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- Kanter-Smoler, Gunilla, et al.
(author)
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Clinical characterization and the mutation spectrum in Swedish adenomatous polyposis families
- 2008
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In: BMC Medicine. - : BioMed Central. - 1741-7015. ; 6
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Journal article (peer-reviewed)abstract
- Background: The dominantly inherited condition familial adenomatous polyposis (FAP) is caused by germline mutations in the APC gene. Finding the causative mutations has great implications for the families. Correlating the genotypes to the phenotypes could help to improve the diagnosis and follow-up of patients.Methods: Mutation screening of APCand the clinical characterization of 96 unrelated FAP patients from the Swedish Polyposis Registry was performed. In addition to generally used mutation screening methods, analyses of splicing-affecting mutations and investigations of the presence of low-frequency mutation alleles, indicating mosaics, have been performed, as well as quantitative real-time polymerase chain reaction to detect lowered expression of APC.Results: Sixty-one different APC mutations in 81 of the 96 families were identified and 27 of those are novel. We have previously shown that 6 of the 96 patients carried biallelic MUTYH mutations. The 9 mutation-negative cases all display an attenuated or atypical phenotype. Probands with a genotype (codon 1250-1464) predicting a severe phenotype had a median age at diagnosis of 21.8 (range, 11-49) years compared with 34.4 (range, 14-57) years among those with mutations outside this region (P < 0.017). Dense polyposis (> 1000) occurred in 75% of the probands with a severe phenotype compared with 30% in those with mutations outside this region. The morbidity in colorectal cancer among probands was 25% at a mean age of 37.5 years and 29% at a mean age of 46.6 years.Conclusion: Using a variety of mutation-detection techniques, we have achieved a 100% detection frequency in classical FAP. Probands with APC mutations outside codon 1250-1464, although exhibiting a less-severe phenotype, are at high risk of having a colorectal cancer at diagnosis indicating that age at diagnosis is as important as the severity of the disease for colorectal cancer morbidity. © 2008 Kanter-Smoler et al; licensee BioMed Central Ltd.
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| 2. |
- Bai, Ge, et al.
(author)
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Frailty and the risk of dementia : is the association explained by shared environmental and genetic factors?
- 2021
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In: BMC Medicine. - : BioMed Central. - 1741-7015. ; 19:1
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Journal article (peer-reviewed)abstract
- Background Frailty has been identified as a risk factor for cognitive impairment and dementia. However, it is not known whether familial factors, such as genetics and shared environmental factors, underlie this association. We analyzed the association between frailty and the risk of dementia in a large twin cohort and examined the role of familial factors in the association. Methods The Rockwood frailty index (FI) based on 44 health deficits was used to assess frailty. The population-level association between FI and the risk of all-cause dementia was analyzed in 41,550 participants of the Screening Across the Lifespan Twin (SALT) study (full sample, aged 41-97 years at baseline), using Cox and competing risk models. A subsample of 10,487 SALT participants aged 65 and older who received a cognitive assessment (cognitive sample) was used in a sensitivity analysis to assess the effect of baseline cognitive level on the FI-dementia association. To analyze the influence of familial effects on the FI-dementia association, a within-pair analysis was performed. The within-pair model was also used to assess whether the risk conferred by frailty varies by age at FI assessment. Results A total of 3183 individuals were diagnosed with dementia during the 19-year follow-up. A 10% increase in FI was associated with an increased risk of dementia (hazard ratio [HR] 1.17 (95% confidence interval [CI] 1.07, 1.18)) in the full sample adjusted for age, sex, education, and tobacco use. A significant association was likewise found in the cognitive sample, with an HR of 1.13 (95% CI 1.09, 1.20), adjusted for age, sex, and cognitive level at baseline. The associations were not attenuated when adjusted for APOE e4 carrier status or considering the competing risk of death. After adjusting for familial effects, we found no evidence for statistically significant attenuation of the effect. The risk conferred by higher FI on dementia was constant after age 50 until very old age. Conclusions A higher level of frailty predicts the risk of dementia and the association appears independent of familial factors. Targeting frailty might thus contribute to preventing or delaying dementia.
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| 3. |
- Karlsson, Ida K., et al.
(author)
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Age-dependent effects of body mass index across the adult life span on the risk of dementia : A cohort study with a genetic approach
- 2020
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In: BMC Medicine. - : BioMed Central. - 1741-7015. ; 18:1
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Journal article (peer-reviewed)abstract
- Background: While a high body mass index (BMI) in midlife is associated with higher risk of dementia, high BMI in late-life may be associated with lower risk. This study combined genetic designs with longitudinal data to achieve a better understanding of this paradox. Methods: We used longitudinal data from 22,156 individuals in the Swedish Twin Registry (STR) and 25,698 from the Health and Retirement Study (HRS). The STR sample had information about BMI from early adulthood through late-life, and the HRS sample from age 50 through late-life. Survival analysis was applied to investigate age-specific associations between BMI and dementia risk. To examine if the associations are influenced by genetic susceptibility to higher BMI, an interaction between BMI and a polygenic score for BMI (PGSBMI) was included in the models and results stratified into those with genetic predisposition to low, medium, and higher BMI. In the STR, co-twin control models were applied to adjust for familial factors beyond those captured by the PGSBMI. Results: At age 35-49, 5 units higher BMI was associated with 15% (95% CI 7-24%) higher risk of dementia in the STR. There was a significant interaction (p = 0.04) between BMI and the PGSBMI, and the association present only among those with genetic predisposition to low BMI (HR 1.38, 95% CI 1.08-1.78). Co-twin control analyses indicated genetic influences. After age 80, 5 units higher BMI was associated with 10-11% lower risk of dementia in both samples. There was a significant interaction between late-life BMI and the PGSBMI in the STR (p = 0.01), but not the HRS, with the inverse association present only among those with a high PGSBMI (HR 0.70, 95% CI 0.52-0.94). No genetic influences were evident from co-twin control models of late-life BMI. Conclusions: Not only does the association between BMI and dementia differ depending on age at BMI measurement, but also the effect of genetic influences. In STR, the associations were only present among those with a BMI in opposite direction of their genetic predisposition, indicating that the association between BMI and dementia across the life course might be driven by environmental factors and hence likely modifiable. © 2020 The Author(s).
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| 4. |
- Li, Xia, et al.
(author)
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The frailty index is a predictor of cause-specific mortality independent of familial effects from midlife onwards : a large cohort study
- 2019
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In: BMC Medicine. - : BioMed Central. - 1741-7015. ; 17:1
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Journal article (peer-reviewed)abstract
- BACKGROUND: Frailty index (FI) is a well-established predictor of all-cause mortality, but less is known for cause-specific mortality and whether familial effects influence the associations. Middle-aged individuals are also understudied for the association between FI and mortality. Furthermore, the population mortality impact of frailty remains understudied.METHODS: We estimated the predictive value of FI for all-cause and cause-specific mortality, taking into account familial factors, and tested whether the associations are time-dependent. We also assessed the proportion of all-cause and cause-specific deaths that are attributable to increased levels of frailty. We analyzed 42,953 participants from the Screening Across the Lifespan Twin Study (aged 41-95 years at baseline) with up to 20 years' mortality follow-up. The FI was constructed using 44 health-related items. Deaths due to cardiovascular disease (CVD), respiratory-related causes, and cancer were considered in the cause-specific analysis. Generalized survival models were used in the analysis.RESULTS: Increased FI was associated with higher risks of all-cause, CVD, and respiratory-related mortality, with the corresponding hazard ratios of 1.28 (1.24, 1.32), 1.31 (1.23, 1.40), and 1.23 (1.11, 1.38) associated with a 10% increase in FI in male single responders, and 1.21 (1.18, 1.25), 1.27 (1.15, 1.34), and 1.26 (1.15, 1.39) in female single responders. No significant associations were observed for cancer mortality. No attenuation of the mortality associations in unrelated individuals was observed when adjusting for familial effects in twin pairs. The associations were time-dependent with relatively greater effects observed in younger ages. Before the age of 80, the proportions of deaths attributable to FI levels > 0.21 were 18.4% of all-cause deaths, 25.4% of CVD deaths, and 20.4% of respiratory-related deaths in men and 19.2% of all-cause deaths, 27.8% of CVD deaths, and 28.5% of respiratory-related deaths in women. After the age of 80, the attributable proportions decreased, most notably for all-cause and CVD mortality.CONCLUSIONS: Increased FI predicts higher risks of all-cause, CVD, and respiratory-related mortality independent of familial effects. Increased FI presents a relatively greater risk factor at midlife than in old age. Increased FI has a significant population mortality impact that is greatest through midlife until the age of 80.
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| 5. |
- Sindi, S., et al.
(author)
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Sleep disturbances and the speed of multimorbidity development in old age : results from a longitudinal population-based study
- 2020
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In: BMC Medicine. - : BioMed Central. - 1741-7015. ; 18:1
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Journal article (peer-reviewed)abstract
- Background: Sleep disturbances are prevalent among older adults and are associated with various individual diseases. The aim of this study was to investigate whether sleep disturbances are associated with the speed of multimorbidity development among older adults. Methods: Data were gathered from the Swedish National study of Aging and Care in Kungsholmen (SNAC-K), an ongoing population-based study of subjects aged 60+ (N = 3363). The study included a subsample (n = 1189) without multimorbidity at baseline (< 2 chronic diseases). Baseline sleep disturbances were derived from the Comprehensive Psychiatric Rating Scale and categorized as none, mild, and moderate–severe. The number of chronic conditions throughout the 9-year follow-up was obtained from clinical examinations. Linear mixed models were used to study the association between sleep disturbances and the speed of chronic disease accumulation, adjusting for sex, age, education, physical activity, smoking, alcohol consumption, depression, pain, and psychotropic drug use. We repeated the analyses including only cardiovascular, neuropsychiatric, or musculoskeletal diseases as the outcome. Results: Moderate–severe sleep disturbances were associated with a higher speed of chronic disease accumulation (ß/year = 0.142, p = 0.008), regardless of potential confounders. Significant positive associations were also found between moderate–severe sleep disturbances and neuropsychiatric (ß/year = 0.041, p = 0.016) and musculoskeletal (ß/year = 0.038, p = 0.025) disease accumulation, but not with cardiovascular diseases. Results remained stable when participants with baseline dementia, cognitive impairment, or depression were excluded. Conclusion: The finding that sleep disturbances are associated with faster chronic disease accumulation points towards the importance of early detection and treatment of sleep disturbances as a possible strategy to reduce chronic multimorbidity among older adults.
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