15 research outputs found
Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases
Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r =-0.62, P = 5.30 Ă 10-5) but not between CCT and primary open-angle glaucoma (r =-0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation
Multi-trait genome-wide association study identifies new loci associated with optic disc parameters
A new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH
BAG-1 immunostaining and survival in early breast cancer
To the Editor: We read with interest the article by Turner et al1 in the February 15, 2001, issue describing the association between increased levels of cytosolic, but not nuclear, BAG-1 immunostaining and long-term survival in early breast cancer. There is, however, some difficulty in determining the precise relationship between BAG-1 expression and the biology of breast cancer. A previous report by this group using a monoclonal antibody described a significant positive correlation between high levels of nuclear BAG-1 immunostaining and overall survival, whereas a report from a different group described inferior survival in patients with high levels of nuclear BAG-1 staining using a polyclonal antibody.From the examples of immunostaining presented in the two articles from Turner and co-workers, it seems that at least some of the same patients were included in the two series with discrepant results. It would be helpful to know the degree of overlap between the two cohorts and whether any potential selection bias may have influenced the results. In particular, the low proportion of estrogen receptorâpositive cases (41% as against an expected level of 70%) suggests that the sample described may not be wholly representative of an early-stage breast cancer population. Tumor grade was not included in the table of patient characteristics, and as correlations have been found between tumor differentiation and BAG-1 status by at least one group, it would be instructive to know if BAG-1 was predictive of outcome independent of tumor grade.It is also possible that the discrepant results relate to differences in methodology, such as antigen retrieval techniques, which were not described in the more recent article. It is clear that further work is required to properly describe the potential role of BAG-1 expression as a biologic variable, and it would be helpful to other investigators to have these critical details
The existence of the strong combined-optimal design
Estimation index, maximum design, minimum aberration, optimal foldover,
Optimal delineation of the clinical target volume for thymomas in the post-resection setting: A multi-center study
Background: The definition of the clinical target volume (CTV) for post-operative radiotherapy (PORT) for thymoma is largely unexplored. The aim of this study was to analyze the difference in CTV delineation between radiation oncologists (RTO) and surgeons. Methods: This retrospective multi-center study enrolled 31 patients who underwent PORT for a thymoma from five hospitals. Three CTVs were delineated per patient: one CTV by the RTO, one CTV by the surgeon (blinded to the results of the RTO) and a joint CTV after collaboration. Volumes (cm3), Hausdorff distances (HD) and Dice similarity coefficients (DSC) were analyzed. Results: RTO delineated significantly bigger CTVs than surgeons (mean: 93.9 ± 63.1, versus 57.9 ± 61.3 cm3, p = 0.003). Agreement was poor between RO and surgeons, with a low mean DSC (0.34 ± 0.21) and high mean HD of 4.5 (±2.2) cm. Collaborative delineation resulted in significantly smaller volumes compared to RTO (mean 57.1 ± 58.6 cm3, p < 0.001). A mean volume of 18.9 (±38.1) cm3 was included in joint contours, but missed by RTO. Conversely, a mean volume of 55.7 (±39.9) cm3 was included in RTO's delineations, but not in the joint delineations. Conclusions: To the best of our knowledge, this is the first study investigating CTV definition in thymoma. We demonstrated a significant variability between RTO and surgeons. Joint delineation prompted revisions in smaller CTV as well as favoring the surgeonsâ judgement, suggesting that surgeons provided relevant insight into other risk areas than RTO. We recommend a multidisciplinary approach to PORT for thymomas in clinical practice