Background: We tested the hypothesis that genetically reduced activity of glutathione S -transferases (GST) T1 and M1 were associated with increased risk for asthma.
Methods: We genotyped participants in the Copenhagen City Heart Study (n=10,335) for the exact number of GSTT1 and GSTM1 gene copies and recorded asthma outcomes. We also performed a meta-analysis of 37 studies comprising 5954 asthma cases and 14513 controls to assess the risk for asthma in GSTT1*0/0 homozygotes.
Results: The odds ratio for asthma was stepwise increased with decreasing number of GSTT1 gene copies (P=0.03): GSTT1*0/0 homozygotes and *1/0 heterozygotes had adjusted odds ratios for asthma of 1.27 (95%CI: 1.03-1.56) and 1.07 (0.92-1.25), respectively, compared with *1/1 homozygotes. When the asthma definition was restricted to participants who only had allergic asthma or took asthma medication, GSTT1*0/0 versus *1/1 homozygotes had adjusted odds ratios of 1.34 (1.01-1.79) for allergic asthma and of 1.20 (0.88-1.64) for asthma medication. When the asthma definition included any of the three different asthma definitions, GSTT1*0/0 homozygotes had an adjusted odds ratio for any asthma of 1.24 (1.02-1.51) compared with *1/1 homozygotes. In meta-analysis, random effects odds ratio for asthma was increased at 1.35 (1.14-1.59) in GSTT1*0/0 homozygotes versus individuals with *1/0 or *1/1 genotypes. None of the risk estimates for GSTM1 genotypes differed from 1.0 for any of the four different definitions of asthma (P=0.17-0.95).
Conclusion: The results suggest that individuals with genetic GSTT1 deficiency have increased risk for asthma, while asthma risk is unaffected by GSTM1 deficiency.
To compare day-to-day and within-day variability in glucose-lowering effect between insulin degludec (IDeg) and insulin glargine 300 U/mL (IGlar-U300) in type 1 diabetes.In this double-blind, crossover study, patients were randomly assigned to 0.4 U/kg of IDeg or IGlar-U300 once daily for two treatment periods lasting 12 days each. Pharmacodynamic variables were assessed at steady-state from the glucose infusion rate profiles of three 24-hour euglycaemic glucose clamps (days 6, 9 and 12) during each treatment period.Overall, 57 patients completed both treatment periods (342 clamps). The potency of IGlar-U300 was 30% lower than IDeg (estimated ratio 0.70, 95% confidence interval [CI] 0.61; 0.80; P < .0001). The distribution of glucose-lowering effect was stable across 6-hour intervals (24%-26%) for IDeg, while IGlar-U300 had greater effects in the first (35%) and last (28%) intervals compared with 6 to 12 hours (20%) and 12 to 18 hours (17%). Within-day variability (relative fluctuation) was 37% lower with IDeg than with IGlar-U300 (estimated ratio IDeg/IGlar-U300: 0.63, 95% CI 0.54; 0.73; P < .0001). The day-to-day variability in glucose-lowering effect with IDeg was approximately 4 times lower than IGlar-U300 (variance ratio IGlar-U300/IDeg: 3.70, 95% CI 2.42; 5.67; P < .0001). The day-to-day variability in glucose-lowering effect assessed in 2-hour intervals was consistently low with IDeg over 24 hours, but steadily increased with IGlar-U300 to a maximum at 10 to 12 hours and 12 to 14 hours after dosing (variance ratios 12.4 and 11.4, respectively).IDeg has lower day-to-day and within-day variability than IGlar-U300 and a more stable glucose-lowering effect, which might facilitate titration and enable tighter glycaemic control with a reduced risk of hypoglycaemia.
Background: The enzyme glutathione-S-transferase (GST) P1 metabolises carcinogens from tobacco smoke in the lung. We tested whether genetically altered GSTP1 activity affects lung function and risk of lung cancer, tobacco-related cancer and death in the general population. Methods: We genotyped 66,069 individuals from the Danish general population for two functional polymorphisms in the GSTP1 gene (Ile105Val and Ala114Val), and recorded lung function, lung cancer, tobacco-related cancer, and death as outcomes. Results: Lung function was stepwise increased with Ile105Val genotype overall (P Conclusion: The common GSTP1 Ile105Val variant was associated with elevated lung function and reduced risk of lung cancer, tobacco-related cancer, and death in the general population. The data support a role for GSTP1 in oxidant-mediated events influencing lung function, lung cancer, tobacco-related cancer and death, especially among smokers.
Glutathione S-transferases (GSTs) M1 and T1 detoxify products of oxidative stress and may protect against atherosclerosis and ischemic vascular disease (IVD). We tested the hypothesis that copy number variation (CNV) in GSTM1 and GSTT1 genes, known to be associated with stepwise decreases in catalytic activity, predict risk of IVD.We included 23 059 Danes from 2 general population studies and 2 case-control studies, of whom 4930 had ischemic heart disease (IHD) and 2086 had ischemic cerebrovascular disease. A real-time polymerase chain reaction method genotyped for the exact number of GSTM1 and GSTT1 gene copies. We also performed meta-analyses, including our own and former studies, totaling 13 196 IHD cases and 33 228 controls. CNV in GSTM1 or GSTT1 or genotype combinations were not associated with an increased risk of IHD, myocardial infarction, ischemic cerebrovascular disease, ischemic stroke, or any ischemic vascular event in studies individually or combined or in the meta-analyses. Furthermore, genotypes did not interact with smoking on risk of disease end points. Finally, GST genotypes did not associate with markers of inflammation and oxidation or interact with smoking on markers of inflammation in the general population. In contrast, we observed the well-established association between CNV in GSTM1 and risk of bladder cancer.In studies including 6557 IVD cases and 16 502 controls and in meta-analyses of 13 196 cases and 33 228 controls, CNV in GSTM1 and GSTT1 genes did not associate with risk of IVD or with markers of inflammation. These observations were independent of smoking exposure.
To determine the potential of a non-invasive acoustic device (CADScor®System) to reclassify patients with intermediate pre-test probability (PTP) and clinically suspected stable coronary artery disease (CAD) into a low probability group thereby ruling out significant CAD. Audio recordings and clinical data from three studies were collected in a single database. In all studies, patients with a coronary CT angiography indicating CAD were referred to coronary angiography. Audio recordings of heart sounds were processed to construct a CAD-score. PTP was calculated using the updated Diamond-Forrester score and patients were classified according to the current ESC guidelines for stable CAD: low < 15%, intermediate 15-85% and high > 85% PTP. Intermediate PTP patients were re-classified to low probability if the CAD-score was ≤ 20. Of 2245 patients, 212 (9.4%) had significant CAD confirmed by coronary angiography ( ≥ 50% diameter stenosis). The average CAD-score was higher in patients with significant CAD (38.4 ± 13.9) compared to the remaining patients (25.1 ± 13.8; p < 0.001). The reclassification increased the proportion of low PTP patients from 13.6% to 41.8%, reducing the proportion of intermediate PTP patients from 83.4% to 55.2%. Before reclassification 7 (3.1%) low PTP patients had CAD, whereas post-reclassification this number increased to 28 (4.0%) (p = 0.52). The net reclassification index was 0.209. Utilization of a low-cost acoustic device in patients with intermediate PTP could potentially reduce the number of patients referred for further testing, without a significant increase in the false negative rate, and thus improve the cost-effectiveness for patients with suspected stable CAD.
