1. |
- Alcala, Karine, et al.
(author)
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The relationship between blood pressure and risk of renal cell carcinoma
- 2022
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In: International Journal of Epidemiology. - : Oxford University Press (OUP). - 1464-3685 .- 0300-5771. ; 51:4, s. 1317-1327
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Journal article (peer-reviewed)abstract
- BACKGROUND: The relation between blood pressure and kidney cancer risk is well established but complex and different study designs have reported discrepant findings on the relative importance of diastolic blood pressure (DBP) and systolic blood pressure (SBP). In this study, we sought to describe the temporal relation between diastolic and SBP with renal cell carcinoma (RCC) risk in detail.METHODS: Our study involved two prospective cohorts: the European Prospective Investigation into Cancer and Nutrition study and UK Biobank, including >700 000 participants and 1692 incident RCC cases. Risk analyses were conducted using flexible parametric survival models for DBP and SBP both separately as well as with mutuality adjustment and then adjustment for extended risk factors. We also carried out univariable and multivariable Mendelian randomization (MR) analyses (DBP: ninstruments = 251, SBP: ninstruments = 213) to complement the analyses of measured DBP and SBP.RESULTS: In the univariable analysis, we observed clear positive associations with RCC risk for both diastolic and SBP when measured ≥5 years before diagnosis and suggestive evidence for a stronger risk association in the year leading up to diagnosis. In mutually adjusted analysis, the long-term risk association of DBP remained, with a hazard ratio (HR) per standard deviation increment 10 years before diagnosis (HR10y) of 1.20 (95% CI: 1.10-1.30), whereas the association of SBP was attenuated (HR10y: 1.00, 95% CI: 0.91-1.10). In the complementary multivariable MR analysis, we observed an odds ratio for a 1-SD increment (ORsd) of 1.34 (95% CI: 1.08-1.67) for genetically predicted DBP and 0.70 (95% CI: 0.56-0.88) for genetically predicted SBP.CONCLUSION: The results of this observational and MR study are consistent with an important role of DBP in RCC aetiology. The relation between SBP and RCC risk was less clear but does not appear to be independent of DBP.
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2. |
- Andersen, Kasper, 1974-, et al.
(author)
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Dose–Response Relationship of Total and Leisure Time Physical Activity to Risk of Heart Failure : a prospective cohort study
- 2014
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In: Circulation Heart Failure. - 1941-3289 .- 1941-3297. ; 7:5, s. 701-708
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Journal article (peer-reviewed)abstract
- Background—The nature of the association between levels of physical activity and risk of heart failure is little known. We investigated nonlinear associations of total and leisure time physical activity with risk of heart failure.Methods and Results—In 1997, 39 805 persons without heart failure completed a questionnaire of lifestyle factors and medical history. We used Cox regression models to investigate total (adjusting for education and previous myocardial infarction) and direct (multivariable-adjusted) effects of self-reported total and leisure time physical activity on risk of heart failure of any cause and heart failure of nonischemic origin. Heart failure diagnoses were obtained until December 31, 2010. Higher leisure time physical activity was associated with lower risk of heart failure of any cause; hazard ratio of the total effect of leisure time physical activity was for fifth versus first quintile 0.54; 95% confidence interval was 0.44 to 0.66. The direct effect was similar. High total daily physical activity level was associated with lower risk of heart failure, although the effect was less pronounced than for leisure time physical activity (total effect hazard ratio, 0.81; 95% confidence interval, 0.69–0.95; fifth versus first quintile). A similar direct effect observed.Conclusions—Leisure time physical activity was inversely related to risk of developing heart failure in a dose–response fashion. This was reflected in a similar but less pronounced association of total physical activity with risk of heart failure. Only part of the effects appeared to be mediated by traditional risk factors.
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3. |
- Dimou, Niki L, et al.
(author)
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Circulating adipokine concentrations and risk of five obesity-related cancers : A Mendelian randomization study.
- 2021
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In: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 148:7, s. 1625-1636
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Journal article (peer-reviewed)abstract
- Obesity is considered a chronic inflammatory state characterized by continued secretion of adipokines and cytokines. Experimental and epidemiological evidence indicates that circulating adipokines may be associated with the development of obesity-related cancers, but it is unclear if these associations are causal or confounded. We examined potential causal associations of specific adipokines (adiponectin, leptin, soluble leptin receptor [sOB-R] and plasminogen activator inhibitor-1 [PAI-1]) with five obesity-related cancers (colorectal, pancreatic, renal cell carcinoma [RCC], ovarian and endometrial) using Mendelian randomization (MR) methods. We used summary-level data from large genetic consortia for 114 530 cancer cases and 245 284 controls. We constructed genetic instruments using 18 genetic variants for adiponectin, 2 for leptin and 4 for both sOB-R and PAI-1 (P value for inclusion<5 × 10-8 ). Causal estimates were obtained using two-sample MR methods. In the inverse-variance weighted models, we found an inverse association between adiponectin and risk of colorectal cancer (odds ratio per 1 μg/mL increment in adiponectin concentration: 0.90 [95% confidence interval = 0.84-0.97]; P = .01); but, evidence of horizontal pleiotropy was detected and the association was not present when this was taken into consideration. No association was found for adiponectin and risks of pancreatic cancer, RCC, ovarian cancer and endometrial cancer. Leptin, sOB-R and PAI-1 were also similarly unrelated to risk of obesity-related cancers. Despite the large sample size, our MR analyses do not support causal effects of circulating adiponectin, leptin, sOB-R and PAI-1 concentrations on the development of five obesity-related cancers.
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4. |
- Grotta, Alessandra, et al.
(author)
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Physical activity and body mass index as predictors of prostate cancer risk
- 2015
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In: World journal of urology. - : Springer Science and Business Media LLC. - 0724-4983 .- 1433-8726. ; 33:10, s. 1495-1502
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Journal article (peer-reviewed)abstract
- PURPOSE: Physical activity and body mass index (BMI) are involved in prostate cancer etiology; possible biologic mechanisms include their effects on hormonal levels. Our aim was to investigate the relationship between physical activity, obesity, and prostate cancer.METHODS: We followed a cohort of 13,109 Swedish men for 13 years and investigated the association of self-reported physical activity and BMI at baseline with prostate cancer incidence. We further analyzed whether BMI could modulate effects of physical activity. Occupational, recreational, and total physical activity were analyzed in relation to overall, localized, and advanced prostate cancer.RESULTS: During the study follow-up, we observed a total of 904 cases of prostate cancer (429 localized, 407 advanced, and 68 unclassified). High levels of occupational physical activity were associated with a nonsignificantly decreased risk of overall (HR 0.81, 95 % CI 0.61-1.07), localized (HR 0.75, 95 % CI 0.51-1.12), and advanced (HR 0.85, 95 % CI 0.55-1.31) prostate cancer. We found no association between high BMI and risk of prostate cancer incidence: We observed, however, a significant interaction between BMI and leisure physical activity.CONCLUSION: No association was confirmed between total physical activity and localized or advanced prostate cancer. The highest, relative to the lowest, level of occupational physical activity tended to be linked to a lower risk of prostate cancer, with a suggested dose-response relationship. We found no association between high BMI and risk of prostate cancer incidence; however, our analyses suggested an interaction between BMI and physical activity during recreational time that merits further investigation in future studies.
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5. |
- Haycock, Philip C, et al.
(author)
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The association between genetically elevated polyunsaturated fatty acids and risk of cancer.
- 2023
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In: EBioMedicine. - : Elsevier. - 2352-3964. ; 91
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Journal article (peer-reviewed)abstract
- BACKGROUND: The causal relevance of polyunsaturated fatty acids (PUFAs) for risk of site-specific cancers remains uncertain.METHODS: Using a Mendelian randomization (MR) framework, we assessed the causal relevance of PUFAs for risk of cancer in European and East Asian ancestry individuals. We defined the primary exposure as PUFA desaturase activity, proxied by rs174546 at the FADS locus. Secondary exposures were defined as omega 3 and omega 6 PUFAs that could be proxied by genetic polymorphisms outside the FADS region. Our study used summary genetic data on 10 PUFAs and 67 cancers, corresponding to 562,871 cases and 1,619,465 controls, collected by the Fatty Acids in Cancer Mendelian Randomization Collaboration. We estimated odds ratios (ORs) for cancer per standard deviation increase in genetically proxied PUFA exposures.FINDINGS: Genetically elevated PUFA desaturase activity was associated (P < 0.0007) with higher risk (OR [95% confidence interval]) of colorectal cancer (1.09 [1.07-1.11]), esophageal squamous cell carcinoma (1.16 [1.06-1.26]), lung cancer (1.06 [1.03-1.08]) and basal cell carcinoma (1.05 [1.02-1.07]). There was little evidence for associations with reproductive cancers (OR = 1.00 [95% CI: 0.99-1.01]; Pheterogeneity = 0.25), urinary system cancers (1.03 [0.99-1.06], Pheterogeneity = 0.51), nervous system cancers (0.99 [0.95-1.03], Pheterogeneity = 0.92) or blood cancers (1.01 [0.98-1.04], Pheterogeneity = 0.09). Findings for colorectal cancer and esophageal squamous cell carcinoma remained compatible with causality in sensitivity analyses for violations of assumptions. Secondary MR analyses highlighted higher omega 6 PUFAs (arachidonic acid, gamma-linolenic acid and dihomo-gamma-linolenic acid) as potential mediators. PUFA biosynthesis is known to interact with aspirin, which increases risk of bleeding and inflammatory bowel disease. In a phenome-wide MR study of non-neoplastic diseases, we found that genetic lowering of PUFA desaturase activity, mimicking a hypothetical intervention to reduce cancer risk, was associated (P < 0.0006) with increased risk of inflammatory bowel disease but not bleeding.INTERPRETATION: The PUFA biosynthesis pathway may be an intervention target for prevention of colorectal cancer and esophageal squamous cell carcinoma but with potential for increased risk of inflammatory bowel disease.
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6. |
- Johansson, Mattias, et al.
(author)
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The influence of obesity-related factors in the etiology of renal cell carcinoma—A mendelian randomization study
- 2019
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In: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 16:1
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Journal article (peer-reviewed)abstract
- Background: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation.Methods and findings: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44–1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40–1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44–1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30–2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11–1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84–1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose.Conclusions: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.
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7. |
- Longinetti, Elisa, et al.
(author)
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Neurodegenerative and psychiatric diseases among families with amyotrophic lateral sclerosis
- 2017
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In: Neurology. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 0028-3878 .- 1526-632X. ; 89:6, s. 578-585
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Journal article (other academic/artistic)abstract
- Objective: To estimate risks of neurodegenerative and psychiatric diseases among patients with amyotrophic lateral sclerosis (ALS) and their families. Methods: We conducted a register-based nested case-control study during 1990-2013 in Sweden to assess whether ALS patients had higher risks of other neurodegenerative and psychiatric diseases before diagnosis. We included 3,648 ALS patients and 36,480 age-, sex-, and county-of-birth matched population controls. We further conducted a follow-up study of the cases and controls to assess the risks of other neurodegenerative and psychiatric diseases after ALS diagnosis. To assess the potential contribution of familial factors, we conducted similar studies for the relatives of ALS patients and their controls. Results: Individuals with previous neurodegenerative or psychiatric diseases had a 49% increased risk of ALS (odds ratio=1.49, 95% confidence interval=1.35-1.66), compared to individuals without these diseases. After diagnosis, ALS patients had increased risks of other neurodegenerative or psychiatric diseases (hazard ratio=2.90, 95% confidence interval=2.46-3.43), compared to individuals without ALS. The strongest associations were noted for frontotemporal dementia, Parkinson’s disease, other dementia, Alzheimer’s disease, neurotic disorders, depression, stress-related disorders, and drug abuse/dependence. First-degree relatives of ALS patients had higher risk of neurodegenerative diseases, whereas only children of ALS patients had higher risk of psychiatric disorders, compared to relatives of the controls. Conclusions: Familial aggregation of ALS and other neurodegenerative diseases implies a shared etiopathogenesis among all neurodegenerative diseases. The increased risk of psychiatric disorders among ALS patients and their children might be attributable to non-motor symptoms of ALS and severe stress response toward the diagnosis.
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8. |
- Mariosa, Daniela, et al.
(author)
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Antidiabetics, Statins, and the Risk of Amyotrophic Lateral Sclerosis
- 2020
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In: European Journal of Neurology. - : Blackwell Publishing. - 1351-5101 .- 1468-1331. ; 27:6, s. 1010-1016
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Journal article (peer-reviewed)abstract
- BACKGROUND: Medications that are used for treatment of metabolic disorders have been suggested to be associated with the development of amyotrophic lateral sclerosis (ALS).METHODS: To examine the associations of antidiabetics and statins with the subsequent risk of ALS we conducted a population-based nested case-control study of 2,475 Swedish residents diagnosed with ALS during July 2006-December 2013, and 12,375 population controls (five for each ALS case). We extracted from the Swedish Prescribed Drug Register information on filled prescriptions of antidiabetics and statins for both cases and controls during the years before ALS diagnosis. Conditional logistic regression was used to calculate odds ratios (ORs) for the associations of these medications with ALS risk.RESULTS: ALS patients were less likely to have been prescribed with antidiabetics, compared to controls (OR=0.76, 95%CI=0.65-0.90). Conversely, statins were not associated with ALS risk overall (OR=1.08, 95%CI=0.98-1.19), although a positive association was noted among women (OR=1.28, 95%CI=1.10-1.48). The latter association was mostly explained by ALS cases being more likely to have a first prescription of statins during the year before diagnosis, compared to controls (OR=2.54, 95%CI=1.84-3.49).CONCLUSIONS: The inverse association of antidiabetics with ALS is consistent with the previously reported inverse association between type 2 diabetes and ALS risk. The increase in prescription of statins during the year before ALS diagnosis deserves attention because it might reflect an acceleration of the course of ALS due to statin use.
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9. |
- Mariosa, Daniela
(author)
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Metabolic disorders in the etiology of amyotrophic lateral sclerosis : an epidemiological approach
- 2017
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Doctoral thesis (other academic/artistic)abstract
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a loss of motor neurons in the brain and spinal cord, leading to progressive muscle weakness in multiple regions of the body. No effective treatment is available and the disease progresses rapidly to death with an average survival time of 3-5 years after symptom onset. The etiology of ALS is unknown for the majority of the patients. Alterations in the carbohydrate and lipid metabolisms, together with hypermetabolism, are features of ALS patients that are not yet well characterized. Understanding the early metabolic symptoms of the disease might be a necessary step for the identification of an effective treatment. Paper I describes a nested case-control study on the association between diabetes and the future risk of ALS in the Swedish population. A total of 5,108 new ALS cases among the Swedish residents between 1991 and 2010 were identified from the National Patient Register. Through linkages to several nationwide Swedish registers five controls per case were selected from the entire Swedish population using incidence density sampling and diabetes diagnoses were identified for both cases and controls from hospital admission records, outpatient care records, prescription of antidiabetics, or a combination of the three. An overall inverse association between diabetes and risk of ALS was found. There was however a positive association between insulin-dependent diabetes before age 30 and ALS risk. Paper II describes the association between body mass index (BMI), BMI change and ALS risk and survival in the GENEVA study, a case-control study of United States military veterans. Self-reported BMI at age 25, 40 and at time of ALS diagnosis (interview for controls) was compared. Low BMI at age 40 was associated with increased risk of developing ALS and the association was stronger for cases with diagnostic delay shorter than one year. Stable or decreasing BMI between age 25 and 40 was also associated with higher risk of ALS compared to an increasing BMI. However, premorbid BMI and BMI change did not predict survival of ALS patients. Paper III describes the association between ALS risk and serum glucose, total cholesterol, LDL-C, HDL-C, triglycerides, apolipoprotein B (apoB), and apolipoprotein A-I (apoA-I) in a Swedish populationbased cohort study. High LDL-C, apoB and the LDL-C/HDL-C and apoB/apoA-I ratios were associated with a higher incidence of ALS. These associations seemed to be mainly due to a strong association of apoB with ALS risk. High glucose level ( 6.11 mmol/L) was associated with a lower incidence of ALS. During the 10 years before diagnosis, ALS patients had increasing levels of LDL-C, HDL-C, apoB and apoA-I, whereas gradually decreasing levels of LDL-C/HDL-C and apoB/apoA-I ratios. Paper IV describes a population-based nested case-control study of 2,475 Swedish residents diagnosed with ALS during July 2006-December 2013, and 12,375 population controls. Information on filled prescriptions of antidiabetics and statins were extracted from the Swedish Prescribed Drug Register. Antidiabetics were associated with a lower ALS risk, the association was stronger for men, for individuals above age 65, and for ALS with longer disease duration. Statins were not associated with ALS risk overall, though a positive association was noted among women. The latter association was mostly explained by increased statins use during the year before ALS diagnosis. The studies presented in this thesis have taken advantage of different study designs and populations to systematically investigate the relationship between metabolic disorders and ALS risk and, to a lesser extent, progression. Therefore, they contributed substantially to fill the knowledge gap about the association between metabolic disorders and neurodegeneration in ALS. Furthermore, Paper I and Paper IV serve as excellent examples of the unique possibilities offered by the nationwide health registers in Sweden that can, when equipped with modern analytical methods, contribute to the understanding of complex diseases.
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11. |
- Rogers, Miranda, et al.
(author)
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Genetically proxied impaired GIPR signaling and risk of 6 cancers
- 2023
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In: iScience. - 2589-0042. ; 26:6
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Journal article (peer-reviewed)abstract
- Preclinical and genetic studies suggest that impaired glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling worsens glycemic control. The relationship between GIPR signaling and the risk of cancers influenced by impaired glucose homeostasis is unclear. We examined the association of a variant in GIPR, rs1800437 (E354Q), shown to impair long-term GIPR signaling and lower circulating glucose-dependent insulinotropic peptide concentrations, with risk of 6 cancers influenced by impaired glucose homeostasis (breast, colorectal, endometrial, lung, pancreatic, and renal) in up to 235,698 cases and 333,932 controls. Each copy of E354Q was associated with a higher risk of overall and luminal A-like breast cancer and this association was consistent in replication and colocalization analyses. E354Q was also associated with higher postprandial glucose concentrations but diminished insulin secretion and lower testosterone concentrations. Our human genetics analysis suggests an adverse effect of the GIPR E354Q variant on breast cancer risk, supporting further evaluation of GIPR signaling in breast cancer prevention.
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12. |
- Sun, Jiangwei, et al.
(author)
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Antibiotics Use and Risk of Amyotrophic Lateral Sclerosis in Sweden
- 2019
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In: European Journal of Neurology. - : Blackwell Publishing. - 1351-5101 .- 1468-1331. ; 26:11, s. 1355-1361
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Journal article (peer-reviewed)abstract
- BACKGROUND AND PURPOSE: Previous animal studies have suggested disrupted intestinal microbiome in amyotrophic lateral sclerosis (ALS). Due to the known effect of antibiotics on gut microflora, the potential role of antibiotics use on the risk of ALS deserves an investigation.METHODS: A nested case-control study was conducted using several Swedish national registers. We included 2,484 ALS patients diagnosed between July 1, 2006 and December 31, 2013 as cases and randomly selected five controls per case who were individually matched to the case by sex, birth year, and area of residence from the general Swedish population. Information on antibiotics prescriptions before ALS diagnosis was extracted from the Prescribed Drug Register for both cases and controls. Conditional logistic regression model was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs).RESULTS: After accounting for potential diagnostic delay in ALS by excluding all prescriptions within one year before diagnosis, any antibiotics use was associated with a higher risk of ALS. The ORs (95% CIs) were 1.06 (0.94-1.19), 1.13 (1.00-1.28), and 1.18 (1.03-1.35) when comparing one, 2-3, and ≥4 prescriptions to no prescription (P for trend = 0.0069). Similar results were noted for antibiotics used for respiratory infections and urinary tract as well as skin and soft tissue infections. Among different individual antibiotics, the risk of ALS was especially increased in relation to more than two prescriptions of beta-lactamase sensitive penicillin (OR=1.28; 95% CI 1.10-1.50).CONCLUSIONS: Use of antibiotics, especially repeated, might be associated with a higher subsequent risk of ALS.
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