Citations

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium ( n Stage1 : 111,666; n Stage2 : 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea ( PPM1J , EDEM3, ACP1, SPEG, EYA4, CYP1A1 , and ATXN2L ; P Stage1 <3.7×10 −7 ), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 ( P =5.4×10 −8 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2 -knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

Abstract Targeting membrane PD-1 molecules expressed by tumor-reactive T cells is gaining acceptance as a potentially effective anti-tumor immunotherapy. PD-1 blockade mediated by monoclonal antibodies has yielded promising therapeutic effects in treatment of melanoma, lung cancer and kidney cancers. Although detecting PD-1 expression by T cells is relatively straightforward, a simple and reliable method for determining whether PD-1 on T cells has engaged its ligand B7-H1 (PD-L1) is wanting. Our previous studies have revealed that engagement of PD-1 or B7-1 by B7-H1 results in alternations of apoptosis signaling pathway by up-regulating pro-apoptotic molecules among activated T cells and are correlated with B7-H1-mediated T cell death. Those observations suggest that intracellular levels of apoptosis-related Bcl2 family molecules among PD-1 positive CD8 T cells may be barometers of the extent to which PD-1 has been triggered by B7-H1. Using PD-1 and B7-H1 deficient animal models, we found that lower levels of intracellular pro-apoptosis molecules identify those activated T cells whose PD-1 molecules have not yet been extensively engaged, thus T cell function might be restored to their normal function once PD-1 signals from B7-H1 are blocked. Similarly, human PD-1 positive CD8 T cells engaged by B7-H1 also expressed higher levels of pro-apoptosis molecules during antigen stimulation. Our clinical data demonstrated that pro-apoptosis molecule expression by tumor-reactive T cell levels are higher among advanced melanoma and prostate cancers than healthy controls, reflecting chronic engagement with B7-H1. Thus, using pro-apoptosis status as signaling biomarkers for T cell PD-1 engagement, it may be possible to select patients who are most likely to have strong benefit from PD-1 or B7-H1 (PD-L1) blockade therapy. Citation Format: Wei Zhao, Haidong Dong. T cell apoptosis signaling biomarker of PD-1 engagement in cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2552. doi:10.1158/1538-7445.AM2014-2552

Genetic College Many genomic elements in humans are associated with behavior, including educational attainment. In a genome-wide association study including more than 100,000 samples, Rietveld et al. (p. 1467 , published online 30 May; see the Perspective by Flint and Munafò ) looked for genes related to educational attainment in Caucasians. Small genetic effects at three loci appeared to impact educational attainment.