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Background: Mitochondrial DNA copy number (mtDNA-CN) is associated with aging. A relationship between mtDNA-CN and degenerative disorders, e.g. osteoarthritis (OA) and osteoporosis (OP), has been suggested. We aimed to investigate the relationship of mtDNA-CN and incident OA and OP. Materials and methods: MtDNA-CN was studied in relationship to incident OA and OP in a population-based cohort study of 6916 middle-aged women (52-63 years). Totally 2521 women with sufficient quality of mtDNA were analyzed. After exclusions, 1978 women remained in the study population. Four different endpoints obtained from the National Patient register were studied: 1) OA, 2) OP 3) OA surgery, and 4) OP fracture. In the multivariate model adjustments were made for potential OA and OP risk factors. Results: Women with low mtDNA-CN were older and had more activity at work. 125 women (6.32%) were affected by incident OP and 254 women (12.84%) had an OP fracture. Incident OA affected 451 women (22.80%) and 175 women (8.85%) had OA surgery. There were no associations between mtDNA-CN and incident risk of OA (Hazard ratio â= â1.00, 95% confidence interval 0.83-1.20), OA surgery (0.79, 0.58-1.07), OP (0.89, 0.62-1.27), or OP fracture (1.00, 0.78-1.29). However, incident OP was significantly associated with T-score (bone density), smoking, diabetes mellitus, and chronic obstructive bronchitis (COPD). OA was associated with body mass index and COPD. Conclusions: The present study suggests that mtDNA-CN, reflecting mitochondrial dysfunction, is not a major predictor for incident OA or OP. However, due to the limited study size minor associations cannot be excluded.
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ABSTRACT: Hereditary angioedema (HAE), caused by C1 inhibitor protein deficiency, was recently shown to be associated with an increased risk for venous thromboembolism (VTE). To our knowledge, this is the first national family study of HAE, which aimed to determine the familial risk of VTE. The Swedish Multi-Generation Register was linked to the Swedish National Patient Register for the period of 1964 to 2018. Only patients with HAE 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 patients with HAE in comparison with relatives without HAE. Among 2006 individuals (from 276 pedigrees of 365 patients with HAE), 103 individuals were affected by VTE. In total, 35 (9.6%) patients with HAE were affected by VTE, whereas 68 (4.1%) non-HAE relatives were affected (P < .001). The adjusted HR for VTE among patients with HAE was 2.51 (95% CI, 1.67-3.77). Patients with HAE were younger at the first VTE than their non-HAE relatives (mean age, 51 years vs 63 years; P < .001). Before the age of 70 years, the HR for VTE among patients with HAE was 3.62 (95% CI, 2.26-5.80). The HR for VTE for patients with HAE born after 1964 was 8.29 (95% CI, 2.90-23.71). The HR for VTE for patients with HAE who were born in 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.
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Angioedemas Hereditários , Tromboembolia Venosa , Humanos , Angioedemas Hereditários/genética , Angioedemas Hereditários/epidemiologia , Angioedemas Hereditários/complicações , Feminino , Masculino , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/genética , Tromboembolia Venosa/etiologia , Pessoa de Meia-Idade , Adulto , Suécia/epidemiologia , Fatores de Risco , Idoso , Linhagem , Sistema de Registros , Adulto Jovem , Família , AdolescenteAssuntos
MicroRNAs , Feminino , Humanos , Masculino , Incidência , MicroRNAs/genética , Tromboembolia/genética , Tromboembolia/etiologiaRESUMO
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.
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Multimorbidade , Tromboembolia Venosa , Humanos , Tromboembolia Venosa/epidemiologia , Estudos Transversais , Masculino , Feminino , Suécia/epidemiologia , Pessoa de Meia-Idade , Idoso , Adulto , Sistema de RegistrosRESUMO
Background: Cardiac arrhythmias are a common health problem. Both common and rare genetic risk factors exist for cardiac arrhythmias. Cardiac amyloidosis is a rare disease that may manifest various arrhythmias. Few large-scale whole exome sequencing studies elucidating the contribution of rare variations to arrhythmias have been published. Objective: To access gene collapsing analysis of rare variations for different types of cardiac arrhythmias in UK Biobank. Identified genes were analyzed in silico for probability to form amyloid fibrils. Methods: We used 2 published UK Biobank portals (https://azphewas.com/ and https://app.genebass.org/) to access gene collapsing analysis of rare variations for different types of cardiac arrhythmias. Diagnosis of arrhythmia was based on the International Classification of Diseases, 10th Revision (ICD-10) codes: conduction disorders (I44, I45), paroxysmal tachycardia (I47), atrial fibrillation (I48), and other arrhythmias (I49). Results: Rare variations in 5 genes were linked to conduction disorders (SCN5A, LMNA, SMAD6, HSPB9, TMEM95). The TTN gene was associated with both paroxysmal tachycardia and other arrhythmias. Atrial fibrillation was associated with rare variations in 8 genes (TTN, RPL3L, KLF1, TET2, NME3, KDM5B, PKP2, PMVK). Two of the genes linked to heart conduction disorders were potential amyloid-forming proteins (HSPB9, TMEM95), while none of the 8 genes linked to other types of arrhythmias were potential amyloid-forming proteins. Conclusion: Rare variations in 13 genes were associated with arrhythmias in the UK Biobank. Two of the heart conduction disorder-linked genes are potential amyloid-forming candidates. Amyloid formation may be an underestimated cause of heart conduction disorders.
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Poor self-rated health (SRH) is associated with incident arterial cardiovascular disease in both sexes. Studies on the association between SRH and incident venous thromboembolism (VTE) show divergent results in women and no association in men. This study focuses on the association between change in SRH and incident VTE in a cohort of 11,558 men and 6682 women who underwent a baseline examination and assessment of SRH between 1974 and 1992 and a re-examination in 2002-2006. To investigate if changes in SRH over time affect the risk of incident VTE in men and women. During a follow-up time from the re-examination of more than 16 years, there was a lower risk for incident VTE among women if SRH changed from poor at baseline to very good/excellent (HR 0.46, 95% CI 0.28; 0.74) at the re-examination. Stable good SRH (good to very good/excellent at the re-examination, HR 0.60, 95% CI 0.42; 0.89), or change from good SRH at baseline into poor/fair at the re-examination (HR 0.68, 95% CI 0.51; 0.90) were all significantly associated with a reduced risk for VTE. All comparisons were done with the group with stable poor SRH. This pattern was not found among men. Regardless of a decreased or increased SRH during life, having an SRH of very good/excellent at any time point seems to be associated with a decreased risk of VTE among women.
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Doenças Cardiovasculares , Tromboembolia Venosa , Masculino , Humanos , Feminino , Estudos de Coortes , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/prevenção & controle , Nível de SaúdeRESUMO
BACKGROUND: Most family studies on venous thromboembolism (VTE) have focused on first-degree relatives. OBJECTIVES: We took a pedigree-based approach and examined the risk of VTE and cardiometabolic disorders in offspring from extended pedigrees according to the densities of VTE in pedigrees. METHODS: From the Swedish population, we identified a total of 482 185 pedigrees containing a mean of 14.2 parents, aunts/uncles, grandparents, and cousins of a core full sibship that we termed the pedigree offspring (n = 751 060). We then derived 8 empirical classes of these pedigrees based on the density of cases of VTE. The risk was determined in offspring for VTE and cardiometabolic disorders as a function of VTE density in their pedigrees. Bonferroni correction for multiple comparisons was performed. RESULTS: VTE was unevenly distributed in the population; the Gini coefficient was 0.59. Higher VTE density in pedigrees was associated in the offspring with a higher risk of different VTE manifestations (deep venous thrombosis, pulmonary embolism, pregnancy-related VTE, unusual thrombosis, and superficial thrombophlebitis), thrombophilia, and lower age of first VTE event. Moreover, VTE density in pedigrees was significantly associated in the offspring with obesity, diabetes, gout, varicose veins, and arterial embolism and thrombosis (excluding brain and heart). No significant associations were observed for retinal vein occlusion, hypercholesterolemia, hypertension, coronary heart disease, myocardial infarction, ischemic stroke, atrial fibrillation, heart failure, primary pulmonary hypertension, cerebral hemorrhage, aortic aneurysm, peripheral artery disease, and overall mortality. CONCLUSION: Offspring of pedigrees with a high density of VTE are disadvantaged regarding VTE manifestations and certain cardiometabolic disorders.
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Embolia Pulmonar , Tromboflebite , Tromboembolia Venosa , Humanos , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/genética , Linhagem , Fatores de Risco , Embolia Pulmonar/epidemiologia , Embolia Pulmonar/genéticaRESUMO
OBJECTIVES: Vasospastic 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 genetic and environmental factors remains elusive. Accordingly, we aimed to determine the familial VSA risk among first-degree relatives of affected individuals. METHODS: A population-based multigenerational cohort study was conducted, including full-sibling pairs born to Swedish parents between 1932 and 2018. Register-based diagnoses were ascertained through linkage to the Swedish Multigeneration Register and National Patient Register. Incidence rate ratios (IRRs) and adjusted HRs were calculated for relatives of individuals with VSA compared with relatives of individuals without VSA. RESULTS: The total study population included 5 764 770 individuals. Overall, 3461 (0.06%) individuals (median age at disease onset 59 years, IQR: 63-76) were diagnosed with VSA. Of these, 2236 (64.61%) were women. The incidence rate of VSA for individuals with an affected sibling was 0.31 (95% CI: 0.24 to 0.42) per 1000 person-years compared with 0.04 (95% CI: 0.04 to 0.04) per 1000 person-years for those without an affected sibling, yielding an IRR of 7.58 (95% CI: 5.71 to 10.07). The risk of VSA for siblings with an affected sibling was significantly increased in the fully adjusted model (HR: 2.56; 95% CI: 1.73 to 3.79). No increased risk of VSA was observed in spouses of affected individuals (HR: 0.63; 95% CI: 0.19 to 2.09). CONCLUSIONS: In this nationwide family study, we identified high familial risk for VSA independent of shared environmental risk factors. Our findings indicate that VSA tends to cluster in families, emphasising the need to explore genetic and non-genetic factors that may contribute.
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Vasoespasmo Coronário , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Masculino , Vasoespasmo Coronário/diagnóstico , Vasoespasmo Coronário/epidemiologia , Vasoespasmo Coronário/genética , Suécia/epidemiologia , Estudos de Coortes , Pais , Predisposição Genética para DoençaRESUMO
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.
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INTRODUCTION: Pelvic girdle pain during and after pregnancy is a major public health problem with significant daily problems for affected women and their families. There is now accumulating evidence that pregnancy-related pelvic girdle pain originates from the sacroiliac joints and the pubic symphysis as well as their extra-articular ligaments. However, the heritability of the disease remains to be determined. We hypothesized that there is an increased familial risk of pregnancy-related pelvic girdle pain. MATERIAL AND METHODS: A population-based national database linkage registry study of approximately 9.3 million individuals within 4.2 million families in Sweden with a recruitment period from 1997 to 2018. The Swedish Multi-generation register was used to find female pairs of twins, full siblings, half-siblings and first cousins where both in the pairs had a completed pregnancy. The outcome measure was diagnosis of pregnancy-related pelvic girdle pain (International Classification of Diseases-10 O26.7 [1997-2018]) in the first pregnancy. Data was obtained from the Swedish Hospital Discharge Register, the Swedish Outpatient Care Register, the Swedish Medical Birth Register, the Primary Healthcare Register, and Medical Treatment Register. Cox regression analysis was used to calculate adjusted estimated effect of the exposure variable familial history of pregnancy-related pelvic girdle pain on the outcome variable pregnancy-related pelvic girdle pain at first birth. RESULTS: From the registers, 1 010 064 women pregnant with their first child within 795 654 families were collected. In total, 109 147 women were diagnosed with pregnancy-related pelvic girdle pain. The adjusted hazard ratio for a familial risk of pregnancy-related pelvic girdle pain was 2.09 (95% CI 1.85-2.37) among twins (monozygotic and dizygotic), 1.78 (95% CI 1.74-1.82) in full siblings, 1.16 (95% CI 1.06-1.28) in half-siblings from the mother, 1.09 (95% CI 1.024-1.16) in half-siblings from the father and 1.09 (95% CI 1.07-1.12) in first cousins. CONCLUSIONS: This nationwide observational study showed a familial clustering of pregnancy-related pelvic girdle pain. The hazard ratio for the condition was associated with the degree of relatedness, suggesting that heredity factors contribute to the development of pregnancy-related pelvic girdle pain. There is no causal treatment available for pregnancy-related pelvic girdle pain and further studies are now encouraged to clarify the specific genetic factors that contribute to the disease and for future targeted interventions.
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Hereditariedade , Dor da Cintura Pélvica , Complicações na Gravidez , Feminino , Humanos , Gravidez , Família , Predisposição Genética para Doença , Dor da Cintura Pélvica/epidemiologia , Dor da Cintura Pélvica/genética , Complicações na Gravidez/epidemiologia , Complicações na Gravidez/genética , Suécia/epidemiologiaRESUMO
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.