| 1. |
- Ek, Weronica E, et al.
(författare)
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Causal effects of inflammatory protein biomarkers on inflammatory diseases
- 2021
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 7:50
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Tidskriftsartikel (refereegranskat)abstract
- Many circulating proteins are associated with the presence or severity of disease. However, whether these protein biomarkers are causal for disease development is usually unknown. We investigated the causal effect of 21 well-known or exploratory protein biomarkers of inflammation on 18 inflammatory diseases using two-sample Mendelian randomization. We identified six proteins to have causal effects on any of 11 inflammatory diseases (FDR < 0.05, corresponding to P < 1.4 x 10(-3)). IL-12B protects against psoriasis and psoriatic arthropathy, LAP-TGF-beta-1 protects against osteoarthritis, TWEAK protects against asthma, VEGF-A protects against ulcerative colitis, and LT-alpha protects against both type 1 diabetes and rheumatoid arthritis. In contrast, IL-18R1 increases the risk of developing allergy, hay fever, and eczema. Most proteins showed protective effects against development of disease rather than increasing disease risk, which indicates that many disease-related biomarkers are expressed to protect from tissue damage. These proteins represent potential intervention points for disease prevention and treatment.
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| 2. |
- Feng, Qi, et al.
(författare)
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Null association between serum 25-hydroxyvitamin D levels with allergic rhinitis, allergic sensitization and non-allergic rhinitis : A Mendelian randomization study
- 2021
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Ingår i: Clinical and Experimental Allergy. - : John Wiley & Sons. - 0954-7894 .- 1365-2222. ; 51:1, s. 78-86
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Tidskriftsartikel (refereegranskat)abstract
- Background Previous observational studies have not found a conclusive association between serum 25-hydroxyvitamin D (25(OH)D) levels and allergic rhinitis (AR) or allergic sensitization (AS). Objective To investigate a causal association between 25(OH)D levels with risk of AR and AS, using a two-sample Mendelian randomization (MR) approach. Methods Seven single nucleotide polymorphisms (SNPs), previously shown to be associated with serum 25(OH)D levels, were identified as instrumental variables. The primary outcome was AR, and the secondary outcomes were AS and non-allergic rhinitis (NAR). The genome-wide association (GWA) summary statistics of the outcomes were obtained from two cohort studies (EAGLE Consortium and UK Biobank). An MR analysis with random-effects inverse-variance weighted method was performed as the primary analysis to estimate overall effect size (odds ratio [OR] and 95% confidence interval [CI]). Sensitivity analysis using weighted median method and MR-Egger regression method was conducted. A subgroup analysis based on 25(OH)D synthesis-related SNPs was further applied. Results Serum 25(OH)D levels were not causally associated with risk of AR (OR: 0.960; 95% CI: 0.779-1.184), AS (OR: 1.059; 95% CI: 0.686 to 1.634) or NAR (OR: 0.937; 95% CI: 0.588-1.491). Subgroup analysis also showed null association between 25(OH)D synthesis-related SNPs and the outcomes. Sensitivity analyses yielded similar results. Conclusions and Clinical Relevance This MR study found no evidence supporting a causal association between serum 25(OH)D levels and risk of AR, AS and NAR in European-ancestry population. This argues against the previous postulation that vitamin D supplementation is effective in prevention of allergic diseases.
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| 3. |
- Höglund, Julia, et al.
(författare)
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Characterization of the human ABO genotypes and their association to common inflammatory and cardiovascular diseases in the UK Biobank
- 2021
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Ingår i: American Journal of Hematology. - : John Wiley & Sons. - 0361-8609 .- 1096-8652. ; 96:11, s. 1350-1362
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Tidskriftsartikel (refereegranskat)abstract
- The ABO gene contains three major alleles that encodes different antigens; A, B, and O, which determine an individual's blood group. Previous studies have primarily focused on identifying associations between ABO blood groups and diseases risk. Here, we sought to test for association between ABO genotypes (OO, OA, AA; OB, BB, and AB) and a large set of common inflammatory and cardiovascular diseases in UK Biobank as well as disease-related protein biomarkers in NSPHS. We first tested for association by conducting a likelihood ratio test, testing whether ABO contributed significantly to the risk for 24 diseases, and 438 plasma proteins. For phenotypes with FDR < 0.05, we tested for pair-wise differences between genetically determined ABO genotypes using logistic or linear regression. Our study confirmed previous findings of a strong association between ABO and cardiovascular disease, identified associations for both type 1 and type 2 diabetes, and provide additional evidence of significant differences between heterozygous and homozygous allele carriers for pulmonary embolism, deep vein thrombosis, but also for von Willebrand factor levels. Furthermore, the results indicated an additive effect between genotypes, even between the two most common A subgroups, A1 and A2. Additionally, we found that ABO contributed significantly to 39 plasma proteins, of which 23 have never been linked to the ABO locus before. These results show the need of incorporating ABO genotype information in the consultation and management of patients at risk, rather than classifying patients into blood groups.
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| 4. |
- Karlsson, Torgny, et al.
(författare)
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Time-dependent effects of oral contraceptive use on breast, ovarian and endometrial cancers
- 2021
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Ingår i: Cancer Research. - : American Association For Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 81:4, s. 1153-1162
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Tidskriftsartikel (refereegranskat)abstract
- Oral contraceptive use has been suggested to influence the risk of breast, ovarian, and endometrial cancer. The purpose of this study is to clarify the time-dependent effects between long-term oral contraceptive use and cancer risk. We performed an observational study in 256,661 women from UK Biobank, born between 1939 and 1970. Information on cancer diagnoses were collected from self-reported data and from national registers until March 2019. Cumulative risk of cancer over the timespan of the study, as measured by the odds ratio (OR), and instantaneous risk, as measured by the hazard ratio (HR), were assessed using Logistic and Cox regression analyses, respectively. The odds were lower among ever users, compared with never users, for ovarian cancer: OR=0.72 (95% CI: 0.65-0.81) and endometrial cancer: OR=0.68 (95% CI: 0.62-0.75), an association that was stronger with longer use (P<0.001). Increased odds were seen for breast cancer in women when limiting the follow-up to 55 years of age: OR=1.10 (95% CI: 1.03-1.17), but not for the full timespan. We only found a higher HR for breast cancer in former users immediately (≤2 years) after discontinued oral contraceptive use (HR=1.55, 95% CI: 1.06-2.28), whereas the protective association for ovarian and endometrial cancer remained significant up to 35 years after last use of oral contraceptives. Given the body of evidence presented in our study, we argue that oral contraceptives can dramatically reduce women's risk of ovarian and endometrial cancer, whereas their effect on lifetime risk of breast cancer is limited.
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| 5. |
- Rask-Andersen, Mathias, 1979-, et al.
(författare)
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Modification of Heritability for Educational Attainment and Fluid Intelligence by Socioeconomic Deprivation in the UK Biobank
- 2021
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Ingår i: American Journal of Psychiatry. - : American Psychiatric Association Publishing. - 0002-953X .- 1535-7228. ; 178:7, s. 625-634
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Socioeconomic factors have been suggested to influence the effect of education- and intelligence-associated genetic variants. However, results from previous studies on the interaction between socioeconomic status and education or intelligence have been inconsistent. The authors sought to assess these interactions in the UK Biobank cohort of 500,000 participants.METHODS: The authors assessed the effect of socioeconomic deprivation on education- and intelligence-associated genetic variants by estimating the single-nucleotide polymorphism (SNP) heritability for fluid intelligence, educational attainment, and years of education in subsets of UK Biobank participants with different degrees of social deprivation, using linkage disequilibrium score regression. They also generated polygenic scores with LDpred and tested for interactions with social deprivation.RESULTS: SNP heritability increased with socioeconomic deprivation for fluid intelligence, educational attainment, and years of education. Polygenic scores were also found to interact with socioeconomic deprivation, where the effects of the scores increased with increasing deprivation for all traits.CONCLUSIONS: These results indicate that genetics have a larger influence on educational and cognitive outcomes in more socioeconomically deprived U.K. citizens, which has serious implications for equality of opportunity.
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| 6. |
- Schmitz, Daniel, 1995-, et al.
(författare)
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Genome-Wide Association Study of Estradiol Levels and the Causal Effect of Estradiol on Bone Mineral Density
- 2021
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : Endocrine Society. - 0021-972X .- 1945-7197. ; 106:11, s. e4471-e4486
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Tidskriftsartikel (refereegranskat)abstract
- ContextEstradiol is the primary female sex hormone and plays an important role for skeletal health in both sexes. Several enzymes are involved in estradiol metabolism, but few genome-wide association studies (GWAS) have been performed to characterize the genetic contribution to variation in estrogen levels.ObjectiveIdentify genetic loci affecting estradiol levels and estimate causal effect of estradiol on bone mineral density (BMD).DesignWe performed GWAS for estradiol in males (n = 147 690) and females (n = 163 985) from UK Biobank. Estradiol was analyzed as a binary phenotype above/below detection limit (175 pmol/L). We further estimated the causal effect of estradiol on BMD using Mendelian randomization.ResultsWe identified 14 independent loci associated (P < 5 × 10−8) with estradiol levels in males, of which 1 (CYP3A7) was genome-wide and 7 nominally (P < 0.05) significant in females. In addition, 1 female-specific locus was identified. Most loci contain functionally relevant genes that have not been discussed in relation to estradiol levels in previous GWAS (eg, SRD5A2, which encodes a steroid 5-alpha reductase that is involved in processing androgens, and UGT3A1 and UGT2B7, which encode enzymes likely to be involved in estradiol elimination). The allele that tags the O blood group at the ABO locus was associated with higher estradiol levels. We identified a causal effect of high estradiol levels on increased BMD in both males (P = 1.58 × 10−11) and females (P = 7.48 × 10−6).ConclusionOur findings further support the importance of the body’s own estrogen to maintain skeletal health in males and in females.
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