| 41. |
- Lindström, Sara, et al.
(författare)
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Systematic replication study of reported genetic associations in prostate cancer : Strong support for genetic variation in the androgen pathway
- 2006
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Ingår i: The Prostate. - Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. Umea Univ, Dept Radiat Sci Oncol, Umea, Sweden. Wake Forest Univ, Sch Med, Ctr Human Genome, Winston Salem, NC USA. Karolinska Inst, Ctr Genome & Bioinformat, Stockholm, Sweden. Univ Leicester, Dept Genet, Leicester, Leics, England. Johns Hopkins Med Inst, Dept Urol, Baltimore, MD USA. Karolinska Inst, CLINTEC, Ctr Oncol, Stockholm, Sweden. : WILEY-LISS. - 0270-4137 .- 1097-0045. ; 66:16, s. 1729-1743
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Forskningsöversikt (refereegranskat)abstract
- BACKGROUND. Association studies have become a common and popular method to identify genetic variants predisposing to complex diseases. Despite considerable efforts and initial promising findings, the field of prostate cancer genetics is characterized by inconclusive reports and no prostate cancer gene has yet been established. METHODS. We performed a literature review and identified 79 different polymorphisms reported to influence prostate cancer risk. Of these, 46 were selected and tested for association in a large Swedish population-based case-control prostate cancer population. RESULTS. We observed significant (P < 0.05) confirmation for six polymorphisms located in five different genes. Three of them coded for key enzymes in the androgen biosynthesis and response pathway; the CAG repeat in the androgen receptor (AR) gene (P = 0.03), one SNP in the CYP17 gene (P = 0.04), two SNPs in the SRD5A2 gene (P = 0.02 and 0.02, respectively), a deletion of the GSTT1. gene (P = 0.006), and one SNP in the MSR1 gene, IVS5-59C > A, (P = 0.009). CONCLUSIONS. Notwithstanding the difficulties to replicate findings in genetic association studies, our results strongly support the importance of androgen pathway genes in prostate cancer etiology.
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| 42. |
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| 43. |
- Wahl, Simone, et al.
(författare)
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Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity
- 2017
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Ingår i: Nature. - : NATURE PUBLISHING GROUP. - 0028-0836 .- 1476-4687. ; 541:7635, s. 81-
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Tidskriftsartikel (refereegranskat)abstract
- Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type (2) diabetes, cardiovascular disease and related metabolic and inflammatory disturbances(1,2). Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation(3-6), a key regulator of gene expression and molecular phenotype(7). Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P < 1 x 10(-7), range P = 9.2 x 10(-8) to 6.0 x 10(-46); n = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (P < 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P < 9.0 x 10(-6), range P = 5.5 x 10(-6) to 6.1 x 10(-35), n = 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07-2.56); P = 1.1 x 10(-54)). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type 2 diabetes and other adverse clinical consequences of obesity.
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| 44. |
- Wiklund, Fredrik, et al.
(författare)
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Association of Reported Prostate Cancer Risk Alleles With PSA Levels Among Men Without a Diagnosis of Prostate Cancer
- 2009
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Ingår i: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 69:4, s. 419-427
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND. Prostate specific antigen (PSA) is widely used for prostate cancer screening but its levels are influenced by many non cancer-related factors. The goal of the study is to estimate the effect of genetic variants on PSA levels. METHODS. We evaluated the association of SNPs that were reported to be associated with prostate cancer risk in recent genome-wide association studies with plasma PSA levels in a Swedish study population, including 1,722 control subjects without a diagnosis of prostate cancer. RESULTS. Of the 16 SNPs analyzed in control subjects, significant associations with PSA levels (P <= 0.05) were found for six SNPs. These six SNP's had a cumulative effect on PSA levels; the mean PSA levels in men were almost twofold increased across increasing quintile of number of PSA associated alleles, P-trend = 3.4 x 10(-14). In this Swedish study population risk allele frequencies were similar among T1c case patients (cancer detected by elevated PSA levels alone) as compared to T2 and above prostate cancer case patients. CONCLUSIONS. Results from this study may have two important clinical implications. The cumulative effect of six SNPs on PSA levels suggests genetic-specific PSA cutoff values may be used to improve the discriminatory performance of this test for prostate cancer; and the dual associations of these SNPs with PSA levels and prostate cancer risk raise a concern that some of reported prostate cancer risk-associated SNPs may be confounded by the prevalent use of PSA screening. Prostate 69: 419-427, 2009. (C) 2008 Wiley-Liss, Inc.
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| 45. |
- Wiklund, Fredrik E, et al.
(författare)
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Established prostate cancer susceptibility variants are not associated with disease outcome.
- 2009
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - 1055-9965 .- 1538-7755. ; 18:5, s. 1659-62
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Tidskriftsartikel (refereegranskat)abstract
- Recent genome-wide association studies have been successful in identifying common sequence variants associated with prostate cancer risk; however, their importance in prostate cancer prognosis remains unknown. To assess confirmed prostate cancer susceptibility variants with prostate cancer prognosis, we genotyped 16 established susceptibility variants in a Swedish cohort of 2,875 prostate cancer cases, ascertained between 2001 and 2003, with complete follow-up regarding vital status through January 2008. Cox regression models, adjusted for age, clinical stage, pathologic grade, nodal or distant metastases, and diagnostic serum levels of prostate-specific antigen level, were used to assess association between risk variants and prostate cancer-specific survival. During follow-up, 626 men died, and of those, 440 had prostate cancer classified as their underlying cause of death. We found no association between any of the explored sequence variants and prostate cancer-specific mortality, either in exploring individual variants or in assessing the cumulative effect of all variants. We conclude that hitherto established prostate cancer susceptibility variants are not associated with the lethal potential of prostate cancer.
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| 46. |
- Zheng, S. Lilly, et al.
(författare)
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A comprehensive association study for genes in inflammation pathway provides support for their roles in prostate cancer risk in the CAPS study
- 2006
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Ingår i: The Prostate. - Wake Forest Univ, Bowman Gray Sch Med, Ctr Human Genom, Winston Salem, NC USA. Karolinska Inst, Dept Med Epidemiol & Biotat, Stockholm, Sweden. Orebro Univ Hosp, Dept Urol & Clin Med, Orebro, Sweden. Translat Genom Res Inst, Phoenix, AZ USA. Johns Hopkins Med Inst, Dept Urol, Baltimore, MD 21205 USA. : WILEY-LISS. - 0270-4137 .- 1097-0045. ; 66:14, s. 1556-1564
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND. Recently identified associations of prostate cancer risk with several genes involved in innate immunity support a role of inflammation in the etiology of prostate cancer. Considering inflammation is regulated by a complex system of gene products, we hypothesize sequence variants in many other genes of this pathway are associated with prostate cancer. METHODS. We evaluated 9,275 SNPs; in 1,086 genes of the inflammation pathway using a MegAlleleTM genotyping system among 200 familial cases and 200 unaffected controls selected from a large Swedish case-control population (CAPS). RESULTS. We found that significantly more than the expected numbers of SNPs were significant at a nominal P-value of 0.01, 0.05, and 0.1, providing overall support for our hypothesis. The excess was largest when using a more liberal nominal P-value (0.1); we observed 992 significant SNPs compared with the 854 significant SNPs expected by chance, and this difference was significant based on a permutation test (P = 0.0025). We also began the effort of differentiating true associated SNPs by selecting a small subset of significant SNPs (N = 26) and genotyped these in an independent sample of similar to 1,900 CAPS1 subjects. We were able to confirm 3 of these 26 SNPs. It is expected that many more true associated SNPs will be confirmed among the 992 significant SNPs identified in our pathway screen. CONCLUSIONS. Our study provides the first objective support for an association between prostate cancer and multiple modest-effect genes in inflammatory pathways.
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| 47. |
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| 48. |
- Zheng, S. Lilly, et al.
(författare)
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Genetic variants and family history predict prostate cancer similar to prostate-specific antigen
- 2009
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 15:3, s. 1105-1111
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Although prostate-specific antigen (PSA) is the best biomarker for predicting prostate cancer, its predictive performance needs to be improved. Results from the Prostate Cancer Prevention Trial revealed the overall performance measured by the areas under curve of the receiver operating characteristic at 0.68. The goal of the present study is to assess the ability of genetic variants as a PSA-independent method to predict prostate cancer risk. EXPERIMENTAL DESIGN: We systematically evaluated all prostate cancer risk variants that were identified from genome-wide association studies during the past year in a large population-based prostate cancer case-control study population in Sweden, including 2,893 prostate cancer patients and 1,781 men without prostate cancer. RESULTS: Twelve single nucleotide polymorphisms were independently associated with prostate cancer risk in this Swedish study population. Using a cutoff of any 11 risk alleles or family history, the sensitivity and specificity for predicting prostate cancer were 0.25 and 0.86, respectively. The overall predictive performance of prostate cancer using genetic variants, family history, and age, measured by areas under curve was 0.65 (95% confidence interval, 0.63-0.66), significantly improved over that of family history and age (0.61%; 95% confidence interval, 0.59-0.62; P = 2.3 x 10(-10)). CONCLUSION: The predictive performance for prostate cancer using genetic variants and family history is similar to that of PSA. The utility of genetic testing, alone and in combination with PSA levels, should be evaluated in large studies such as the European Randomized Study for Prostate Cancer trial and Prostate Cancer Prevention Trial.
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