Nationwide Family Study Research Articles

Familial risk of vasospastic angina: a nationwide family study in Sweden

ObjectivesVasospastic angina (VSA) is a complex coronary vasomotor disorder associated with an increased risk of myocardial infarction and sudden death. Despite considerable advances in understanding VSA pathophysiology, the interplay between...

Association between familial aggregation of chronic kidney disease and its incidence and progression

This study aimed to examine the association between familial aggregation of chronic kidney disease (CKD) and risk of CKD development and its progression. This nationwide family study comprised 881,453 cases with newly diagnosed CKD between 2004 and 2017 and 881,453 controls without CKD matched by age and sex, using data from the Korean National Health Insurance Service with linkage to the family tree database. The risks of CKD development and disease progression, defined as an incident end-stage renal disease (ESRD), were evaluated. The presence of any affected family member with CKD was associated with a significantly higher risk of CKD with adjusted ORs (95% CI) of 1.42 (1.38–1.45), 1.50 (1.46–1.55), 1.70 (1.64–1.77), and 1.30 (1.27–1.33) for individuals with affected parents, offspring, siblings, and spouses, respectively. In Cox models conducted on patients with predialysis CKD, risk of incident ESRD was significantly higher in those with affected family members with ESRD. The corresponding HRs (95% CI) were 1.10 (1.05–1.15), 1.38 (1.32–1.46), 1.57 (1.49–1.65), and 1.14 (1.08–1.19) for individuals listed above, respectively. Familial aggregation of CKD was strongly associated with a higher risk of CKD development and disease progression to ESRD.

Familial Segregation of Venous Thromboembolism in Sweden: A Nationwide Family Study of Heritability and Complex Segregation Analysis.

BackgroundThis is the first nationwide segregation analysis that aimed to determine whether familial venous thromboembolism (VTE) is attributable to inheritance and/or shared environment, and the possible mode of inheritance.Methods and ResultsThe Swedish Multi‐Generation Register was linked to the Swedish patient register for the period 1964 to 2015. Three generational families of Swedish‐born individuals were identified. Heritability was examined using Falconer regression. Complex segregation analysis was conducted using the Statistical Analysis for Genetic Epidemiology software (version 6.4, 64‐bit Linux). Among the 4 301 174 relatives from 450 558 pedigrees, 177 865 (52% women) individuals were affected with VTE. VTE occurred in 2 or more affected relatives in 61 217 (13.6%) of the pedigrees. Heritability showed age and sex dependence with higher heritability for men and young individuals. In 18 933 pedigrees, VTE occurred only in the first generation and was not inherited. Segregation analysis was performed in the remaining 42 284 pedigrees with inherited VTE and included 939 192 individuals. Prevalence constraints were imposed in the models to allow for the selection of the pedigrees analyzed. The sporadic nongenetic model could be discarded. The major‐type‐only model, with a correlation structure compatible with some polygenic effects, was the preferred model. Among the Mendelian models, the mixed codominant (plus polygenic) model was preferred.ConclusionsThis nationwide segregation analysis of VTE supports a genetic cause of the familial aggregation of VTE. Heritability was higher for men and younger individuals, suggesting a Carter effect, in agreement with a multifactorial threshold inheritance.

Familial associations between autoimmune hepatitis and primary biliary cholangitis and other autoimmune diseases.

Autoimmune hepatitis (AH) and primary biliary cirrhosis (PBC) are autoimmune diseases (AIDs) targeting cellular components of the liver. Being rare diseases, limited data are available about familial risks among these AIDs (concordant) or between them and other AIDs (discordant). We aimed to carry out an unbiased study on these AIDs based on medically diagnosed patients.We collected data on patients diagnosed in Swedish hospitals with AH, PBC and other AIDs and calculated familial standardized incidence ratios (SIRs) for concordant and discordant familial relative risks. The number of AH patients was 6,269, of whom 43.0% were male; patient numbers for PBC were 4,269, with 17.8% males. AH accounted for 0.8% and 0.6% of all hospitalized AIDs in Sweden. For AH only the familial risk between siblings was significant (3.83). For PBC the risks for offspring of parents (9.05) and siblings (10.88) were high, but only risk for females was significant. Spousal risks were very high, 5.91 and 6.07 for AH. Risk for AH was 2.21 in families of PBC, and it was 2.47 for PBC in families of AH patients. Among other AIDs, 14 showed a significant association with AH, compared to 16 AIDs with PBC. The surprising finding in this nation-wide family study on medically diagnosed patients was the high risk for AH (6.0) between spouses, which exceed the risk between siblings, suggesting the existence of strong environmental risk factors. AH and PBC were associated with multiple other AIDs. The results call attention to environmental factors in AID etiology which should also be in focus in taking anamnestic data from patients.

Familial associations for rheumatoid autoimmune diseases.

ObjectivePrevious studies have shown a familial component in RA and in some other rheumatic autoimmune diseases (RAIDs), but because of the different study designs the risk estimates for familial risks differ extensively. The objective of this study is to identify familial components for RAIDs.MethodsWe collected data on patients diagnosed in Swedish hospitals with RA, AS, PM/DM, SS, SLE and SSc (and scleroderma) and calculated familial standardized incidence ratios (SIRs) for each of these (concordant) and between them (discordant).ResultsThe combined number of RAID patients in the offspring population (for whom SIRs were calculated) was 71 544, and in the whole population the number was 152 714, accounting for 19.8% of all autoimmune diseases in Sweden. AS showed the highest concordant familial risk of 18.42, followed by SLE (14.04), SS (8.63), SSc (4.50), PM/DM (4.03) and RA (3.03). There was no sex difference in SIRs. Risks for AS and SLE were 80.28 and 19.53 for persons whose parents and siblings were affected. Discordant risks were far lower than concordant risks, but they were significant for RA with all the other five RAIDs, for SLE and SSc with four RAIDs, for AS and SS with three RAIDs and for PM/DM with two RAIDs, attesting to extensive polyautoimmunity between RAIDs.ConclusionThe derived familial risks in this nationwide family study on medically diagnosed RAID are compatible with emerging evidence on the polygenic background of these complex diseases. Novel genetic pathways offer new therapeutic targets that alleviate disease onset optimally in high-risk familial patients and others.

Venous thromboembolism does not share familial susceptibility with retinal vascular occlusion or glaucoma: a nationwide family study.

Inherited hypercoagulable states (i.e. thrombophilia) have been suggested to be involved in retinal vascular occlusion but results are divergent. Vascular micronutrition and ischemia have been hypothesised to be involved in the pathogenesis of glaucoma. This nationwide study determines the importance of family history of venous thromboembolism (VTE) as a risk factor for retinal vein occlusion (RVO), retinal artery occlusion (RAO), primary open angle glaucoma (POAG) and primary angle-closure glaucoma (PACG). A total of 6,007,042 Swedish individuals were studied. Data from the Swedish Multigeneration Register for subjects aged 0-78years old for the period 1997-2010 were linked to the Swedish Hospital Discharge Register and the Hospital Outpatient Register. Main exposure measure was family history of VTE in first-degree relatives (parents and/or siblings). Main outcomes were hazard ratios (HRs) for RVO, RAO, POAG, and PACG. During follow-up 9036 individuals developed RVO, 2137 individuals developed RAO, 29,176 individuals developed POAG and 1498 individuals developed PACG. There was no association between family history of VTE and risk of RVO (HR=1.04, 95% CI 0.98-1.10), RAO (HR=1.00, 95% CI 0.89-1.13), POAG (HR=0.96, 95% CI 0.93-0.99), and PACG (HR=0.92, 95% CI 0.80-1.06) in the crude age and sex adjusted model. The results were similar in the fully adjusted model: RVO (HR=1.04, 95% CI 0.99-1.11), RAO (HR=1.01, 95% CI 0.89-1.13), POAG (HR=0.97, 95% CI 0.94-1.00), and PACG (HR=0.91, 95% CI 0.79-1.05). Family history of VTE is not a risk factor for RVO, RAO, POAG and PACG. Thus, it is unlikely that strong and common genetic variants associated with VTE are of importance for these disorders.

Cognitive ability and risk for substance misuse in men: genetic and environmental correlations in a longitudinal nation-wide family study.

To investigate the association in males between cognitive ability in late adolescence and subsequent substance misuse-related events, and to study the underlying genetic and environmental correlations. A population-based longitudinal study with three different family-based designs. Cox proportional hazards models were conducted to investigate the association at the individual level. Bivariate quantitative genetic modelling in (1) full brothers and maternal half-brothers, (2) full brothers reared together and apart and (3) monozygotic and dizygotic twin brothers was used to estimate genetic and environmental correlations. Register-based study in Sweden. The full sample included 1 402 333 Swedish men born 1958-91 and conscripted at mean age 18.2 [standard deviation (SD) = 0.5] years. A total of 1 361 066 men who had no substance misuse events before cognitive assessment at mandatory military conscription were included in the Cox regression models, with a follow-up time of up to 35.6 years. Cognitive ability was assessed at conscription with the Swedish Enlistment Battery. Substance misuse events included alcohol- and drug-related court convictions, medical treatments and deaths, available from governmental registries. Lower cognitive ability in late adolescence predicted an increased risk for substance misuse events [hazard ratio (HR) for a 1-stanine unit decrease in cognitive ability: 1.29, 95% confidence interval (CI) = 1.29-1.30]. The association was somewhat attenuated within clusters of full brothers (HR = 1.21, 95% CI = 1.20-1.23). Quantitative genetic analyses indicated that the association was due primarily to genetic influences; the genetic correlations ranged between -0.39 (95% CI = -0.45, -0.34) and -0.52 (95% CI -0.55, -0.48) in the three different designs. Shared genetic influences appear to underlie the association between low cognitive ability and subsequent risk for substance misuse events among Swedish men.

Familial risks of glomerulonephritis – a nationwide family study in Sweden

Objective: Familial risks of glomerulonephritis (acute, chronic and unspecified glomerulonephritis) have not been studied. This study aims to determine the familial risks of glomerulonephritis.Methods: Individuals born from1932 onwards diagnosed with glomerulonephritis (acute [n = 7011], chronic [n = 10,242] and unspecified glomerulonephritis [n = 5762]) were included. The familial risk (Standardized incidence ratio = SIR) was calculated for individuals whose parents/full-siblings were diagnosed with glomerulonephritis compared to those whose parents/full-siblings were not. The procedure was repeated for spouses. Familial concordant risk (same disease in proband and exposed relative) and discordant risk (different disease in proband and exposed relative) of glomerulonephritis were determined.Results: Familial concordant risks (parents/full-sibling history) were: SIR = 3.57 (95% confidence interval, 2.77–4.53) for acute glomerulonephritis, SIR = 3.84 (3.37–4.36) for chronic glomerulonephritis and SIR = 3.75 (2.85–4.83) for unspecified glomerulonephritis. High familial risks were observed if two or more relatives were affected; the SIR was 209.83 (150.51–284.87) in individuals with at least one affected parent as well as one full-sibling. The spouse risk was only moderately increased (SIR = 1.53, 1.33–1.75).Conclusions: Family history of glomerulonephritis is a strong predictor for glomerulonephritis, and is a potentially useful tool in clinical risk assessment. Our data emphasize the contribution of familial factors to the glomerulonephritis burden in the community.Key MessagesThe familial risks (full-sibling/parent history) of glomerulonephritis (acute, chronic and unspecified glomerulonephritis) have not been determined previously.The familial risks of glomerulonephritis were increased among individuals with family history of acute, chronic or unspecified glomerulonephritis.The familial risks of glomerulonephritis were slightly increased among spouses indicating a modest non-genetic contribution.Very high familial risks were observed in multiplex families, i.e. with one or more affected first-degree relatives.

A nationwide family study of venous thromboembolism and risk of arterial vascular disease

ObjectiveThis nationwide study aimed to determine whether venous thromboembolism (VTE) shares familial susceptibility with aortic aneurysm (AA), peripheral artery disease (PAD) and arterial thrombosis and embolisation (ATE) in locations other...

Family history of venous thromboembolism and risk of hospitalized thromboembolism in cancer patients: A nationwide family study

BackgroundThe importance of family history of venous thromboembolism (VTE) in cancer patients is unclear. We conducted a nationwide study to determine whether family history of VTE is a risk factor for hospitalized VTE in cancer patients. MethodsThe Swedish Multi-Generation Register was linked to the Swedish Hospital Discharge Register and the Swedish Cancer Registry. Familial (sibling/parent history of VTE) hazard ratios (HRs) for VTE in 20 cancer types were determined by cause-specific Cox regression for 258877 cancer patients in 1987–2010 without previous VTE. Familial HRs were also determined in 7644203 individuals without cancer or VTE before 1987, with follow-up in 1987–2010. ResultsSignificant familial HRs for VTE in cancer patients were observed for the following cancer types: cancers of the breast (HR=1.79), lung (HR=1.21), colon (HR=1.30), prostate (HR=1.46), testis (HR=2.02), nervous system (HR=1.31), stomach (HR=1.73), and rectum (HR=1.77), as well as melanoma (HR=1.71), non-Hodgkin lymphoma (HR=1.32), myeloma (HR=1.69), and leukemia (HR=1.44). In a time-dependent analysis the familial HRs for VTE were significant before diagnosis of cancer (p-values <0.0001). After diagnosis of cancer the familial HRs VTE were weaker, with significant HRs for 12 cancer types. On an additive scale, the joint effect of cancer and family history was significantly increased compared to separate effects in four cancer types. However, for certain cancers the familial VTE cases were limited. ConclusionsFamily history of VTE is a risk factor for VTE in several cancer types. However, familial factors are relatively more important in non-cancer than in cancer patients.

Familial transmission of chronic obstructive pulmonary disease in adoptees: a Swedish nationwide family study

ObjectivesFamilial clustering of chronic obstructive pulmonary disease (COPD) is well established, but the familial risk of COPD has not been determined among adoptees. The aim was to determine whether the...

Familial Risks of Kidney Failure in Sweden: A Nationwide Family Study

BackgroundThe value of family history as a risk factor for kidney failure has not been determined in a nationwide setting.AimThis nationwide family study aimed to determine familial risks for kidney failure in Sweden.MethodsThe Swedish multi-generation register on 0–78-year-old subjects were linked to the Swedish patient register and the Cause of death register for 1987–2010. Individuals diagnosed with acute kidney failure (n = 10063), chronic kidney failure (n = 18668), or unspecified kidney failure (n = 3731) were included. Kidney failure patients with cystic kidney disease, congenital kidney and urinary tract malformations, urolithiasis, and rare inherited kidney syndromes, and hyperoxaluria were excluded. Standardized incidence ratios (SIRs) were calculated for individuals whose parents/siblings were diagnosed with kidney failure compared to those whose parents or siblings were not.ResultsThe concordant (same disease) familial risks (sibling/parent history) were increased for chronic kidney failure SIR = 2.02 (95% confidence interval, CI 1.90–2.14) but not for acute kidney failure SIR = 1.08 (95% CI 0.94–1.22) and for unspecified kidney failure SIR = 1.25 (95% CI 0.94–1.63). However, the discordant (different disease) familial risk for acute kidney failure SIR = 1.19 (95% CI 1.06–1.32) and unspecified kidney failure SIR = 1.63 (95% CI 1.40–1.90) was significantly increased in individuals with a family history of chronic kidney failure. The familial risk for chronic kidney failure was similar for males SIR = 2.04 (95% CI 1.90–2.20) and females SIR = 1.97 (95% CI 1.78–2.17). Familial risks for chronic kidney failure were highest at age of 10–19 years SIR = 6.33 (95% CI 4.16–9.22).ConclusionsThe present study shows that family history is an important risk factor for chronic kidney failure but to a lower degree for acute kidney failure and unspecified kidney failure.

Venous thromboembolism and varicose veins share familial susceptibility: a nationwide family study in Sweden.

BackgroundVaricose veins (VVs) have been associated with venous thromboembolism (VTE), but whether these diseases share familial susceptibility has not been determined. This nationwide study aimed to determine whether VTE shares familial susceptibility with VVs.Methods and ResultsSwedish Multigeneration Register data for persons aged 0 to 76 years during the period 1964–2008 were linked to the Swedish Inpatient and Outpatient Registers. Familial risks (standardized incidence ratios [SIRs]) of VTE and VVs were examined in 2 ways (ie, bidirectionally): risk of VTE in subjects whose siblings had been diagnosed with VVs and risk of VVs in persons whose siblings had been diagnosed with VTE. The analyses were repeated for spouses to determine the importance of shared adult family environment. In total, 96 810 siblings had VVs and 87 564 had VTE. An increased risk of VTE was observed in persons whose siblings had VVs (SIR 1.30, 95% CI 1.26 to 1.33), whereas persons whose siblings had VTE had an increased risk of VVs (SIR 1.30, 95% CI 1.27 to 1.34). If 2 or more siblings were affected by VTE, the risk for VVs was 1.70 (95% CI 1.53 to 1.88). Conversely, if 2 or more siblings were affected by VVs, the risk for VTE was 1.52 (95% CI 1.38 to 1.67). In spouses of VTE patients, a minor increased risk of VVs was observed (SIR 1.05 for husbands, SIR 1.06 for wives). The risk of VTE in spouses of VV patients was similarly small (SIR 1.01 for husbands, SIR 1.05 for wives).ConclusionsVVs and VTE share familial susceptibility. This novel finding suggests the existence of shared familial and possibly genetic factors.

Familial transmission of prostate, breast and colorectal cancer in adoptees is related to cancer in biological but not in adoptive parents: A nationwide family study

AimFamilial clustering of prostate, breast and colorectal cancer is well established, but the familial risk of these cancers has not been determined among adoptees. The aim was to disentangle the contributions of genetic and environmental factors to the familial transmission of prostate, breast and colorectal cancer. MethodsThe Swedish Multi-Generation Register was used to follow all adoptees born between 1932 and 1969 (n=70,965) for prostate, breast and colorectal cancer from January 1958 up to December 2010. The risk of prostate, breast and colorectal cancer was estimated in adoptees with at least one biological parent with the same cancer type compared with adoptees without a biological parent with the same cancer type. The risk of cancer was also determined in adoptees with at least one adoptive parent with cancer compared with adoptees with an adoptive parent without cancer. ResultsAdoptees with at least one biological parent with prostate, breast or colorectal cancer were more likely to have cancer of the same type than adoptees with biological parents not affected by these respective cancer types (standardised incidence ratio=SIR: 1.8 [95% confidence interval 1.2–2.7], 2.0 [1.6–2.5] and 1.9 [1.2–2.9], respectively). In contrast, adoptees with at least one adoptive parent with prostate, breast or colorectal cancer were not at an increased risk of these respective cancer types (SIR=1.2 [0.94–1.6], 0.97 [0.71–1.3], and 1.1 [0.71–1.5], respectively). ConclusionsThe findings of the study support the importance of genetic/biological factors in the familial transmission of prostate, breast and colorectal cancer.

Risk of irritable bowel syndrome in first-degree, second-degree and thirddegree relatives of affected individuals: a nationwide family study in Sweden

ObjectivesIBS aggregates in families, but the familial risk of IBS has only been determined in first-degree relatives and spouses. This nationwide study aimed to determine the familial risk of IBS...

Family history of venous thromboembolism (VTE) and risk of recurrent hospitalization for VTE: a nationwide family study in Sweden

Data concerning the importance of a family history of venous thromboembolism (VTE) for the risk of recurrent VTE are sparse. The aim of this nationwide study was to determine whether a family history of VTE is a risk factor for recurrent hospitalization for unprovoked VTE (deep vein thrombosis of the lower extremities or pulmonary embolism). We linked Multigeneration Register data on individuals aged 0-77years to the Swedish nationwide Hospital Discharge Register data for the period 1987-2009 to compare the risk of hospitalization for unprovoked recurrent VTE among individuals with and without a parental or sibling history of VTE. We calculated hazard ratios (HRs) to determine the familial HR for recurrent hospitalization for VTE. The risk of recurrent VTE hospitalization was 1.20 (95% confidence interval [CI]1.10-1.32) for individuals with affected parents, and 1.30 (95%CI1.14-1.49) for those with affected siblings. The risk of recurrent VTE hospitalization in individuals with two affected parents was 1.92 (95%CI1.44-2.58). There was an interaction between age at diagnosis of VTE and a family history of VTE, with a family history having a stronger effect on VTE risk in younger patients. We conclude that a family history of VTE is a modest risk factor for recurrent VTE hospitalization in Sweden.

Venous thromboembolism does not share strong familial susceptibility with pre‐eclampsia/eclampsia: a nationwide family study in Sweden

Genetic variants associated with venous thromboembolism (VTE) have been suggested to be involved in the pathogenesis of pre-eclampsia/eclampsia (PEC/EC). This nationwide study aimed to determine whether VTE shares familial susceptibility with PEC/EC. Population-based cohort study. Sweden. A total of 941841 Swedish women delivering their first child between 1987 and 2008. Data from the Swedish Multigeneration Register were linked to the Swedish Hospital Discharge Register. The risk of PEC/EC was determined in primiparous women with a family history of VTE (in parents and/or siblings), compared with primiparous women without a family history of VTE. Odds ratios (ORs) were calculated by logistic regression. PEC/EC in first pregnancy. In total, 43621 women had PEC/EC in association with their first pregnancy. The OR for PEC/EC in women with a family history of VTE was 1.06 (95%CI 1.01-1.11); however, a family history of VTE was associated with higher odds of PEC/EC among women with previous hypertension (OR1.38, 95%CI 1.25-1.52). A family history of VTE is weakly associated with PEC/EC risk, and is not clinically useful for the prediction of PEC/EC. The results of the present study suggest that it is unlikely that strong disease-causing mutations shared by VTE and PEC/EC are common in the Swedish population. The novel association between family history and PEC/EC among the subgroup with previous hypertension needs further confirmation in future studies.

High Familial Risk of Atrial Fibrillation/Atrial Flutter in Multiplex Families: A Nationwide Family Study in Sweden

BackgroundAlthough the heritability of atrial fibrillation/atrial flutter (AF/AFl) has been determined, the familial risk in multiplex families is unclear. The main aim of this nationwide study was to determine the familial risk of AF/AFl in multiplex families.Methods and ResultsWe examined the familial risk of AF/AFl in the entire Swedish population. We linked Multigeneration Register data on individuals aged 0 to 76 years with Hospital Discharge Register data for 1987–2008 and Outpatient Register data for 2001–2008 to compare AF/AFl risk among relatives of all 300 586 individuals with AF/AFl with that among relatives of unaffected individuals. We used conditional logistic regression to investigate differences in exposure between cases and controls. Parents (odds ratio [OR] 1.95 [95% CI 1.89 to 2.00]) and siblings (OR=3.08 [3.00 to 3.16]) of cases had higher odds of AF/AFl than did parents and siblings of controls. AF/AFl ORs were increased in both sexes. For 2% of cases, both parents had AF/AFl, compared with only 0.7% of controls (OR=3.60 [3.30 to 3.92]). Moreover, 3% of cases had ≥2 siblings with AF/AFl, compared with 1% of controls (OR=5.72 [5.28 to 6.19]). In premature cases (diagnosed at age <50 years), the ORs were 5.04 (4.36 to 5.82) and 8.51 (6.49 to 11.15) for AF/AFl in both parents and AF/AFl in ≥2 siblings, respectively. The overall spouse OR was 1.16 (1.13 to 1.19).ConclusionsFamily history of AF/AFl increases the odds of AF/AFl in first‐degree relatives. High familial risks were observed in multiplex families.

Erratum to Zöller et al. “Familial risk of venous thromboembolism in first-, second- and third-degree relatives: a nationwide family study in Sweden” (Thromb Haemost 2013; 109: 458–463)

Erratum to Zöller et al. “Familial risk of venous thromboembolism in first-, second- and third-degree relatives: a nationwide family study in Sweden” (Thromb Haemost 2013; 109: 458–463)

Familial risk of venous thromboembolism in first-, second- and third-degree relatives: a nationwide family study in Sweden

Venous thromboembolism (VTE) clusters in families, but the familial risk of VTE has only been determined in first-degree relatives. This nationwide study aimed to determine the familial risk of VTE in first-, second- and third-degree relatives of affected individuals. The Swedish Multi-Generation Register was linked to Hospital Discharge Register data for the period 1987-2009. This was a case-cohort study. Odds ratios (ORs) for VTE were calculated for individuals whose relatives were hospitalised for VTE, as determined by the International Classification of Diseases (ICD), and those whose relatives were unaffected by VTE. The familial OR for VTE was 2.49 in siblings (95% confidence interval [CI] 2.40-2.58), 2.65 in children (2.50-2.80), 2.09 in parents (2.03-2.15), 1.52 in maternal half-siblings (1.26-1.85), 2.34 in paternal half-siblings (2.00-2.73), 1.69 in nieces/nephews (1.57-1.82), 1.47 in cousins (1.33-1.64), and 1.14 in spouses of individuals diagnosed with VTE (1.09-1.18). Familial clustering was stronger at young ages. The familial transmission was slightly stronger for males compared with females but was only significant for siblings 1.13 (1.05-1.22) and parents 1.11 (1.05-1.78) of probands. The present data showing an increased VTE risk among not only first-degree relatives but also second- and third-degree relatives indicate that the genetic component of the familial clustering of VTE is strong. Family history is a potentially useful genetic surrogate marker for clinical VTE risk assessment, even in second- and third degree-relatives.