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- 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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| 2. |
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| 3. |
- 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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| 4. |
- 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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| 5. |
- 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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