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Sökning: WFRF:(Szulkin Robert)

  • Resultat 11-14 av 14
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11.
  • Szulkin, Robert, et al. (författare)
  • Prostate cancer risk variants are not associated with disease progression.
  • 2012
  • Ingår i: The Prostate. - 1097-0045 .- 0270-4137. ; 72:1, s. 30-39
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Currently used prognostic markers are limited in their ability to accurately predict disease progression among patients with localized prostate cancer. We examined 23 reported prostate cancer susceptibility variants for association with disease progression. METHODS: Disease progression was explored among 4,673 Swedish patients treated for clinically localized prostate cancer between 1997 and 2002. Prostate cancer progression was defined according to primary treatment as a composed event reflecting termination of deferred treatment, biochemical recurrence, local progression, or presence of distant metastasis. Association between single variants, and all variants combined, were performed in Cox regression analysis assuming both log-additive and co-dominant genetic models. RESULTS: Three of the 23 genetic variants explored were nominally associated with prostate cancer progression; rs9364554 (P = 0.041) on chromosome 6q25 and rs10896449 (P = 0.029) on chromosome 11q13 among patients treated with curative intent; and rs4054823 (P = 0.008) on chromosome 17p12 among patients on surveillance. However, none of these associations remained statistically significant after correction for multiple testing. The combined effect of all susceptibility variants was not associated with prostate cancer progression neither among patients receiving treatment with curative intent (P = 0.14) nor among patients on surveillance (P = 0.92). CONCLUSIONS: We observed no evidence for an association between any of 23 established prostate cancer genetic risk variants and disease progression. Accumulating evidence suggests separate genetic components for initiation and progression of prostate cancer. Future studies systematically searching for genetic risk variants associated with prostate cancer progression and prognosis are warranted. Prostate © 2011 Wiley-Liss, Inc.
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12.
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13.
  • Sundquist, Kristina, et al. (författare)
  • Elucidating causal effects of type 2 diabetes on ischemic heart disease from observational data on middle-aged Swedish women : a triangular analytical approach
  • 2021
  • Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 11
  • Tidskriftsartikel (refereegranskat)abstract
    • The association between type 2 diabetes (T2D) and ischemic heart disease (IHD) is well established but the potential causal association needs further studying. In an attempt to elucidate the causal effect of T2D on IHD, we used three different analytical approaches in two different datasets. A well-defined cohort of 6047 women aged 50–59 years were included at baseline (1995 to 2000) and followed until 2015 for IHD. The median follow-up was 16.3 years. We used a Marginal Structural Cox model (MSM Cox) to account for time-varying exposure (time at onset of T2D) and for ten confounders (using inverse probability weighting, IPW). We also compared the MSM-Cox models with traditional Cox regression modelling in the cohort. Finally, we analyzed information on individuals from Swedish population-based registers with national coverage in a comprehensive co-relative design and extrapolated the results to MZ twins. The Hazard Ratio (HR) for IHD in relation to T2D at baseline and T2D occurring during the follow-up in the MSM Cox model weighted by IPW (based on the ten included confounders) was 1.43 (95% confidence interval [CI] 1.07–1.92). The corresponding HR from the traditional Cox regression model was of similar effect size. The average extrapolated MZ twin estimate from our co-relative model was 1.61 (95% CI 1.48–1.86). Our findings, based on a triangular approach, support the existence of a causal association between T2D and IHD and that preventive long-term measures in order to avoid or postpone IHD should include monitoring and treatment of both the T2D itself as well as other cardiovascular risk factors.
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14.
  • Szulkin, Robert (författare)
  • Genetic determinants for susceptibility, progression and prognosis of prostate cancer
  • 2015
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Prostate cancer is the most commonly diagnosed form of non-skin cancer among men in developed countries. Although a large proportion of patients eventually die from the disease, many indolent tumors are found via prostate specific antigen (PSA) testing. However, todays diagnostic tools are unable to distinguish small localized tumors that will have a benign development from early stage aggressive disease. Thus, over-diagnosis and over-treatment are two major concerns in prostate cancer management. Genetics have been shown to play an important role for prostate cancer initiation with an estimated heritability of 58% and over 100 identified single nucleotide polymorphisms (SNPs) associated with prostate cancer risk. However, much less is known about the involvement of genes in the progression and prognosis of the disease. The overall objective of this thesis is to enhance the understanding of genetic determinants for initiation, progression and prognosis of prostate cancer. The purpose of Study I was to develop a prediction model for prostate cancer susceptibility, based on the current knowledge of genetic risk variants. Furthermore, we aimed to study the potential role of established prostate cancer risk variants in disease progression among men with a localized disease (Study III). In Study II, the heritability of prostate cancer-specific survival among diagnosed men was estimated and a genome-wide search for genetic determinants of the same outcome was performed in Study IV. We found that a polygenic risk score model with 65 established prostate cancer risk SNPs and 68 novel variants optimally separates prostate cancer cases from healthy controls, with a prediction accuracy measured using the area under the curve (AUC) of 0.68. Furthermore, we observed that these 133 SNPs could be used for risk stratification; compared with an intermediate genetic risk score category (40%-60%), men with a low genetic risk score (lowest 5% percentile) had 84% decreased relative risk of prostate cancer and men with 5% highest risk scores had a four-fold increased relative risk. Using a novel conditional likelihood approach for time-to-event data in brother pairs and father-son pairs, the heritability of prostate cancer survival was estimated to be 10%. We could also observe that common family environment had no effect (estimated to 0%) on prostate cancer survival. However, data simulations suggest that this may be underestimated. Furthermore, we could not find any association between SNPs and prostate cancer prognosis. None of 23 established prostate cancer risk SNPs investigated were found to be associated with disease progression in a cohort of men with localized disease. Moreover, in a genome-wide association study (GWAS) we did not find any association with prostate cancer survival at a genome-wide significant level. In conclusion, with the current knowledge of prostate cancer genetics it is possible to identify men with high and low prostate cancer susceptibility risk. However, the predictive performance of established SNPs is not yet sufficient to be used alone in a screening program of prostate cancer. Furthermore, the findings in this thesis regarding prostate cancer progression and survival suggest that development of prostate cancer and progression to lethal disease may be two separate biological mechanisms that involve different genes. In order to identify genetic risk variants associated with prostate cancer progression, future studies should be designed to find common variants with very low penetrance or rare variants with moderate to large effect.
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