Polymorphisms in the carcinogen detoxification genes CYB5A and CYB5R3 and breast cancer risk in African American women

Cytochrome b5 (encoded by CYB5A) and NADH cytochrome b5 reductase (encoded by CYB5R3) detoxify aromatic and heterocyclic amine mammary carcinogens found in cigarette smoke. We hypothesized that CYB5A and CYB5R3 polymorphisms would be associated with breast cancer risk in women

Glutathione S‐transferase theta genotypes and environmental exposures in the risk of canine transitional cell carcinoma

Abstract Introduction Transitional cell carcinoma (TCC) in humans is associated with environmental exposures and variants in glutathione S‐transferase (GST) genes. Scottish Terriers have a high breed risk for TCC, but the relationship between genetic and environmental risk in dogs is not fully understood. Hypotheses Scottish Terriers have a higher frequency of GST‐theta variants compared to lower risk breeds. Dogs with TCC of any breed have a higher frequency of GST‐theta variants along with higher environmental exposures, compared to controls. Animals One hundred and five Scottish Terriers and 68 controls from lower risk breeds; 69 dogs of various breeds with TCC, and 72 breed‐ and sex‐matched unaffected geriatric dogs. Methods In this prospective case‐control study, dogs were genotyped for 3 canine GST‐theta variants: GSTT1 I2+28 G>A, a GSTT1 3′UTR haplotype, and GSTT5 Asp129_Gln130del. Owners of dogs with TCC and unaffected geriatric controls completed a household environmental questionnaire. Results The GSTT1 3′UTR haplotype and GSTT5 Asp129_Gln130del variants were significantly underrepresented in Scottish Terriers (minor allele frequency [MAF] = 0.000 for both), compared to dogs from lower risk breeds (MAF = 0.108 and 0.100; P ≤ .0002). Dogs with TCC did not differ from unaffected geriatric controls across the 3 investigated loci. Transitional cell carcinoma was associated with household insecticide use (odds ratio [OR] = 4.28, 95% confidence interval [CI] = 1.44‐12.33, P = .02), and was negatively associated with proximity to a farm (OR = 0.49, 95% CI = 0.25‐0.99, P = .04). Conclusions and Clinical Importance Low‐activity GST‐theta loci are unlikely contributors to TCC risk in dogs. Increased risk is associated with household insecticide use, and possibly with less rural households

Environmental exposures and lymphoma risk: a nested case–control study using the Golden Retriever Lifetime Study cohort

Plain English Summary Lymphoma is a common cancer affecting dogs, particularly Golden Retrievers. By identifying risk factors for lymphoma, work can be done to reduce harmful exposures or increase monitoring among dogs at a higher risk of disease. Using a subset of dogs from the Golden Retriever Lifetime Study, we sought to investigate whether dogs with lymphoma were more likely to live near certain environmental pollutant sources than dogs without lymphoma. Forty-nine Golden Retrievers with non-cutaneous lymphoma and 98 Golden Retrievers without a history of cancer were selected from the Golden Retriever Lifetime Study Cohort. We evaluated how close each dog lived to nine environmental pollutant sources: chemical plants, municipal dumps, manufacturing plants, incineration plants, railroad embankment tracks, landfills, coal plants, high-voltage transmission lines, and nuclear power plants. Additionally, we evaluated individual exposure to secondhand smoke, and average annual ozone and particulate matter exposure (as surrogate measures for air pollution) for each dog’s county of residence. None of the exposures examined were associated with an increased lymphoma risk in this population. More research is needed, including direct biomonitoring, to determine whether specific environmental exposures are associated with lymphoma in the Golden Retriever breed

Genome-Wide Association Study in Immunocompetent Patients with Delayed Hypersensitivity to Sulfonamide Antimicrobials

<div><p>Background</p><p>Hypersensitivity (HS) reactions to sulfonamide antibiotics occur uncommonly, but with potentially severe clinical manifestations. A familial predisposition to sulfonamide HS is suspected, but robust predictive genetic risk factors have yet to be identified. Strongly linked genetic polymorphisms have been used clinically as screening tests for other HS reactions prior to administration of high-risk drugs.</p><p>Objective</p><p>The purpose of this study was to evaluate for genetic risk of sulfonamide HS in the immunocompetent population using genome-wide association.</p><p>Methods</p><p>Ninety-one patients with symptoms after trimethoprim-sulfamethoxazole (TMP-SMX) attributable to “probable” drug HS based on medical record review and the Naranjo Adverse Drug Reaction Probability Scale, and 184 age- and sex-matched patients who tolerated a therapeutic course of TMP-SMX, were included in a genome-wide association study using both common and rare variant techniques. Additionally, two subgroups of HS patients with a more refined clinical phenotype (fever and rash; or fever, rash and eosinophilia) were evaluated separately.</p><p>Results</p><p>For the full dataset, no single nucleotide polymorphisms were suggestive of or reached genome-wide significance in the common variant analysis, nor was any genetic locus significant in the rare variant analysis. A single, possible gene locus association (<i>COL12A1</i>) was identified in the rare variant analysis for patients with both fever and rash, but the sample size was very small in this subgroup (n = 16), and this may be a false positive finding. No other significant associations were found for the subgroups.</p><p>Conclusions</p><p>No convincing genetic risk factors for sulfonamide HS were identified in this population. These negative findings may be due to challenges in accurately confirming the phenotype in exanthematous drug eruptions, or to unidentified gene-environment interactions influencing sulfonamide HS.</p></div

Role of NADPH-Cytochrome P450 Reductase and Cytochrome-b5/NADH-b5 Reductase in Variability of CYP3A Activity in Human Liver Microsomes

NADPH-cytochrome P450 reductase (CPR) and cytochrome- b 5 ( b 5 ) together with NADH- b 5 reductase ( b 5 R) play important roles in cytochrome P450 3A-mediated drug metabolism via electron transfer. However, it is not clear whether variability in expression of these accessory proteins contributes to the known interindividual variability in CYP3A activity. CPR and b 5 were measured in human liver microsomes (HLMs) by spectrophotometry and immunoblotting. HLMs from elderly (≥46 years) male donors ( n = 11) averaged 27% ( P = 0.034) and 41% ( P = 0.011) lower CPR levels than young (≤45 years) male donors ( n = 21) for spectrophotometric and immunoblot values, respectively. Similarly, HLMs from elderly male donors averaged 43% ( P = 0.034) and 47% ( P = 0.011) lower b 5 levels than young male donors for spectrophotometric and immunoblot values, respectively. α-Lipoic acid and 6-propyl-2-thiouracil were evaluated for selectivity of inhibition of CPR and b 5 R activities, respectively, using recombinant enzymes and HLMs, as well as for effects on CYP3A-mediated triazolam hydroxylation in HLMs with either NADH or β-NADPH. The results indicate that both compounds are relatively nonselective inhibitors of CPR and b 5 R activities. Finally, we used multivariate regression analysis and showed that variability in CPR or b 5 expression between HLMs does not contribute significantly to variability in CYP3A-mediated midazolam hydroxylation. Consequently, while aging is associated with decreased CPR and b 5 expression in human livers, this effect does not contribute to CYP3A variability

Manhattan plot for common variant analysis of full set of sulfonamide hypersensitive (HS) vs. drug tolerant (TOL) patients.

<p>No SNPs were suggestive of (p ≤ 6.03 x 10⁻⁷) or reached genome-wide significance (p ≤ 6.03 x 10⁻⁹).</p

Candidate genes within the GWAS hypothesized to be involved in the pathogenesis of sulfonamide HS, and the mechanistic rationale for inclusion of each candidate gene.

<p>Candidate genes within the GWAS hypothesized to be involved in the pathogenesis of sulfonamide HS, and the mechanistic rationale for inclusion of each candidate gene.</p

Manhattan plot for common variant analysis of HS subgroup with fever, rash and eosinophilia (FEV-RASH-EOS) vs. all TOL patients.

<p>No SNPs were suggestive of (p ≤ 6.02 x 10⁻⁷) or reached genome-wide significance (p ≤ 6.02 x 10⁻⁹).</p

Inclusion and exclusion of recruited subjects.

<p>Inclusion and exclusion of recruited subjects.</p