| 1. |
- Sampson, Joshua N., et al.
(författare)
-
Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types
- 2015
-
Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 107:12
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
|
|
| 2. |
- Stener-Victorin, Elisabet, et al.
(författare)
-
Proteomic analysis shows decreased Type I fibers and ectopic fat accumulation in skeletal muscle from women with PCOS
- 2024
-
Ingår i: eLife. - : eLife Sciences Publications Ltd. - 2050-084X. ; 12
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Polycystic ovary syndrome’s (PCOS) main feature is hyperandrogenism, which is linked to a higher risk of metabolic disorders in women. Gene expression analyses in adipose tissue and skeletal muscle reveal dysregulated metabolic pathways in women with PCOS, but these differences do not necessarily lead tochanges in protein levels and biological function. Methods: To advance our understanding of the molecular alterations in PCOS, we performed global proteomic and phosphorylation site analysis using tandem mass spectrometry. Adipose tissue and skeletal muscle were collected at baseline from 10 women with and without PCOS, and in women with PCOS after 5 weeks of treatment with electrical stimulation. Results: Perilipin-1, a protein that typically coats the surface of lipid droplets in adipocytes, was increased whereas proteins involved in muscle contraction and type I muscle fiber function were downregulated in PCOS muscle. Proteins in the thick and thin filaments had many altered phosphorylation sites, indicating differences in protein activity and function. The upregulated proteins in muscle post treatment were enriched in pathways involved in extracellular matrix organization and wound healing, which may reflect a protective adaptation to repeated contractions and tissue damage due to needling. A similar, albeit less pronounced, upregulation in extracellular matrix organization pathways was also seen in adipose tissue. Conclusions: Our results suggest that hyperandrogenic women with PCOS have higher levels of extramyocellular lipids and fewer oxidative insulin-sensitive type I muscle fibers. These could be key factors leading insulin resistance in PCOS muscle while electric stimulation-induced tissue remodeling may be protective.
|
|
| 3. |
- Berndt, Sonja, I, et al.
(författare)
-
Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes
- 2022
-
Ingår i: Leukemia. - : Springer Nature. - 0887-6924 .- 1476-5551. ; 36:12, s. 2835-2844
-
Tidskriftsartikel (refereegranskat)abstract
- Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genome-wide significant loci (P < 5 × 10−8) for subsets of NHL subtypes, including a novel locus at 10q23.33 (HHEX) (P = 3.27 × 10−9). Most subset associations were driven primarily by only one subtype. Genome-wide genetic correlations between pairs of subtypes varied broadly from 0.20 to 0.86, suggesting substantial heterogeneity in the extent of shared heritability among subtypes. Polygenic risk score analyses of established loci for different lymphoid malignancies identified strong associations with some NHL subtypes (P < 5 × 10−8), but weak or null associations with others. Although our analyses suggest partially shared heritability and biological pathways, they reveal substantial heterogeneity among NHL subtypes with each having its own distinct germline genetic architecture.
|
|
| 4. |
- Caminade, Cyril, et al.
(författare)
-
Global risk model for vector-borne transmission of Zika virus reveals the role of El Nino 2015
- 2017
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 114:1, s. 119-124
-
Tidskriftsartikel (refereegranskat)abstract
- Zika, a mosquito-borne viral disease that emerged in South America in 2015, was declared a Public Health Emergency of International Concern by the WHO in February of 2016. We developed a climate-driven R-0 mathematical model for the transmission risk of Zika virus (ZIKV) that explicitly includes two keymosquito vector species: Aedes aegypti and Aedes albopictus. The model was parameterized and calibrated using the most up to date information from the available literature. It was then driven by observed gridded temperature and rainfall datasets for the period 1950-2015. We find that the transmission risk in South America in 2015 was the highest since 1950. This maximum is related to favoring temperature conditions that caused the simulated biting rates to be largest and mosquito mortality rates and extrinsic incubation periods to be smallest in 2015. This event followed the suspected introduction of ZIKV in Brazil in 2013. The ZIKV outbreak in Latin America has very likely been fueled by the 2015-2016 El Nino climate phenomenon affecting the region. The highest transmission risk globally is in South America and tropical countries where Ae. aegypti is abundant. Transmission risk is strongly seasonal in temperate regions where Ae. albopictus is present, with significant risk of ZIKV transmission in the southeastern states of the United States, in southern China, and to a lesser extent, over southern Europe during the boreal summer season.
|
|
| 5. |
|
|
| 6. |
- Machiela, Mitchell J., et al.
(författare)
-
Genetically predicted longer telomere length is associated with increased risk of B-cell lymphoma subtypes
- 2016
-
Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 25:8, s. 1663-1676
-
Tidskriftsartikel (refereegranskat)abstract
- Evidence from a small number of studies suggests that longer telomere length measured in peripheral leukocytes is associated with an increased risk of non-Hodgkin lymphoma (NHL). However, these studies may be biased by reverse causation, confounded by unmeasured environmental exposures and might miss time points for which prospective telomere measurement would best reveal a relationship between telomere length and NHL risk. We performed an analysis of genetically inferred telomere length and NHL risk in a study of 10 102 NHL cases of the four most common B-cell histologic types and 9562 controls using a genetic risk score (GRS) comprising nine telomere length-associated single-nucleotide polymorphisms. This approach uses existing genotype data and estimates telomere length by weighing the number of telomere length-associated variant alleles an individual carries with the published change in kb of telomere length. The analysis of the telomere length GRS resulted in an association between longer telomere length and increased NHL risk [four B-cell histologic types combined; odds ratio (OR) = 1.49, 95% CI 1.22-1.82, P-value = 8.5 x 10(-5)]. Subtype-specific analyses indicated that chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the principal NHL subtype contributing to this association (OR = 2.60, 95% CI 1.93-3.51, P-value = 4.0 x 10(-10)). Significant interactions were observed across strata of sex for CLL/SLL and marginal zone lymphoma subtypes as well as age for the follicular lymphoma subtype. Our results indicate that a genetic background that favors longer telomere length may increase NHL risk, particularly risk of CLL/SLL, and are consistent with earlier studies relating longer telomere length with increased NHL risk.
|
|
| 7. |
- Wang, Gang, et al.
(författare)
-
Spirometric phenotypes from early childhood to young adulthood : a Chronic Airway Disease Early Stratification study
- 2021
-
Ingår i: ERJ Open Research. - : ERS Publications. - 2312-0541. ; 7:4
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The prevalences of obstructive and restrictive spirometric phenotypes, and their relation to early-life risk factors from childhood to young adulthood remain poorly understood. The aim was to explore these phenotypes and associations with well-known respiratory risk factors across ages and populations in European cohorts.Methods: We studied 49334 participants from 14 population-based cohorts in different age groups (⩽10, >10–15, >15–20, >20–25 years, and overall, 5–25 years). The obstructive phenotype was defined as forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) z-score less than the lower limit of normal (LLN), whereas the restrictive phenotype was defined as FEV1/FVC z-score ⩾LLN, and FVC z-score Results: The prevalence of obstructive and restrictive phenotypes varied from 3.2–10.9% and 1.8–7.7%, respectively, without clear age trends. A diagnosis of asthma (adjusted odds ratio (aOR=2.55, 95% CI 2.14–3.04), preterm birth (aOR=1.84, 1.27–2.66), maternal smoking during pregnancy (aOR=1.16, 95% CI 1.01–1.35) and family history of asthma (aOR=1.44, 95% CI 1.25–1.66) were associated with a higher prevalence of obstructive, but not restrictive, phenotype across ages (5–25 years). A higher current body mass index (BMI was more often observed in those with the obstructive phenotype but less in those with the restrictive phenotype (aOR=1.05, 95% CI 1.03–1.06 and aOR=0.81, 95% CI 0.78–0.85, per kg·m−2 increase in BMI, respectively). Current smoking was associated with the obstructive phenotype in participants older than 10 years (aOR=1.24, 95% CI 1.05–1.46).Conclusion: Obstructive and restrictive phenotypes were found to be relatively prevalent during childhood, which supports the early origins concept. Several well-known respiratory risk factors were associated with the obstructive phenotype, whereas only low BMI was associated with the restrictive phenotype, suggesting different underlying pathobiology of these two phenotypes.
|
|
| 8. |
- Cheung Mak, Wing, et al.
(författare)
-
Surface-Engineered Contact Lens as an Advanced Theranostic Platform for Modulation and Detection of Viral Infection
- 2015
-
Ingår i: ACS Applied Materials and Interfaces. - : American Chemical Society (ACS). - 1944-8244 .- 1944-8252. ; 7:45, s. 25487-25494
-
Tidskriftsartikel (refereegranskat)abstract
- We have demonstrated an entirely new concept of a wearable theranostic device in the form of a contact lens (theranostic lens) with a dual-functional hybrid surface to modulate and detect a pathogenic attack, using a the corneal HSV serotype-1 (HSV-1) model. The theranostic lenses were constructed using a facile layer-by-layer surface engineering technique, keeping the theranostic lenses with good surface wettability, optically transparency, and nontoxic toward human corneal epithelial cells. The theranostic lenses were used to capture and concentrate inflammatory cytokines such as interleukin-1 alpha (IL-1 alpha), which is upregulated during HSV-1 reactivation, for sensitive, noninvasive diagnostics. The theranostic lens also incorporated an antiviral coating to serve as a first line of defense to protect patients against disease. Our strategy tackles major problems in tear diagnostics that are mainly associated with the sampling of a relatively small volume of fluid and the low concentration of biomarkers. The theranostic lenses show effective anti-HSV-1 activity and good analytical performance for the detection of IL-1a, with a limit of detection of 1.43 pg mL(-1) and a wide linear range covering the clinically relevant region. This work offers a new paradigm for wearable noninvasive healthcare devices combining diagnosis and protection against disease, while supporting patient compliance. We believe that this approach holds immense promise as a next-generation point-of-care and decentralized diagnostic/theranostic platform for a range of biomarkers.
|
|
| 9. |
|
|
| 10. |
- Smits, Anne, et al.
(författare)
-
Current knowledge, challenges and innovations in developmental pharmacology: A combined conect4children Expert Group and European Society for Developmental, Perinatal and Paediatric Pharmacology White Paper.
- 2021
-
Ingår i: British journal of clinical pharmacology. - : Wiley. - 1365-2125 .- 0306-5251. ; 88:12, s. 4965-84
-
Tidskriftsartikel (refereegranskat)abstract
- Developmental pharmacology describes the impact of maturation on drug disposition (pharmacokinetics, PK) and drug effects (pharmacodynamics, PD) throughout the paediatric age range. This paper, written by a multidisciplinary group of experts, summarizes current knowledge, and provides suggestions to pharmaceutical companies, regulatory agencies and academicians on how to incorporate the latest knowledge regarding developmental pharmacology and innovative techniques into neonatal and paediatric drug development. Biological aspects of drug absorption, distribution, metabolism and excretion throughout development are summarized. Although this area made enormous progress during the last two decades, remaining knowledge gaps were identified. Minimal risk and burden designs allow for optimally informative but minimally invasive PK sampling, while concomitant profiling of drug metabolites may provide additional insight in the unique PK behaviour in children. Furthermore, developmental PD needs to be considered during drug development, which is illustrated by disease- and/or target organ-specific examples. Identifying and testing PD targets and effects in special populations, and application of age- and/or population-specific assessment tools are discussed. Drug development plans also need to incorporate innovative techniques such as preclinical models to study therapeutic strategies, and shift from sequential enrolment of subgroups, to more rational designs. To stimulate appropriate research plans, illustrations of specific PK/PD-related as well as drug safety-related challenges during drug development are provided. The suggestions made in this joint paper of the Innovative Medicines Initiative conect4children Expert group on Developmental Pharmacology and the European Society for Developmental, Perinatal and Paediatric Pharmacology, should facilitate all those involved in drug development.
|
|
