| 1. |
- Gregson, J., et al.
(författare)
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Cardiovascular Risk Factors Associated With Venous Thromboembolism
- 2019
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Ingår i: JAMA Cardiology. - : American Medical Association (AMA). - 0965-2590 .- 2380-6583 .- 2380-6591. ; 4:2, s. 163-173
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE It is uncertain to what extent established cardiovascular risk factors are associated with venous thromboembolism (VTE). OBJECTIVE To estimate the associations of major cardiovascular risk factors with VTE, ie, deep vein thrombosis and pulmonary embolism. DESIGN, SETTING, AND PARTICIPANTS This study included individual participant data mostly from essentially population-based cohort studies from the Emerging Risk Factors Collaboration (ERFC; 731728 participants; 75 cohorts; years of baseline surveys, February 1960 to June 2008; latest date of follow-up, December 2015) and the UK Biobank (421537 participants; years of baseline surveys, March 2006 to September 2010; latest date of follow-up, February 2016). Participants without cardiovascular disease at baseline were included. Data were analyzed from June 2017 to September 2018. MAIN OUTCOMES AND MEASURES Hazard ratios (HRs) per 1-SD higher usual risk factor levels (or presence/absence). Incident fatal outcomes in ERFC (VTE, 1041; coronary heart disease [CND], 25131) and incident fatal/nonfatal outcomes in UK Biobank (VTE, 2321; CHD, 3385). Hazard ratios were adjusted for age, sex, smoking status, diabetes, and body mass index (BMI). RESULTS Of the 731728 participants from the ERFC. 403 396 (55.1%) were female, and the mean (SD) age at the time of the survey was 51.9 (9.0) years; of the 421537 participants from the UK Biobank, 233 699 (55.4%) were female, and the mean (SD) age at the time of the survey was 56.4 (8.1) years. Risk factors for VTE included older age (ERFC: HR per decade, 2.67; 95% CI, 2.45-2.91; UK Biobank: HR, 1.81; 95% CI, 1.71-1.92), current smoking (ERFC: HR, 1.38; 95% CI, 1.20-1.58; UK Biobank: HR, 1.23; 95% CI, 1.08-1.40), and BMI (ERFC: HR per 1-SD higher BMI, 1.43; 95% CI, 1.35-1.50; UK Biobank: HR, 1.37; 95% CI, 1.32-1.41). For these factors, there were similar HRs for pulmonary embolism and deep vein thrombosis in UK Biobank (except adiposity was more strongly associated with pulmonary embolism) and similar HRs for unprovoked vs provoked VTE. Apart from adiposity, these risk factors were less strongly associated with VTE than CHD. There were inconsistent associations of VTEs with diabetes and blood pressure across ERFC and UK Biobank, and there was limited ability to study lipid and inflammation markers. CONCLUSIONS AND RELEVANCE Older age, smoking, and adiposity were consistently associated with higher VTE risk.
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| 2. |
- Lanke, E., et al.
(författare)
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Co-segregation of the PROS1 locus and protein S deficiency in families having no detectable mutations in PROS1
- 2004
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Ingår i: Journal of Thrombosis and Haemostasis. - : Wiley-Blackwell. - 1538-7933 .- 1538-7836. ; 2:11, s. 1918-1923
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Tidskriftsartikel (refereegranskat)abstract
- Inherited deficiency of protein S constitutes an important risk factor of venous thrombosis. Many reports have demonstrated that causative mutations in the protein S gene are found only in approximately 50% of the cases with protein S deficiency. It is uncertain whether the protein S gene is causative in all cases of protein S deficiency or if other genes are involved in cases where no mutation is identified. The aim of the current study was to determine whether haplotypes of the protein S gene cosegregate with the disease phenotype in cases where no mutations have been found. Eight protein S-deficient families comprising 115 individuals where previous DNA sequencing had failed to detect any causative mutations were analyzed using four microsatellite markers in the protein S gene region. Co-segregation between microsatellite haplotypes and protein S deficiency was found in seven of the investigated families, one family being uninformative. This suggests that the causative genetic defects are located in or close to the protein S gene in a majority of such cases where no mutations have been found.
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| 3. |
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| 4. |
- Simmonds, R E, et al.
(författare)
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Clarification of the risk for venous thrombosis associated with hereditary protein S deficiency by investigation of a large kindred with a characterized gene defect
- 1998
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Ingår i: Annals of Internal Medicine. - : American College of Physicians. - 0003-4819. ; 128:1, s. 8-14
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Protein S is an important regulatory protein of the coagulation cascade. The risk for venous thrombosis associated with protein S deficiency has been uncertain because all previous risk estimates used phenotypic evaluation alone, which can be ambiguous.OBJECTIVE: To quantitate the risk for thrombosis associated with a characterized protein S gene mutation that causes a Gly295-->Val substitution and protein S deficiency.DESIGN: Retrospective study of a single extended family.SETTING: University hospital referral center.PARTICIPANTS: A 122-member protein S-deficient family, in which 44 members had a recently characterized gene defect.MEASUREMENTS: Comprehensive history of thrombosis, history of exposure to acquired risk factors for thrombosis, levels of total and free protein S antigen, and genotype for the mutation causing the Gly295-->Val substitution.RESULTS: Kaplan-Meier analysis of thrombosis-free survival showed that the probability of remaining free of thrombosis at 30 years of age is 0.5 (95% CI, 0.33 to 0.66) for carriers of the Gly295-->Val mutation compared with 0.97 (CI, 0.93 to 1.0) for normal family members (P < 0.001). In a multivariate Cox regression model that included smoking and obesity, the mutation was a strong independent risk factor for thrombosis (hazard ratio, 11.5 [CI, 4.33 to 30.6]; P < 0.001). For free (but not total) protein S antigen levels, the distributions of persons with and persons without the mutation did not overlap.CONCLUSIONS: Protein S deficiency, as defined by the presence of a causative gene mutation or a reduced level of free protein S antigen, is a strong independent risk factor for venous thrombosis in a clinical affected family.
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| 5. |
- Svensson, P.J., et al.
(författare)
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The factor VR5O6Q mutation causing APC resistance is highly prevalent amongst unselected outpatients with clinically suspected deep venous thrombosis
- 1997
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Ingår i: Journal of Internal Medicine. - 1365-2796 .- 0954-6820. ; 241:5, s. 379-385
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Tidskriftsartikel (refereegranskat)abstract
- Objective. Resistance to activated protein C (APC resistance), caused by a single point mutation in the factor V gene (FV:R506Q), is a major risk factor for venous thrombosis. As the significance of this mutation among unselected outpatients with deep-vein thrombosis (DVT) is not established, we have studied its prevalence among consecutive outpatients attending the emergency room due to a clinically suspected DVT. Design, setting and subjects. The FV:R506Q mutation was determined in 223 consecutive Swedish outpatients with clinically suspected DVT, and in 288 healthy controls. Using phlebography, the patients were classified as DVT-positive or DVT-negative. Main outcome measure. The prevalence of FV: R506Q mutation. Results. The prevalence of the FV:R506Q mutation was 28% (28/99) in the DVT-positive subgroup (relative risk: 3.1; 95% CI: 1.7 5.5), and 23% (28/124) in the DVT negative subgroup (relative risk: 2.0; 95% CI: 1.1-3.6), as compared to 11% (32/288) in the control group. In the DVT-positive subgroup, the FV:R506Q mutation was most common among younger patients with primary thrombosis (47%) and least common among older patients with secondary thrombosis (19%). The high prevalence of FV:R506Q mutation among DVT-negative patients was associated with a high frequency of previous venous thrombosis. Thus, 46% (13/28) of the DVT-negative FV:R506Q carriers had a history of thrombosis, compared with only 22% (21/96) of the DVT-negative patients lacking the mutation (P = 0.01). Conclusion. To sum up, the FV:R506Q mutation is present in more than a quarter of Swedish DVT-positive outpatients with clinically suspected DVT, indicating that APC-resistance is a major thrombotic risk factor contributing to the high incidence of venous thrombosis in Sweden.
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| 6. |
- Ji, J., et al.
(författare)
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Risk of ocular manifestations in patients with giant cell arteritis : a nationwide study in Sweden
- 2017
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Ingår i: Scandinavian Journal of Rheumatology. - : Informa UK Limited. - 0300-9742 .- 1502-7732. ; 46:6, s. 484-489
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Tidskriftsartikel (refereegranskat)abstract
- Objective: No large-scale nationwide study has determined the risk of ocular manifestations in patients with giant cell arteritis (GCA). The aim was to study the incidence and risk factors of ocular manifestations in patients with GCA in Sweden. Method: A national cohort was created by linking Swedish nationwide registers. GCA patients were identified from the Swedish Hospital Inpatient and Outpatient Registers between 2002 and 2010, and were followed until the development of ocular manifestations. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated for ocular manifestations in patients with GCA compared to those without GCA. Results: We identified 3737 males and 8311 females with GCA. A total of 1618 individuals had subsequent ocular manifestations, representing 13.4% of the GCA patients. The overall SIR of ocular manifestations was 6.96 (95% CI 6.63–7.31). The risk for disorders of the optic nerve or visual tract was particularly high (SIR = 51.68, 95% CI 46.12–57.73). Men with GCA had a higher risk than women, and GCA patients without polymyalgia rheumatica (PMR) symptoms had a higher risk than those with PMR symptoms. Living outside big cities was negatively associated with ocular manifestations in GCA patients, whereas hypertension and diabetes were associated with an increased risk of ocular manifestations. Conclusion: The overall risk of ocular manifestations was higher in GCA patients than in the general population, especially for men and for those without PMR symptoms.
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| 7. |
- Manderstedt, Eric, et al.
(författare)
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Genetic variation of the blood coagulation regulator tissue factor pathway inhibitor and venous thromboembolism among middle-aged and older adults: A population-based cohort study
- 2022
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Ingår i: Research and practice in thrombosis and haemostasis. - : Elsevier BV. - 2475-0379. ; 6:7
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Tidskriftsartikel (refereegranskat)abstract
- Background: Tissue factor is the main initiator of blood coagulation, and tissue factor pathway inhibitor (TFPI) is the primary inhibitor of the initiation of blood coagulation. The genetic variation of TFPI and the relation to venous thromboembolism (VTE), that is, venous thrombosis and pulmonary embolism, remains to be clarified. This exome sequencing study aimed to determine the molecular epidemiology of the TFPI gene and the relation to VTE in a large population-based cohort of middle-aged and older adults. Methods: The exomes of TFPI were analyzed for variants in 28,794 subjects without previous VTE (born 1923–1950, 60% women), who participated in the Malmö Diet and Cancer Study (1991–1996). Patients were followed until the first event of VTE, death, or 2018. Qualifying variants were defined as loss-of-function or nonbenign (PolyPhen-2) missense variants with minor allele frequency less than 0.1%. Results: No common variant was associated with VTE. Nine rare variants (two loss-of-function and seven nonbenign missense) were classified as qualifying and included in collapsing analysis. Prevalence of qualifying variants was 0.09%. Five individuals with VTE compared to 17 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 ancestry showed a hazard ratio of 2.9 (95% CI, 1.2–7.1) for rare qualifying variants. Conclusion: Rare qualifying TFPI variants were associated with VTE, suggesting that rare variants in TFPI contribute to the development of VTE. The qualifying TFPI gene variants were very rare, suggesting a constrained gene. © 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).
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| 8. |
- 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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| 9. |
- Peric, Zoran, et al.
(författare)
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Quartz OSL dating of late quaternary Chinese and Serbian loess : A cross Eurasian comparison of dust mass accumulation rates
- 2019
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Ingår i: Quaternary International. - : Elsevier BV. - 1040-6182 .- 1873-4553. ; 502:Part A, s. 30-44
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Tidskriftsartikel (refereegranskat)abstract
- Reconstructing dust Mass Accumulation Rate (MAR) from loess deposits is critical to understanding past atmospheric mineral dust activity and requires accurate independent age models from loess deposits across Europe and Asia. Previous correlations of loess in Europe and China have tended to focus on multi-millennial timescales, with no detailed examination of dust MAR at the two ends of the Eurasian loess belt on shorter, sub-orbital scales. Here we present a detailed quartz optically stimulated luminescence (OSL) chronology from the Serbian Titel Loess Plateau (Veliki Surduk loess core) and the Chinese Loess Plateau (Lingtai section). The luminescence ages pass internal tests and show consistent increases in age with depth, with no obvious major hiatuses. However, as reported before, it seems the quartz OSL technique is only capable of accurate age determination up to accrued doses of ca. 150 Gy (ca. 30–40 ka) due to approaching field saturation of the quartz OSL signal. Two age-depth models were used to reconstruct dust MARs, where one utilises OSL data solely and the other additionally makes assumptions about sedimentation rates. Although short-term fluctuations in MAR are model dependent, general MAR patterns between the two sites are very similar, with peak MAR occurring rather late in the last glacial (ca. 13–25 ka). This suggests that at least broad scale trends in dust activity within the last glacial period may be similar at a continental scale.
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| 10. |
- Rezende, SM, et al.
(författare)
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Genetic and phenotypic variability between families with hereditary protein S deficiency
- 2002
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Ingår i: Thrombosis and Haemostasis. - 0340-6245. ; 87:2, s. 258-265
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Tidskriftsartikel (refereegranskat)abstract
- While many mutations thought to result in protein S (PS) deficiency are known. there have been few attempts to relate genotype expression with plasma phenotype. We have investigated the nature and consequence of PS gene (PROS 1) mutations in 17 PS-deficient families who presented with mixed type I and type III phenotypes. Seven different mutations were found in nine families: delG-34 (STOP codon at -24), Val-24Glu, Arg49Cys. Asn217Ser, Gly295Val, +5 G to A intron j and His623Pro. PS wild type (PSWT) and the five missense mutants were transiently expressed in COS-1 cells. All mutants expressed lower (p<0.05) PS antigen compared to PSWT (100%). The mutants Val-24Glu, Gly295Val and His623Pro expressed very low/undetectable PS levels. The Mutant Asn217Ser produced around 30% of PSWT, while the mutant Arg49Cys had the highest PS levels (around 50%). Metabolic labelling and pulse-chase experiments showed that all of the mutants had impaired secretion, but this was of variable severity. Also, enhanced intracellular degradation of unsecreted material was found for all mutants. There was a strong correspondence between plasma free PS levels in carriers of the mutations. secreted PS from transfected COS-1 cells and labelled PS from 24 h conditioned medium in pulse-chase experiment. We conclude that the magnitude of secretion defect depends on the nature of the PROS1 mutation and influences the level of free PS in plasma. It is likely that the severity of the secretion defect will determine the risk for venous thrombosis.
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