Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes.

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs

Leptin's Activity on the Hydroxyl Radical: A Possible Link to the Oxidative Stress-Related Endothelial Vasodilation in Patients with Obstructive Sleep Apnea

Purpose: Obstructive sleep apnea (OSA) is associated with increased cardiovascular morbidity, whereas the underlying mechanism is still eluding, the thought participants are chronic intermittent hypoxia with consequent increase in the reactive oxygen species, leading to endothelial cell damage and dysfunction in these patients. As the hydroxyl radical (·OH) mediates the vascular smooth muscle relaxation, identification of its scavengers might reveal sentinel markers of decreased vascular responsiveness and worse long-term comorbid outcome. We therefore assessed leptin's scavenger effect on • OH using the electronic paramagnetic resonance (EPR) method. Methods: The • OH was generated by the Fenton reaction in the presence of spin-trap 5-diethoxyphosphoryl-5-methyl-1-pyrroline N-oxide (DMPO) with various concentrations of leptin (0.25, 2.5, and 25 μg/ml) and without leptin. EPR spectrometer settings were: modulation frequency, 100 kHz; X band microwave frequency, 9.5 GHz; microwave power, 20 mW (milliwatts); modulation amplitude, 1.0 G (gauss); time constant, 160 s; scan time, 200 s; and receiver gain, 1 × l0 5 . EPR signal intensity between 3,440 and 3,540 G of measurements taken in at least three separate experiments was reported. Mannitol, a known • OH scavenger, at 100 mM significantly decreased the DMPO-OH adduct formation and was used as the active-control agent. Results: Leptin added to aqueous solutions at all concentrations was associated with a statistically significant decrease in EPR signal compared with controls due to its scavenging activity towards the ·OH. Conclusions: Leptin could be further investigated as a sentinel biomarker of decreased vascular responsiveness and future risk of atherosclerotic disease in obese OSA patients