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- Graff, M., et al.
(författare)
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Genome-wide physical activity interactions in adiposity. A meta-analysis of 200,452 adults
- 2017
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Ingår i: PLoS Genet. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 13:4
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Tidskriftsartikel (refereegranskat)abstract
- Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by similar to 30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.
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| 5. |
- Marouli, Eirini, et al.
(författare)
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Rare and low-frequency coding variants alter human adult height
- 2017
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 542:7640, s. 186-190
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Tidskriftsartikel (refereegranskat)abstract
- Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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- Pantazis, N, et al.
(författare)
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Determining the likely place of HIV acquisition for migrants in Europe combining subject-specific information and biomarkers data
- 2019
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Ingår i: Statistical methods in medical research. - : SAGE Publications. - 1477-0334 .- 0962-2802. ; 28:7, s. 1979-1997
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Tidskriftsartikel (refereegranskat)abstract
- In most HIV-positive individuals, infection time is only known to lie between the time an individual started being at risk for HIV and diagnosis time. However, a more accurate estimate of infection time is very important in certain cases. For example, one of the objectives of the Advancing Migrant Access to Health Services in Europe (aMASE) study was to determine if HIV-positive migrants, diagnosed in Europe, were infected pre- or post-migration. We propose a method to derive subject-specific estimates of unknown infection times using information from HIV biomarkers’ measurements, demographic, clinical, and behavioral data. We assume that CD4 cell count (CD4) and HIV-RNA viral load trends after HIV infection follow a bivariate linear mixed model. Using post-diagnosis CD4 and viral load measurements and applying the Bayes’ rule, we derived the posterior distribution of the HIV infection time, whereas the prior distribution was informed by AIDS status at diagnosis and behavioral data. Parameters of the CD4–viral load and time-to-AIDS models were estimated using data from a large study of individuals with known HIV infection times (CASCADE). Simulations showed substantial predictive ability (e.g. 84% of the infections were correctly classified as pre- or post-migration). Application to the aMASE study ( n = 2009) showed that 47% of African migrants and 67% to 72% of migrants from other regions were most likely infected post-migration. Applying a Bayesian method based on bivariate modeling of CD4 and viral load, and subject-specific information, we found that the majority of HIV-positive migrants in aMASE were most likely infected after their migration to Europe.
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- Kjellman, M., et al.
(författare)
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A Plasma Protein Biomarker Strategy for Detection of Small Intestinal Neuroendocrine Tumors
- 2021
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Ingår i: Neuroendocrinology. - : S. Karger AG. - 0028-3835 .- 1423-0194. ; 111:9, s. 840-849
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Tidskriftsartikel (refereegranskat)abstract
- Background: Small intestinal neuroendocrine tumors (SI-NETs) are difficult to diagnose in the early stage of disease. Current blood biomarkers such as chromogranin A (CgA) and 5-hydroxyindolacetic acid have low sensitivity (SEN) and specificity (SPE). This is a first preplanned interim analysis (Nordic non-interventional, prospective, exploratory, EXPLAIN study [NCT02630654]). Its objective is to investigate if a plasma protein multi-biomarker strategy can improve diagnostic accuracy (ACC) in SI-NETs. Methods: At the time of diagnosis, before any disease-specific treatment was initiated, blood was collected from patients with advanced SI-NETs and 92 putative cancer-related plasma proteins from 135 patients were analyzed and compared with the results of age- and sex-matched controls (n = 143), using multiplex proximity extension assay and machine learning techniques. Results: Using a random forest model including 12 top ranked plasma proteins in patients with SI-NETs, the multi-biomarker strategy showed SEN and SPE of 89 and 91%, respectively, with negative predictive value (NPV) and positive predictive value (PPV) of 90 and 91%, respectively, to identify patients with regional or metastatic disease with an area under the receiver operator characteristic curve (AUROC) of 99%. In 30 patients with normal CgA concentrations, the model provided a diagnostic SPE of 98%, SEN of 56%, and NPV 90%, PPV of 90%, and AUROC 97%, regardless of proton pump inhibitor intake. Conclusion: This interim analysis demonstrates that a multi-biomarker/machine learning strategy improves diagnostic ACC of patients with SI-NET at the time of diagnosis, especially in patients with normal CgA levels. The results indicate that this multi-biomarker strategy can be useful for early detection of SI-NETs at presentation and conceivably detect recurrence after radical primary resection.
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- Beral, V, et al.
(författare)
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Alcohol, tobacco and breast cancer - collaborative reanalysis of individual data from 53 epidemiological studies, including 58515 women with breast cancer and 95067 women without the disease
- 2002
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 1532-1827 .- 0007-0920. ; 87, s. 1234-45
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Tidskriftsartikel (refereegranskat)abstract
- Alcohol and tobacco consumption are closely correlated and published results on their association with breast cancer have not always allowed adequately for confounding between these exposures. Over 80% of the relevant information worldwide on alcohol and tobacco consumption and breast cancer were collated, checked and analysed centrally. Analyses included 58515 women with invasive breast cancer and 95067 controls from 53 studies. Relative risks of breast cancer were estimated, after stratifying by study, age, parity and, where appropriate, women's age when their first child was born and consumption of alcohol and tobacco. The average consumption of alcohol reported by controls from developed countries was 6.0 g per day, i.e. about half a unit/drink of alcohol per day, and was greater in ever-smokers than never-smokers, (8.4 g per day and 5.0 g per day, respectively). Compared with women who reported drinking no alcohol, the relative risk of breast cancer was 1.32 (1.19 - 1.45, P < 0.00001) for an intake of 35 - 44 g per day alcohol, and 1.46 (1.33 - 1.61, P < 0.00001) for greater than or equal to 45 g per day alcohol. The relative risk of breast cancer increased by 7.1% (95% CI 5.5-8.7%; P<0.00001) for each additional 10 g per day intake of alcohol, i.e. for each extra unit or drink of alcohol consumed on a daily basis. This increase was the same in ever-smokers and never-smokers (7.1 % per 10 g per day, P < 0.00001, in each group). By contrast, the relationship between smoking and breast cancer was substantially confounded by the effect of alcohol. When analyses were restricted to 22 255 women with breast cancer and 40 832 controls who reported drinking no alcohol, smoking was not associated with breast cancer (compared to never-smokers, relative risk for ever-smokers= 1.03, 95% CI 0.98 - 1.07, and for current smokers=0.99, 0.92 - 1.05). The results for alcohol and for tobacco did not vary substantially across studies, study designs, or according to 15 personal characteristics of the women; nor were the findings materially confounded by any of these factors. If the observed relationship for alcohol is causal, these results suggest that about 4% of the breast cancers in developed countries are attributable to alcohol. In developing countries, where alcohol consumption among controls averaged only 0.4 g per day, alcohol would have a negligible effect on the incidence of breast cancer. In conclusion, smoking has little or no independent effect on the risk of developing breast cancer; the effect of alcohol on breast cancer needs to be interpreted in the context of its beneficial effects, in moderation, on cardiovascular disease and its harmful effects on cirrhosis and cancers of the mouth, larynx, oesophagus and liver. (C) 2002 Cancer Research UK.
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