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Heredity in Sarcoidosis: a Registry-Based Twin Study Thorax: First Published As 10.1136/Thx.2007.094060 on 5 June 2008

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Heredity in Sarcoidosis: a Registry-Based Twin Study Thorax: First Published As 10.1136/Thx.2007.094060 on 5 June 2008 Sarcoidosis Heredity in sarcoidosis: a registry-based twin study Thorax: first published as 10.1136/thx.2007.094060 on 5 June 2008. Downloaded from A Sverrild,1 V Backer,1 K O Kyvik,2 J Kaprio,3 N Milman,4 C B Svendsen,5 S F Thomsen1 1 Department of Respiratory ABSTRACT Prevalence and incidence are dependent on age, sex Medicine, Bispebjerg University Background: Sarcoidosis is a multiorgan granulomatous and ethnicity.1 2 8–10 Hospital, Copenhagen, Denmark; The present understanding of the pathogenesis 2 Institute of Regional Health inflammatory disease of unknown aetiology. Familial Research Services and The clustering of cases and ethnic variation in the epidemiol- of the disease is that sarcoidosis is triggered by an Danish Twin Registry, University ogy suggests a genetic influence on susceptibility to the abnormal immune response to an environmental of Southern Denmark, Odense, agent in a genetically predisposed individual.1 3 disease. This paper reports twin concordance and Denmark; The Finnish Twin heritability estimates of sarcoidosis in order to assess the Genetic factors are considered to contribute to Cohort Study, Department of Public Health, University of overall contribution of genetic factors to the disease the development of sarcoidosis for two main 12610 Helsinki, Helsinki, Finland and susceptibility. reasons ; (1) epidemiological studies have Department of Mental Health Methods: Monozygotic and dizygotic twins enrolled in identified ethnicity as an important risk factor; and Alcohol Research, National the Danish and the Finnish population-based national twin and (2) familial clustering of cases has been Public Health Institute, Helsinki, 4 observed frequently over the last decades. A Finland; The Heart Centre, cohorts (61 662 pairs in total) were linked to diagnostic Department of Lung information on sarcoidosis obtained from the Danish previous study has suggested an up to 5.7-fold Transplantation, Rigshospitalet, National Patient Registry or the Social Insurance increased risk of developing sarcoidosis in siblings Copenhagen, Denmark; of affected individuals.9 However, the fact that 5 Institution, Finland registry of reimbursed medication using Department of Bacteriology, families do not only share genes but also environ- Mycology and Parasitology, the 8th and 10th editions of the International Classification Statens Serum Institut, of Diseases. The Fisher exact test was used to compare ment makes it difficult to determine the relative Copenhagen, Denmark probandwise concordance rates in different zygosity contribution of genetic versus environmental groups. Heritability was estimated based on a multi- factors to the susceptibility to the disease. Correspondence to: Susceptibility loci have been mapped to the human Dr A Sverrild, Department of factorial threshold liability model. Respiratory Medicine, Bispebjerg Results: A total of 210 twin pairs with at least one leucocyte antigen (HLA) gene complex located on the Hospital, DK-2400 Copenhagen proband with a diagnosis of sarcoidosis were identified. short arm of chromosome 6, whereas a number of NV, Denmark; asgersverrild@ The probandwise concordance rate was higher in non-HLA candidate genes map to other locations in stud.ku.dk 10–12 monozygotic than in dizygotic twins (0.148 vs 0.012). the genome. This suggests the influence of a large Compared with the general population there was an 80- number of interacting genes. The specific gene Received 28 November 2007 findings, however, account for only a small fraction Accepted 23 April 2008 fold increased risk of developing sarcoidosis in co-twins of of the variance in risk to the disease. Published Online First affected monozygotic brothers or sisters. The increased http://thorax.bmj.com/ 5 June 2008 risk in dizygotic twins was only 7-fold. Aetiological model This study is the first to use the classical twin fitting gave a heritability of sarcoidosis of 0.66 (95% CI method to systematically describe the occurrence 0.45 to 0.80). of sarcoidosis in Danish and Finnish twins in order Conclusions: This study suggests that genetic factors to address the overall contribution of genetic play an important role in the susceptibility to sarcoidosis. factors to the susceptibility to the disease. This result should encourage the search for molecular genetic markers of susceptibility to the disease. METHODS The twin method is a classic approach to study the on September 30, 2021 by guest. Protected copyright. heredity of a disease. Besides sharing their upbring- Sarcoidosis is a rare multiorgan immune-mediated ing and early environment, monozygotic twins have disease of unknown aetiology characterised by the all their genes in common whereas dizygotic twins formation of non-caseating granulomas. Ninety only share genes like normal siblings. Therefore, if a percent of patients are affected in the lungs or disease is more correlated in monozygotic than in intrathoracic lymph nodes, but large differences in dizygotic twins, it provides evidence that genetic organ involvement are found between ethnic factors contribute to the aetiology of the disease.13 groups and in different parts of the world.1–4 The prognosis and course of the disease depends Danish and Finnish twin cohorts on the severity and phenotypic characteristics. The Scandinavian countries have some of the Overall, 30% undergo spontaneous remission while oldest and most well characterised twin registries another 30% progress with chronic manifestations. in the world, making collaboration between In addition, a significant number of asymptomatic countries advantageous when studying rare dis- cases with sarcoidosis have been identified in mass eases such as sarcoidosis.14 15 The Danish study screenings using chest radiographs.235 Mortality population included all twins enrolled in the rates in patients with sarcoidosis have been nationwide Danish Twin Registry who were alive reported to be 1–6%.235 at some point between 1977 and 2004.16 This The occurrence of sarcoidosis in the general comprises a total number of 60 756 pairs. The Old population remains difficult to establish due to the Finnish Twin Cohort consists of 13 888 pairs of wide spectrum of phenotypes, differing diagnostic known zygosity comprising all same-sex twins criteria and the variable study designs.126 born before 1958 with both twins alive in 1975. In Incidence rates in Denmark and Finland are 7.2 both registries zygosity has been determined using and 11.4 per 100 000 person-years, respectively.67 questions of similarity and mistaken identity.17 This 894 Thorax 2008;63:894–896. doi:10.1136/thx.2007.094060 Sarcoidosis method is widely accepted and assigns zygosity correctly in more Moreover, a co-twin of an affected identical twin has an 80- Thorax: first published as 10.1136/thx.2007.094060 on 5 June 2008. Downloaded from than 96% of cases.18 fold increased risk of getting sarcoidosis compared with the general population, whereas the risk was increased only 7-fold Case identification in a co-twin of an affected dizygotic twin. Diagnostic criteria were limited to codes 135.99 and D86.0–D86.9 We found that an aetiological model including genetic and of the 8th and 10th editions of the International Classification of non-shared environmental effects fitted the data best with a Diseases. Information on sarcoidosis in the Danish cohort was heritability estimate of 0.66 (95% confidence interval (CI) 0.45 gathered from the Danish National Patient Registry (DNPR) at to 0.80). The proportion of variance explained by non-shared the Danish Board of Health on all twins alive between 1977 and environmental factors was 0.34 (95% CI 0.20 to 0.55). 2004. The DNPR contains details on all hospital admissions in Denmark including information on all diagnostic coding. Cases in DISCUSSION the Finnish cohort included all twins who had applied for medical Sarcoidosis has been studied in affected families to reveal any reimbursement associated with a diagnosis of sarcoidosis in the possible genetic influence on susceptibility. Since families share not period from 1976 to 2004 (which included 11 186 twin pairs of only genes but also environment, aggregation of cases may be due working age and not on disability pension in 1975). The Social either to inherited factors or environmental exposures. The Insurance Institution, Finland, grants the right to full reimburse- increased relative risk of 5.8 in siblings found in the ACCESS ment based on a medical certificate from an appropriate medical study9 concurs well with our equivalent finding in dizygotic twins. specialist or hospital unit. However, no studies have partitioned observed familial clustering into genetic and environmental components of variance. Statistical analysis The significantly higher concordance rate in monozygotic The Fisher exact test was used to compare probandwise twins in this study shows that genetic factors appear to play a concordance rates in different zygosity groups. The probandwise substantial role in the susceptibility to sarcoidosis. The concordance rate denotes the probability that one twin has the heritability reflects the difference between monozygotic and disease given the co-twin is affected, and is estimated as two times dizygotic twin pairs, which tells us that genetic factors account the number of concordant affected pairs (both twins are affected) for two-thirds of the variation in the susceptibility to the divided by two times the number of concordant affected pairs disease whereas environmental factors account for one-third. 19
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