Increased risk of venous thromboembolism in young and middle-aged individuals with hereditary angioedema: a family study.

Hereditary angioedema (HAE) due to C1 inhibitor protein (C1-INH) deficiency was recently shown to be associated with increased risk of venous thromboembolism (VTE). This is the first national family study of HAE with the aim to determine the familial risk of VTE. The Swedish Multi-Generation Register was linked to the Swedish National Patient Register during the period 1964-2018. Only HAE patients with a validated diagnosis were included in the study and were linked to their family members. Hazard ratios (HRs) and 95% confidence intervals (CIs) for VTE were calculated for HAE patients compared with relatives without HAE. Among 2,006 individuals (from 276 pedigrees of 365 patients with HAE), 103 individuals were affected by VTE. In total 35 (9.6%) of HAE patients compared to 68 (4.1%) of non-HAE relatives were affected by VTE (p<0.001). The adjusted HR for VTE among HAE patients was 2.51 (95% CI 1.67-3.77). HAE patients were younger at the first VTE than their non-HAE relatives (mean age 51 versus 63 years, p<0.001). Before the age of 70 years the HR for VTE among HAE patients was 3.62 (95%CI 2.26-5.80). The HR for VTE for HAE patients born after 1964 was 8.29 (95%CI 2.90-23.71). The HR for VTE for HAE patients born 1964 or earlier was 1.82 (95%CI 1.14-2.91). HAE is associated with VTE among young and middle-aged individuals in Swedish families with HAE. The effect size of the association is in the order of other thrombophilias. We suggest that HAE may be considered a new rare thrombophilia.

Multimorbidity disease clusters are associated with venous thromboembolism: an extended cross-sectional national study.

Multimorbidity, i.e., two or more non-communicable diseases (NCDs), is an escalating challenge for society. Venous thromboembolism (VTE) is a common cardiovascular disease and it is unknown which multimorbidity clusters associates with VTE. Our aim was to examine the association between different common disease clusters of multimorbidity and VTE. The study is an extended (1997-2015) cross-sectional Swedish study using the National Patient Register and the Multigeneration Register. A total of 2,694,442 Swedish-born individuals were included in the study. Multimorbidity was defined by 45 NCDs. A principal component analysis (PCA) identified multimorbidity disease clusters. Odds ratios (OR) for VTE were calculated for the different multimorbidity disease clusters. There were 16% (n = 440,742) of multimorbid individuals in the study population. Forty-four of the individual 45 NCDs were associated with VTE. The PCA analysis identified nine multimorbidity disease clusters, F1-F9. Seven of these multimorbidity clusters were associated with VTE. The adjusted OR for VTE in the multimorbid patients was for the first three clusters: F1 (cardiometabolic diseases) 3.44 (95%CI 3.24-3.65), F2 (mental disorders) 2.25 (95%CI 2.14-2.37) and F3 (digestive system diseases) 4.35 (95%CI 3.63-5.22). There was an association between multimorbidity severity and OR for VTE. For instance, the occurrence of at least five diseases was in F1 and F2 associated with ORs for VTE: 8.17 (95%CI 6.32-10.55) and 6.31 (95%CI 4.34-9.17), respectively. In this nationwide study we have shown a strong association between VTE and different multimorbidity disease clusters that might be useful for VTE prediction.

Arts and culture engagement and mortality: A population-based prospective cohort study.

AIMS: The aim of this study was to investigate associations between having visited the theatre/cinema and an arts exhibition during the past year and all-cause, cardiovascular disease (CVD), cancer and other-cause mortality. METHODS: The 2008 public health postal survey in Scania, Sweden, was distributed to a stratified random sample of the adult population (18-80 years old). The participation rate was 54.1%, and 25,420 participants were included in the present study. The baseline 2008 survey data were linked to cause-of-death register data to create a prospective cohort with 8.3-year follow-up. Associations between visit to the theatre/cinema, visit to an arts exhibition and mortality were investigated in survival (Cox) regression models. RESULTS: Just over a quarter (26.5%) had visited both the theatre/cinema and an arts exhibition during the past year, 36.6% only the theatre/cinema, 4.9% only an arts exhibition and 32% neither of the two. Not visiting the theatre/cinema during the past year was associated with higher all-cause and CVD mortality. Not visiting an arts exhibition was associated with higher all-cause and other-cause mortality. The combination of having visited neither the theatre/cinema nor an arts exhibition during the past year was associated with higher all-cause, CVD and other-cause mortality. CONCLUSIONS: There is an association between attending arts and culture activities and a reduced risk of CVD and other-cause mortality but not cancer mortality, although model imperfections are possible.

Familial Mortality Risks in Patients With Ischemic Stroke: A Swedish Sibling Study.

BACKGROUND: The influence of familial factors on the prognosis of ischemic stroke (IS) is unknown. This nationwide follow-up study evaluated familial mortality risks of IS among Swedish sibling pairs hospitalized for IS. METHODS: We linked Swedish nationwide registers for the identification of 1380 Swedish born sibling pairs (2760 cases), where both siblings were hospitalized for first-time IS between 1991 and 2010. Median age was 62 years (range, 26-78 years). Sibling pairs with cancer were excluded. Familial hazard ratios (FHRs) for mortality after first IS hospitalization were determined with Cox regression. The influence of proband survival after IS was categorized as short sibling survival (<1, 2, 3, 4, or 5 years) or long sibling survival (≥1, 2, 3, 4, or 5 years) after IS. FHRs were adjusted for age at onset, sex, education, county, year of diagnosis, days of hospitalization, and comorbidities. RESULTS: Short sibling survival (ie, <3 or <4 years) after IS was associated with an adjusted FHR of 1.29 (95% CI, 1.05-1.58) and 1.24 (95% CI, 1.02-1.51), respectively, for overall mortality after IS. Stratified analysis showed that short sibling survival (ie, <2-<5 years) was stronger and significant only among younger individuals (<62 years) and males. Highest FHR for short sibling survival (ie, <4 years) was 1.42 (95% CI, 1.08-1.88) for younger individuals and 1.50 (95% CI, 1.21-1.87) for males. For young male subjects, FHR was 1.80 (95% CI, 1.33-2.46). In the adjusted model, mortality was also associated with sex, education, age at onset, year of diagnosis, days of hospitalization, coronary heart disease, diabetes, dementia, heart failure, obesity, alcoholism, and hyperlipidemia. CONCLUSIONS: Our results suggest that family history of short survival in siblings after IS is associated with mortality after IS for younger male subjects. Additional studies are needed to characterize possible genetic and nongenetic familial environmental causes of this association.

Health locus of control and all-cause, cardiovascular, cancer and other cause mortality: A population-based prospective cohort study in southern Sweden.

The aim was to investigate associations between health locus of control (HLC) and all-cause, cardiovascular (CVD), cancer and other cause mortality. A public health postal questionnaire was distributed in the autumn of 2008 to a stratified random sample of the 18-80 year old adult population in Scania in southernmost Sweden. The participation rate was 54.1%, and 25,517 participants were included in the present study. Baseline 2008 survey data was linked to cause of death register data to create a prospective cohort with 8.3-year follow-up. Associations between health locus of control and mortality were investigated in survival (Cox) regression models. Prevalence of internal HLC was 69.0% and external HLC 31.0% among women. Internal HLC was 67.6% and external HLC 32.4% among men. In the models with women and men combined, external HLC had significantly higher all-cause, CVD, cancer and other cause mortality even after adjustments for sociodemographic factors and chronic disease at baseline, but after the introduction of health-related behaviors, external HLC only displayed higher cancer mortality compared to internal HLC. External HLC displayed higher all-cause, cancer and other cause mortality for men in the final model adjusted for health-related behaviors, but not for women. Other pathways than health-related behaviors may exist for the association between external HLC and cancer mortality, particularly among men.

Heritability of glomerulonephritis: A Swedish adoption study.

BACKGROUND: Glomerulonephritis clusters in families. However, infections are common inducers of glomerulonephritis and may also cluster in families. Studies of adoptees and their biological and adoptive parents may disentangle genetic from environmental causes of familial clustering. This is the first adoption study aimed to estimate the genetic contribution to the familial transmission of glomerulonephritis. MATERIALS AND METHODS: We performed a family study for Swedish-born adoptees (born 1945-2000) and their biological and adoptive parents. The Swedish Multi-Generation Register was linked to the Hospital Inpatient Register for the period 1964-2012 and the Hospital Outpatient Register for 2001-2012. Odds ratio (OR) for glomerulonephritis was determined for adoptees with a biological parent with glomerulonephritis compared with adoptees without an affected biological parent. Similarly, the OR for glomerulonephritis was also determined in adoptees with an affected adoptive parent compared with adoptees without an affected adoptive parent. Heritability was estimated to be twice the observed tetrachoric correlation among adoptees and biological parents, under the assumption that only additive genetic factors contribute to the similarity between biological parents and adoptees. RESULTS: The OR for glomerulonephritis was 4.08 in adoptees (95% confidence interval [CI] 1.79-9.27, P-value = 0.001) of biological parents diagnosed with glomerulonephritis. The OR for glomerulonephritis was 1.67 in adoptees (95% CI 0.53-5.26, P-value = 0.380) of adoptive parents diagnosed with glomerulonephritis. The heritability was 48%. CONCLUSION: Family history of glomerulonephritis in a biological parent is a risk factor for glomerulonephritis. The present study indicates that genetic factors play an important role in the aetiology of glomerulonephritis.

Identification of novel diagnostic biomarkers for deep venous thrombosis.

The combination of a negative D-dimer and a Wells score can rule out, but not confirm, a diagnosis of deep venous thrombosis (DVT). We aimed to identify new diagnostic biomarkers for DVT and to investigate their relationship with hypercoagulability markers [D-dimer and activated protein C-protein C inhibitor (APC-PCI) complex]. We screened 92 cardiovascular-specific proteins in plasma samples from 45 confirmed DVT patients and 45 age- and sex-matched non-DVT patients selected from a prospective multicentre diagnostic management study (SCORE) by Proseek Multiplex CVDIII96×96 . Plasma levels of 30 proteins were significantly different between DVT and non-DVT patients. After Bonferroni correction, plasma levels of seven proteins: P-selectin, transferrin receptor protein 1, von Willebrand factor, tissue factor pathway inhibitor, osteopontin (OPN), bleomycin hydrolase and ST2 protein remained significantly different. The area under curve (AUC) for these proteins ranged from 0·70 to 0·84. Furthermore, all seven identified proteins were significantly associated with markers of hypercoagulability. A combination of OPN and APC-PCI had the best ability to discriminate DVT from non-DVT patients (AUC = 0·94; sensitivity = 89% and specificity = s84%). In conclusion, we identified multiple proteins associated with markers of hypercoagulability and with a potential to become novel diagnostic biomarkers for DVT.

Risk of pulmonary embolism and deep venous thrombosis in patients with asthma: a nationwide case-control study from Sweden.

Asthma is associated with an increased risk of pulmonary embolism (PE) but little is known about whether asthma is associated with an increased risk of deep venous thrombosis (DVT). The aim in this study was to determine the risk of the first event of PE, DVT or a combination of PE and DVT in patients with asthma.We conducted this nationwide case-control study using data from Swedish nationwide registries. We included 114 366 Swedish-born patients with a first hospital diagnosis of PE, 76 494 patients with DVT and 6854 patients with both PE and DVT in Sweden between 1981 and 2010. We also included five age-, sex- and education-matched population controls. All previous hospital diagnoses of asthma were identified. Conditional logistic regression was used to compute odds ratios with adjustment for potential confounders.Asthma was associated with an adjusted odds ratio for PE of 1.43 (95% CI 1.37-1.50), for DVT of 1.56 (95% CI 1.47-1.65) and for combined PE and DVT of 1.60 (95% CI 1.32-1.93). Asthma was associated with an increased risk of PE, DVT and combined PE and DVT.Thus, the inflammation conferred by asthma seems to have systemic (and not just local) prothrombotic effects with increased risk of both DVT and PE.

Family history of venous thromboembolism and mortality after venous thromboembolism: a Swedish population-based cohort study.

Studies on whether family history (FH) of venous thromboembolism (VTE) affects long-term mortality after VTE are missing. The aim of this study was to determine whether FH of VTE affects long-term mortality after a first episode of VTE. Using Swedish medical databases, we conducted a 30-year nationwide cohort study of 49,159 adult Swedish born patients included in the multi-generation register (born 1932 or later) with a first-time VTE (1981-2010). Using Cox regression, we assessed mortality Hazard ratios (HRs) with 95% confidence intervals (CIs). Totally 10,093 (20.5%) patients with VTE had a first-degree FH of VTE (parent/sibling). Patients without FH of VTE had significantly more VTE provoking risk factors and comorbidities than those with FH. The mortality HR the first 10-years after first time VTE was decreased for those with FH of VTE compared to for those without FH: crude HR 0.807, 95% CI 0.771-0.845 and adjusted HR 0.864, 95% CI 0.826-0.905. After 10-years of follow-up there was no significant effect of FH of VTE on mortality: crude HR = 1.018, 95% CI 0.905-1.145 and adjusted HR = 0.995, 95% CI 0.884-1.119. Cancer-associated mortality was more common in those without FH the first 10 years (56.9 vs. 53.4%, p = 0.002). After 10 years there were no difference in cancer-associated mortality (4.9 vs. 5.6%, p = 0.604). The results suggest that patients with FH of VTE have lower thrombotic threshold and need less provoking factors and comorbidities. They have also slightly lower total and cancer mortality the first 10 years after VTE.

Health enhancing physical activity in patients with hip or knee osteoarthritis - an observational intervention study.

BACKGROUND: Osteoarthritis is one of the leading causes of inactivity worldwide. The recommended level of health enhancing physical activity (HEPA) is at least 150 min of moderate intensity physical activity per week. The purpose of this study was to explore how the proportion of patients, who reached the recommended level of HEPA, changed following a supported osteoarthritis self-management programme in primary care, and to explore how reaching the level of HEPA was influenced by body mass index (BMI), gender, age and comorbidity. METHODS: An observational study was conducted using data from a National Quality Registry in which 6810 patients in primary care with clinically verified hip or knee osteoarthritis with complete data at baseline, 3 and 12 months follow-up before December 31st 2013 were included. HEPA was defined as self-reported physical activity of at least moderate intensity either a) at least 30 min per day on four days or more per week, or b) at least 150 min per week. HEPA was assessed at baseline, and again at 3 and 12 months follow-up. Cochran's Q test was used to determine change in physical activity over time. The association between reaching the level of HEPA and time, age, BMI, gender, and Charnley classification was investigated using the generalized estimation equation (GEE) model. RESULTS: The proportion of patients who reached the level of HEPA increased by 345 patients, from 77 to 82%, from baseline to 3 months follow-up. At 12 months, the proportion of patients who reached the level of HEPA decreased to 76%. Not reaching the level of HEPA was associated with overweight, obesity, male gender and Charnley category C, i.e. osteoarthritis in multiple joint sites (hip and knee), or presence of any other disease that affects walking ability. CONCLUSIONS: Following the supported osteoarthritis self-management programme there was a significant increase in the proportion of patients who reached the recommended level of HEPA after 3 months. Improvements were lost after 12 months. To increase physical activity and reach long-lasting changes in levels of physical activity, more follow-up sessions might be needed.

A National Swedish Twin-Sibling Study of Alcohol Use Disorders.

The relationship between the genetic and environmental risk factors for alcohol use disorders (AUD) detected in Swedish medical, pharmacy, and criminal registries has not been hitherto examined. Prior twin studies have varied with regard to the detection of shared environmental effects and sex differences in the etiology of AUD. In this report, structural equation modeling in OpenMx was applied to (1) the three types of alcohol registration in a population-based sample of male-male twins and reared-together full and half siblings (total 208,810 pairs), and (2) AUD, as a single diagnosis, in male-male, female-female, and opposite-sex (OS) twins and reared-together full and half siblings (total 787,916 pairs). An independent pathway model fit best to the three forms of registration and indicated that between 70% and 92% of the genetic and 63% and 98% of the shared environmental effects were shared in common with the remainder unique to each form of AUD registration. Criminal registration had the largest proportion of unique genetic and environmental factors. The best fit model for AUD estimated the heritability to be 22% and 57%, respectively, in females and males. Both shared (12% vs. 6%) and special twin environment (29% vs. 2%) were substantially more important in females versus males. In conclusion, AUD ascertained from medical, pharmacy, and criminal Swedish registries largely share the same genetic and environmental risk factors. Large sex differences in the etiology of AUD were seen in this sample, with substantially stronger familial environmental and weaker genetic effects in females versus males.

Blood pressure level and risk of major cardiovascular events and all-cause of mortality in patients with type 2 diabetes and renal impairment: an observational study from the Swedish National Diabetes Register.

AIMS/HYPOTHESIS: We assessed the relationship between BP and risk of cardiovascular events (CVEs) and all-cause mortality in patients with type 2 diabetes and renal impairment (estimated GFR < 60 ml min(-1) 1.73 m(-2)) treated in clinical practice. METHODS: A total of 33,356 patients (aged 75 ± 9 years, diabetes duration of 10 ± 8 years) with at least one serum creatinine and BP value available in the Swedish National Diabetes Register between 2005 and 2007 were followed up until 2011 or death. The relationships between mean BPs, CVEs and all-cause mortality were examined using time-dependent Cox models to estimate HRs, adjusting for cardiovascular risk factors and ongoing medications. RESULTS: During the follow-up period (mean 5.3 years), 11,317 CVEs and 10,738 deaths occurred. The lowest risks of CVEs and all-cause mortality were observed with a systolic BP (SBP) of 135-139 and a diastolic BP (DBP) of 72-74 mmHg, and the highest risks were observed for those with SBP intervals 80-120 (CVE HR 2.3 [95% CI 2.0, 2.6] and all-cause mortality HR 2.4, [95% CI 2.1, 2.7]) and 160-230 mmHg (CVE HR 3.0 [95% CI 2.6, 3.3] and all-cause mortality HR 2.0 [95% CI 1.8-2.3]) and DBP intervals 40-63 mmHg (CVE HR 2.0 [95% CI 1.8, 2.2], all-cause mortality HR 2.0 [95% CI 1.8, 2.2]) and 83-125 mmHg (CVE HR 2.3 [95% CI 2.0, 2.5], all-cause mortality HR 2.3 [95% CI 2.0, 2.6]). CONCLUSIONS/INTERPRETATION: In this nationwide cohort of patients with type 2 diabetes and renal impairment, the risk of CVEs and all-cause mortality increased significantly with both high and low BPs, while an SBP of 135-139 mmHg and DBP of 72-74 mmHg were associated with the lowest risks of CVEs and death.

Marital status and cause-specific mortality: A population-based prospective cohort study in southern Sweden.

The aim was to investigate associations between marital status and mortality with a prospective cohort study design. A public health survey including adults aged 18-80 was conducted with a postal questionnaire in southern Sweden in 2008 (54.1% participation). The survey formed a baseline that was linked to 8.3-year follow-up all-cause, cardiovascular (CVD), cancer and other cause mortality. The present investigation entails 14,750 participants aged 45-80. Associations between marital status and mortality were investigated with multiple Cox-regression analyses. A 72.8% prevalence of respondents were married/cohabitating, 9.1% never married, 12.2% divorced and 5.9% widows/widowers. Marital status was associated with age, sex, socioeconomic status (SES) by occupation, country of birth, chronic disease, Body Mass Index (BMI), health-related behaviors and generalized trust covariates. Never married/single, divorced, and widowed men had significantly higher hazard rate ratios (HRRs) of all-cause mortality than the reference category married/cohabitating men throughout the multiple analyses. For men, CVD and other cause mortality showed similar significant results, but not cancer. No significant associations were displayed for women in the multiple analyses. Associations between marital status and mortality are stronger among men than women. Associations between marital status and cancer mortality are not statistically significant with low effect measures throughout the multiple analyses among both men and women.

Religious service attendance and mortality: A population-based prospective cohort study in southern Sweden.

Aims: The aim is to investigate associations between attendance in religious service during the past year and all-cause, cardiovascular (CVD), cancer and other cause mortality. Study design: Prospective cohort study. Methods: A public health survey with three reminders was sent to a stratified random sample of the adult 18-80 population in southernmost Sweden in 2008. The response rate was 54.1%, and 24,855 participants were included in this study. The cross-sectional baseline survey was connected to mortality data with 8.3-year follow-up. Analyses were conducted in Cox regression models. Results: 13.9% had attended religious service at least once during the past year, and 86.1% had not attended. The group with religious attendance contained significantly higher proportions of women, high and medium position non-manual employees, participants born abroad, never alcohol consumers, respondents with high trust in others and respondents with high social participation. It also contained significantly lower proportions with low leisure-time physical activity (LTPA) and daily smokers. Religious service attendance during the past year was significantly associated with lower hazard rate ratios (HRRs) of all-cause mortality compared to non-attendance until social participation items were introduced in the final model. HRRs of CVD mortality were significantly lower for religious attendance in the multiple models until BMI and health-related behaviors were introduced. No significant results were observed for cancer and other cause mortality. Conclusions: The results suggest that religious service attendance in a highly secularized country such as Sweden is significantly associated with lower all-cause mortality, which may be explained by a social network pathway in this highly secularized population.

Trust in regional politicians and mortality: A population-based prospective cohort study.

The aim was to study associations between trust in regional politicians responsible for the healthcare system and mortality in survival analyses. A public health survey in southern Sweden with a 54.1% response rate based on a postal questionnaire and three postal reminders was conducted in 2008. The baseline survey was linked to 8.3-year follow-up all-cause, cardiovascular (CVD), cancer and other causes mortality register data. The present prospective cohort study includes 24,699 respondents. Relevant covariates/confounders from the baseline questionnaire were included in the multi-adjusted models. Hazard rate ratios (HRRs) of all-cause mortality were consistently lower for the rather high trust and not particularly high trust respondent categories compared to the very high trust reference category. CVD, cancer and other causes mortality did not display statistically significant results, but all contributed to the significant patterns for all-cause mortality. In some political and administrative settings with longer queueing times for investigation and treatment of some medical conditions including some cancer and CVD diagnoses than officially affirmed, rather high and not particularly high trust in politicians responsible for the healthcare system may be associated with lower mortality compared to the very high trust group.

Leisure-time physical activity, desire to increase physical activity, and mortality: A population-based prospective cohort study.

The aim was to investigate associations between leisure-time physical activity (LTPA) and mortality, and associations between desire to increase LTPA and mortality within the low LTPA group. A public health survey questionnaire was sent in 2008 to a stratified random sample of the population aged 18-80 in southernmost Sweden, yielding a 54.1% response rate. Baseline 2008 survey data with 25,464 respondents was linked to cause of death register data to create a prospective cohort with 8.3-year follow-up. Associations between LTPA, desire to increase LTPA and mortality were analyzed in logistic regression models. An 18.4% proportion performed regular exercise (at least 90 min/week, leading to sweating), 23.2% moderate regular exercise (once or twice a week at least 30 min/occasion, leading to sweating), 44.3% moderate exercise (more than two hours walking or equivalent activity/week) and 14.1% reported low LTPA (less than two hours walking or equivalent activity/week). These four LTPA groups were significantly associated with covariates included in the multiple analyses. The results showed significantly higher all-cause, cardiovascular (CVD), cancer and other cause mortality for the low LTPA group but not for the moderate regular exercise and moderate exercise groups compared to the regular exercise group. Both the "Yes, but I need support" and the "No" fractions within the low LTPA group had significantly increased ORs of all-cause mortality compared to the "Yes, and I can do it myself" reference, while no significant associations were observed for CVD mortality. Physical activity promotion is particularly warranted in the low LTPA group.

Familial aggregation of multimorbidity in Sweden: national explorative family study.

Objectives: To examine whether multimorbidity aggregates in families in Sweden. Design: National explorative family study. Setting: Swedish Multigeneration Register linked to the National Patient Register, 1997-2015. Multimorbidity was assessed with a modified counting method of 45 chronic non-communicable diseases according to ICD-10 (international classification of diseases, 10th revision) diagnoses. Participants: 2 694 442 Swedish born individuals (48.73% women) who could be linked to their Swedish born first, second, and third degree relatives. Twins were defined as full siblings born on the same date. Main outcome measures: Multimorbidity was defined as two or more non-communicable diseases. Familial associations for one, two, three, four, and five or more non-communicable diseases were assessed to examine risks depending on the number of non-communicable diseases. Familial adjusted odds ratios for multimorbidity were calculated for individuals with a diagnosis of multimorbidity compared with relatives of individuals unaffected by multimorbidity (reference). An initial principal component decomposition followed by a factor analysis with a principal factor method and an oblique promax rotation was used on the correlation matrix of tetrachoric correlations between 45 diagnoses in patients to identify disease clusters. Results: The odds ratios for multimorbidity were 2.89 in twins (95% confidence interval 2.56 to 3.25), 1.81 in full siblings (1.78 to 1.84), 1.26 in half siblings (1.24 to 1.28), and 1.13 in cousins (1.12 to 1.14) of relatives with a diagnosis of multimorbidity. The odds ratios for multimorbidity increased with the number of diseases in relatives. For example, among twins, the odds ratios for multimorbidity were 1.73, 2.84, 4.09, 4.63, and 6.66 for an increasing number of diseases in relatives, from one to five or more, respectively. Odds ratios were highest at younger ages: in twins, the odds ratio was 3.22 for those aged ≤20 years, 3.14 for those aged 21-30 years, and 2.29 for those aged >30 years at the end of follow-up. Nine disease clusters (factor clusters 1-9) were identified, of which seven aggregated in families. The first three disease clusters in the principal component decomposition were cardiometabolic disease (factor 1), mental health disorders (factor 2), and disorders of the digestive system (factor 3). Odds ratios for multimorbidity in twins, siblings, half siblings, and cousins for the factor 1 cluster were 2.79 (95% confidence interval 0.97 to 8.06), 2.62 (2.39 to 2.88), 1.52 (1.34 to 1.73), and 1.31 (1.23 to 1.39), and for the factor 2 cluster, 5.79 (4.48 to 7.48) 3.24 (3.13 to 3.36), 1.51 (1.45 to 1.57), and 1.37 (1.341.40). Conclusions: The results of this explorative family study indicated that multimorbidity aggregated in Swedish families. The findings suggest that map clusters of diseases should be used for the genetic study of common diseases to show new genetic patterns of non-communicable diseases.

Familial risk of dilated and hypertrophic cardiomyopathy: a national family study in Sweden.

AIMS: This study aims to determine the familial incidence of dilated (DCM) and hypertrophic cardiomyopathy (HCM) in first-degree, second-degree, and third-degree relatives of affected individuals. METHODS AND RESULTS: In this population-based multigenerational cohort study, full-siblings, half-siblings, and cousin pairs born to Swedish parents between 1932 and 2015 were included, and register-based DCM and HCM diagnoses among relatives were ascertained. Adjusted odds ratios (ORs) for DCM and HCM were calculated for relatives of individuals with DCM and HCM compared with relatives of individuals without DCM and HCM for reference. Total study population included 6 334 979 subjects and consisted of 5 577 449 full-siblings, 1 321 414 half-siblings, and 3 952 137 cousins. Overall, 10 272 (0.16%) unique individuals were diagnosed with DCM and 3769 (0.06%) with HCM. Of these, 7716 (75.12%) and 2375 (63.01%) were males, respectively. Familial risk ORs for DCM were 5.35 [95% confidence intervals (CI): 4.85-5.90] for full-siblings, 2.68 (95% CI:1.86-3.87) for half-siblings, and 1.72 (95% CI:1.12-2.64) for cousins of affected individuals. The ORs for HCM were 42.44 (95% CI:37.66-47.82) for full-siblings, 32.70 (95% CI:21.32-50.15) for half-siblings, and 36.96 (95% CI:29.50-46.31) for cousins of affected individuals. In sex-stratified analysis, relatives of affected females were found more likely to be affected than were relatives of affected males, with stronger aggregation observed for HCM. CONCLUSIONS: Familial risk of HCM and DCM is high and associated with genetic resemblance, with strongest aggregations observed in relatives of affected females with HCM, whereas this association was distinctly attenuated for DCM. The finding of a Carter effect, more pronounced in HCM, suggests a multifactorial threshold model of inheritance.

Familial Associations of Complete Atrioventricular Block: A National Family Study in Sweden.

BACKGROUND: Complete atrioventricular block (CAVB) is a major reason for implantation of permanent pacemakers, but knowledge of CAVB inheritance is sparse. This nationwide study aimed to determine the occurrence of CAVB in first-, second-, and third-degree relatives (full siblings, half-siblings, and cousins). METHODS: The Swedish multigeneration register was linked to the Swedish nationwide patient register for the period 1997 to 2012. All Swedish full sibling, half-sibling, and cousin pairs born to Swedish parents between 1932 and 2012 were included. Competing risks and time-to-event, subdistributional hazard ratios (SHRs) according to Fine and Gray and hazard ratios using Cox proportional hazards model were estimated using robust SEs and considering the relatedness of relatives (full siblings, half-siblings, cousins). Additionally, odds ratios (ORs) for CAVB were calculated for traditional cardiovascular comorbidities. RESULTS: The study population (N=6 113 761) consisted of 5 382 928 full siblings, 1 266 391 half-siblings, and 3 750 913 cousins. In total, 6442 (0.11%) unique individuals were diagnosed with CAVB. Of these, 4200 (65.2%) were males. SHRs for CAVB were 2.91 for full siblings (95% CI, 2.43-3.49), 1.51 for half-siblings (0.56-4.10), and 3.54 for cousins (1.73-7.26) of affected individuals. Age-stratified analysis showed higher risk in young individuals born from 1947 to 1986: SHR, 5.30 (3.78-7.43) for full siblings, SHR, 3.30 (1.06-10.31) for half-siblings, and SHR, 3.15 (1.39-7.17) for cousins. Similar familial HRs according to Cox proportional hazard model and ORs were obtained without any major differences. Apart from familial relationship, CAVB was associated with hypertension (OR, 1.83), diabetes (OR, 1.41), coronary heart disease (OR, 2.08), heart failure (OR, 5.01), and structural heart disease (OR, 4.59). CONCLUSIONS: Risk of CAVB among relatives of affected individuals depends on relationship degree, being strongest in young siblings. The familial association extending to third-degree relatives indicates presence of genetic components in the cause of CAVB.

A hypothesis - generating Swedish extended national cross-sectional family study of multimorbidity severity and venous thromboembolism.

OBJECTIVES: Venous thromboembolism (VTE) is a common worldwide disease. The burden of multimorbidity, that is, two or more chronic diseases, has increased. Whether multimorbidity is associated with VTE risk remains to be studied. Our aim was to determine any association between multimorbidity and VTE and any possible shared familial susceptibility. DESIGN: A nationwide extended cross-sectional hypothesis - generating family study between 1997 and 2015. SETTING: The Swedish Multigeneration Register, the National Patient Register, the Total Population Register and the Swedish cause of death register were linked. PARTICIPANTS: 2 694 442 unique individuals were analysed for VTE and multimorbidity. MAIN OUTCOMES AND MEASURES: Multimorbidity was determined by a counting method using 45 non-communicable diseases. Multimorbidity was defined by the occurrence of ≥2 diseases. A multimorbidity score was constructed defined by 0, 1, 2, 3, 4 or 5 or more diseases. RESULTS: Sixteen percent (n=440 742) of the study population was multimorbid. Of the multimorbid patients, 58% were females. There was an association between multimorbidity and VTE. The adjusted odds ratio (OR) for VTE in individuals with multimorbidity (2 ≥ diagnoses) was 3.16 (95% CI: 3.06 to 3.27) compared with individuals without multimorbidity. There was an association between number of diseases and VTE. The adjusted OR was 1.94 (95% CI: 1.86 to 2.02) for one disease, 2.93 (95% CI: 2.80 to 3.08) for two diseases, 4.07 (95% CI: 3.85 to 4.31) for three diseases, 5.46 (95% CI: 5.10 to 5.85) for four diseases and 9.08 (95% CI: 8.56 to 9.64) for 5 ≥ diseases. The association between multimorbidity and VTE was stronger in males OR 3.45 (3.29 to 3.62) than in females OR 2.91 (2.77 to 3.04). There were significant but mostly weak familial associations between multimorbidity in relatives and VTE. CONCLUSIONS: Increasing multimorbidity exhibits a strong and increasing association with VTE. Familial associations suggest a weak shared familial susceptibility. The association between multimorbidity and VTE suggests that future cohort studies where multimorbidity is used to predict VTE might be worthwhile.