| 1. |
- Aglago, Elom K., et al.
(författare)
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A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk
- 2023
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Ingår i: Cancer Research. - : American Association For Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 83:15, s. 2572-2583
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer.SIGNIFICANCE: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.
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| 2. |
- Al-Zalabani, Abdulmohsen H., et al.
(författare)
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Tea consumption and risk of bladder cancer in the Bladder Cancer Epidemiology and Nutritional Determinants (BLEND) Study : Pooled analysis of 12 international cohort studies
- 2022
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Ingår i: Clinical Nutrition. - : Elsevier BV. - 0261-5614. ; 41:5, s. 1122-1130
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Tidskriftsartikel (refereegranskat)abstract
- Background & aims: Tea has been shown to be associated with reduced risk of several diseases including cardiovascular diseases, stroke, metabolic syndrome, and obesity. However, the results on the relationship between tea consumption and bladder cancer are conflicting. This research aimed to assess the association between tea consumption and risk of bladder cancer using a pooled analysis of prospective cohort data. Methods: Individual data from 532,949 participants in 12 cohort studies, were pooled for analyses. Cox regression models stratified by study centre was used to estimate hazard ratios (HR) and corresponding 95% CIs. Fractional polynomial regression models were used to examine the dose–response relationship. Results: A higher level of tea consumption was associated with lower risk of bladder cancer incidence (compared with no tea consumption: HR = 0.87, 95% C.I. = 0.77–0.98 for low consumption; HR = 0.86, 95% C.I. = 0.77–0.96 for moderate consumption; HR = 0.84, 95% C.I. = 0.75–0.95 for high consumption). When stratified by sex and smoking status, this reduced risk was statistically significant among men and current and former smokers. In addition, dose–response analyses showed a lower bladder cancer risk with increment of 100 ml of tea consumption per day (HR-increment = 0.97; 95% CI = 0.96–0.98). A similar inverse association was found among males, current and former smokers while never smokers and females showed non-significant results, suggesting potential sex-dependent effect. Conclusions: Higher consumption of tea is associated with reduced risk of bladder cancer with potential interaction with sex and smoking status. Further studies are needed to clarify the mechanisms for a protective effect of tea (e.g. inhibition of the survival and proliferation of cancer cells and anti-inflammatory mechanisms) and its interaction with smoking and sex.
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| 3. |
- Allwell-Brown, Gbemisola
(författare)
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Antibiotic use among children in low- and middle-income countries : Studies on global trends, and contextual determinants of antibiotic prescribing in Eastern Uganda
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis aimed to systematically map trends in reported antibiotic use (RAU) among sick under-five children across low- and middle-income countries (LMICs) in 2005-2017, and, to understand the contextual determinants of antibiotic prescribing in Eastern Uganda. Based on 132 national surveys from 73 LMICs, and using Bayesian linear regression models, trends in RAU among sick under-five children (with symptoms of fever, diarrhoea or cough with fast/difficult breathing) across LMICs in 2005-2017 were mapped by WHO region, World Bank country income group, symptom complaint (Study-I), and by the following user characteristics: rural/urban residence, maternal education, household wealth and source of care (Study-II). To provide context, Study-III investigated patterns and contextual determinants of antibiotic prescribing for febrile under-five outpatients (FUO) attending 37 primary and secondary healthcare facilities across Bugisu, a sub-region in Eastern Uganda, based on a healthcare facility survey, and a two-year retrospective review of outpatient registers from January 2019-December 2020. To further strengthen the understanding of contextual determinants of antibiotic prescribing, in Study-IV, 10 focus group discussions and 10 in-depth interviews were conducted with 85 healthcare providers across primary and secondary healthcare facilities in Bugisu, and analysed using thematic analysis.A modest (17%) relative increase in RAU for sick under-five children across LMICs in 2005-2017 was found, with about 43% of the children reportedly receiving antibiotics for their illness in 2017. Low-income, African, and South-East Asian countries consistently recorded the lowest RAU for sick under-five children. Within LMICs, RAU for sick under-five children increased across all user groups in 2005-2017 but remained lowest among the poorest children, those living in rural areas, and having mothers with the lowest education levels. In Bugisu, 62.2% of FUO in surveyed healthcare facilities received antibiotic prescriptions. Amoxicillin and co-trimoxazole accounted for two-thirds of all antibiotic prescriptions. Cotrimoxazole and ampicillin/cloxacillin were prescribed, despite not being indicated in any of the reported conditions in Study-III. Among other interrelated factors across multiple levels of the health system, availability of antibiotics and diagnostics within healthcare facilities, caregiver demands, and governance at national and sub-national levels were important health worker considerations in antibiotic prescribing for febrile under-five patients.These studies suggest that inequitable access to antibiotics remains a challenge between and within LMICs. Yet, misuse and wastage of antibiotics persists in the same populations with the greatest lack of access to antibiotics and formal healthcare services. A health systems strengthening approach is required to improve antibiotic stewardship and overall quality of care in LMICs.
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| 4. |
- Allwell-Brown, Gbemisola, et al.
(författare)
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Determinants of trends in reported antibiotic use among sick children under five years of age across low-income and middle-income countries in 2005–17: A systematic analysis of user characteristics based on 132 national surveys from 73 countries
- 2021
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Ingår i: International Journal of Infectious Diseases. - : Elsevier BV. - 1201-9712 .- 1878-3511. ; 108, s. 473-482
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: This study aimed to analyze any reported antibiotic use for children aged <5 years with fever, diarrhea or cough with fast or difficult breathing (outcome) from low-income and middle-income countries (LMICs) during 2005–2017 by user characteristics: rural/urban residence, maternal education, household wealth, and healthcare source visited. Methods: Based on 132 demographic and health surveys and multiple indicator cluster surveys from 73 LMICs, the outcome by user characteristics for all country-years was estimated using a hierarchical Bayesian linear regression model. Results: Across LMICs during 2005–2017, the greatest relative increases in the outcome occurred in rural areas, poorest quintiles and least educated populations, particularly in low-income countries and South-East Asia. In low-income countries, rural areas had a 72% relative increase from 17.8% (Uncertainty Interval (UI): 5.2%–44.9%) in 2005 to 30.6% (11.7%–62.1%) in 2017, compared to a 29% relative increase in urban areas from 27.1% (8.7%–58.2%) in 2005 to 34.9% (13.3%–67.3%) in 2017. Despite these increases, the outcome was consistently highest in urban areas, wealthiest quintiles, and populations with the highest maternal education. Conclusion: These estimates suggest that the increasing reported antibiotic use for sick children aged <5 years in LMICs during 2005–2017 was driven by gains among groups often underserved by formal health services. © 2021 The Author(s)
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| 5. |
- Allwell-Brown, Gbemisola, et al.
(författare)
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Patterns and contextual determinants of antibiotic prescribing for febrile under-five outpatients at primary and secondary healthcare facilities in Bugisu, Eastern Uganda
- 2022
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Ingår i: JAC-ANTIMICROBIAL RESISTANCE. - : Oxford University Press (OUP). - 2632-1823. ; 4:5
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To describe patterns and contextual determinants of antibiotic prescribing for febrile under-five outpatients at primary and secondary healthcare facilities across Bugisu, Eastern Uganda. Methods: We surveyed 37 public and private-not-for-profit healthcare facilities and conducted a retrospective review of antimicrobial prescribing patterns among febrile under-five outpatients (with a focus on antibiotics) in 2019-20, based on outpatient registers. Multilevel Logistic regression analysis was used to identify determinants of antibiotic prescribing at patient- and healthcare facility-Levels. Results: Antibiotics were prescribed for 62.2% of 3471 febrile under-five outpatients. There were a total of 2478 antibiotic prescriptions of 22 antibiotic types: amoxicillin (52.2%), co-trimoxazole (14.7%), metronidazole (6.9%), gentamicin (5.7%), ceftriaxone (5.3%), ampicillin/cloxacillin (3.6%), penicillin (3.1%), and others (8.6%). Acute upper respiratory tract infection (AURTI) was the commonest single indication for antibiotic prescribing, with 76.3% of children having AURTI as their only documented diagnosis receiving antibiotic prescriptions. Only 9.2% of children aged 2-59 months with non-severe pneumonia received antibiotic prescriptions in Line with national guidelines. Higher health centre Levels, and private-not-for-profit ownership (adjusted OR, 4.30; 95% CI, 1.91-9.72) were significant contextual determinants of antibiotic prescribing. Conclusions: We demonstrated a high antibiotic prescribing prevalence among febrile under-five outpatients in Bugisu, Eastern Uganda, including prescriptions for co-trimoxazole and ampicillin/cloxacillin (which are not indicated in the management of the common causes of under-five febrile illness in Uganda). Study findings may be Linked to Limited diagnostic capacity and inadequate antibiotic availability, which require prioritization in interventions aimed at improving rational antibiotic prescribing among febrile under-five outpatients.
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| 6. |
- Allwell-Brown, Gbemisola, et al.
(författare)
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Trends in reported antibiotic use among children under 5 years of age with fever, diarrhoea, or cough with fast or difficult breathing across low-income and middle-income countries in 2005-17: a systematic analysis of 132 national surveys from 73 countries.
- 2020
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Ingår i: The Lancet. Global health. - : ELSEVIER SCI LTD. - 2214-109X. ; 8:6
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Tidskriftsartikel (refereegranskat)abstract
- Global assessments of antibiotic consumption have relied on pharmaceutical sales data that do not measure individual-level use, and are often unreliable or unavailable for low-income and middle-income countries (LMICs). To help fill this evidence gap, we compiled data from national surveys in LMICs in 2005-17 reporting antibiotic use for sick children under the age of 5 years.Based on 132 Demographic and Health Surveys and Multiple Indicator Cluster Surveys from 73 LMICs, we analysed trends in reported antibiotic use among children under 5 years of age with fever, diarrhoea, or cough with fast or difficult breathing by WHO region, World Bank income classification, and symptom complaint. A logit transformation was used to estimate the outcome using a linear Bayesian regression model. The model included country-level socioeconomic, disease incidence, and health system covariates to generate estimates for country-years with missing values.Across LMICs, reported antibiotic use among sick children under 5 years of age increased from 36·8% (uncertainty interval [UI] 28·8-44·7) in 2005 to 43·1% (33·2-50·5) in 2017. Low-income countries had the greatest relative increase; in these countries, reported antibiotic use for sick children under 5 years of age rose 34% during the study period, from 29·6% (21·2-41·1) in 2005 to 39·5% (32·9-47·6) in 2017, although it remained the lowest of any income group throughout the study period.We found a limited but steady increase in reported antibiotic use for sick children under 5 years of age across LMICs in 2005-17, although overlapping UIs complicate interpretation. The increase was largely driven by gains in low-income countries. Our study expands the evidence base from LMICs, where strengthening antibiotic consumption and resistance surveillance is a global health priority.Uppsala Antibiotic Centre, Uppsala University, Uppsala University Hospital, Makerere University, Gothenburg University.
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| 7. |
- Alwers, Elizabeth, et al.
(författare)
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Smoking Behavior and Prognosis after Colorectal Cancer Diagnosis : A Pooled Analysis of 11 Studies
- 2021
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Ingår i: JNCI Cancer Spectrum. - : Oxford University Press. - 2515-5091. ; 5:5
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Tidskriftsartikel (refereegranskat)abstract
- Background: Smoking has been associated with colorectal cancer (CRC) incidence and mortality in previous studies, but current evidence on smoking in association with survival after CRC diagnosis is limited.Methods: We pooled data from 12 345 patients with stage I-IV CRC from 11 epidemiologic studies in the International Survival Analysis in Colorectal Cancer Consortium. Cox proportional hazards regression models were used to evaluate the associations of prediagnostic smoking behavior with overall, CRC-specific, and non-CRC-specific survival.Results: Among 12 345 patients with CRC, 4379 (35.5%) died (2515 from CRC) over a median follow-up time of 7.5years. Smoking was strongly associated with worse survival in stage I-III patients, whereas no associa-tion was observed among stage IV patients. Among stage I-III patients, clear dose-response relationships with all survival outcomes were seen for current smokers. For example, current smokers with 40 or more pack-years had statistically significantly worse over-all, CRC-specific, and non-CRC-specific survival compared with never smokers (hazard ratio [HR] 1/41.94, 95% confidence interval [CI] 1/41.68 to 2.25; HR = 1.41, 95% CI = 1.12 to 1.78; and HR = 2.67, 95% CI = 2.19 to 3.26, respectively). Similar associations with all sur-vival outcomes were observed for former smokers who had quit for less than 10years, but only a weak association with non-CRC-specific survival was seen among former smokers who had quit for more than 10years.Conclusions: This large consortium of CRC patient studies provides compelling evidence that smoking is strongly associated with worse survival of stage I-III CRC patients in a clear dose-response manner. The detrimental effect of smoking was primarily related to noncolorectal cancer events, but current heavy smoking also showed an association with CRC-specific survival.
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| 8. |
- Archambault, Alexi N., et al.
(författare)
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Cumulative Burden of Colorectal Cancer Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer
- 2020
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 158:5, s. 1274-1286.e12
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC.METHODS: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants.RESULTS: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 x 10(-5)). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings.CONCLUSIONS: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.
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| 9. |
- Bien, Stephanie A., et al.
(författare)
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Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer
- 2019
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Ingår i: Human Genetics. - : Springer. - 0340-6717 .- 1432-1203. ; 138:4, s. 307-326
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have reported 56 independently associated colorectal cancer (CRC) risk variants, most of which are non-coding and believed to exert their effects by modulating gene expression. The computational method PrediXcan uses cis-regulatory variant predictors to impute expression and perform gene-level association tests in GWAS without directly measured transcriptomes. In this study, we used reference datasets from colon (n=169) and whole blood (n=922) transcriptomes to test CRC association with genetically determined expression levels in a genome-wide analysis of 12,186 cases and 14,718 controls. Three novel associations were discovered from colon transverse models at FDR0.2 and further evaluated in an independent replication including 32,825 cases and 39,933 controls. After adjusting for multiple comparisons, we found statistically significant associations using colon transcriptome models with TRIM4 (discovery P=2.2x10(-4), replication P=0.01), and PYGL (discovery P=2.3x10(-4), replication P=6.7x10(-4)). Interestingly, both genes encode proteins that influence redox homeostasis and are related to cellular metabolic reprogramming in tumors, implicating a novel CRC pathway linked to cell growth and proliferation. Defining CRC risk regions as one megabase up- and downstream of one of the 56 independent risk variants, we defined 44 non-overlapping CRC-risk regions. Among these risk regions, we identified genes associated with CRC (P<0.05) in 34/44 CRC-risk regions. Importantly, CRC association was found for two genes in the previously reported 2q25 locus, CXCR1 and CXCR2, which are potential cancer therapeutic targets. These findings provide strong candidate genes to prioritize for subsequent laboratory follow-up of GWAS loci. This study is the first to implement PrediXcan in a large colorectal cancer study and findings highlight the utility of integrating transcriptome data in GWAS for discovery of, and biological insight into, risk loci.
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| 10. |
- Boot, Iris W. A., et al.
(författare)
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Dietary B group vitamin intake and the bladder cancer risk : a pooled analysis of prospective cohort studies
- 2022
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Ingår i: European Journal of Nutrition. - : Springer Nature. - 1436-6207 .- 1436-6215. ; 61:5, s. 2397-2416
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Diet may play an essential role in the aetiology of bladder cancer (BC). The B group complex vitamins involve diverse biological functions that could be influential in cancer prevention. The aim of the present study was to investigate the association between various components of the B group vitamin complex and BC risk.Methods: Dietary data were pooled from four cohort studies. Food item intake was converted to daily intakes of B group vitamins and pooled multivariate hazard ratios (HRs), with corresponding 95% confidence intervals (CIs), were obtained using Cox-regression models. Dose–response relationships were examined using a nonparametric test for trend.Results: In total, 2915 BC cases and 530,012 non-cases were included in the analyses. The present study showed an increased BC risk for moderate intake of vitamin B1 (HRB1: 1.13, 95% CI: 1.00–1.20). In men, moderate intake of the vitamins B1, B2, energy-related vitamins and high intake of vitamin B1 were associated with an increased BC risk (HR (95% CI): 1.13 (1.02–1.26), 1.14 (1.02–1.26), 1.13 (1.02–1.26; 1.13 (1.02–1.26), respectively). In women, high intake of all vitamins and vitamin combinations, except for the entire complex, showed an inverse association (HR (95% CI): 0.80 (0.67–0.97), 0.83 (0.70–1.00); 0.77 (0.63–0.93), 0.73 (0.61–0.88), 0.82 (0.68–0.99), 0.79 (0.66–0.95), 0.80 (0.66–0.96), 0.74 (0.62–0.89), 0.76 (0.63–0.92), respectively). Dose–response analyses showed an increased BC risk for higher intake of vitamin B1 and B12.Conclusion: Our findings highlight the importance of future research on the food sources of B group vitamins in the context of the overall and sex-stratified diet.
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