Biomedical subjects

Robert Welch

Publications and source records attributed to Robert Welch.

41 records · Page 3Linked to original sources

PubMed2003

Widespread purifying selection at polymorphic sites in human protein-coding loci.

Estimation of gene diversity (heterozygosity) at 1442 single-nucleotide polymorphism (SNP) loci in an ethnically diverse sample of humans revealed consistently reduced gene diversities at SNP loci causing amino acid changes, particularly those causing amino acid changes predicted to be disruptive to protein structure. The reduction of gene diversity at these SNP loci, in comparison to SNPs in the same genes not affecting protein structure, is evidence that negative natural selection (purifying selection) has reduced the population frequencies of deleterious SNP alleles. This, in turn, suggests that slightly deleterious mutations are widespread in the human population and that estimation of gene diversity even in a sample of modest size can help guide the search for disease-associated genes.

Chromosome Mapping↗

PubMed2003

Mortality benefit of immediate revascularization of acute ST-segment elevation myocardial infarction in patients with contraindications to thrombolytic therapy: a propensity analysis.

CONTEXT: There are no definitive recommendations for the management of acute myocardial infarction (AMI) in patients with ST-segment elevation who have contraindications to thrombolytic therapy. It is not clear whether, and the extent to which, immediate mechanical reperfusion (IMR) reduces in-hospital mortality in this population. OBJECTIVE: To determine whether IMR (defined as percutaneous coronary intervention or coronary artery bypass graft surgery) is associated with a mortality benefit in patients with acute ST-segment elevation AMI who are eligible for IMR but have contraindications to thrombolytic therapy. DESIGN, SETTING, AND PATIENTS: From June 1994 to January 2003, the National Registry of Myocardial Infarction 2, 3, and 4 enrolled 1 799 704 patients with AMI. A total of 19 917 patients with acute ST-segment elevation were eligible for IMR but had thrombolytic contraindications after excluding patients who were transferred in from or out to other facilities, patients who received intracoronary thrombolytics, and those who received no medications within 24 hours of arrival. MAIN OUTCOME MEASURE: In-hospital mortality. RESULTS: Of the 19 917 patients, 4705 patients (23.6%) received IMR and 5173 patients (25.9%) died. In-hospital mortality rates in the IMR and non-IMR treated groups in the unadjusted analysis were 11.1%, representing 521 of 4705 patients, and 30.6%, representing 4652 of 15 212 patients, respectively, for a risk reduction of 63.7% (odds ratio [OR], 0.28; 95% confidence interval [CI], 0.26-0.31). In a further analysis using a propensity matching score to reduce the effects of bias, 3905 patients who received IMR remained at lower risk for in-hospital mortality than 3905 matched patients (10.9% vs 20.1%, respectively, for a risk reduction of 45.8%; OR, 0.48; 95% CI, 0.43-0.55). Following a second logistic model applied to the matched groups to adjust for residual differences, a significant treatment effect persisted (OR, 0.64; 95% CI, 0.56-0.75). CONCLUSIONS: In this population, IMR was associated with a reduced risk of in-hospital mortality after appropriate adjustments. Of those we studied who were eligible for IMR, 15 212 patients (76.4%) did not receive it. These results suggest that using IMR in patients with acute ST-segment elevation AMI and contraindications to thrombolytics should be strongly considered.

Aged↗

PubMed2003

Effects of electron-beam irradiation on buccal-cell DNA.

Buccal cells were collected from 29 participants, by use of mouthwash rinses, and were split into equal aliquots, with one aliquot irradiated by electron-beam (E-beam) irradiation equivalent to the sterilizing dosage used by the U.S. Postal Service and the other left untreated. Aliquots were extracted and tested for DNA yields (e.g., TaqMan assay for quantifying human genomic DNA), genomic integrity, and amplification-based analysis of genetic variants (e.g., single-nucleotide polymorphisms [SNPs] and single tandem repeats [STRs]). Irradiated aliquots had lower median DNA yields (3.7 microg/aliquot) than untreated aliquots (7.6 microg/aliquot) (P<.0005) and were more likely to have smaller maximum DNA fragment size, on the basis of genomic integrity gels, than untreated aliquots (P<.0005). Irradiated aliquots showed poorer PCR amplification of a 989-bp beta-globin target (97% for weak amplification and 3% for no amplification) than untreated aliquots (7% for weak amplification and 0% for no amplification) (P<.0005), but 536-bp and 268-bp beta-globin targets were amplified from all aliquots. There was no detectable irradiation effect on SNP assays, but there was a significant trend for decreased detection of longer STRs (P=.01) in irradiated versus untreated aliquots. We conclude that E-beam irradiation reduced the yield and quality of buccal-cell specimens, and, although irradiated buccal-cell specimens may retain sufficient DNA integrity for some amplified analyses of many common genomic targets, assays that target longer DNA fragments (>989 bp) or require whole-genome amplification may be compromised.

Bioterrorism↗

PubMedDate not supplied

NAT2 slow acetylation, GSTM1 null genotype, and risk of bladder cancer: results from the Spanish Bladder Cancer Study and meta-analyses.

BACKGROUND: Many reported associations between common genetic polymorphisms and complex diseases have not been confirmed in subsequent studies. An exception could be the association between NAT2 slow acetylation, GSTM1 null genotype, and bladder-cancer risk. However, current evidence is based on meta-analyses of relatively small studies (range 23-374 cases) with some evidence of publication bias and study heterogeneity. Associations between polymorphisms in other NAT and GST genes and bladder-cancer risk have been inconsistent. METHODS: We investigated polymorphisms in NAT2, GSTM1, NAT1, GSTT1, GSTM3, and GSTP1 in 1150 patients with transitional-cell carcinoma of the urinary bladder and 1149 controls in Spain; all the participants were white. We also carried out meta-analyses of NAT2, GSTM1, and bladder cancer that included more than twice as many cases as in previous reports. FINDINGS: In our study, the odds ratios for bladder cancer for individuals with deletion of one or two copies of the GSTM1 gene were 1.2 (95% CI 0.8-1.7) and 1.9 (1.4-2.7) respectively (p for trend <0.0001). Compared with NAT2 rapid or intermediate acetylators, NAT2 slow acetylators had an increased overall risk of bladder cancer (1.4 [1.2-1.7]) that was stronger for cigarette smokers than for never smokers (p for interaction 0.008). No significant associations were found with the other polymorphisms. Meta-analyses showed that the overall association for NAT2 was robust (p<0.0001), and case-only meta-analyses provided support for an interaction between NAT2 and smoking (p for interaction 0.009). The overall association for GSTM1 was also robust (p<0.0001) and was not modified by smoking status (p=0.86). INTERPRETATION: The GSTM1 null genotype increases the overall risk of bladder cancer, and the NAT2 slow-acetylator genotype increases risk particularly among cigarette smokers. These findings provide compelling evidence for the role of common polymorphisms in the aetiology of cancer. RELEVANCE TO PRACTICE: Although the relative risks are modest, these polymorphisms could account for up to 31% of bladder cancers because of their high prevalence.

Acetylation↗

PubMedDate not supplied

Polymorphisms in the DNA base excision repair genes APEX1 and XRCC1 and lung cancer risk in Xuan Wei, China.

The lung cancer mortality rate in Xuan Wei is among the highest in China and has been causally attributed to high exposure to indoor smoky coal emissions, which contain high levels of PAHs and can lead to modified bases. We studied genetic polymorphisms in four DNA base excision repair genes in a population-based case-control study in Xuan Wei with 122 lung cancer cases and 122 controls. Homozygous carriers of the APEX1 148Glu variant had an increased risk (OR, 2.13; 95% CI, 0.96-4.74), whereas persons with the XRCC1 399Gln allele had a decreased risk (OR, 0.60; 95% CI, 0.35-1.02) of lung cancer compared with wild-type carriers. Subjects with both at-risk genotypes (APEX1 Glu148Glu and XRCC1 Arg399Arg) had a higher risk of lung cancer (OR: 3.34; 95% CI: 1.16-9.67). We found genetic variants in APEX1 and XRCC1 may alter the risk of lung cancer in a special population in China.

Adult↗