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W J Butler

Publications and source records attributed to W J Butler.

At least 19 recordsLinked to original sources
PubMed2003

CARD15/NOD2 risk alleles in the development of Crohn's disease in the Australian population.

We have previously reported strong evidence for linkage between IBD1 and Crohn's disease (CD) in Australian Crohn's disease families. Three risk alleles for Crohn's disease, (Arg702Trp (C/T), Gly908Arg (G/C) and 980fs981 (-/C), were recently identified in the CARD15/NOD2 gene on chromosome 16, implicating this as the IBD1 locus. Using a novel diagnostic PCR-RFLP, we have examined the frequency of these alleles in 205 multiplex IBD families, 107 sporadic Crohn's disease cases and 409 normal individuals. We demonstrate that the three risk alleles are more frequent in Crohn's disease, than in controls, with allelic frequencies of 0.11, 0.02 and 0.07 respectively. Heterozygosity for individual variants conferred a three-fold increase in risk for Crohn's disease while substantially higher risks were associated with being homozygous or compound heterozygous. Despite a significantly lower population allele frequency for the frameshift mutation than reported by other groups, we see a similar contribution by this allele to the risk of developing Crohn's disease. While the three risk alleles influence susceptibility to Crohn's disease in Australia, we show that these alleles do not fully explain the linkage evidence and suggest that there are very likely additional IBD1 susceptibility alleles yet to be described in Australian CD at the NOD2 locus. We also show a second linkage peak in Australian CD that provides some support for a second disease susceptibility locus on chromosome 16.

Alleles↗
PubMed2001

Metabolic genotypes and risk for colorectal cancer.

BACKGROUND: Inherited polymorphisms that influence carcinogen metabolism or the composition of bile may influence the risk for the development of colorectal cancer. METHODS: The frequency of polymorphisms involving N-acetyltransferase 1 (NAT1), NAT2, cytochrome P450 1A1 (CYP1A1), CYP2D6, CYP2E1, glutathione S-transferase M1 (GSTM1), GSTT1 and apolipoprotein E were compared in 219 white adults with sporadic colorectal cancer and 200 white controls attending for blood donation at a blood bank. Polymorphisms were determined by using restriction fragment length polymorphism (RFLP) after amplification of genomic DNA by polymerase chain reaction (PCR). Data were analyzed by using standard statistical methods for a case- control study, and reported as odds ratios (OR) with 95% confidence intervals (CI). RESULTS: None of the genotypes, either alone or in combination, showed a strong association with colorectal cancer. Inheritance of the GSTT1 null genotype conferred a twofold risk of cancer that was statistically significant with crude data (OR 2.18; 95% CI 1.38-3.43), but not after adjustment for age (OR 1.91; 95% CI 0.99-3.70). There was also a trend towards a lower risk for proximal (right-sided) cancers in patients with apolipoprotein epsilon4 (OR 0.64; 95% CI 0.31-1.33). CONCLUSION: No strong associations have been found between metabolic genotypes and colorectal cancer risk in Australia. Large studies will be required to confirm weak associations and to establish relationships between cancer risk, metabolic genotypes and exposure to dietary or other environmental carcinogens.

Acetyltransferases↗
PubMed1999

Meat, metabolic genotypes and risk for colorectal cancer.

Persuasive data exist as to the importance of environmental factors in the pathogenesis of sporadic colorectal cancer. One possibility is that the effect of environmental factors varies between individuals, perhaps on the basis of inherited variation (polymorphism) in genes which influence the activation or inactivation of dietary carcinogens. Thus far, the focus has been on acetylator genes (NAT1, NAT2) and the activation of heterocyclic amines, carcinogens generated by cooking meat for prolonged periods at high temperature. Three case-control studies and one prospective study have shown a consistent trend towards higher risks for cancer with higher intakes of meat in rapid acetylators for NAT1, NAT2 or both genotypes. Other links between meat, cooking methods, metabolic genotypes and risk for cancer might include enhanced activation of polycyclic aromatic hydrocarbons and N-nitroso compounds by variant genotypes of CYP1A1 and CYP2E1, respectively, and modulation by meat of the protective effect of the E4 allele of apolipoprotein E on risk for cancer of the proximal colon.

Acetylation↗
PubMed1998

Down-regulation of Fas gene expression in colon cancer is not a result of allelic loss or gene rearrangement.

Expression of Fas, an apoptosis-inducing receptor, in colonic epithelium is progressively reduced during malignant transformation. We have examined the human Fas gene for loss of heterozygosity (LOH) and gross rearrangements in colon tumours and matched normal mucosa. Polymerase chain reaction (PCR) primers were designed to span a DraI restriction fragment length polymorphic site in the gene. Heterozygosity was detected in normal DNA samples by PCR amplification of the polymorphic site and restriction enzyme digestion. Thirty-eight of 88 patients (43%) with colon carcinomas were informative for the assay, and LOH was detected in 6 of the 38 (16%) corresponding tumours. Tumours from three patients with LOH did not express detectable Fas mRNA, and Fas expression was reduced or absent in 7 of 11 tumours from informative patients without LOH. Southern blotting of tumour DNA samples was used to detect rearrangement of the Fas gene, but no altered hybridization patterns were observed in 64 tumours analysed. These findings indicate that disruption of the Fas gene is not primarily responsible for the loss of Fas protein expression reported in colon cancer. We have also shown that loss of Fas gene transcription is common in these tumours, which may be due to epigenetic gene silencing.

Antigens, Neoplasm↗
PubMed1998

Somatic mutations, acetylator status, and prognosis in colorectal cancer.

BACKGROUND: Somatic mutations in K-ras and TP53 may be associated with both acetylator status and prognosis in colorectal cancer. AIMS: To determine whether cancers with somatic mutations are more frequent in fast acetylators and whether mutations or acetylator status influence prognosis after colorectal surgery. PATIENTS: One hundred consecutive subjects undergoing elective surgery for colorectal cancer. METHODS: Acetylator status was determined by polymerase chain reaction (PCR) genotyping for polymorphism in the N-acetyltransferase 2 (NAT2) gene. Mutations in K-ras (codon 12) and TP53 were determined by PCR analysis using restriction enzyme digestion and single strand conformation polymorphism respectively. Survival from colorectal cancer for up to five years after diagnosis was analysed using the Kaplan-Meier product limit estimator. Cox proportional hazards regression was used to compare survival rates after adjusting for tumour stage. RESULTS: Mutations in K-ras and TP53 were independent of acetylator status. By log rank test, survival was significantly reduced in subjects with TP53 mutations (p = 0.003) but was not significantly related to acetylator status or the presence of K-ras mutations. After adjustment for tumour stage, subjects with both TP53 and K-ras mutations had a 4.2-fold case fatality (95% confidence interval 1.5 to 11.6) when compared with that of a TP53 negative reference group. CONCLUSION: The presence of both TP53 and K-ras mutations in colorectal tumours is an adverse prognostic marker which is independent of tumour stage.

Acetylation↗
PubMed1997

Evidence for the presence of the platelet-activating factor receptor in the CFW mouse preimplantation two-cell-stage embryo.

Platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine; PAF), a potent signaling phospholipid, has a significant role in preimplantation embryo development. CFW mouse embryos respond to PAF with improved development and implantation rates. PAF's signal transduction mechanism in other cell types is receptor mediated. However, embryonic mRNA for the PAF receptor has not been detected. The study objectives were to determine the presence of PAF receptor mRNA in CFW mouse two-cell embryos by reverse transcription (RT)-polymerase chain reaction and Northern blot analysis and to ascertain the effect of PAF on intracellular calcium levels (a receptor-mediated event). Total RNA was purified by acid-phenol extraction and ethanol precipitation. Complementary DNA was synthesized by RT. RNA was primed with oligo-dT plus PAF receptor-specific primer (3' to 5') at 42 degrees C for 60 min, 95 degrees C for 10 min, and 5 degrees C for 5 min. The RT product was amplified with Taq polymerase and PAF receptor-specific primer (5' to 3') at 94 degrees C for 5 min and 54 degrees C for 5 min for one cycle, and at 72 degrees C for 3 min, 93 degrees C for 90 sec, and 61 degrees C for 150 sec for 30 cycles followed by 72 degrees C for 10 min and then holding at 4 degrees C. The product was analyzed by agarose gel electrophoresis, producing a single band (610 base pairs [bp]), thus demonstrating the presence of PAF-receptor mRNA. Sequence analysis of the cloned 610-bp fragment confirmed that it is the PAF receptor. Northern blot analysis also confirmed the expression of the PAF receptor in the CFW mouse preimplantation two-cell-stage embryo. PAF treatment of the two-cell-stage CFW mouse embryo resulted in a fourfold increase in intracellular calcium over background levels.

Animals↗