not associate with RA as such, but rather with a particular phenotype.

Arthritis, Rheumatoid↗

PubMed2005

New joint covariance- and marginal-based tests for association and linkage for quantitative traits for random and non-random sampling.

We develop novel statistical tests for transmission disequilibrium testing (tests of linkage in the presence of association) for quantitative traits using parents and offspring. These joint tests utilize information in both the covariance (or more generally, dependency) between genotype and phenotype and the marginal distribution of genotype. Using computer simulation we test the validity (Type I error rate control) and power of the proposed methods, for additive, dominant, and recessive modes of inheritance, locus-specific heritability of the trait 0.05, 0.1, 0.2 with allele frequencies of P=0.2 and 0.4, and sample sizes of 500, 200, and 100 trios. Both random sampling and extreme sampling schemes were investigated. A multinomial logistic joint test provides the highest overall power irrespective of sample size, allele frequency, heritability, and modes of inheritance.

Algorithms↗

PubMed2005

Predicting the oncogenicity of missense mutations reported in the International Agency for Cancer Research (IARC) mutation database on p53.

Many mutation databases, comprising thousands of reported mutations, are available. Often the clinical significance of the reported mutations is unknown. In this study we developed an algorithm that allows prediction of the clinical significance of missense mutations reported in a mutation database. Nonsense mutations are used as a referent group for this assessment. We used the International Association for Research on Cancer (IARC) mutation database on TP53 to implement the algorithm. First, on the basis of published data [Nachman MW, Crowell SL. 2000. Genetics 156:297-304], we ascribed mutation rates to every single nucleotide substitution (SNS) in the core domain of the TP53 gene. Second, for every possible SNS we computed the expected number of missense mutations, under the assumption that missense mutations are as oncogenic as nonsense ones. The natural logarithm of the ratio of the observed to the expected number of missense mutations (LR) was used as a quantitative measure of oncogenicity (i.e., the ability of a mutation to produce cancer). We estimated the relative oncogenicity of all missense mutations reported in the IARC p53 mutation database, and constructed a profile of oncogenicity of the missense mutations along the DNA-binding region of p53.

Algorithms↗