Cumulative Risk of End-Stage Renal Disease Among Patients With Type 2 Diabetes : A Nationwide Inception Cohort Study

OBJECTIVE To estimate long-term cumulative risk of end-stage renal disease (ESRD) after diagnosis of type 2 diabetes. RESEARCH DESIGN AND METHODS This nationwide population-based inception cohort study included 421,429 patients with type 2 diabetes diagnosed in 1990-2011; patients were followed until the end of 2013. Data linkage between several national health care registers in Finland, covering 100% of the population, enabled the inclusion of almost all inhabitants who started taking diabetes medication or were hospitalized for diabetes. Cumulative risk of ESRD and hazard ratios [HR] for ESRD and death were estimated according to age, sex, and time period of diabetes diagnosis. RESULTS Among 421,429 patients with type 2 diabetes, 1,516 developed ESRD and 150,524 died during 3,458,797 patient-years of follow-up. Cumulative risk of ESRD was 0.29% at 10 years and 0.74% at 20 years from diagnosis of diabetes. Risk was higher among men than among women (HR 1.93 [95% CI 1.72-2.16]), decreased with older age at diagnosis (HR 0.70 [95% CI 0.60-0.81] for age 60-69 vs. 40-49 years), and was lower for those diagnosed in 2000-2011 than in 1990-1994 (HR 0.72 [95% CI 0.63-0.81]). Patients diagnosed with diabetes in 2000-2011 had lower risk of death during follow-up than those diagnosed in 1990-1994 (HR 0.64 [95% CI 0.63-0.65]). CONCLUSIONS Cumulative risk of ESRD is minimal among patients with type 2 diabetes compared with their risk of death. Patients diagnosed with diabetes at an older age have a lower risk of ESRD due to higher competing mortality.Peer reviewe

Incidence of End-Stage Renal Disease in Patients With Type 1 Diabetes

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Bevasitsumabi ei-pienisoluisen keuhkosyövän hoidossa

Edenneen tai levinneen ei-pienisoluisen keuhkosyövän hoito nykyisillä solunsalpaajilla parhaimmillaan vain hidastaa taudin etenemistä, eikä parantavaa hoitoa tunneta. Uusien antiangiogeneettisten lääkkeiden, kuten bevasitsumabin, on odotettu muuttavan taudin hoitoa ja ennustetta. Bevasitsumabista on tehty kaksi satunnaistettua tutkimusta, joissa sen todettiin tehostavan hoitoa yhdistettynä platinasolunsalpaajayhdistelmään valikoidussa potilasryhmässä. Mielestämme nykyinen tutkimusnäyttö ei kuitenkaan puolla bevasitsumabin käyttöä keuhkosyövän standardihoitona. Haittavaikutukset on opittu hallitsemaan hyvin, mutta vielä tulisi pystyä määrittämään se ryhmä hoitoon soveltuvista potilaista, joka hyötyisi merkittävästi. Tämän ryhmän löytämiseksi tarvitaan kliinisten ennustetekijöiden ja mahdollisten biologisten merkkiaineiden tutkimusta. English summary: Bevasizumab in the treatment of non-small cell lung cancer Treatment of advanced or metastatic non-small cell lung cancer with current cytotoxic agents is at its best able to only slow down the progression of the disease, while no curative treatment is known. Novel antiangiogenetic agents such as Bevacizumab have been expected to bring about a change in the treatment and prognosis of this disease. Two randomized studies have been conducted with Bevacizumab, whereby it was observed to make the therapeutic results more effective when combined with a cytotoxic platinum agent in a selected patient group. In our opinion the current scientific evidence does not yet support the use of Bevacizumab as the standard therapy for lung cancer

Germline variation at 8q24 and prostate cancer risk in men of European ancestry

Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10−15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62–4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Peer reviewe

Proteomic Changes of Alveolar Lining Fluid in Illnesses Associated with Exposure to Inhaled Non-Infectious Microbial Particles

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Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation

Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa