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- Kaasinen, E, et al.
(författare)
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Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 1252-
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Tidskriftsartikel (refereegranskat)abstract
- Clonal hematopoiesis driven by somatic heterozygous TET2 loss is linked to malignant degeneration via consequent aberrant DNA methylation, and possibly to cardiovascular disease via increased cytokine and chemokine expression as reported in mice. Here, we discover a germline TET2 mutation in a lymphoma family. We observe neither unusual predisposition to atherosclerosis nor abnormal pro-inflammatory cytokine or chemokine expression. The latter finding is confirmed in cells from three additional unrelated TET2 germline mutation carriers. The TET2 defect elevates blood DNA methylation levels, especially at active enhancers and cell-type specific regulatory regions with binding sequences of master transcription factors involved in hematopoiesis. The regions display reduced methylation relative to all open chromatin regions in four DNMT3A germline mutation carriers, potentially due to TET2-mediated oxidation. Our findings provide insight into the interplay between epigenetic modulators and transcription factor activity in hematological neoplasia, but do not confirm the putative role of TET2 in atherosclerosis.
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- Hiilamo, A, et al.
(författare)
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Within-individual analysis of pain and sickness absence among employees from low and high occupational classes: a record linkage study
- 2019
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Ingår i: BMJ open. - : BMJ. - 2044-6055. ; 9:3, s. e026994-
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Tidskriftsartikel (refereegranskat)abstract
- Pain is linked to an increased risk of sickness absence (SA); however, the extent to which unmeasured time-invariant differences explain this association is yet unknown. Therefore, we determined the within-individual associations between pain and short-term (in the survey year) and long-term (2 years following the survey years) SA risk in high and low occupational classes while controlling for the potential bias due to unobservable time-invariant characteristics.MethodsThe Helsinki Health Study data consisting of midlife public sector employees with mailed surveys from up to four time points, and SA record linkage were used (3983 persons). The within-individual estimates were calculated using hybrid negative binomial regression models.ResultsAcute/subacute pain was associated with a 13% increase in the rate of short-term SA days (incidence rate ratio 1.13 [95% CI 1.01 to 1.27]), while the association was somewhat stronger for chronic pain (1.32 [1.19–1.47]). For the employees in the low occupational class, these associations were robust (1.29 [1.10–1.50] for acute/subacute and 1.43 [1.23–1.66] for chronic pain), whereas only chronic pain was associated with SA among those in the high occupational class (1.25 [1.08–1.46]). Chronic pain was also associated with SA days in the long term without occupational class differences. Similar results were obtained for multisite pain (pain in several locations).ConclusionsThese results indicate that particularly chronic and multisite pain have a within-individual link to SA but ignoring unobservable differences between those reporting pain and those not might yield overstated effect sizes. Pain might have a different relation to SA in low and high occupational classes.
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- Joshi, Peter K, et al.
(författare)
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Directional dominance on stature and cognition in diverse human populations
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 523:7561, s. 459-462
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Tidskriftsartikel (refereegranskat)abstract
- Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
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