| 1. |
- Verweij, Niek, et al.
(författare)
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Germline Mutations in CIDEB and Protection against Liver Disease
- 2022
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Ingår i: New England Journal of Medicine. - 0028-4793. ; 387:4, s. 332-344
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Exome sequencing in hundreds of thousands of persons may enable the identification of rare protein-coding genetic variants associated with protection from human diseases like liver cirrhosis, providing a strategy for the discovery of new therapeutic targets. METHODS We performed a multistage exome sequencing and genetic association analysis to identify genes in which rare protein-coding variants were associated with liver phenotypes. We conducted in vitro experiments to further characterize associations. RESULTS The multistage analysis involved 542,904 persons with available data on liver aminotransferase levels, 24,944 patients with various types of liver disease, and 490,636 controls without liver disease. We found that rare coding variants in APOB, ABCB4, SLC30A10, and TM6SF2 were associated with increased aminotransferase levels and an increased risk of liver disease. We also found that variants in CIDEB, which encodes a structural protein found in hepatic lipid droplets, had a protective effect. The burden of rare predicted loss-of-function variants plus missense variants in CIDEB (combined carrier frequency, 0.7%) was associated with decreased alanine aminotransferase levels (beta per allele, -1.24 U per liter; 95% confidence interval [CI], -1.66 to -0.83; P=4.8×10-9) and with 33% lower odds of liver disease of any cause (odds ratio per allele, 0.67; 95% CI, 0.57 to 0.79; P=9.9×10-7). Rare coding variants in CIDEB were associated with a decreased risk of liver disease across different underlying causes and different degrees of severity, including cirrhosis of any cause (odds ratio per allele, 0.50; 95% CI, 0.36 to 0.70). Among 3599 patients who had undergone bariatric surgery, rare coding variants in CIDEB were associated with a decreased nonalcoholic fatty liver disease activity score (beta per allele in score units, -0.98; 95% CI, -1.54 to -0.41 [scores range from 0 to 8, with higher scores indicating more severe disease]). In human hepatoma cell lines challenged with oleate, CIDEB small interfering RNA knockdown prevented the buildup of large lipid droplets. CONCLUSIONS Rare germline mutations in CIDEB conferred substantial protection from liver disease.
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| 2. |
- Giontella, Alice, et al.
(författare)
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Calcium, Its Regulatory Hormones, and Their Causal Role on Blood Pressure : A Two-Sample Mendelian Randomization Study
- 2022
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 107:11, s. 3080-3085
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Vitamin D (Vit-D), parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23) are the major calciotropic hormones involved in the regulation of blood calcium levels from the intestine, kidney, and bone through a tight endocrine feedback loop system. Altered levels of calcium itself or through the effect of its regulatory hormones could affect blood pressure (BP), but the exact mechanisms remain unclear. OBJECTIVE: To evaluate whether a causal relationship exists between serum calcium level and/or the regulatory hormones involved in its homeostasis with BP, we performed a two-sample Mendelian randomization (MR) study. METHODS: From 4 large genome-wide association studies (GWAS) we obtained independent (r2 < 0.001) single nucleotide polymorphisms (SNPs) associated with serum calcium (119 SNPs), Vit-D (78 SNPs), PTH (5 SNPs), and FGF23 (5 SNPs), to investigate through MR their association with systolic BP (SBP) and diastolic BP (DBP) in a Swedish urban-based study, the Malmö Diet and Cancer study (n = 29 298). Causality was evaluated by the inverse variance weighted method (IVW) and weighted median, while MR Egger and MR-PRESSO were used as sensitivity analyses. RESULTS: Genetically predicted serum calcium level was found to be associated with DBP (IVW: beta = 0.10, SE = 0.04, P = 0.007) and SBP (IVW: beta = 0.07, SE = 0.04, P = 0.04). Genetically predicted Vit-D and PTH showed no association with the traits, while FGF23 was inversely associated with SBP (IVW: beta = -0.11, SE = 0.04, P = 0.01), although this association lost statistical significance in sensitivity analysis. CONCLUSION: Our study shows a direct association between genetically predicted calcium level and DBP, and a weaker association with SBP. No such clear association was found for genetically predicted calciotropic hormone levels. It is of interest to detect which target genes involved in calcium homeostasis mediate the effect of calcium on BP, particularly for improving personalized intervention strategies.
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| 3. |
- Kanoni, Stavroula, et al.
(författare)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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| 4. |
- Manderstedt, Eric, et al.
(författare)
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Classic Thrombophilias and Thrombotic Risk Among Middle-Aged and Older Adults : A Population-Based Cohort Study
- 2022
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Ingår i: Journal of the American Heart Association. - : Wiley-Blackwell Publishing Ltd. - 2047-9980. ; 11:4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Five classic thrombophilias have been recognized: factor V Leiden (rs6025), the prothrombin G20210A variant (rs1799963), and protein C, protein S, and antithrombin deficiencies. This study aimed to determine the thrombotic risk of classic thrombophilias in a cohort of middle-aged and older adults. METHODS AND RESULTS: Factor V Leiden, prothrombin G20210A and protein-coding variants in the PROC (protein C), PROS1 (protein S), and SERPINC1 (antithrombin) anticoagulant genes were determined in 29 387 subjects (born 1923–1950, 60% women) who participated in the Malmö Diet and Cancer study (1991–1996). The Human Gene Mutation Database was used to define 68 disease-causing mutations. Patients were followed up from baseline until the first event of venous thromboembolism (VTE), death, or Dec 31, 2018. Carriership (n=908, 3.1%) for disease-causing mutations in the PROC, PROS1, and SERPINC1 genes was associated with incident VTE: Hazard ratio (HR) was 1.6 (95% CI, 1.3–1.9). Variants not in Human Gene Mutation Database were not linked to VTE (HR, 1.1; 95% CI, 0.8–1.5). Heterozygosity for rs6025 and rs1799963 was associated with incident VTE: HR, 1.8 (95% CI, 1.6–2.0) and HR, 1.6 (95% CI, 1.3–2.0), respectively. The HR for carrying 1 classical thrombophilia variant was 1.7 (95% CI, 1.6–1.9). HR was 3.9 (95% CI, 3.1–5.0) for carriers of ≥2 thrombophilia variants. CONCLUSIONS: The 5 classic thrombophilias are associated with a dose-graded risk of VTE in middle-aged and older adults. Disease-causing variants in the PROC, PROS1, and SERPINC1 genes were more common than the rs1799963 variant but the conferred genetic risk was comparable with the rs6025 and rs1799963 variants.
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| 5. |
- Manderstedt, Eric, et al.
(författare)
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Thrombomodulin (THBD) gene variants and thrombotic risk in a population-based cohort study
- 2022
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 20:4, s. 929-935
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Tidskriftsartikel (refereegranskat)abstract
- Background: The protein C anticoagulant system plays a key role in maintaining the hemostatic balance. Although several studies have identified thrombomodulin gene (THBD) variants among venous thromboembolism (VTE) patients, the role of THBD in relation to VTE in humans remains to be clarified. Objectives: This study aimed to determine the thrombotic risk of rare and common THBD variants in a large population-based cohort of middle-aged and older adults. Patients/Methods: The exome sequence of THBD was analyzed for qualifying variants in 28,794 subjects (born 1923–1950, 60% women), who participated in the Malmö Diet and Cancer study (1991–1996). Patients were followed from baseline until the first event of VTE, death, or 2018. Qualifying variants were defined as loss-of-function or non-benign (PolyPhen-2) missense variants with minor allele frequency <0.1%. Results: The single common coding variant rs1042579 was not associated with incident VTE. Sixteen rare variants were classified as qualifying and included in collapsing analysis. Seven individuals with VTE compared to 24 individuals without VTE carried one qualifying variant. Cox multivariate regression analysis adjusted for age, sex, body mass index, systolic blood pressure, smoking and alcohol consumption, rs6025, rs1799963, and the top two eigenvectors from a principal components analysis showed a hazard ratio of 3.0 (95% confidence interval 1.4–6.3) for the rare qualifying variants. The distributions of qualifying variants in THBD showed a difference for individuals with and without incident VTE indicating a possible position effect. Conclusions: Rare qualifying THBD variants were associated with VTE, suggesting that rare variants in THBD contribute to development of VTE.
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| 6. |
- Manderstedt, Eric, et al.
(författare)
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Thrombotic Risk Determined by Protein C Receptor (PROCR) Variants among Middle-Aged and Older Adults : A Population-Based Cohort Study
- 2022
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Ingår i: Thrombosis and Haemostasis. - : Georg Thieme Verlag KG. - 0340-6245 .- 2567-689X. ; 122:8, s. 1326-1332
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Tidskriftsartikel (refereegranskat)abstract
- Background The protein C (PC) anticoagulant system has a key role in maintaining hemostatic balance. One missense (Ser219Gly) variant in the PC receptor (PROCR) was associated with venous thromboembolism (VTE) in genome-wide association studies. Objectives This study aimed to determine the thrombotic risk of rare and common PROCR variants in a large population-based cohort of middle-aged and older adults. Methods The exonic sequence of PROCR was analyzed for the Ser219Gly variant and other qualifying variants in 28,794 subjects (born 1923-1950, 60% women) without previous VTE, who participated in the Malmö Diet and Cancer study (1991-1996). Incidence of VTE was followed up until 2018. Qualifying variants were defined as loss-of-function or nonbenign (PolyPhen-2) missense variants with minor allele frequencies (MAFs) <0.1%. Results Re-sequencing identified 36 PROCR variants in the study population (26,210 non-VTE exomes and 2,584 VTE exomes), 11 synonymous, 22 missense, and three loss-of-function variants. Kaplan-Meier analysis of the known Ser219Gly variant (rs867186) showed that homozygosity for this variant increased the risk of disease, whereas heterozygosity showed no effect. Cox multivariate regression analysis revealed an adjusted hazard ratio (HR) of 1.5 (95% confidence interval [CI]: 1.1-2.0). Fifteen rare variants were classified as qualifying and were included in collapsing analysis (burden test and SKAT-O). They did not contribute to risk. However, a Arg113Cys missense variant (rs146420040; MAF = 0.004) showed an increased VTE risk (HR = 1.3; 95% CI: 1.0-1.9). Conclusion Homozygosity for the Ser219Gly variant and a previously identified functional PROCR variant (Arg113Cys) was associated with VTE. Other variants did not contribute to VTE.
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| 7. |
- Manderstedt, Eric, et al.
(författare)
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Thrombotic risk determined by rare and common SERPINA1 variants in a population-based cohort study
- 2022
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 20:6
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Tidskriftsartikel (refereegranskat)abstract
- Background: Severe alpha-1-antitrypsin deficiency (AATD), phenotype PiZZ, was associated with venous thromboembolism (VTE) in a case-control study. Objectives: This study aimed to determine the genetic variation in the SERPINA1 gene and a possible thrombotic risk of these variants in a population-based cohort study. Patients/Methods: The coding sequence of SERPINA1 was analyzed for the Z (rs28929474), S (rs17580), and other qualifying variants in 28,794 subjects without previous VTE (born 1923–1950, 60% women), who participated in the Malmö Diet and Cancer study (1991–1996). Individuals were followed from baseline until the first event of VTE, death, or 2018. Results: Resequencing the coding sequence of SERPINA1 identified 84 variants in the total study population, 21 synonymous, 62 missense, and 1 loss-of-function variant. Kaplan-Meier analysis showed that homozygosity for the Z allele increased the risk of VTE whereas heterozygosity showed no effect. The S (rs17580) variant was not associated with VTE. Thirty-one rare variants were qualifying and included in collapsing analysis using the following selection criteria, loss of function, in frame deletion or non-benign (PolyPhen-2) missense variants with minor allele frequency (MAF)
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| 8. |
- Praveen, Kavita, et al.
(författare)
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Population-scale analysis of common and rare genetic variation associated with hearing loss in adults
- 2022
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 5:1, s. 540-540
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Tidskriftsartikel (refereegranskat)abstract
- To better understand the genetics of hearing loss, we performed a genome-wide association meta-analysis with 125,749 cases and 469,497 controls across five cohorts. We identified 53/c loci affecting hearing loss risk, including common coding variants in COL9A3 and TMPRSS3. Through exome sequencing of 108,415 cases and 329,581 controls, we observed rare coding associations with 11 Mendelian hearing loss genes, including additive effects in known hearing loss genes GJB2 (Gly12fs; odds ratio [OR] = 1.21, P = 4.2 × 10-11) and SLC26A5 (gene burden; OR = 1.96, P = 2.8 × 10-17). We also identified hearing loss associations with rare coding variants in FSCN2 (OR = 1.14, P = 1.9 × 10-15) and KLHDC7B (OR = 2.14, P = 5.2 × 10-30). Our results suggest a shared etiology between Mendelian and common hearing loss in adults. This work illustrates the potential of large-scale exome sequencing to elucidate the genetic architecture of common disorders where both common and rare variation contribute to risk.
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