Differential Effects of MYH9 and APOL1 Risk Variants on FRMD3 Association with Diabetic ESRD in African Americans

Single nucleotide polymorphisms (SNPs) in MYH9 and APOL1 on chromosome 22 (c22) are powerfully associated with non-diabetic end-stage renal disease (ESRD) in African Americans (AAs). Many AAs diagnosed with type 2 diabetic nephropathy (T2DN) have non-diabetic kidney disease, potentially masking detection of DN genes. Therefore, genome-wide association analyses were performed using the Affymetrix SNP Array 6.0 in 966 AA with T2DN and 1,032 non-diabetic, non-nephropathy (NDNN) controls, with and without adjustment for c22 nephropathy risk variants. No associations were seen between FRMD3 SNPs and T2DN before adjusting for c22 variants. However, logistic regression analysis revealed seven FRMD3 SNPs significantly interacting with MYH9—a finding replicated in 640 additional AA T2DN cases and 683 NDNN controls. Contrasting all 1,592 T2DN cases with all 1,671 NDNN controls, FRMD3 SNPs appeared to interact with the MYH9 E1 haplotype (e.g., rs942280 interaction p-value = 9.3E−7 additive; odds ratio [OR] 0.67). FRMD3 alleles were associated with increased risk of T2DN only in subjects lacking two MYH9 E1 risk haplotypes (rs942280 OR = 1.28), not in MYH9 E1 risk allele homozygotes (rs942280 OR = 0.80; homogeneity p-value = 4.3E−4). Effects were weaker stratifying on APOL1. FRMD3 SNPS were associated with T2DN, not type 2 diabetes per se, comparing AAs with T2DN to those with diabetes lacking nephropathy. T2DN-associated FRMD3 SNPs were detectable in AAs only after accounting for MYH9, with differential effects for APOL1. These analyses reveal a role for FRMD3 in AA T2DN susceptibility and accounting for c22 nephropathy risk variants can assist in detecting DN susceptibility genes

Estimating PM\u3csub\u3e2.5\u3c/sub\u3ein Southern California using satellite data: Factors that affect model performance

Background: Studies of PM2.5 health effects are influenced by the spatiotemporal coverage and accuracy of exposure estimates. The use of satellite remote sensing data such as aerosol optical depth (AOD) in PM2.5 exposure modeling has increased recently in the US and elsewhere in the world. However, few studies have addressed this issue in southern California due to challenges with reflective surfaces and complex terrain. Methods: We examined the factors affecting the associations with satellite AOD using a two-stage spatial statistical model. The first stage estimated the temporal PM2.5/AOD relationships using a linear mixed effects model at 1 km resolution. The second stage accounted for spatial variation using geographically weighted regression. Goodness of fit for the final model was evaluated by comparing the daily PM2.5 concentrations generated by cross-validation (CV) with observations. These methods were applied to a region of southern California spanning from Los Angeles to San Diego. Results: Mean predicted PM2.5 concentration for the study domain was 8.84 µg m-3. Linear regression between CV predicted PM2.5 concentrations and observations had an R 2 of 0.80 and RMSE 2.25 µg m-3. The ratio of PM2.5 to PM10 proved an important variable in modifying the AOD/PM2.5 relationship (β = 14.79, p ≤ 0.001). Including this ratio improved model performance significantly (a 0.10 increase in CV R 2 and a 0.56 µg m-3 decrease in CV RMSE). Discussion: Utilizing the high-resolution MAIAC AOD, fine-resolution PM2.5 concentrations can be estimated where measurements are sparse. This study adds to the current literature using remote sensing data to achieve better exposure data in the understudied region of Southern California. Overall, we demonstrate the usefulness of MAIAC AOD and the importance of considering coarser particles in dust prone areas

Effects of MCF2L2, ADIPOQ and SOX2 genetic polymorphisms on the development of nephropathy in type 1 Diabetes Mellitus

<p>Abstract</p> <p>Background</p> <p><it>MCF2L2, ADIPOQ </it>and <it>SOX2 </it>genes are located in chromosome 3q26-27, which is linked to diabetic nephropathy (DN). <it>ADIPOQ </it>and <it>SOX2 </it>genetic polymorphisms are found to be associated with DN. In the present study, we first investigated the association between <it>MCF2L2 </it>and DN, and then evaluated effects of these three genes on the development of DN.</p> <p>Methods</p> <p>A total of 1177 type 1 diabetes patients with and without DN from the GoKinD study were genotyped with TaqMan allelic discrimination. All subjects were of European descent.</p> <p>Results</p> <p>Leu359Ile T/G variant in the <it>MCF2L2 </it>gene was found to be associated with DN in female subjects (P = 0.017, OR = 0.701, 95%CI 0.524-0.938) but not in males. The GG genotype carriers among female patients with DN had tendency decreased creatinine and cystatin levels compared to the carriers with either TT or TG genotypes. This polymorphism <it>MCF2L2-</it>rs7639705 together with SNPs of <it>ADIPOQ</it>-rs266729 and <it>SOX2</it>-rs11915160 had combined effects on decreased risk of DN in females (P = 0.001).</p> <p>Conclusion</p> <p>The present study provides evidence that <it>MCF2L2</it>, <it>ADIPOQ </it>and <it>SOX2 </it>genetic polymorphisms have effects on the resistance of DN in female T1D patients, and suggests that the linkage with DN in chromosome 3q may be explained by the cumulated genetic effects.</p

Preliminary Report: Missense mutations in the APOL gene family are associated with end stage kidney disease risk previously attributed to the MYH9 gene

MYH9 has been proposed as a major genetic risk locus for a spectrum of non-diabetic end stage kidney disease (ESKD). We use recently released sequences from the 1000 Genomes Project to identify two western African specific missense mutations (S342G and I384M) in the neighbouring APOL1 gene, and demonstrate that these are more strongly associated with ESKD than previously reported MYH9 variants. We also show that the distribution of these risk variants in African populations is consistent with the pattern of African ancestry ESKD risk previously attributed to the MYH9 gene. Additional associations were also found among other members of the APOL gene family, and we propose that ESKD risk is caused by western African variants in members of the APOL gene family, which evolved to confer protection against pathogens, such as Trypanosoma.Comment: 25 pages, 6 figure

Alternative Splicing Promotes Tumour Aggressiveness and Drug Resistance in African American Prostate Cancer.

linical challenges exist in reducing prostate cancer (PCa) disparities. The RNA splicing landscape of PCa across racial populations has not been fully explored as a potential molecular mechanism contributing to race-related tumour aggressiveness. Here, we identify novel genome-wide, race-specific RNA splicing events as critical drivers of PCa aggressiveness and therapeutic resistance in African American (AA) men. AA-enriched splice variants of PIK3CD, FGFR3, TSC2 and RASGRP2 contribute to greater oncogenic potential compared with corresponding European American (EA)-expressing variants. Ectopic overexpression of the newly cloned AA-enriched variant, PIK3CD-S, in EA PCa cell lines enhances AKT/mTOR signalling and increases proliferative and invasive capacity in vitro and confers resistance to selective PI3Kδ inhibitor, CAL-101 (idelalisib), in mouse xenograft models. High PIK3CD-S expression in PCa specimens associates with poor survival. These results highlight the potential of RNA splice variants to serve as novel biomarkers and molecular targets for developmental therapeutics in aggressive PCa

Alternative Splicing Promotes Tumour Aggressiveness and Drug Resistance in African American Prostate Cancer.

linical challenges exist in reducing prostate cancer (PCa) disparities. The RNA splicing landscape of PCa across racial populations has not been fully explored as a potential molecular mechanism contributing to race-related tumour aggressiveness. Here, we identify novel genome-wide, race-specific RNA splicing events as critical drivers of PCa aggressiveness and therapeutic resistance in African American (AA) men. AA-enriched splice variants of PIK3CD, FGFR3, TSC2 and RASGRP2 contribute to greater oncogenic potential compared with corresponding European American (EA)-expressing variants. Ectopic overexpression of the newly cloned AA-enriched variant, PIK3CD-S, in EA PCa cell lines enhances AKT/mTOR signalling and increases proliferative and invasive capacity in vitro and confers resistance to selective PI3Kδ inhibitor, CAL-101 (idelalisib), in mouse xenograft models. High PIK3CD-S expression in PCa specimens associates with poor survival. These results highlight the potential of RNA splice variants to serve as novel biomarkers and molecular targets for developmental therapeutics in aggressive PCa

Anyons in a weakly interacting system

We describe a theoretical proposal for a system whose excitations are anyons with the exchange phase pi/4 and charge -e/2, but, remarkably, can be built by filling a set of single-particle states of essentially noninteracting electrons. The system consists of an artificially structured type-II superconducting film adjacent to a 2D electron gas in the integer quantum Hall regime with unit filling fraction. The proposal rests on the observation that a vacancy in an otherwise periodic vortex lattice in the superconductor creates a bound state in the 2DEG with total charge -e/2. A composite of this fractionally charged hole and the missing flux due to the vacancy behaves as an anyon. The proposed setup allows for manipulation of these anyons and could prove useful in various schemes for fault-tolerant topological quantum computation.Comment: 7 pages with 3 figures. For related work and info visit http://www.physics.ubc.ca/~fran

Alternative Splicing Promotes Tumour Aggressiveness and Drug Resistance in African American Prostate Cancer.

linical challenges exist in reducing prostate cancer (PCa) disparities. The RNA splicing landscape of PCa across racial populations has not been fully explored as a potential molecular mechanism contributing to race-related tumour aggressiveness. Here, we identify novel genome-wide, race-specific RNA splicing events as critical drivers of PCa aggressiveness and therapeutic resistance in African American (AA) men. AA-enriched splice variants of PIK3CD, FGFR3, TSC2 and RASGRP2 contribute to greater oncogenic potential compared with corresponding European American (EA)-expressing variants. Ectopic overexpression of the newly cloned AA-enriched variant, PIK3CD-S, in EA PCa cell lines enhances AKT/mTOR signalling and increases proliferative and invasive capacity in vitro and confers resistance to selective PI3Kδ inhibitor, CAL-101 (idelalisib), in mouse xenograft models. High PIK3CD-S expression in PCa specimens associates with poor survival. These results highlight the potential of RNA splice variants to serve as novel biomarkers and molecular targets for developmental therapeutics in aggressive PCa

Non-Equilibrium Field Dynamics of an Honest Holographic Superconductor

Most holographic models of superconducting systems neglect the effects of dynamical boundary gauge fields during the process of spontaneous symmetry-breaking. Usually a global symmetry gets broken. This yields a superfluid, which then is gauged "weakly" afterwards. In this work we build (and probe the dynamics of) a holographic model in which a local boundary symmetry is spontaneously broken instead. We compute two-point functions of dynamical non-Abelian gauge fields in the normal and in the broken phase, and find non-trivial gapless modes. Our AdS3 gravity dual realizes a p-wave superconductor in (1+1) dimensions. The ground state of this model also breaks (1+1)-dimensional parity spontaneously, while the Hamiltonian is parity-invariant. We discuss possible implications of our results for a wider class of holographic liquids.Comment: 32 pages, 12 figures; v3: string theory derivation of setup added (section 3.1), improved presentation, version accepted by JHEP; v2: paragraph added to discussion, figure added, references added, typos correcte