7 research outputs found
Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome
To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP
microarray intensity data of 38,303 women from cancer genome-wide association studies
(20,878 cases and 17,425 controls) and detected 124 mosaic X events42Mb in 97 (0.25%)
women. Here we show rates for X-chromosome mosaicism are four times higher than mean
autosomal rates; X mosaic events more often include the entire chromosome and participants
with X events more likely harbour autosomal mosaic events. X mosaicism frequency
increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and
autosomes. Methylation array analyses of 33 women with X mosaicism indicate events
preferentially involve the inactive X chromosome. Our results provide further evidence that
the sex chromosomes undergo mosaic events more frequently than autosomes, which could
have implications for understanding the underlying mechanisms of mosaic events and their
possible contribution to risk for chronic diseases
Detectable clonal mosaicism and its relationship to aging and cancer
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
White cell counts in relation to mortality in a general population of cohort study in the Netherlands: a mediating effect or not?
Background: White cell count (WCC) is a clinical marker
of inflammation. Data are limited regarding the association
of total and differential WCC with risk of mortality, and its
role related with smoking and body mass index (BMI).
Methods: A total of 14 433 participants (4150 men;
10 283 women; average age 47.3±11.8 years) from the
Dutch European Prospective Investigation into Cancer
and Nutrition-Netherlands cohort were included. The
associations between prediagnostic total WCC and its
subtypes and risk of all-cause, cancer and cardiovascular
disease (CVD) mortality were assessed. The role of WCC
related with smoking and BMI on mortality was further
explored. Multivariate Cox regression models were
performed to estimate the HR and 95% CI.
Results: After an average follow-up of 15.8 years, a
total of 936 death cases were identified (466 cancer;
179 CVD; 291 other causes). Statistically significant
graded associations between total WCC, and counts of
lymphocytes, monocytes, neutrophils and eosinophils and
risk of total mortality were observed. These associations
were more apparent in current smokers. Strong
associations for all-cause mortality or cancer mortality
were observed in subjects with BMI ≥25 kg/m2
, ever
smoking and elevated WCC (HR 3.92, 95%CI 2.76 to
5.57; HR 3.93, 95%CI 2.30 to 6.72). WCC partly mediated
the associations between smoking or BMI and all-cause
mortality.
Conclusions: Prediagnostic WCC and its subtypes are
associated with all-cause, cancer and CVD mortality risk.
It may play a partially mediate role on the association
between smoking or obesity and mortalit
White cell counts in relation to mortality in a general population of cohort study in the Netherlands: a mediating effect or not?
Background: White cell count (WCC) is a clinical marker
of inflammation. Data are limited regarding the association
of total and differential WCC with risk of mortality, and its
role related with smoking and body mass index (BMI).
Methods: A total of 14 433 participants (4150 men;
10 283 women; average age 47.3±11.8 years) from the
Dutch European Prospective Investigation into Cancer
and Nutrition-Netherlands cohort were included. The
associations between prediagnostic total WCC and its
subtypes and risk of all-cause, cancer and cardiovascular
disease (CVD) mortality were assessed. The role of WCC
related with smoking and BMI on mortality was further
explored. Multivariate Cox regression models were
performed to estimate the HR and 95% CI.
Results: After an average follow-up of 15.8 years, a
total of 936 death cases were identified (466 cancer;
179 CVD; 291 other causes). Statistically significant
graded associations between total WCC, and counts of
lymphocytes, monocytes, neutrophils and eosinophils and
risk of total mortality were observed. These associations
were more apparent in current smokers. Strong
associations for all-cause mortality or cancer mortality
were observed in subjects with BMI ≥25 kg/m2
, ever
smoking and elevated WCC (HR 3.92, 95%CI 2.76 to
5.57; HR 3.93, 95%CI 2.30 to 6.72). WCC partly mediated
the associations between smoking or BMI and all-cause
mortality.
Conclusions: Prediagnostic WCC and its subtypes are
associated with all-cause, cancer and CVD mortality risk.
It may play a partially mediate role on the association
between smoking or obesity and mortalit
WHO guidelines for a healthy diet and mortality from cardiovascular disease in European and American elderly
__Background:__ Cardiovascular disease (CVD) represents a leading cause of mortality worldwide, especially in the elderly. Lowering the number of CVD deaths requires preventive strategies targeted on the elderly.
__Objective:__ The objective was to generate evidence on the association between WHO dietary recommendations and mortality from CVD, coronary artery disease (CAD), and stroke in the elderly aged ≥60 y.
__Design:__ We analyzed data from 10 prospective cohort studies from Europe and the United States comprising a total sample of 281,874 men and women free from chronic diseases at baseline. Components of the Healthy Diet Indicator (HDI) included saturated fatty acids, polyunsaturated fatty acids, mono- and disaccharides, protein, cholesterol, dietary fiber, and fruit and vegetables. Cohort-specific HRs adjusted for sex, education, smoking, physical activity, and energy and alcohol intakes were pooled by using a random-effects model.
__Results:__ During 3,322,768 person-years of follow-up, 12,492 people died of CVD. An increase of 10 HDI points was, on average, not associated with CVD mortality, CAD mortality, or stroke mortality. However, after stratification of the data by geographic region, adherence to the HDI was associated with reduced CVD mortality in the southern European cohorts and in the US cohort.
__Conclusion:__ Overall, greater adherence to the WHO dietary guidelines was not significantly associated with CVD mortality, but the results varied across regions. Clear inverse associations were observed in elderly populations in southern Europe and the United States
A meta-analysis of individual participant data reveals an association between circulating levels of IGF-I and prostate cancer risk
The role of insulin-like growth factors (IGF) in prostate cancer development is not fully understood. To investigate the association between circulating concentrations of IGFs (IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3) and prostate cancer risk, we pooled individual participant data from17 prospective and two cross-sectional studies, including up to 10,554 prostate cancer cases and 13,618 control participants. Conditional logistic regression was used to estimate the ORs for prostate cancer based on the study-specific fifth of each analyte. Overall, IGF-I, IGF-II, IGFBP-2, and IGFBP-3 concentrations were positively associated with prostate cancer risk (Ptrend all ≤ 0.005), and IGFBP-1 was inversely associated weakly with risk (Ptrend = 0.05). However, heterogeneity between the prospective and cross-sectional studies was evident (Pheterogeneity = 0.03), unless the analyses were restricted to prospective studies (with the exception of IGF-II, Pheterogeneity = 0.02). For prospective studies, the OR for men in the h
Detectable clonal mosaicism and its relationship to aging and cancer
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