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- Köttgen, Anna, et al.
(författare)
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New loci associated with kidney function and chronic kidney disease
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:5, s. 376-384
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Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m2; n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide–significant loci (P < 5 × 10−8) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.
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2. |
- Watts, Eleanor L., et al.
(författare)
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Circulating insulin-like growth factors and risks of overall, aggressive and early-onset prostate cancer : a collaborative analysis of 20 prospective studies and Mendelian randomization analysis
- 2023
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Ingår i: International Journal of Epidemiology. - : Oxford University Press. - 0300-5771 .- 1464-3685. ; 52:1, s. 71-86
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Tidskriftsartikel (refereegranskat)abstract
- Background: Previous studies had limited power to assess the associations of circulating insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) with clinically relevant prostate cancer as a primary endpoint, and the association of genetically predicted IGF-I with aggressive prostate cancer is not known. We aimed to investigate the associations of IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 concentrations with overall, aggressive and early-onset prostate cancer.Methods: Prospective analysis of biomarkers using the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset (up to 20 studies, 17 009 prostate cancer cases, including 2332 aggressive cases). Odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression. For IGF-I, two-sample Mendelian randomization (MR) analysis was undertaken using instruments identified using UK Biobank (158 444 men) and outcome data from PRACTICAL (up to 85 554 cases, including 15 167 aggressive cases). Additionally, we used colocalization to rule out confounding by linkage disequilibrium.Results: In observational analyses, IGF-I was positively associated with risks of overall (OR per 1 SD = 1.09: 95% CI 1.07, 1.11), aggressive (1.09: 1.03, 1.16) and possibly early-onset disease (1.11: 1.00, 1.24); associations were similar in MR analyses (OR per 1 SD = 1.07: 1.00, 1.15; 1.10: 1.01, 1.20; and 1.13; 0.98, 1.30, respectively). Colocalization also indicated a shared signal for IGF-I and prostate cancer (PP4: 99%). Men with higher IGF-II (1.06: 1.02, 1.11) and IGFBP-3 (1.08: 1.04, 1.11) had higher risks of overall prostate cancer, whereas higher IGFBP-1 was associated with a lower risk (0.95: 0.91, 0.99); these associations were attenuated following adjustment for IGF-I.Conclusions: These findings support the role of IGF-I in the development of prostate cancer, including for aggressive disease.
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- Allen, Naomi E, et al.
(författare)
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Selenium and Prostate Cancer : Analysis of Individual Participant Data From Fifteen Prospective Studies.
- 2016
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 108:11
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Some observational studies suggest that a higher selenium status is associated with a lower risk of prostate cancer but have been generally too small to provide precise estimates of associations, particularly by disease stage and grade.METHODS: Collaborating investigators from 15 prospective studies provided individual-participant records (from predominantly men of white European ancestry) on blood or toenail selenium concentrations and prostate cancer risk. Odds ratios of prostate cancer by selenium concentration were estimated using multivariable-adjusted conditional logistic regression. All statistical tests were two-sided.RESULTS: Blood selenium was not associated with the risk of total prostate cancer (multivariable-adjusted odds ratio [OR] per 80 percentile increase = 1.01, 95% confidence interval [CI] = 0.83 to 1.23, based on 4527 case patients and 6021 control subjects). However, there was heterogeneity by disease aggressiveness (ie, advanced stage and/or prostate cancer death, Pheterogeneity = .01), with high blood selenium associated with a lower risk of aggressive disease (OR = 0.43, 95% CI = 0.21 to 0.87) but not with nonaggressive disease. Nail selenium was inversely associated with total prostate cancer (OR = 0.29, 95% CI = 0.22 to 0.40, Ptrend < .001, based on 1970 case patients and 2086 control subjects), including both nonaggressive (OR = 0.33, 95% CI = 0.22 to 0.50) and aggressive disease (OR = 0.18, 95% CI = 0.11 to 0.31, Pheterogeneity = .08).CONCLUSIONS: Nail, but not blood, selenium concentration is inversely associated with risk of total prostate cancer, possibly because nails are a more reliable marker of long-term selenium exposure. Both blood and nail selenium concentrations are associated with a reduced risk of aggressive disease, which warrants further investigation.
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4. |
- Huffman, Jennifer E., et al.
(författare)
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Modulation of Genetic Associations with Serum Urate Levels by Body-Mass-Index in Humans
- 2015
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:3
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Tidskriftsartikel (refereegranskat)abstract
- We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, P-inter= 2.6 x 10(-8)). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDAR-ADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10(-8)), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10(-8)), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10(-4)). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.
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5. |
- Koettgen, Anna, et al.
(författare)
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Genome-wide association analyses identify 18 new loci associated with serum urate concentrations
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:2, s. 145-154
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Tidskriftsartikel (refereegranskat)abstract
- Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SEMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
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7. |
- Simpkin, Andrew J., et al.
(författare)
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Prostate-specific antigen patterns in US and European populations : comparison of six diverse cohorts
- 2016
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Ingår i: BJU International. - : Wiley. - 1464-4096 .- 1464-410X. ; 118:6, s. 911-918
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To determine whether there are differences in prostate-specific antigen (PSA) levels at diagnosis or changes in PSA levels between US and European populations of men with and without prostate cancer (PCa).SUBJECTS AND METHODS: We analysed repeated measures of PSA from six clinically and geographically diverse cohorts of men: two cohorts with PSA-detected PCa, two cohorts with clinically detected PCa and two cohorts without PCa. Using multilevel models, average PSA at diagnosis and PSA change over time were compared among study populations.RESULTS: The annual percentage PSA change of 4-5% was similar between men without cancer and men with PSA-detected cancer. PSA at diagnosis was 1.7 ng/mL lower in a US cohort of men with PSA-detected PCa (95% confidence interval 1.3-2.0 ng/mL), compared with a UK cohort of men with PSA-detected PCa, but there was no evidence of a different rate of PSA change between these populations.CONCLUSION: We found that PSA changes over time are similar in UK and US men diagnosed through PSA testing and even in men without PCa. Further development of PSA models to monitor men on active surveillance should be undertaken in order to take advantage of these similarities. We found no evidence that guidelines for using PSA to monitor men cannot be passed between US and European studies.
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8. |
- Travis, Ruth C., et al.
(författare)
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A Meta-analysis of Individual Participant Data Reveals an Association between Circulating Levels of IGF-I and Prostate Cancer Risk
- 2016
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 76:8, s. 2288-2300
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Tidskriftsartikel (refereegranskat)abstract
- The role of insulin-like growth factors (IGF) in prostate cancer development is not fully understood. To investigate the association between circulating concentrations of IGFs (IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3) and prostate cancer risk, we pooled individual participant data from 17 prospective and two cross-sectional studies, including up to 10,554 prostate cancer cases and 13,618 control participants. Conditional logistic regression was used to estimate the ORs for prostate cancer based on the study-specific fifth of each analyte. Overall, IGF-I, IGF-II, IGFBP-2, and IGFBP-3 concentrations were positively associated with prostate cancer risk (P-trend all <= 0.005), and IGFBP-1 was inversely associated weakly with risk (P-trend = 0.05). However, heterogeneity between the prospective and cross-sectional studies was evident (P-heterogeneity = 0.03), unless the analyses were restricted to prospective studies (with the exception of IGF-II, P-heterogeneity = 0.02). For prospective studies, the OR for men in the highest versus the lowest fifth of each analyte was 1.29 (95% confidence interval, 1.16-1.43) for IGF-I, 0.81 (0.68-0.96) for IGFBP-1, and 1.25 (1.12-1.40) for IGFBP-3. These associations did not differ significantly by time-to-diagnosis or tumor stage or grade. After mutual adjustment for each of the other analytes, only IGF-I remained associated with risk. Our collaborative study represents the largest pooled analysis of the relationship between prostate cancer risk and circulating concentrations of IGF-I, providing strong evidence that IGF-I is highly likely to be involved in prostate cancer development.
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9. |
- Watts, Eleanor L., et al.
(författare)
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Circulating free testosterone and risk of aggressive prostate cancer : Prospective and Mendelian randomisation analyses in international consortia
- 2022
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 151:7, s. 1033-1046
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies had limited power to assess the associations of testosterone with aggressive disease as a primary endpoint. Further, the association of genetically predicted testosterone with aggressive disease is not known. We investigated the associations of calculated free and measured total testosterone and sex hormone-binding globulin (SHBG) with aggressive, overall and early-onset prostate cancer. In blood-based analyses, odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression from prospective analysis of biomarker concentrations in the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group (up to 25 studies, 14 944 cases and 36 752 controls, including 1870 aggressive prostate cancers). In Mendelian randomisation (MR) analyses, using instruments identified using UK Biobank (up to 194 453 men) and outcome data from PRACTICAL (up to 79 148 cases and 61 106 controls, including 15 167 aggressive cancers), ORs were estimated using the inverse-variance weighted method. Free testosterone was associated with aggressive disease in MR analyses (OR per 1 SD = 1.23, 95% CI = 1.08-1.40). In blood-based analyses there was no association with aggressive disease overall, but there was heterogeneity by age at blood collection (OR for men aged <60 years 1.14, CI = 1.02-1.28; Phet =.0003: inverse association for older ages). Associations for free testosterone were positive for overall prostate cancer (MR: 1.20, 1.08-1.34; blood-based: 1.03, 1.01-1.05) and early-onset prostate cancer (MR: 1.37, 1.09-1.73; blood-based: 1.08, 0.98-1.19). SHBG and total testosterone were inversely associated with overall prostate cancer in blood-based analyses, with null associations in MR analysis. Our results support free testosterone, rather than total testosterone, in the development of prostate cancer, including aggressive subgroups.
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10. |
- Watts, Eleanor L., et al.
(författare)
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Circulating sex hormones in relation to anthropometric, sociodemographic and behavioural factors in an international dataset of 12,300 men
- 2017
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:12
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Sex hormones have been implicated in the etiology of a number of diseases. To better understand disease etiology and the mechanisms of disease-risk factor associations, this analysis aimed to investigate the associations of anthropometric, sociodemographic and behavioural factors with a range of circulating sex hormones and sex hormone-binding globulin.Methods: Statistical analyses of individual participant data from 12,330 male controls aged 25–85 years from 25 studies involved in the Endogenous Hormones Nutritional Biomarkers and Prostate Cancer Collaborative Group. Analysis of variance was used to estimate geometric means adjusted for study and relevant covariates.Results: Older age was associated with higher concentrations of sex hormone-binding globulin and dihydrotestosterone and lower concentrations of dehydroepiandrosterone sulfate, free testosterone, androstenedione, androstanediol glucuronide and free estradiol. Higher body mass index was associated with higher concentrations of free estradiol, androstanediol glucuronide, estradiol and estrone and lower concentrations of dihydrotestosterone, testosterone, sex hormone-binding globulin, free testosterone, androstenedione and dehydroepiandrosterone sulfate. Taller height was associated with lower concentrations of androstenedione, testosterone, free testosterone and sex hormone-binding globulin and higher concentrations of androstanediol glucuronide. Current smoking was associated with higher concentrations of androstenedione, sex hormone-binding globulin and testosterone. Alcohol consumption was associated with higher concentrations of dehydroepiandrosterone sulfate, androstenedione and androstanediol glucuronide. East Asians had lower concentrations of androstanediol glucuronide and African Americans had higher concentrations of estrogens. Education and marital status were modestly associated with a small number of hormones.Conclusion: Circulating sex hormones in men are strongly associated with age and body mass index, and to a lesser extent with smoking status and alcohol consumption.
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