| 1. |
- Lango Allen, Hana, et al.
(författare)
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Hundreds of variants clustered in genomic loci and biological pathways affect human height.
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 467:7317, s. 832-8
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Tidskriftsartikel (refereegranskat)abstract
- Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
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| 2. |
- Lundell, Anna-Carin, 1976, et al.
(författare)
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Dihydrotestosterone levels at birth associate positively with higher proportions of circulating immature/naïve CD5+ B cells in boys.
- 2017
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Boys present with higher proportions of immature/naïve CD5+ B cells than girls up to 3 years of age. Boys also have higher fractions of regulatory T cells (Tregs) in early infancy, but the mechanisms for these sex-related differences are unknown. In the prospective FARMFLORA follow-up study of 23 boys and 25 girls, we investigated if these immunological differences remained at 8 years of age. We also examined if testosterone or dihydrotestosterone (DHT) levels at birth and at 8 years of age were associated with immune maturation. Immunological variables and androgen levels were examined and measured in blood samples obtained at birth, 3-5 days and at 8 years of age. Boys had higher proportions of CD5+ and immature/transitional CD24hiCD38hi B cells, whereas girls had higher fractions of B cells with a memory phenotype at 8 years of age. School-aged boys also presented with higher frequencies of Tregs, and a greater capacity to produce T-cell-associated cytokines. Among boys, higher cord blood DHT levels were associated with higher proportions of CD5+ B cells in early infancy and at 8 years of life. These results suggest that DHT actions in utero might be involved in the mechanism for delayed peripheral B-cell maturation in boys.
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| 3. |
- Nilsson, Maria E., et al.
(författare)
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Measurement of a comprehensive sex steroid profile in rodent serum by high-sensitive gas chromatography-tandem mass spectrometry.
- 2015
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Ingår i: Endocrinology. - : The Endocrine Society. - 1945-7170 .- 0013-7227. ; 156:7, s. 2492-502
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Tidskriftsartikel (refereegranskat)abstract
- Accurate measurement of sex steroid concentrations in rodent serum is essential to evaluate mouse and rat models for sex steroid-related disorders. The aim of the present study was to develop a sensitive and specific gas chromatography-tandem mass spectrometry (GC-MS/MS) method to assess a comprehensive sex steroid profile in rodent serum. A major effort was invested in reaching an exceptionally high sensitivity for measuring serum estradiol concentrations. We established a GC-MS/MS assay with a lower limit of detection for estradiol, estrone, testosterone, dihydrotestosterone, progesterone, androstenedione and dehydroepiandrosterone of 0.3, 0.5, 4, 1.6, 8, 4 and 50 pg/ml, respectively, while the corresponding values for the lower limit of quantification were 0.5, 0.5, 8, 2.5, 74, 12 and 400 pg/ml, respectively. Calibration curves were linear, intra- and inter-assay CVs were low and accuracy was excellent for all analytes. The established assay was used to accurately measure a comprehensive sex steroid profile in female rats and mice according to estrus cycle phase. In addition, we characterized the impact of age, sex, gonadectomy, and estradiol treatment on serum concentrations of these sex hormones in mice. In conclusion, we have established a highly sensitive and specific GC-MS/MS method to assess a comprehensive sex steroid profile in rodent serum in a single run. This GC-MS/MS assay has, to the best of our knowledge, the best detectability reported for estradiol. Our method therefore represents an ideal tool to characterize sex steroid metabolism in a variety of sex steroid-related rodent models and in human samples with low estradiol levels.
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| 4. |
- Wilhelmson, Anna S K, et al.
(författare)
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Androgens regulate bone marrow B lymphopoiesis in male mice by targeting osteoblast-lineage cells.
- 2015
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Ingår i: Endocrinology. - : The Endocrine Society. - 1945-7170 .- 0013-7227. ; 156:4, s. 1228-36
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Tidskriftsartikel (refereegranskat)abstract
- Testosterone has profound immune-modulatory actions, which may be important for the sexual dimorphism in immune-related disorders, such as autoimmune diseases. A well-known effect of androgens is inhibition of bone marrow B lymphopoiesis; however, a plausible target cell for this effect has not yet been presented. The aim of this study was to determine the target cell for androgen-mediated regulation of bone marrow B lymphopoiesis in males. We confirm higher number of bone marrow B cells in male mice with global inactivation of the androgen receptor (AR) and these global AR knockout (G-ARKO) mice had increased number of B cell precursors from the pro-B stage. Because osteoblast-lineage cells are known to support B lymphopoiesis at the pro-B stage, we investigated the effect on B lymphopoiesis in osteoblast-lineage cell-specific ARKO (O-ARKO) mice; O-ARKO mice had increased number of B cells in the bone marrow, and the number of B cell precursors was increased from the pro-B stage, demonstrating that O-ARKO mimics the bone marrow B lymphopoiesis pattern of G-ARKO mice. By contrast, O-ARKO mice displayed only minor changes in B cell numbers in the splenic compartment compared with G-ARKO. Further, O-ARKO mice had moderately reduced number of bone trabeculae in the vertebrae, whereas cortical bone was unaffected. In conclusion, androgens exert inhibitory effects on bone marrow B lymphopoiesis in males by targeting the AR in osteoblast-lineage cells. The identification of the likely target cell for androgen-mediated regulation of bone marrow B lymphopoiesis will contribute to elucidation of the mechanisms by which androgens modulate immune-related disorders.
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| 5. |
- Beausang, Angela, et al.
(författare)
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"Möjligheten att rädda några av dessa kvinnors liv har inte vägts in"
- 2014
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Ingår i: Dagens Medicin. - : Dagens Medicin.
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Tidskriftsartikel (populärvet., debatt m.m.)abstract
- Namnet på Socialstyrelsens vägledning lyder: Hur upptäcka våldsutsatthet? Ja, det kan man verkligen fråga sig efter att ha läst detta föga vägledande dokument, skriver ett stort antal kritiska debattörer.
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| 6. |
- Benrick, Anna, 1979, et al.
(författare)
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A non-conservative polymorphism in the IL-6 signal transducer (IL6ST)/gp130 is associated with myocardial infarction in a hypertensive population.
- 2008
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Ingår i: Regulatory peptides. - : Elsevier BV. - 0167-0115. ; 146:1-3, s. 189-96
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Tidskriftsartikel (refereegranskat)abstract
- Inflammation is a key component in the development of atherosclerosis, and myocardial infarction (MI); therefore we investigated the association between an interleukin-6 signal transducer (IL6ST)/gp130 polymorphism, gp130 function and risk of MI. Structural modeling suggested that a non-conservative single nucleotide polymorphism in the gp130, Gly148Arg, can change the stability and functional properties of the molecule. In vitro studies were done with BAF/3 cells lacking endogenous gp130. Cells stably transfected with the gp130 148Arg variant proliferated less and showed slightly lower STAT-3 phosphorylation in response to gp130 stimulation as compared to cells transfected with gp130 148Gly. In a prospectively followed hypertensive cohort we identified 167 patients who suffered a MI during the study and compared them to matched controls (mean age 57 years, 73% males, n=482). Carriers of the 148Arg variant (f(Arg)=0.12) of the gp130 receptor had decreased odds ratio for MI in univariate analysis (0.56, 95% CI 0.34-0.91, p=0.02). In conclusion, a genetically determined structural variant of the IL-6 receptor subunit gp130 is, independently of other known risk factors, associated with decreased risk of MI. The variant is also associated with decreased IL-6 responsiveness and could lead to a configuration change in the gp130 receptor.
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| 7. |
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| 8. |
- Berndt, Sonja I., et al.
(författare)
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Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 501-U69
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Tidskriftsartikel (refereegranskat)abstract
- Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
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| 9. |
- Bruce, Peter, 1986-, et al.
(författare)
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Inconsistencies in How Environmental Risk Is Evaluated in Sweden for Dumping Dredged Sediment at Sea
- 2021
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Ingår i: Frontiers in Marine Science. - : Frontiers Media SA. - 2296-7745. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Millions of tons of dredged sediment are dumped at sea annually. International conventions limit dumping when there is a risk of adverse ecological effects, for example if the sediment is contaminated. However, the perception of risk differs substantially among stakeholders and in Sweden there is a lack of guidelines for how to address such risk. In the current study, we examined exemptions to the Swedish ban on dumping at sea, to explore the extent of dumping and how ecological aspects were considered in the evaluation of risks. We analyzed data from all cases granted exemption by county administrative boards and all court cases considering exemption to the ban from the beginning of 2015 to June 2020. We found that while dumping is the least common alternative management method for dredged sediment in total number of cases (98/792), dumping is the main method in terms of volume (30.8/38.2 million m3). When considering exemptions, the courts mainly evaluated the risk of exposure to contaminants and resuspended sediment for the environment adjacent to the dumpsite. The risks from contaminants were characterized based on various lines of reasoning, mainly relying on reference values not based on a scientific correlation to environmental risk. We argue that the evaluations were not in line with current regulations and international conventions as they insufficiently accounted for the ecotoxicological risk of the dumped sediment. These issues are potentially similar in other Baltic Sea countries, where there is a similar dependency on binary chemical limit values.
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| 10. |
- Coviello, Andrea D, et al.
(författare)
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A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple Loci implicated in sex steroid hormone regulation.
- 2012
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 8:7
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Tidskriftsartikel (refereegranskat)abstract
- Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p=1.8×10(-106)), PRMT6 (rs17496332, 1p13.3, p=1.4×10(-11)), GCKR (rs780093, 2p23.3, p=2.2×10(-16)), ZBTB10 (rs440837, 8q21.13, p=3.4×10(-09)), JMJD1C (rs7910927, 10q21.3, p=6.1×10(-35)), SLCO1B1 (rs4149056, 12p12.1, p=1.9×10(-08)), NR2F2 (rs8023580, 15q26.2, p=8.3×10(-12)), ZNF652 (rs2411984, 17q21.32, p=3.5×10(-14)), TDGF3 (rs1573036, Xq22.3, p=4.1×10(-14)), LHCGR (rs10454142, 2p16.3, p=1.3×10(-07)), BAIAP2L1 (rs3779195, 7q21.3, p=2.7×10(-08)), and UGT2B15 (rs293428, 4q13.2, p=5.5×10(-06)). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p=2.5×10(-08), women p=0.66, heterogeneity p=0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ∼15.6% and ∼8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.
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