BackgroundAlthough diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown.MethodsTo identify genetic variants predisposing to diabetic kidney disease, we performed genome-wide association study (GWAS) analyses. Through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, we assembled a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes. We used a spectrum of ten diabetic kidney disease definitions based on albuminuria and renal function.ResultsOur GWAS meta-analysis included association results for up to 19,406 individuals of European descent with type 1 diabetes. We identified 16 genome-wide significant risk loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain (COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM). Mutations in COL4A3 are implicated in heritable nephropathies, including the progressive inherited nephropathy Alport syndrome. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of diabetic kidney disease, including albuminuria and ESKD, and demonstrated a significant association with GBM width; protective allele carriers had thinner GBM before any signs of kidney disease, and its effect was dependent on glycemia. Three other loci are in or near genes with known or suggestive involvement in this condition (BMP7) or renal biology (COLEC11 and DDR1).ConclusionsThe 16 diabetic kidney disease–associated loci may provide novel insights into the pathogenesis of this condition and help identify potential biologic targets for prevention and treatment.

Obg-like ATPase 1 (OLA1) belongs to the Obg family of P-loop NTPases, and may serve as a “molecular switch” regulating multiple cellular processes. Aberrant expression of OLA1 has been observed in several human malignancies. However, the role of OLA1 in cancer progression remains poorly understood. In this study, we used the Kaplan-Meier plotter search tool to show that increased expression of OLA1 mRNA was significantly associated with shorter overall survival in lung cancer patients. By immunohistochemical analysis we discovered that levels of OLA1 protein in lung cancer tissues were positively correlated with TNM stage and lymph node metastasis, but negatively correlated with the epithelial-mesenchymal transition (EMT) marker E-cadherin. Knockdown of OLA1 in a lung adenocarcinoma cell line rendered the cells more resistant to TGF- β-induced EMT and the accompanied repression of E-cadherin. Furthermore, our results demonstrated that OLA1 is a GSK3 β-interacting protein and inhibits GSK3 β activity by mediating its Ser9 phosphorylation. During EMT, OLA1 plays an important role in suppressing the GSK3 β-mediated degradation of Snail protein, which in turn promotes downregulation of E-cadherin. These data suggest that OLA1 contributes to EMT by modulating the GSK3 β/Snail/E-cadherin signaling, and its overexpression is associated with clinical progression and poor survival in lung cancer patients.

Glypican-5 (GPC5) is a member of the heparin sulfate proteoglycans. Previous studies of GPC5 in lung tumorigenesis showed conflicting results. In this study, we confirmed that GPC5 was downregulated in lung adenocarcinoma tissues compared with adjacent normal lung tissues. The low expression of GPC5 was significantly associated with poor outcome in lung adenocarcinoma. To understand the biological mechanism of the downregulation, we examined the promoter methylation status of GPC5 gene. We found that GPC5 was significantly hypermethylated in lung cancer tissues and lung cancer cell lines compared with normal lung tissues. The methylation level of GPC5 was negatively correlated with its transcriptional expression. De-methylation experiments further confirmed that the loss of GPC5 expression was regulated by its hypermethylation. Overexpression of GPC5 inhibited proliferation, migration and invasion of lung cancer cells in vitro, and repressed tumor growth in vivo, whereas knockdown of GPC5 was able to reverse the effect. Furthermore, we demonstrated that GPC5 could suppress the Wnt/β-catenin signaling by binding to Wnt3a at the cell surface, which mediated its function as a tumor suppressor. Overall, these findings demonstrate that GPC5 is a novel epigenetically silenced tumor suppressor, which inhibits tumor growth by suppressing Wnt/β-catenin signaling in lung adenocarcinoma. Our findings substantially expand our understanding about the role and the molecular mechanism of GPC5 in tumorigenesis of lung cancer.

Increased circulating CRP and IL-6 levels were significantly associated with poor prognosis especially in patients with unresectable NSCLC.

Recent familial segregation studies supported a multifactorial genetic model for the etiology of adolescent idiopathic scoliosis (AIS). However, the extent of quantitative genetic effects, such as heritability, have not been fully evaluated. This genetic epidemiology study examined the sibling recurrent risk and heritability of AIS in first-degree relatives of 415 Chinese female patients, which is up to now the largest cohort. They were first diagnosed by community screening program and compared to 203 age-matched normal controls. Out of the total 531 sibs of AIS cases, 94 sibs had scoliosis (sibling recurrence risk ¼ 17.7%). The prevalence of AIS among male and female sibs of an index case were 11.5% (95% CI ¼ 7.5-15.5) and 23.0% (95% CI ¼ 18.1-27.9), respectively. Female sibs of an index case had an increased risk of 8.9-fold (95% CI ¼ 3.2-34.4) for developing AIS. These recurrent risks were significantly higher than the risk in the control group (p < 0.0001). Overall, heritability was estimated to be 87.5 AE 11.1%. The results confirmed the prevailing impression of strong genetic influence on the risk of AIS. Here we provided a large-scale study for the genetic aggregation estimates in an Asian population for the first time. The finding also positioned AIS among other common disease or complex traits with a high heritability. ß