Genetic Variation in GSTP1, Lung Function, Risk of Lung Cancer, and Mortality.

INTRODUCTION: Glutathione S-transferase pi 1 metabolizes carcinogens from tobacco smoke in the lung. We tested whether genetically altered glutathione S-transferase pi 1 activity affects lung function and risk for tobacco-related cancer and mortality in the general population. METHODS: We genotyped 66,069 individuals from the white general population for two common functional variants in the glutathione S-transferase pi 1 gene (GSTP1)-amino acid isoleucine 105 changed to a valine (Ile105Val) and amino acid alanine 114 changed to a valine (Ala114Val)-and recorded lung function, lung cancer, tobacco-related cancer, and death as outcomes. RESULTS: Lung function was increased stepwise with the Ile105Val genotype overall (p < 0.01) and among smokers separately (p < 0.01). Adjusted hazard ratios for lung cancer, tobacco-related cancer, and death were reduced stepwise with the Ile105Val genotype (p < 0.02): Ile105Val homozygotes and heterozygotes versus noncarriers had hazard ratios for lung cancer of 0.64 (0.47-0.89) and 0.93 (0.78-1.11), for tobacco-related cancer of 0.74 (0.60-0.92) and 0.92 (0.81-1.04), and hazard ratios for death of 0.87 (0.80-0.95) and 0.94 (0.89-0.99), respectively. Population prevented fractions of lung cancer, tobacco-related cancer, and death due to Ile105Val homozygosity were 4%, 3% and 2%, respectively. The Ala114Val genotype was associated with reduced mortality (p < 0.01) but not with lung function, lung cancer, or tobacco-related cancer. CONCLUSION: GSTP1 Ile105Val was associated with increased lung function, reduced risk for lung cancer and tobacco-related cancer, and reduced all-cause mortality in the general population.

Insulin degludec: Lower day-to-day and within-day variability in pharmacodynamic response compared with insulin glargine 300 U/mL in type 1 diabetes.

AIM: 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. MATERIALS AND METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Copy number variation in glutathione S-transferases M1 and T1 and ischemic vascular disease: four studies and meta-analyses.

BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.

High-throughput genotyping of copy number variation in glutathione S-transferases M1 and T1 using real-time PCR in 20,687 individuals.

OBJECTIVES: Characteristic for the genes encoding glutathione S-transferase (GST) M1 and GSTT1 is a null allele, suggested to increase susceptibility to chronic diseases. We report an optimized method for the determination of copy number variation (CNV) in GST genes. DESIGN AND METHODS: Real-time multiplex PCR reactions were optimized for quantification of GSTM1 and GSTT1 CNV using the DeltaCt method, a fixed volume of diluted DNA, a total volume of 10 microL, 384-well formats, and single determinations of each sample. RESULTS: Consistent genotyping was obtained using DNA in a range of 0.41 ng to 100 ng. In a general population sample of 20,687 individuals the genotype frequencies were concordant with other methods used as standards. Throughput was 4600 genotypes per day at a reagent price of 0.5 euros per sample. CONCLUSIONS: This high-throughput, low cost method accurately determines CNV in the GST genes enabling reliable estimates of disease prediction in large epidemiological samples.