Familial thrombophilia : Resistance to activated protein C and protein S deficiency

Inherited resistance to activated protein C (APC-resistance) and protein S deficiency are associated with functional impairment of the protein C anticoagulant system, resulting in lifelong hypercoagulability andincreased risk of thrombosis. APC-resistance is the most common genetic cause of thrombosis being present in 20% to 60% of thrombosis patients.A linkage study was performed in a large thrombophilic family with independent inheritance of APCresistance and protein S deficiency. APC-resistance was found to co-segregate with two neutral polymorphisms in the factor V gene. A point mutation changing Arg506 to a Gln in the factor V gene was the cause of APC-resistance in the family. The mutation (FV:Q506) is localised in one of the APC-cleavage sites of factor V, rendering mutated factor Va resistant to cleavage by activated protein C (APC). The factor V mutation was analysed in 308 members from 50 thrombosis-prone families with inherited APC-resistance.In 94% (47/50) of APC-resistant families the same factor V gene mutation was identified. The magnitude of thrombotic risk was dependent on the factor V genotype. We investigated 327 individuals in 18 thrombosis-prone families with inherited deficiency of free protein S. Deficiency of free protein S was caused by equimolar relationship between total protein S and B-chain containing isoforms of C4BP. Moreover, type I deficiency (low free and total protein S) and type IIIdeficiency (low free but normal total protein S) coexisted in 14 out of 18 families, demonstrating the twotypes to be phenotypic variants of the same genetic disease. Deficiency of free protein S was a strong riskfactor for thrombosis in these families. However, thrombophilia penetrance was highly variable. TheFV:Q506 mutation causing APC-resistance was identified as an additional genetic risk factor in 39% (7/18)of the families. Thus, familial thrombophilia isa multiple genetic disorder.Biochemically affected family members had higher levels of prothrombin fragment Fl +2 than their normalrelatives. The results demonstrate that individuals with APC-resistance or protein S deficiency have animbalance between pro- and anti-coagulant forces, resulting in increased thrombin generation andhypercoagulability

Family history as a risk factor for recurrent hospitalization for lone atrial fibrillation: a nationwide family study in Sweden.

ABSTRACT: BACKGROUND: Although the heritability of atrial fibrillation (AF) has been determined, the relevance of family history of AF for the likelihood of recurrent hospitalization for AF is unknown. The aim of this nationwide study was to determine whether family history of AF is a risk factor of recurrent hospitalization for lone AF (LAF), i.e., AF with unknown etiology. The familial risk for first time LAF hospitalization was also determined and compared to the risk of recurrent hospitalization for LAF. METHODS: We examined whether family history of AF is a risk factor for recurrent hospitalization for LAF in the whole Swedish population. We linked Multigeneration Register data on individuals aged 0-60 years to Hospital Discharge Register data for the period 1987-2009 to compare LAF recurrent hospitalization risk among individuals with and without parental or sibling history of AF. We calculated hazard ratios (HRs) to determine the familial HR of recurrent hospitalization for LAF. Odds ratios (OR) were calculated for familial risk of first time LAF hospitalization. RESULTS: The risk of recurrent LAF hospitalization was 1.23 (95% CI 1.17-1.30) for individuals with affected parents compared to 1.30 (95% CI 1.22-1.38) for those with affected siblings. After 10 years of follow up 50% of those without and 60% of those with family history had recurrent hospitalization for LAF. The risk of recurrent LAF hospitalization in individuals with two affected parents was 1.65 (95% CI 1.44-1.90). There was an interaction between age and family history, with family history having a weaker effect on LAF hospitalization risk in older age groups. The OR for first time LAF hospitalization was 2.08 (95% CI 2.02-2.15) for offspring with affected parents and 3.23 (95% CI 3.08-3.39) for individuals with affected siblings. CONCLUSIONS: Family history of AF is a novel risk factor for recurrent LAF hospitalization. The higher recurrence hospitalization risk in multiplex families and younger individuals suggests a genetic contribution. However, the familial risk for recurrent LAF hospitalization was much lower than the risk for first time LAF hospitalization, suggesting that familial and possibly genetic factors are more important for first time LAF hospitalization than recurrent LAF hospitalization

Neighbourhood Deprivation, Individual-Level and Familial-Level Socio-demographic Factors and Risk of Congenital Heart Disease: A Nationwide Study from Sweden.

The purpose of the study is to examine whether there is an association between neighbourhood deprivation and incidence of congenital heart disease (CHD), after accounting for family- and individual-level potential confounders

Neighborhood, family, and childhood and adolescent epilepsy: A nationwide epidemiological study from Sweden.

To examine whether neighborhood deprivation increases the odds of hospital registration for childhood and adolescent epilepsy, after accounting for family- and individual-level sociodemographic characteristics

Risk of hospitalization for type 2 diabetes in first- and second-generation immigrants in Sweden: a nationwide follow-up study.

OBJECTIVES: This is the first nationwide study with the aim to analyze whether there is an association between country of birth in first-generation immigrants and hospitalization for type 2 diabetes (T2D), and to study whether any such association remains in second-generation immigrants. DESIGN: In this follow-up study, the Swedish Hospital Discharge Register was used to identify all hospital diagnoses of T2D in first- and second-generation immigrants in Sweden between January 1, 1964 and December 31, 2007. Hospitalization rate ratios standardized with regard to gender, age, geographical region, socioeconomic status, obesity, and family history of hospitalization for T2D were estimated in first- and second-generation immigrants. RESULTS: Both increased and decreased risks of hospitalization for T2D were shown for several first-generation immigrant groups. However, only second-generation immigrants with Finnish or former Yugoslavian parents had higher rates of hospitalization for T2D than the reference group. No other differences remained in the second-generation immigrants. CONCLUSIONS: The present study suggests that ethnic environmental factors may be more important than ethnic genetic factors in explaining the observed variation in hospitalization for T2D among first-generation immigrants

Identification of polymorphisms in Apolipoprotein M gene and their relationship with risk of recurrent venous thromboembolism

Apolipoprotein M (ApoM) plasma levels have been reported to be associated with risk of venous thromboembolism (VTE) recurrence. However, the role of genetic alterations in the ApoM gene in VTE recurrence remains unknown. The aim of this study was to identify genetic aberrations in ApoM gene in VTE recurrence and their role in prediction of VTE recurrence in a prospective follow-up study of 1465 VTE patients. During follow-up, 156 (10.6 %) patients had VTE recurrence. First screening of whole ApoM gene was performed by Sanger's sequencing in selected age and sex matched non-recurrent and recurrent patients (n=95). In total six polymorphisms were identified and two polymorphisms (rs805297 and rs9404941) with minor allele frequency (MAF) ≥5 % were further genotyped in the whole cohort by Taqman PCR. ApoM rs805297 polymorphism was significantly associated with higher risk of VTE recurrence in males but not in females on both univariate (p= 0.038, hazard ratio = 1.72, confidence interval = 1.03-2.88) and on multivariate analysis adjusted with mild and severe thrombophilia, family history, location and acquired risk factors for VTE. However, ApoM rs9404941 polymorphism showed no significant association with risk of VTE recurrence in all patients as well as in different gender groups. Moreover, ApoM rs805297 and rs9404941 polymorphisms were not associated with the ApoM plasma levels. In conclusion, for the first time we have sequenced whole ApoM gene in VTE and identified six polymorphisms. ApoM rs805297 was significantly associated with higher risk of VTE recurrence in male but not in female patients

The association between apolipoprotein M and insulin resistance varies with country of birth.

Risk of type 2 diabetes mellitus (T2DM) differs according to ethnicity. Levels of apolipoprotein M (ApoM) have been shown to be decreased in T2DM. However, its role in different ethnicities is not known. We examined the differences in plasma ApoM levels in Swedish residents born in Iraq (Iraqis) and Sweden (Swedes) in relation to T2DM and insulin resistance (IR)

Plasminogen activator inhibitor-1 4G/5G polymorphism, factor V Leiden, prothrombin mutations and the risk of VTE recurrence.

Plasminogen-activator inhibitor (PAI)-1 is an important inhibitor of the plasminogen/plasmin system. PAI-1 levels are influenced by the 4G/5G polymorphism in the PAI-1 promoter. We investigated the relationship between the PAI-1 polymorphism and VTE recurrence, and its possible modification by factor V Leiden (FVL) and prothrombin (PTM) mutations. Patients (n=1,069) from the Malmö Thrombophilia Study were followed from discontinuation of anticoagulant treatment until diagnosis of VTE recurrence or the end of the study (maximum follow-up 9.8 years). One hundred twenty-seven patients (11.9 %) had VTE recurrence. PAI-1 was genotyped by TaqMan PCR. Cox regression analysis adjusted for age, sex and acquired risk factors of VTE showed no evidence of an association between PAI-1 genotype and risk of VTE recurrence in the study population as a whole. However, by including an interaction term in the analysis we showed that FVL but not PTM modified the effect of PAI-1 genotype: patients with the 4G allele plus FVL had a higher risk of VTE recurrence [hazard ratio (HR) =2.3, 95 % confidence interval (CI) =1.5-3.3] compared to patients with the 4G allele but no FVL (reference group) or FVL irrespective of PAI-1 genotype (HR=1.8, 95 % CI=1.3-2.5). Compared to reference group, 5G allele irrespective of FVL was associated with lower risk of VTE recurrence only when compared with 4G allele together with FVL. In conclusion, FVL has a modifying effect on PAI-1 polymorphism in relation to risk of VTE recurrence. The role of PAI-1 polymorphism as a risk factor of recurrent VTE may be FVL dependent

Cardiovascular Risk Factors Associated With Venous Thromboembolism

Importance It is uncertain to what extent established cardiovascular risk factors are associated with venous thromboembolism (VTE). Objective To estimate associations between major cardiovascular risk factors and VTE, i.e., deep-vein thrombosis (DVT) and pulmonary embolism (PE). Design Analysis of individual-participant data from the Emerging Risk Factors Collaboration (ERFC; 731,728 participants; 75 cohorts; latest date of follow-up 2015), and UK Biobank (UKBB; 421,537 participants; latest date of follow-up 2016). Setting Approximately population-based prospective cohort studies. Participants Individuals without cardiovascular disease at baseline. Exposures A panel of several established cardiovascular risk factors. Main Outcomes and Measures Hazard ratios (HRs) per 1-SD higher risk factor levels (or presence/absence). Incident fatal outcomes in ERFC (n=1041 VTE, n=25,131 CHD) and incident fatal/non-fatal outcomes in UKBB (n=2321 VTE, n=3385 CHD). HRs were adjusted for age, sex, smoking status, diabetes mellitus, and body-mass index. Results Adjusted HRs for VTE were: 2.67 (2.45-2.91) in ERFC and 1.81 (1.71-1.92) in UKBB per decade older age; 1.38 (1.20-1.58) in ERFC and 1.23 (1.08-1.40) in UKBB with smoking; 1.43 (1.35-1.50) in ERFC and 1.37 (1.32-1.41) in UKBB per 1-SD higher body-mass index; and 0.75 (0.61-0.93) in ERFC and 0.82 (0.71-0.94) in UKBB with current alcohol consumption. For the preceding factors, there were similar HRs for pulmonary embolism versus deep vein thrombosis in UKBB (except adiposity was more strongly associated with PE; P<0.01), and similar HRs for unprovoked versus provoked VTE. Apart from adiposity, these risk factors were less strongly associated with VTE than coronary heart disease. We noted inconsistent associations with diabetes and blood pressure for VTEs across ERFC and UKBB, and had limited ability to study lipid and inflammation markers. Conclusions and Relevance Older age, smoking, adiposity, and lower alcohol consumption were consistently associated with higher VTE risk.A study website (http://www.phpc.cam.ac.uk/ceu/erfc/list-of-studies/) includes a list that investigators have provided of funding agencies that have supported individual cohorts in the ERFC contributing to the present consortium. This research has been conducted using the UK Biobank resource (application 26865)