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- Jacobs, Kevin B, et al.
(author)
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Detectable clonal mosaicism and its relationship to aging and cancer.
- 2012
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In: Nature Genetics. - New York : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 44:6, s. 651-658
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Journal article (peer-reviewed)abstract
- In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.
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- Machiela, Mitchell J., et al.
(author)
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Characterization of Large Structural Genetic Mosaicism in Human Autosomes
- 2015
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In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 96:3, s. 487-497
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Journal article (peer-reviewed)abstract
- Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 x 3 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.
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- Clarke, Robert, et al.
(author)
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Lowering blood homocysteine with folic acid based supplements : Meta-analysis of randomised trials
- 1998
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In: British Medical Journal. - : BMJ. - 0959-8146. ; 316:7135, s. 894-898
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Research review (peer-reviewed)abstract
- Objective: To determine the size of reduction in homocysteine concentrations produced by dietary supplementation with folic acid and with vitamins B-12 or B-6. Design: Meta-analysis of randomised controlled trials that assessed the effects of folic acid based supplements on blood homocysteine concentration. Multivariate regression analysis was used to determine the effects on homocysteine concentrations of different doses of folic acid and of the addition of vitamin B-12 or B-6. Subjects: Individual data on 1114 people included in 12 trials. Findings: The proportional and absolute reductions in blood homocysteine produced by folic acid supplements were greater at higher pretreatment blood homocysteine concentrations (P < 0.001) and at lower pretreatment blood folate concentrations (P < 0.001). After standardisation to pretreatment blood concentrations of homocysteine of 12 μmol/l and of folate of 12 nmol/l (approximate average concentrations for Western populations), dietary folic acid reduced blood homocysteine concentrations by 25% (95% confidence interval 23% to 28%; P < 0.001), with similar effects in the range of 0.5-5 mg folic acid daily. Vitamin B-12 (mean 0.5 mg daily) produced an additional 7% (3% to 10%) reduction in blood homocysteine. Vitamin B-6 (mean 16.5 mg daily) did not have a significant additional effect. Conclusions: Typically in Western populations, daily supplementation with both 0.5-5 mg folic acid and about 0.5 mg vitamin B-12 would be expected to reduce blood homocysteine concentrations by about a quarter to a third (for example, from about 12 μmol/l to 8-9 μmol/l). Large scale randomised trials of such regimens in high risk populations are now needed to determine whether lowering blood homocysteine concentrations reduces the risk of vascular disease.
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- Ingvarsson, R. F., et al.
(author)
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Good survival rates in systemic lupus erythematosus in southern Sweden, while the mortality rate remains increased compared with the population.
- 2019
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In: Lupus. - : SAGE Publications. - 1477-0962 .- 0961-2033. ; 28:12, s. 1488-1494
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Journal article (peer-reviewed)abstract
- To ascertain the mortality rate and causes of death in patients with systemic lupus erythematosus (SLE) within a defined region in southern Sweden during the time period 1981-2014 and determine whether these have changed over time.In 1981, a prospective observation study of patients with SLE was initiated in southern Sweden. All incident SLE patients within a defined geographic area were identified using previously validated methods including diagnosis and immunology registers. Patients with a confirmed SLE diagnosis were then followed prospectively at the Department of Rheumatology in Lund. Clinical data was collected at regular visits. Patients were recruited from 1981 to 2006 and followed until 2014. The patient cohort was split into two groups based on the year of diagnosis to determine secular trends. Causes of death were retrieved from medical records and from the cause of death registry at The National Board of Health and Welfare in Sweden.In all, 175 patients were diagnosed with SLE during the study period. A total of 60 deaths occurred during a total of 3053 years of follow-up. In the first half of the study inclusion period 46 patients died, compared with 14 in the latter. The majority of patients (51.7%) died of cardiovascular disease. Infections caused 15% of the deaths and malignancy was the cause of death in 13.3% of patients. SLE was the main cause of death for 6.7% of the patients and a contributing factor for half of the patients. Standardized mortality ratio was increased in patients by a factor of 2.5 compared with the general population. Deaths occurred at an even rate throughout the whole observation period. No significant difference in standardized mortality ratio was observed between genders but was increased in older female patients. Furthermore, secular mortality trends were not identified.In this long-term epidemiologic follow-up study of incident SLE, we report a substantially raised mortality rate amongst SLE patients compared with the general population. The mortality rates have not changed significantly during the observation period that spanned three decades. The main cause of death was cardiovascular disease and this finding was consistent over time.
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