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This study explored gene-disrupting variants as risk factors for allosensitization in kidney transplant recipients. Genomic collision at the LIMS1 locus, which encodes a minor histocompatibility antigen, was associated with allograft rejection and production of anti-LIMS1 IgG2 and IgG3.

In the version of this article initially published, affiliation 38 incorrectly read “ICNU-Nephrology and Urology Department, Barcelona, Spain”; “Renal Division, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain” is the correct affiliation. The error has been corrected in the HTML and PDF versions of the article.

Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.25, P  = 3.4 × 10 −12 ) and IRF4 (rs9405192, OR = 1.29, P = 1.4 × 10 −14 ), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P  = 4.7 × 10 −103 ) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P  = 2.0 × 10 −49 ), DQA1*0501 in Europeans (OR = 2.88, P  = 5.7 × 10 −93 ), and DRB1*0301 in both ethnicities (OR = 3.50, P  = 9.2 × 10 −23 and OR = 3.39, P  = 5.2 × 10 −82 , respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20–37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk. Membranous nephropathy (MN) is a rare autoimmune disease of podocyte-directed antibodies, such as anti-phospholipase A2 receptor. Here, the authors report a genome-wide association study for MN and identify two previously unreported loci encompassing the NFKB1 and IRF4 genes and additional ancestry-specific effects.

IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. Here we performed a genome-wide association study of 10,146 kidney-biopsy-diagnosed IgAN cases and 28,751 controls across 17 international cohorts. We defined 30 genome-wide significant risk loci explaining 11% of disease risk. A total of 16 loci were new, including TNFSF4/TNFSF18 , REL , CD28 , PF4V1 , LY86 , LYN , ANXA3 , TNFSF8/TNFSF15 , REEP3 , ZMIZ1 , OVOL1/RELA , ETS1 , IGH , IRF8 , TNFRSF13B and FCAR . The risk loci were enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. We also observed a positive genetic correlation between IgAN and serum IgA levels. High polygenic score for IgAN was associated with earlier onset of kidney failure. In a comprehensive functional annotation analysis of candidate causal genes, we observed convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand–receptor pairs, prioritizing potential new drug targets. Genome-wide association analyses identify 30 risk loci for IgA nephropathy. Functional annotations of putative causal genes converge on inflammatory signaling pathways and cytokine ligand–receptor pairs, prioritizing potential new drug targets.

All eukaryotic genomes have genes with introns in variable sizes. As far as spliceosomal introns are concerned, there are at least three basic parameters to stratify introns across diverse eukaryotic taxa： size, number, and sequence context. The number parameter is highly variable in lower eukaryotes, especially among protozoan and fungal species, which ranges from less than 4% to 78% of the genes. Over greater evolutionary time scales, the number parameter undoubtedly increases as observed in higher plants and higher vertebrates, reaching greater than 12.5 exons per gene in average among mammalian genomes. The size parameter is more complex, where multiple modes appear at work. Aside from intronless genes, there are three other types of intron-containing genes： half-sized, minimal, and size-expandable introns. The half-sized introns have only been found in a limited number of genomes among protozoan and fungal lineages and the other two types are prevalent in all animal and plant genomes. Among the size-expandable introns, the sizes of plant introns are expansion-limited in that the large introns exceed- ing 1000 bp are fewer in numbers and transposon-free as compared to the large introns among animals, where the larger in- trons are filled with transposable elements and appear expansion-flexible, reaching several kilobasepairs （kbp） and even thou- sands of kbp in size. Most of the intron parameters can be studied as signatures of the specific splicing machineries of different eukaryotic lineages and are highly relevant to the regulation of gene expression and functionality. In particular, the transcrip- tion-splicing-export coupling of eukaryotic intron dispensing leads to a working hypothesis that all intron parameters are evolved to be efficient and function-related in processing and routing the spliced transcripts.

Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2,824 cases and 21,498 controls. Affected individuals carried a significant burden of rare exonic (that is, affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Kidney anomaly (KA) cases were most enriched for exonic CNVs, encompassing GD-CNVs and novel deletions; obstructive uropathy (OU) had a lower CNV burden and an intermediate prevalence of GD-CNVs; and vesicoureteral reflux (VUR) had the fewest GD-CNVs but was enriched for novel exonic CNVs, particularly duplications. Six loci (1q21, 4p16.1-p16.3, 16p11.2, 16p13.11, 17q12 and 22q11.2) accounted for 65% of patients with GD-CNVs. Deletions at 17q12, 4p16.1-p16.3 and 22q11.2 were specific for KA; the 16p11.2 locus showed extensive pleiotropy. Using a multidisciplinary approach, we identified TBX6 as a driver for the CAKUT subphenotypes in the 16p11.2 microdeletion syndrome. Genome-wide analysis of copy number variants in 2,824 cases across the phenotypic spectrum of CAKUT sheds light on the genomic architecture of disease and identifies TBX6 as a driver for CAKUT subphenotypes in the 16p11.2 microdeletion syndrome.

Congenital anomalies of the kidneys and urinary tract (CAKUT) are developmental disorders that commonly cause pediatric chronic kidney disease and mortality. We examine here rare coding variants in 248 CAKUT trios and 1742 singleton CAKUT cases and compare them to 22,258 controls. Diagnostic and candidate diagnostic variants are detected in 14.1% of cases. We find a significant enrichment of rare damaging variants in constrained genes expressed during kidney development and in genes associated with other developmental disorders, suggesting phenotype expansion. Consistent with these data, 18% of CAKUT patients with diagnostic variants have neurodevelopmental or cardiac phenotypes. We identify 40 candidate genes, including CELSR1 , SSBP2, XPO1, NR6A1 , and ARID3A . Two are confirmed as CAKUT genes: ARID3A and NR6A1 . This study suggests that many yet-unidentified syndromes would be discoverable with larger cohorts and cross-phenotype analysis, leading to clarification of the genetic and phenotypic spectrum of developmental disorders. The authors analyze rare coding variants in 1990 individuals with congenital kidney anomalies, finding diagnostic variants in 14.1% of cases. They identify two new causal genes, ARID3A and NR6A1 , along with 38 candidate genes, providing evidence for shared genetics with other developmental disorders.

Aim： To improve the therapeutic efficacy of cancer treatments, combinational therapies based on nanosized drug delivery system （NDDS） has been developed recently. In this study we designed a new NDDS loaded with an anti-metastatic drug silibinin and a photothermal agent indocyanine green （ICG）, and investigated its effects on the growth and metastasis of breast cancer cells in vitro. Methods： Silibinin and ICG were self-assembled into PCL lipid nanoparticles （SIPNs）. Their physical characteristics including the particle size, zeta potential, morphology and in vitro drug release were examined. 4T1 mammalian breast cancer cells were used to evaluate their cellular internalization, cytotoxicity, and their influences on wound healing, in vitro cell migration and invasion. Results： SIPNs showed a well-defined spherical shape with averaged size of 126.3＋0.4 nm and zeta potential of -10.3＋0.2 mV. NIR laser irradiation substantially increased the in vitro release of silibinin from the SIPNs （58.3% at the first 8 h, and 97.8% for the total release）. Furthermore, NIR laser irradiation markedly increased the uptake of SIPNs into 4T1 cells. Under the NIR laser irradiation, both SIPNs and IPNs （PCL lipid nanoparticles loaded with ICG alone） caused dose-dependent ablation of 4T1 cells. The wound healing, migration and invasion experiments showed that SIPNs exposed to NiR laser irradiation exhibited dramatic in vitro anti-metastasis effects. Conclusion： SIPNs show temperature-sensitive drug release following NIR laser irradiation, which can inhibit the growth and metastasis of breast cancer cells in vitro.

Cancer hazards from pesticide residues in food have been much discussed in the past decade. In this study, we showed that dichlorvos and dimethoate affect hemoglobin content and hematocrit value, but had no effect on red blood cell counts and total plasma protein in mice. A 40-mg/kg/day dose of dichlorvos upregulated the expression of p16, Bcl-2 and c-myc genes in mouse gastric tissue. By contrast, expression of the p16, Bcl-2 and c-myc genes induced by low doses (5, 10 and 20 mg/kg/day) of dichlorvos demonstrated no change in the control check group (CK; 200 μl sterile saline perfused group; 0 mg/kg/day). Different doses of dimethoate all upregulated the expression of p16, Bcl-2 and c-myc genes in mouse gastric tissue. The results further demonstrated that mouse gastric tissue, exposed in the long-term to low doses of dichlorvos and dimethoate, has the potential to become cancerous.