Background: In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the... Show moreBackground: In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear.Methods: We conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium.Results: All sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p = 5.09 x 10(-4)], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p = 4.02 x 10(-4)), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p = 5.05 x 10(-19)) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p = 9.22 x 10(-6)). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer.Conclusions: We confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer. Show less
We present a candidate for the most distant galaxy known to date with a photometric redshift of z = 10.7$^{+0.6}$ $_{-0.4}$ (95% confidence limits; with z {lt} 9.5 galaxies of known types ruled... Show moreWe present a candidate for the most distant galaxy known to date with a photometric redshift of z = 10.7$^{+0.6}$ $_{-0.4}$ (95% confidence limits; with z {lt} 9.5 galaxies of known types ruled out at 7.2{$σ$}). This J-dropout Lyman break galaxy, named MACS0647-JD, was discovered as part of the Cluster Lensing and Supernova survey with Hubble (CLASH). We observe three magnified images of this galaxy due to strong gravitational lensing by the galaxy cluster MACSJ0647.7+7015 at z = 0.591. The images are magnified by factors of ~{}80, 7, and 2, with the brighter two observed at ~{}26th magnitude AB (~{}0.15 {$μ$}Jy) in the WFC3/IR F160W filter (~{}1.4-1.7 {$μ$}m) where they are detected at gsim12{$σ$}. All three images are also confidently detected at gsim6{$σ$} in F140W (~{}1.2-1.6 {$μ$}m), dropping out of detection from 15 lower wavelength Hubble Space Telescope filters (~{}0.2-1.4 {$μ$}m), and lacking bright detections in Spitzer/IRAC 3.6 {$μ$}m and 4.5 {$μ$}m imaging (~{}3.2-5.0 {$μ$}m). We rule out a broad range of possible lower redshift interlopers, including some previously published as high-redshift candidates. Our high-redshift conclusion is more conservative than if we had neglected a Bayesian photometric redshift prior. Given CLASH observations of 17 high-mass clusters to date, our discoveries of MACS0647-JD at z ~{} 10.8 and MACS1149-JD at z ~{} 9.6 are consistent with a lensed luminosity function extrapolated from lower redshifts. This would suggest that low-luminosity galaxies could have reionized the universe. However, given the significant uncertainties based on only two galaxies, we cannot yet rule out the sharp drop-off in number counts at z {gt}~{} 10 suggested by field searches. Show less
