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Clinical epidemiology of familial sarcoidosis: A systematic literature review

  • Michelle Terwiel
    Affiliations
    Department of Pulmonology, St Antonius ILD Center of Excellence, St Antonius Hospital, Nieuwegein, the Netherlands
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  • Coline H.M. van Moorsel
    Correspondence
    Corresponding author. Interstitial Lung Diseases Centre of Excellence, Dept of Pulmonology, St Antonius Hospital, Koekoekslaan 1, 3435 CM, Nieuwegein, the Netherlands.
    Affiliations
    Department of Pulmonology, St Antonius ILD Center of Excellence, St Antonius Hospital, Nieuwegein, the Netherlands

    Division of Heart and Lung, University Medical Center Utrecht, Utrecht, the Netherlands
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Open ArchivePublished:December 13, 2018DOI:https://doi.org/10.1016/j.rmed.2018.11.022

      Highlights

      • Family members of patients with sarcoidosis are more likely to develop sarcoidosis.
      • Pooled prevalence of familial sarcoidosis from heterogeneous studies is 9.5%.
      • Estimated heritability of 60–70% in diverse studies suggests a shared determinant.
      • Characteristics of familial sarcoidosis differ between study populations.

      Abstract

      Introduction

      Although the presence of familial sarcoidosis has been confirmed, clinical and epidemiological data on its characteristics are scattered and sometimes paradoxical. The objective of this review is to assess what is known on the clinical epidemiology of familial sarcoidosis, by combining data from early case reports with recent population based data; aiming to support in clinical decision making and providing information to patients.

      Method

      A systematic review of the literature in PubMed was done and 27 studies with clinical or epidemiological data on familial sarcoidosis, published between 1947 and 2017, were included.

      Results

      The pooled prevalence proportion of familial sarcoidosis, based on twelve study populations, was 9.5% (CI 4.6–16.1), highest in French, African American, Dutch and Irish patients. A heritability of 60–70% was estimated in diverse studies. Relative types and relationships most often reported in familial sarcoidosis were siblings and mother-child relationships. Familial risk is heterogeneous. In African Americans specific environmental factors have been associated with familial sarcoidosis (OR between 1.5 and 3.2). European American and African American subjects had different relative risks for first degree familial relationships (OR of 16.6 vs 3.1) and relative risk differed between relative types. Clinical findings in familial sarcoidosis are still obscure.

      Conclusions

      Prevalence of familial sarcoidosis is high in specific study populations from countries worldwide. The estimated heritability of 60–70%, suggests a shared determinant, and the heterogeneous familial risk, associated with both genetic and environmental factors. Familial relative risks and clinical phenotypes may differ between ethnic groups and relative types, but require further study.

      Keywords

      1. Introduction

      Sarcoidosis is a disease of unknown etiology. It is characterized by the presence of non-caseating granulomas in one or multiple organs of the patients [
      • Statement on sarcoidosis
      Joint statement of the American thoracic society (ATS), the European respiratory society (ERS) and the world association of sarcoidosis and other granulomatous disorders (WASOG) adopted by the ATS board of directors and by the ERS executive committee, february 1999.
      ]. The aggregation of sarcoidosis in families has been described since the early 20th century. It was first confirmed by Rybicki and colleagues in the multicenter ‘A Case–Control Etiology Study of Sarcoidosis’ (ACCESS) study, from 1996 to 1999 [
      • Rybicki B.A.
      • Iannuzzi M.C.
      • Frederick M.M.
      • Thompson B.W.
      • Rossman M.D.
      • Bresnitz E.A.
      • Terrin M.L.
      • Moller D.R.
      • Barnard J.
      • Baughman R.P.
      • DePalo L.
      • Hunninghake G.
      • Johns C.
      • Judson M.A.
      • Knatterud G.L.
      • McLennan G.
      • Newman L.S.
      • Rabin D.L.
      • Rose C.
      • Teirstein A.S.
      • Weinberger S.E.
      • Yeager H.
      • Cherniack R.
      ACCESS Research Group
      Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS).
      ]. In addition to measuring familial relative risks, an extensive clinical characterization of the sarcoidosis cases was done. A major strength of the study is the large sample size (706 case–control pairs) with subjects from various areas in the United States. Recently, studies on familial aggregation of disease have regained interest, because findings are potentially useful in the clinic and important to patients [
      • Frisell T.
      • Saevarsdottir S.
      • Askling J.
      Family history of rheumatoid arthritis: an old concept with new developments.
      ]. Familial occurrence of a disease is commonly linked to shared genetic or environmental exposures. However, in sarcoidosis there is little evidence for a strong determining role of any of these. Furthermore, clinical and epidemiological data on the characteristics of familial sarcoidosis are scattered and sometimes paradoxical. By means of a literature review on the clinical epidemiology of familial sarcoidosis, we sought for information on familial sarcoidosis that is useful to inform patients and might aid in clinical decision making. We describe epidemiological and clinical findings on familial sarcoidosis from early case reports together with more recent population based findings, including estimates for prevalence and heritability, familial risks with associated factors, relative risks for different relative types and clinical findings.

      2. Method

      To identify studies a systematic literature search was done in PubMed in collaboration with a clinical librarian from St. Antonius hospital Nieuwegein. Included were original clinical or epidemiological studies on familial sarcoidosis, with abstracts available in PubMed. Language was restricted to English. No further limits were applied, nor were specific types of records excluded. The search was run on March 20, 2017 and contained the following terms: (neuro)sarcoidosis, genetic predisposition to disease, familial/family/families, proband, relatives, sibling and ancestry. Articles reporting Blau syndrome or only genetic associations with familial disease were outside the scope of this review.
      The full search: ("Sarcoidosis"[Mesh] OR sarcoidos*[tiab] OR neurosarcoidos*[tiab]) AND ("Genetic Predisposition to Disease"[Majr] OR familial[tiab] OR family[tiab] OR families[tiab] OR proband*[tiab] OR relatives[tiab] OR sibling*[tiab] OR ancestry[tiab]) AND (english[la]).
      Identified articles were screened by title and abstract reading first, followed by full text reading of the remaining articles. Eligible articles contained original clinical or epidemiological data on familial sarcoidosis. Familial sarcoidosis was defined as presence or history of sarcoidosis in one or more family members of index patients with sarcoidosis. We present the pooled prevalence proportion among the included studies for the appropriate model (based on the results of a heterogeneity test), together with the forest plot. Statistical analyses were performed using MedCalc for Windows, version 18.6 (MedCalc Software, Ostend, Belgium). For all measures, the estimation and the 95% confidence interval (CI) are presented.

      3. Results

      3.1 Familial reports

      Pubmed database searching identified 459 articles. Title and abstract screening resulted in 118 articles with possibly relevant information, that were assessed for eligibility. After full text reading 91 articles were excluded, because they did not contain clinical or epidemiological data on familial sarcoidosis. Finally, 27 studies were included in qualitative synthesis. The study selection process is summarized in the PRISMA flow diagram (Fig. 1).

      3.2 Prevalence of familial sarcoidosis among sarcoidosis patients

      Since the beginning of the 20th century, there are mainly case reports and surveys on the familial aggregation of sarcoidosis [
      • Turner R.G.
      • James D.G.
      • Friedmann A.I.
      • Vijendram M.
      • Davies J.P.
      Neuro-ophthalmic sarcoidosis.
      ,
      • Headings V.E.
      • Weston D.
      • Young Jr., R.C.
      • hackney Jr., R.L.
      Familial sarcoidosis with multiple occurrences in eleven families: a possible mechanism of inheritance.
      ,
      • Cheng D.S.
      • Kitahara M.
      • Logan K.H.
      Chronic granulocytic leukemia: long-term remission in a patient with familial sarcoidosis.
      ,
      • Nowinski T.
      • Flanagan J.
      • Ruchman M.
      Lacrimal gland enlargement in familial sarcoidosis.
      ,
      • Brennan N.J.
      • Crean P.
      • Long J.P.
      • Fitzgerald M.X.
      High prevalence of familial sarcoidosis in an Irish population.
      ,
      • Kremer J.M.
      Histologic findings in siblings with acute sarcoid arthritis: association with the B8,DR3 phenotype.
      ,
      • Luisetti M.
      • Cremaschi P.
      • Rizzo S.
      • Martinetti M.
      • Belvedere M.
      Report of one case of familial sarcoidosis.
      ,
      • Carmichael A.J.
      • Tan C.Y.
      • Smith A.G.
      Familial sarcoidosis: high ethnic prevalence.
      ,
      • Soria L.M.
      • Valverde Garcia J.
      • Sole J.M.
      • Badrinas Vancells F.
      Familial sarcoidosis: a case report.
      ,
      • Bambery P.
      • Kaur U.
      • Bhusnurmath S.R.
      • Dilawari J.B.
      Familial idiopathic granulomatosis: sarcoidosis and Crohn's disease in two Indian families.
      ,
      • Rybicki B.A.
      • Harrington D.
      • Major M.
      • Simoff M.
      • Popovich Jr., J.
      • Maliarik M.
      • Iannuzzi M.C.
      Heterogeneity of familial risk in sarcoidosis.
      ,
      • Fite E.
      • Alsina J.M.
      • Anto J.M.
      • Morera J.
      Sarcoidosis: family contact study.
      ,
      • Wirnsberger R.M.
      • de Vries J.
      • Wouters E.F.
      • Drent M.
      Clinical presentation of sarcoidosis in The Netherlands an epidemiological study.
      ,
      • Pietinalho A.
      • Ohmichi M.
      • Hirasawa M.
      • Hiraga Y.
      • Lofroos A.B.
      • Selroos O.
      Familial sarcoidosis in Finland and Hokkaido, Japan--a comparative study.
      ,
      • Elford J.
      • Fitch P.
      • Kaminski E.
      • McGavin C.
      • Wells I.P.
      Five cases of sarcoidosis in one family: a new immunological link?.
      ,
      • McGrath D.S.
      • Daniil Z.
      • Foley P.
      • du Bois J.L.
      • Lympany P.A.
      • Cullinan P.
      • du Bois R.M.
      Epidemiology of familial sarcoidosis in the UK.
      ]. In 2001, Rybicki and colleagues were the first to confirm the familial aggregation of sarcoidosis in the ACCESS study, including 355 European American and 291 African American case-control pairs [
      • Rybicki B.A.
      • Iannuzzi M.C.
      • Frederick M.M.
      • Thompson B.W.
      • Rossman M.D.
      • Bresnitz E.A.
      • Terrin M.L.
      • Moller D.R.
      • Barnard J.
      • Baughman R.P.
      • DePalo L.
      • Hunninghake G.
      • Johns C.
      • Judson M.A.
      • Knatterud G.L.
      • McLennan G.
      • Newman L.S.
      • Rabin D.L.
      • Rose C.
      • Teirstein A.S.
      • Weinberger S.E.
      • Yeager H.
      • Cherniack R.
      ACCESS Research Group
      Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS).
      ]. Prevalence of familial sarcoidosis, defined as presence or history of sarcoidosis in one or more family members of index patients with sarcoidosis, has been reported or can be obtained from different study populations from nine countries, of which seven European [
      • Headings V.E.
      • Weston D.
      • Young Jr., R.C.
      • hackney Jr., R.L.
      Familial sarcoidosis with multiple occurrences in eleven families: a possible mechanism of inheritance.
      ,
      • Brennan N.J.
      • Crean P.
      • Long J.P.
      • Fitzgerald M.X.
      High prevalence of familial sarcoidosis in an Irish population.
      ,
      • Rybicki B.A.
      • Harrington D.
      • Major M.
      • Simoff M.
      • Popovich Jr., J.
      • Maliarik M.
      • Iannuzzi M.C.
      Heterogeneity of familial risk in sarcoidosis.
      ,
      • Fite E.
      • Alsina J.M.
      • Anto J.M.
      • Morera J.
      Sarcoidosis: family contact study.
      ,
      • Wirnsberger R.M.
      • de Vries J.
      • Wouters E.F.
      • Drent M.
      Clinical presentation of sarcoidosis in The Netherlands an epidemiological study.
      ,
      • Pietinalho A.
      • Ohmichi M.
      • Hirasawa M.
      • Hiraga Y.
      • Lofroos A.B.
      • Selroos O.
      Familial sarcoidosis in Finland and Hokkaido, Japan--a comparative study.
      ,
      • McGrath D.S.
      • Daniil Z.
      • Foley P.
      • du Bois J.L.
      • Lympany P.A.
      • Cullinan P.
      • du Bois R.M.
      Epidemiology of familial sarcoidosis in the UK.
      ,
      • Musellim B.
      • Kumbasar O.O.
      • Ongen G.
      • Cetinkaya E.
      • Turker H.
      • Uzaslan E.
      • Yenturk E.
      • Uzun O.
      • Saglam L.
      • Celik G.
      • Okumus G.
      • Annakkaya A.N.
      • Altiay G.
      • Tabak L.
      • Sakar A.
      • Kiter G.
      • Erturan S.
      • Turktas H.
      • Yalniz E.
      • Akkoclu A.
      • Ogus C.
      • Dogan O.T.
      • Ozkan M.
      • Aktogu S.
      • Uzel I.
      Epidemiological features of Turkish patients with sarcoidosis.
      ,
      • Pacheco Y.
      • Calender A.
      • Israel-Biet D.
      • Roy P.
      • Lebecque S.
      • Cottin V.
      • Bouvry D.
      • Nunes H.
      • Seve P.
      • Perard L.
      • Devouassoux G.
      • Freymond N.
      • Khouatra C.
      • Wallaert B.
      • Lamy R.
      • Elsensohn M.H.
      • Bardel C.
      • Valeyre D.
      GSF group
      Familial vs. sporadic sarcoidosis: BTNL2 polymorphisms, clinical presentations, and outcomes in a French cohort.
      ]. Two studies were done in het United States, the first in an African American study population [
      • Headings V.E.
      • Weston D.
      • Young Jr., R.C.
      • hackney Jr., R.L.
      Familial sarcoidosis with multiple occurrences in eleven families: a possible mechanism of inheritance.
      ], the second in a study population of both African American and European American patients [
      • Rybicki B.A.
      • Harrington D.
      • Major M.
      • Simoff M.
      • Popovich Jr., J.
      • Maliarik M.
      • Iannuzzi M.C.
      Heterogeneity of familial risk in sarcoidosis.
      ]. The diagnosis of sarcoidosis in patients and relatives is mostly either biopsy proven or confirmed by medical record information. In some studies, the diagnosis of sarcoidosis in family members is only self-reported [
      • Wirnsberger R.M.
      • de Vries J.
      • Wouters E.F.
      • Drent M.
      Clinical presentation of sarcoidosis in The Netherlands an epidemiological study.
      ,
      • Pietinalho A.
      • Ohmichi M.
      • Hirasawa M.
      • Hiraga Y.
      • Lofroos A.B.
      • Selroos O.
      Familial sarcoidosis in Finland and Hokkaido, Japan--a comparative study.
      ,
      • Pacheco Y.
      • Calender A.
      • Israel-Biet D.
      • Roy P.
      • Lebecque S.
      • Cottin V.
      • Bouvry D.
      • Nunes H.
      • Seve P.
      • Perard L.
      • Devouassoux G.
      • Freymond N.
      • Khouatra C.
      • Wallaert B.
      • Lamy R.
      • Elsensohn M.H.
      • Bardel C.
      • Valeyre D.
      GSF group
      Familial vs. sporadic sarcoidosis: BTNL2 polymorphisms, clinical presentations, and outcomes in a French cohort.
      ]. It should be noted that the time (span) of inclusion of sarcoidosis index patients differs substantially between studies, varying from a prevalence over 1 year [
      • Pietinalho A.
      • Ohmichi M.
      • Hirasawa M.
      • Hiraga Y.
      • Lofroos A.B.
      • Selroos O.
      Familial sarcoidosis in Finland and Hokkaido, Japan--a comparative study.
      ] to prevalence over 40 years [
      • Rybicki B.A.
      • Harrington D.
      • Major M.
      • Simoff M.
      • Popovich Jr., J.
      • Maliarik M.
      • Iannuzzi M.C.
      Heterogeneity of familial risk in sarcoidosis.
      ]. Taken the preceding into account, the prevalence of familial sarcoidosis among sarcoidosis patients is highest in French (44.7%), African American (35.0%), Dutch (16.5%) and Irish (9.6%) patients. The I2 statistic, as a measure for heterogeneity among the studies, was 98.30% (CI 97.81–98.68); P < 0.0001. Therefore the pooled prevalence proportion with 95% CI was calculated for the random effects model (9.5%; CI 4.6–16.1). Table 1 and Fig. 2 present the results of these analyses together with the forest plot (results for the fixed model are also shown).
      Table 1Prevalence of familial sarcoidosis, defined as presence or history of sarcoidosis in one or more family members of index patients with sarcoidosis.
      StudyCountrySample sizeProportion (%)95% CIWeight (%)
      FixedRandom
      1 Headings (1976)United States8035.024.7 to 46.51.37.8
      2 Brennan (1984)Ireland1149.64.9 to 16.61.88.0
      3 Rybicki (1996)United States80912.610.4 to 15.113.08.5
      4 Wirnsberger (1998)The Netherlands102616.614.3to 19.016.58.5
      5 Fité (1998)Spain1882.10.6 to 5.43.08.2
      6 Pietinalho (1999)Finland13783.62.7to 4.822.18.5
      7 Pietinalho (1999)Japan2084.32.0 to 8.13.48.3
      8 Pietinalho (1999)Finland5714.73.1 to 6.89.28.5
      9 Pietinalho (1999)Japan6862.91.8 to 4.511.08.5
      10 McGrath (2000)United Kingdom4065.93.8 to 8.76.58.4
      11 Musellim (2009)Turkey2931.00.2 to 3.04.78.4
      12 Pacheco (2016)
      In this study prevalence of familial sarcoidosis was not estimated, we calculated a prevalence proportion with the available data.
      France46344.740.1to 49.47.48.4
      Total (fixed effects)62228.88.1 to 9.5100.0100.0
      Total (random effects)62229.54.6 to 16.1100.0100.0
      a In this study prevalence of familial sarcoidosis was not estimated, we calculated a prevalence proportion with the available data.
      Fig. 2
      Fig. 2Pooled prevalence of familial sarcoidosis among sarcoidosis patients.

      3.3 Heritability estimates for sarcoidosis

      In one of the early studies on familial sarcoidosis, heritability of sarcoidosis was estimated to be between 60 and 70% (SE ± 11–18), based on female probands from a study population of 80 African American sarcoidosis patients [
      • Headings V.E.
      • Weston D.
      • Young Jr., R.C.
      • hackney Jr., R.L.
      Familial sarcoidosis with multiple occurrences in eleven families: a possible mechanism of inheritance.
      ]. The findings were mainly limited by a small sample size [
      • Headings V.E.
      • Weston D.
      • Young Jr., R.C.
      • hackney Jr., R.L.
      Familial sarcoidosis with multiple occurrences in eleven families: a possible mechanism of inheritance.
      ]. Later on, Sverrild and colleagues estimated a heritability of sarcoidosis of 66% (CI 45-80), by means of etiological model fitting, in a Danish and Finnish population of 210 twin pairs with at least one proband diagnosed with sarcoidosis. The authors used their national twin registries, that are known as some of the oldest and most well characterized twin registries in the world [
      • Sverrild A.
      • Backer V.
      • Kyvik K.O.
      • Kaprio J.
      • Milman N.
      • Svendsen C.B.
      • Thomsen S.F.
      Heredity in sarcoidosis: a registry-based twin study.
      ]. There were many differences between these heritability studies, for example the study population, the sample size, the time period at which the studies were conducted, and the method used to estimate heritability. It is then striking that both heritability estimates were in between 60 and 70%. These results do suggest the presence of a shared determinant in familial sarcoidosis, as McGrath and colleagues concluded earlier in their study with an ethnically diverse study population from London [
      • McGrath D.S.
      • Daniil Z.
      • Foley P.
      • du Bois J.L.
      • Lympany P.A.
      • Cullinan P.
      • du Bois R.M.
      Epidemiology of familial sarcoidosis in the UK.
      ].
      Although heritability is high, genetic determinants specific for familial sarcoidosis have not been identified. Articles reporting Blau syndrome or genetic associations with disease were outside the scope of this review. Some findings on this topic are however interesting with respect to our review. Early onset sarcoidosis was shown to be linked to the nucleotide binding oligomerization domain containing 2 (NOD2) gene, previously known as CARD15, the same gene that harbors mutations causative of Blau syndrome [
      • Kanazawa N.
      • Okafuji I.
      • Kambe N.
      • Nishikomori R.
      • Nakata-Hizume M.
      • Nagai S.
      • Fuji A.
      • Yuasa T.
      • Manki A.
      • Sakurai Y.
      • Nakajima M.
      • Kobayashi H.
      • Fujiwara I.
      • Tsutsumi H.
      • Utani A.
      • Nishigori C.
      • Heike T.
      • Nakahata T.
      • Miyachi Y.
      Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-kappaB activation: common genetic etiology with Blau syndrome.
      ]. Several studies have shown that this gene is not involved in risk for familial sarcoidosis [
      • Rybicki B.A.
      • Maliarik M.J.
      • Bock C.H.
      • Elston R.C.
      • Baughman R.P.
      • Kimani A.P.
      • Sheffer R.G.
      • Chen K.M.
      • Major M.
      • Popovich Jr., J.
      • Iannuzzi M.C.
      The Blau syndrome gene is not a major risk factor for sarcoidosis.
      ,
      • Schurmann M.
      • Valentonyte R.
      • Hampe J.
      • Muller-Quernheim J.
      • Schwinger E.
      • Schreiber S.
      CARD15 gene mutations in sarcoidosis.
      ]. The strongest genetic associations that were found for sarcoidosis are located at the human leukocyte antigen (HLA) region. In a study of the HLA-region in a German cohort of familial patients with sarcoidosis, significant excess of marker haplotype sharing was found among affected siblings [
      • Schurmann M.
      • Lympany P.A.
      • Reichel P.
      • Muller-Myhsok B.
      • Wurm K.
      • Schlaak M.
      • Muller-Quernheim J.
      • du Bois R.M.
      • Schwinger E.
      Familial sarcoidosis is linked to the major histocompatibility complex region.
      ]. In sarcoidosis, a polymorphism in the HLA class III gene BTNL2 is the strongest risk factor for development of sarcoidosis [
      • Valentonyte R.
      • Hampe J.
      • Huse K.
      • Rosenstiel P.
      • Albrecht M.
      • Stenzel A.
      • Nagy M.
      • Gaede K.I.
      • Franke A.
      • Haesler R.
      • Koch A.
      • Lengauer T.
      • Seegert D.
      • Reiling N.
      • Ehlers S.
      • Schwinger E.
      • Platzer M.
      • Krawczak M.
      • Muller-Quernheim J.
      • Schurmann M.
      • Schreiber S.
      Sarcoidosis is associated with a truncating splice site mutation in BTNL2.
      ]. Analysis of one family with 5 members through 3 generations with severe sarcoidosis showed that all subjects were homozygous for this risk allele [
      • Coudurier M.
      • Freymond N.
      • Aissaoui S.
      • Calender A.
      • Pacheco Y.
      • Devouassoux G.
      Homozygous variant rs2076530 of BTNL2 and familial sarcoidosis.
      ], however, analysis of the BTNL2 variant in French and African American familial cohorts showed that the frequency of the risk allele in familial sarcoidosis was more or less equal to that in sporadic patients with sarcoidosis [
      • Pacheco Y.
      • Calender A.
      • Israel-Biet D.
      • Roy P.
      • Lebecque S.
      • Cottin V.
      • Bouvry D.
      • Nunes H.
      • Seve P.
      • Perard L.
      • Devouassoux G.
      • Freymond N.
      • Khouatra C.
      • Wallaert B.
      • Lamy R.
      • Elsensohn M.H.
      • Bardel C.
      • Valeyre D.
      GSF group
      Familial vs. sporadic sarcoidosis: BTNL2 polymorphisms, clinical presentations, and outcomes in a French cohort.
      ,
      • Rybicki B.A.
      • Walewski J.L.
      • Maliarik M.J.
      • Kian H.
      • Iannuzzi M.C.
      ACCESS Research Group
      The BTNL2 gene and sarcoidosis susceptibility in African Americans and Whites.
      ]. It may therefore be concluded that, so far, common genetic risk factors for familial sarcoidosis are not different from those observed in sporadic disease and that genetic variants with high penetrance have not been identified in familial sarcoidosis. The heritability is used to quantify the role of genetic factors, however, a significant part of familial occurrence cannot be explained by heritable factors and may be explained by environmental factors.

      3.4 Familial sarcoidosis and environmental factors

      In African American siblings, a variety of occupational risk factors have been associated with the occurrence of familial sarcoidosis [
      • Kucera G.P.
      • Rybicki B.A.
      • Kirkey K.L.
      • Coon S.W.
      • Major M.L.
      • Maliarik M.J.
      • Iannuzzi M.C.
      Occupational risk factors for sarcoidosis in African-American siblings.
      ,
      • Rybicki B.A.
      • Amend K.L.
      • Maliarik M.J.
      • Iannuzzi M.C.
      Photocopier exposure and risk of sarcoidosis in African-American sibs.
      ]. Some specific occupational exposures were found to associate with familial sarcoidosis, when exposed for more than 1 year, including titanium (OR, 3.15; CI 1.02 to 9.68) and vegetable dust (OR, 1.82; CI 1.01 to 3.27), and indoor exposure to high humidity (OR, 1.51; CI 1.13 to 2.02), water damage (OR, 1.50; CI 1.11 to 2.03), or musty odours (OR, 1.78; CI 1.32 to 2.40) [
      • Kucera G.P.
      • Rybicki B.A.
      • Kirkey K.L.
      • Coon S.W.
      • Major M.L.
      • Maliarik M.J.
      • Iannuzzi M.C.
      Occupational risk factors for sarcoidosis in African-American siblings.
      ]. Photocopier toner dust was considered an unrecognized antigen in the pathophysiology of some familial patients with sarcoidosis [
      • Rybicki B.A.
      • Amend K.L.
      • Maliarik M.J.
      • Iannuzzi M.C.
      Photocopier exposure and risk of sarcoidosis in African-American sibs.
      ]. In the study by Sverrild and colleagues on familial sarcoidosis with Scandinavian twins, the etiological model that fitted their data best, included both genetic and non-shared environmental effects. The proportion of variance explained by the environmental factors was 34% (CI 20- 55) [
      • Sverrild A.
      • Backer V.
      • Kyvik K.O.
      • Kaprio J.
      • Milman N.
      • Svendsen C.B.
      • Thomsen S.F.
      Heredity in sarcoidosis: a registry-based twin study.
      ]. Gene-environment interactions are particularly interesting, because they might explain the high degree of heterogeneity in disease risk between families. Evidence for such interactions has been presented by Rossman and colleagues, who observed suggestive interaction between HLA DRB1*1101 and exposure to musty odours in the occurrence of pulmonary sarcoidosis in a study population from the ACCESS study, that included the first 474 cases and matched controls [
      • Rossman M.D.
      • Thompson B.
      • Frederick M.
      • Iannuzzi M.C.
      • Rybicki B.A.
      • Pander J.P.
      • Newman L.S.
      • Rose C.
      • Magira E.
      • Monos D.
      ACCESS Group
      HLA and environmental interactions in sarcoidosis.
      ]. Although in the Scandinavian twin study by Sverrild and colleagues on familial sarcoidosis no specific environmental factors were investigated, they confirmed a combined role of genetic and non-shared environmental factors [
      • Sverrild A.
      • Backer V.
      • Kyvik K.O.
      • Kaprio J.
      • Milman N.
      • Svendsen C.B.
      • Thomsen S.F.
      Heredity in sarcoidosis: a registry-based twin study.
      ]. The case series described by Piotrowski and colleagues [
      • Piotrowski W.J.
      • Gorski P.
      • Duda-Szymanska J.
      • Kwiatkowska S.
      Mycobacterium tuberculosis as a sarcoid factor? A case report of family sarcoidosis.
      ] highlights the co-incidence of tuberculosis and familial sarcoidosis and shows that an etiologic role for Mycobacterium tuberculosis in familial sarcoidosis still cannot be excluded. Current understanding on the etiology of sarcoidosis is that there is a role for exogenous and endogenous triggers and, in part genetically determined, cellular function of both innate as well as adaptive immunity [
      • Beijer E.
      • Veltkamp M.
      • Meek B.
      • Moller D.R.
      Etiology and immunopathogenesis of sarcoidosis: novel insights.
      ]. Interestingly, it is known that successful intracellular pathogens can limit parts of immunity, especially M. tuberculosis, that has been found able to evade both innate and adaptive immunity [
      • Goldberg M.F.
      • Saini N.K.
      • Porcelli S.A.
      Evasion of innate and adaptive immunity by Mycobacterium tuberculosis.
      ].

      3.5 Reported relative types in familial sarcoidosis

      Familial relationships in sarcoidosis have been assessed for various relative types, that is (grand)parents, siblings, uncles, nieces etc. Most often, first degree relatives, especially siblings and parents, were reported. Sarcoidosis in grandparents was described in few studies and avuncular relationships have been reported in several studies. Articles reporting relative types in familial sarcoidosis are summarized in Table 2. This includes many case reports or small case series of familial cases; the results of individual studies may therefore be biased. Together, however, the results may be more informative (Table 2). In the study by McGrath and colleagues [
      • McGrath D.S.
      • Daniil Z.
      • Foley P.
      • du Bois J.L.
      • Lympany P.A.
      • Cullinan P.
      • du Bois R.M.
      Epidemiology of familial sarcoidosis in the UK.
      ] there was an equal distribution of mother-child and father-child pairs. However, together, the results do support that familial sarcoidosis occurs more often in siblings compared to parent-child relationships and more often in mother-child relationships compared to father-child relationships. Although findings can be study population specific. In some studies, familial relationships by marriage are reported [
      • Rybicki B.A.
      • Iannuzzi M.C.
      • Frederick M.M.
      • Thompson B.W.
      • Rossman M.D.
      • Bresnitz E.A.
      • Terrin M.L.
      • Moller D.R.
      • Barnard J.
      • Baughman R.P.
      • DePalo L.
      • Hunninghake G.
      • Johns C.
      • Judson M.A.
      • Knatterud G.L.
      • McLennan G.
      • Newman L.S.
      • Rabin D.L.
      • Rose C.
      • Teirstein A.S.
      • Weinberger S.E.
      • Yeager H.
      • Cherniack R.
      ACCESS Research Group
      Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS).
      ,
      • Fite E.
      • Alsina J.M.
      • Anto J.M.
      • Morera J.
      Sarcoidosis: family contact study.
      ,
      • Elford J.
      • Fitch P.
      • Kaminski E.
      • McGavin C.
      • Wells I.P.
      Five cases of sarcoidosis in one family: a new immunological link?.
      ]. As expected, in the ACCESS study the relative risk for spouses was not higher (OR 0.2; CI 0.04–1.1; not statistically significant) [
      • Rybicki B.A.
      • Iannuzzi M.C.
      • Frederick M.M.
      • Thompson B.W.
      • Rossman M.D.
      • Bresnitz E.A.
      • Terrin M.L.
      • Moller D.R.
      • Barnard J.
      • Baughman R.P.
      • DePalo L.
      • Hunninghake G.
      • Johns C.
      • Judson M.A.
      • Knatterud G.L.
      • McLennan G.
      • Newman L.S.
      • Rabin D.L.
      • Rose C.
      • Teirstein A.S.
      • Weinberger S.E.
      • Yeager H.
      • Cherniack R.
      ACCESS Research Group
      Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS).
      ]. Interestingly, in the study by Elford and colleagues [
      • Elford J.
      • Fitch P.
      • Kaminski E.
      • McGavin C.
      • Wells I.P.
      Five cases of sarcoidosis in one family: a new immunological link?.
      ], two genetically unrelated affected family members shared the same HLA haplotype A11-B7-DR15.
      Table 2Reported relative types in familial sarcoidosis.
      Familial relationshipStudy ref (nr)
      First degree relatives[
      • Musellim B.
      • Kumbasar O.O.
      • Ongen G.
      • Cetinkaya E.
      • Turker H.
      • Uzaslan E.
      • Yenturk E.
      • Uzun O.
      • Saglam L.
      • Celik G.
      • Okumus G.
      • Annakkaya A.N.
      • Altiay G.
      • Tabak L.
      • Sakar A.
      • Kiter G.
      • Erturan S.
      • Turktas H.
      • Yalniz E.
      • Akkoclu A.
      • Ogus C.
      • Dogan O.T.
      • Ozkan M.
      • Aktogu S.
      • Uzel I.
      Epidemiological features of Turkish patients with sarcoidosis.
      ]
      First, second and third degree relatives[
      • Wirnsberger R.M.
      • de Vries J.
      • Wouters E.F.
      • Drent M.
      Clinical presentation of sarcoidosis in The Netherlands an epidemiological study.
      ]
      Siblings[
      • Rybicki B.A.
      • Iannuzzi M.C.
      • Frederick M.M.
      • Thompson B.W.
      • Rossman M.D.
      • Bresnitz E.A.
      • Terrin M.L.
      • Moller D.R.
      • Barnard J.
      • Baughman R.P.
      • DePalo L.
      • Hunninghake G.
      • Johns C.
      • Judson M.A.
      • Knatterud G.L.
      • McLennan G.
      • Newman L.S.
      • Rabin D.L.
      • Rose C.
      • Teirstein A.S.
      • Weinberger S.E.
      • Yeager H.
      • Cherniack R.
      ACCESS Research Group
      Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS).
      ,
      • Headings V.E.
      • Weston D.
      • Young Jr., R.C.
      • hackney Jr., R.L.
      Familial sarcoidosis with multiple occurrences in eleven families: a possible mechanism of inheritance.
      ,
      • Cheng D.S.
      • Kitahara M.
      • Logan K.H.
      Chronic granulocytic leukemia: long-term remission in a patient with familial sarcoidosis.
      ,
      • Nowinski T.
      • Flanagan J.
      • Ruchman M.
      Lacrimal gland enlargement in familial sarcoidosis.
      ,
      • Brennan N.J.
      • Crean P.
      • Long J.P.
      • Fitzgerald M.X.
      High prevalence of familial sarcoidosis in an Irish population.
      ,
      • Kremer J.M.
      Histologic findings in siblings with acute sarcoid arthritis: association with the B8,DR3 phenotype.
      ,
      • Luisetti M.
      • Cremaschi P.
      • Rizzo S.
      • Martinetti M.
      • Belvedere M.
      Report of one case of familial sarcoidosis.
      ,
      • Carmichael A.J.
      • Tan C.Y.
      • Smith A.G.
      Familial sarcoidosis: high ethnic prevalence.
      ,
      • Bambery P.
      • Kaur U.
      • Bhusnurmath S.R.
      • Dilawari J.B.
      Familial idiopathic granulomatosis: sarcoidosis and Crohn's disease in two Indian families.
      ,
      • Rybicki B.A.
      • Harrington D.
      • Major M.
      • Simoff M.
      • Popovich Jr., J.
      • Maliarik M.
      • Iannuzzi M.C.
      Heterogeneity of familial risk in sarcoidosis.
      ,
      • Fite E.
      • Alsina J.M.
      • Anto J.M.
      • Morera J.
      Sarcoidosis: family contact study.
      ,
      • Wirnsberger R.M.
      • de Vries J.
      • Wouters E.F.
      • Drent M.
      Clinical presentation of sarcoidosis in The Netherlands an epidemiological study.
      ,
      • Pietinalho A.
      • Ohmichi M.
      • Hirasawa M.
      • Hiraga Y.
      • Lofroos A.B.
      • Selroos O.
      Familial sarcoidosis in Finland and Hokkaido, Japan--a comparative study.
      ,
      • Elford J.
      • Fitch P.
      • Kaminski E.
      • McGavin C.
      • Wells I.P.
      Five cases of sarcoidosis in one family: a new immunological link?.
      ,
      • McGrath D.S.
      • Daniil Z.
      • Foley P.
      • du Bois J.L.
      • Lympany P.A.
      • Cullinan P.
      • du Bois R.M.
      Epidemiology of familial sarcoidosis in the UK.
      ,
      • Sverrild A.
      • Backer V.
      • Kyvik K.O.
      • Kaprio J.
      • Milman N.
      • Svendsen C.B.
      • Thomsen S.F.
      Heredity in sarcoidosis: a registry-based twin study.
      ,
      • Kucera G.P.
      • Rybicki B.A.
      • Kirkey K.L.
      • Coon S.W.
      • Major M.L.
      • Maliarik M.J.
      • Iannuzzi M.C.
      Occupational risk factors for sarcoidosis in African-American siblings.
      ,
      • Rybicki B.A.
      • Amend K.L.
      • Maliarik M.J.
      • Iannuzzi M.C.
      Photocopier exposure and risk of sarcoidosis in African-American sibs.
      ,
      • Piotrowski W.J.
      • Gorski P.
      • Duda-Szymanska J.
      • Kwiatkowska S.
      Mycobacterium tuberculosis as a sarcoid factor? A case report of family sarcoidosis.
      ,
      • Rybicki B.A.
      • Kirkey K.L.
      • Major M.
      • Maliarik M.J.
      • Popovich Jr., J.
      • Chase G.A.
      • Iannuzzi M.C.
      Familial risk ratio of sarcoidosis in African-American sibs and parents.
      ,
      • Judson M.A.
      • Hirst K.
      • Iyengar S.K.
      • Rybicki B.A.
      • El-Ghormli L.
      • Baughman R.P.
      • Donohue J.F.
      • Elston R.C.
      • Kavuru M.S.
      • Moller D.R.
      • Newman L.S.
      • Rabin D.L.
      • Rossman M.D.
      • Teirstein A.S.
      • Iannuzzi M.C.
      SAGA Study Consortium
      Comparison of sarcoidosis phenotypes among affected African-American siblings.
      ,
      • Lazzarini L.C.
      • de Fatima do Amparo Teixeira M.
      • Souza Rodrigues R.
      • Marcos Nunes Valiante P.
      Necrotizing sarcoid granulomatosis in a family of patients with sarcoidosis reinforces the association between both entities.
      ]
      Parent-child[
      • Rybicki B.A.
      • Iannuzzi M.C.
      • Frederick M.M.
      • Thompson B.W.
      • Rossman M.D.
      • Bresnitz E.A.
      • Terrin M.L.
      • Moller D.R.
      • Barnard J.
      • Baughman R.P.
      • DePalo L.
      • Hunninghake G.
      • Johns C.
      • Judson M.A.
      • Knatterud G.L.
      • McLennan G.
      • Newman L.S.
      • Rabin D.L.
      • Rose C.
      • Teirstein A.S.
      • Weinberger S.E.
      • Yeager H.
      • Cherniack R.
      ACCESS Research Group
      Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS).
      ,
      • Rybicki B.A.
      • Harrington D.
      • Major M.
      • Simoff M.
      • Popovich Jr., J.
      • Maliarik M.
      • Iannuzzi M.C.
      Heterogeneity of familial risk in sarcoidosis.
      ,
      • McGrath D.S.
      • Daniil Z.
      • Foley P.
      • du Bois J.L.
      • Lympany P.A.
      • Cullinan P.
      • du Bois R.M.
      Epidemiology of familial sarcoidosis in the UK.
      ,
      • Rybicki B.A.
      • Kirkey K.L.
      • Major M.
      • Maliarik M.J.
      • Popovich Jr., J.
      • Chase G.A.
      • Iannuzzi M.C.
      Familial risk ratio of sarcoidosis in African-American sibs and parents.
      ]
      Mother-child[
      • Headings V.E.
      • Weston D.
      • Young Jr., R.C.
      • hackney Jr., R.L.
      Familial sarcoidosis with multiple occurrences in eleven families: a possible mechanism of inheritance.
      ,
      • Cheng D.S.
      • Kitahara M.
      • Logan K.H.
      Chronic granulocytic leukemia: long-term remission in a patient with familial sarcoidosis.
      ,
      • Soria L.M.
      • Valverde Garcia J.
      • Sole J.M.
      • Badrinas Vancells F.
      Familial sarcoidosis: a case report.
      ,
      • Fite E.
      • Alsina J.M.
      • Anto J.M.
      • Morera J.
      Sarcoidosis: family contact study.
      ,
      • Wirnsberger R.M.
      • de Vries J.
      • Wouters E.F.
      • Drent M.
      Clinical presentation of sarcoidosis in The Netherlands an epidemiological study.
      ,
      • Pietinalho A.
      • Ohmichi M.
      • Hirasawa M.
      • Hiraga Y.
      • Lofroos A.B.
      • Selroos O.
      Familial sarcoidosis in Finland and Hokkaido, Japan--a comparative study.
      ,
      • Elford J.
      • Fitch P.
      • Kaminski E.
      • McGavin C.
      • Wells I.P.
      Five cases of sarcoidosis in one family: a new immunological link?.
      ,
      • Piotrowski W.J.
      • Gorski P.
      • Duda-Szymanska J.
      • Kwiatkowska S.
      Mycobacterium tuberculosis as a sarcoid factor? A case report of family sarcoidosis.
      ,
      • Lazzarini L.C.
      • de Fatima do Amparo Teixeira M.
      • Souza Rodrigues R.
      • Marcos Nunes Valiante P.
      Necrotizing sarcoid granulomatosis in a family of patients with sarcoidosis reinforces the association between both entities.
      ,
      • Perng R.P.
      • Chou K.T.
      • Chu H.
      • Chung Y.M.
      Familial sarcoidosis in Taiwan.
      ]
      Father-child[
      • Wirnsberger R.M.
      • de Vries J.
      • Wouters E.F.
      • Drent M.
      Clinical presentation of sarcoidosis in The Netherlands an epidemiological study.
      ,
      • Pietinalho A.
      • Ohmichi M.
      • Hirasawa M.
      • Hiraga Y.
      • Lofroos A.B.
      • Selroos O.
      Familial sarcoidosis in Finland and Hokkaido, Japan--a comparative study.
      ]
      Grandparents[
      • Rybicki B.A.
      • Iannuzzi M.C.
      • Frederick M.M.
      • Thompson B.W.
      • Rossman M.D.
      • Bresnitz E.A.
      • Terrin M.L.
      • Moller D.R.
      • Barnard J.
      • Baughman R.P.
      • DePalo L.
      • Hunninghake G.
      • Johns C.
      • Judson M.A.
      • Knatterud G.L.
      • McLennan G.
      • Newman L.S.
      • Rabin D.L.
      • Rose C.
      • Teirstein A.S.
      • Weinberger S.E.
      • Yeager H.
      • Cherniack R.
      ACCESS Research Group
      Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS).
      ,
      • Headings V.E.
      • Weston D.
      • Young Jr., R.C.
      • hackney Jr., R.L.
      Familial sarcoidosis with multiple occurrences in eleven families: a possible mechanism of inheritance.
      ]
      Avuncular[
      • Rybicki B.A.
      • Iannuzzi M.C.
      • Frederick M.M.
      • Thompson B.W.
      • Rossman M.D.
      • Bresnitz E.A.
      • Terrin M.L.
      • Moller D.R.
      • Barnard J.
      • Baughman R.P.
      • DePalo L.
      • Hunninghake G.
      • Johns C.
      • Judson M.A.
      • Knatterud G.L.
      • McLennan G.
      • Newman L.S.
      • Rabin D.L.
      • Rose C.
      • Teirstein A.S.
      • Weinberger S.E.
      • Yeager H.
      • Cherniack R.
      ACCESS Research Group
      Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS).
      ,
      • Turner R.G.
      • James D.G.
      • Friedmann A.I.
      • Vijendram M.
      • Davies J.P.
      Neuro-ophthalmic sarcoidosis.
      ,
      • Headings V.E.
      • Weston D.
      • Young Jr., R.C.
      • hackney Jr., R.L.
      Familial sarcoidosis with multiple occurrences in eleven families: a possible mechanism of inheritance.
      ,
      • Bambery P.
      • Kaur U.
      • Bhusnurmath S.R.
      • Dilawari J.B.
      Familial idiopathic granulomatosis: sarcoidosis and Crohn's disease in two Indian families.
      ,
      • Fite E.
      • Alsina J.M.
      • Anto J.M.
      • Morera J.
      Sarcoidosis: family contact study.
      ,
      • Pietinalho A.
      • Ohmichi M.
      • Hirasawa M.
      • Hiraga Y.
      • Lofroos A.B.
      • Selroos O.
      Familial sarcoidosis in Finland and Hokkaido, Japan--a comparative study.
      ,
      • McGrath D.S.
      • Daniil Z.
      • Foley P.
      • du Bois J.L.
      • Lympany P.A.
      • Cullinan P.
      • du Bois R.M.
      Epidemiology of familial sarcoidosis in the UK.
      ,
      • Lazzarini L.C.
      • de Fatima do Amparo Teixeira M.
      • Souza Rodrigues R.
      • Marcos Nunes Valiante P.
      Necrotizing sarcoid granulomatosis in a family of patients with sarcoidosis reinforces the association between both entities.
      ]
      Relationships by marriage[
      • Rybicki B.A.
      • Iannuzzi M.C.
      • Frederick M.M.
      • Thompson B.W.
      • Rossman M.D.
      • Bresnitz E.A.
      • Terrin M.L.
      • Moller D.R.
      • Barnard J.
      • Baughman R.P.
      • DePalo L.
      • Hunninghake G.
      • Johns C.
      • Judson M.A.
      • Knatterud G.L.
      • McLennan G.
      • Newman L.S.
      • Rabin D.L.
      • Rose C.
      • Teirstein A.S.
      • Weinberger S.E.
      • Yeager H.
      • Cherniack R.
      ACCESS Research Group
      Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS).
      ,
      • Fite E.
      • Alsina J.M.
      • Anto J.M.
      • Morera J.
      Sarcoidosis: family contact study.
      ,
      • Elford J.
      • Fitch P.
      • Kaminski E.
      • McGavin C.
      • Wells I.P.
      Five cases of sarcoidosis in one family: a new immunological link?.
      ]

      3.6 Measurement of familial aggregation for various relative types

      Familial clustering of disease is most commonly measured by two methods that use relative risks [
      • Frisell T.
      • Saevarsdottir S.
      • Askling J.
      Family history of rheumatoid arthritis: an old concept with new developments.
      ]. The first method: λ = risk in relative of affected individual/risk in the general population; and the second method: familial risk = risk in relative of affected individual/risk in relative of unaffected individual. In most situations, with these two definitions the familial risk will be roughly equal; the translation between measures is dependent on disease prevalence [
      • Frisell T.
      • Saevarsdottir S.
      • Askling J.
      Family history of rheumatoid arthritis: an old concept with new developments.
      ]. A major limitation to the measurement of familial aggregation of sarcoidosis so far, is that the absolute number of (familial) cases is generally low, even in the largest study [
      • Rybicki B.A.
      • Iannuzzi M.C.
      • Frederick M.M.
      • Thompson B.W.
      • Rossman M.D.
      • Bresnitz E.A.
      • Terrin M.L.
      • Moller D.R.
      • Barnard J.
      • Baughman R.P.
      • DePalo L.
      • Hunninghake G.
      • Johns C.
      • Judson M.A.
      • Knatterud G.L.
      • McLennan G.
      • Newman L.S.
      • Rabin D.L.
      • Rose C.
      • Teirstein A.S.
      • Weinberger S.E.
      • Yeager H.
      • Cherniack R.
      ACCESS Research Group
      Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS).
      ].
      In three of the included studies, by Rybicki and McGrath and colleagues [
      • Rybicki B.A.
      • Iannuzzi M.C.
      • Frederick M.M.
      • Thompson B.W.
      • Rossman M.D.
      • Bresnitz E.A.
      • Terrin M.L.
      • Moller D.R.
      • Barnard J.
      • Baughman R.P.
      • DePalo L.
      • Hunninghake G.
      • Johns C.
      • Judson M.A.
      • Knatterud G.L.
      • McLennan G.
      • Newman L.S.
      • Rabin D.L.
      • Rose C.
      • Teirstein A.S.
      • Weinberger S.E.
      • Yeager H.
      • Cherniack R.
      ACCESS Research Group
      Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS).
      ,
      • McGrath D.S.
      • Daniil Z.
      • Foley P.
      • du Bois J.L.
      • Lympany P.A.
      • Cullinan P.
      • du Bois R.M.
      Epidemiology of familial sarcoidosis in the UK.
      ,
      • Rybicki B.A.
      • Kirkey K.L.
      • Major M.
      • Maliarik M.J.
      • Popovich Jr., J.
      • Chase G.A.
      • Iannuzzi M.C.
      Familial risk ratio of sarcoidosis in African-American sibs and parents.
      ], familial aggregation of sarcoidosis was measured with these different methods. In the ACCESS study, a particular statistical method (method of Liang) was used to account for possible family correlation structures. With this method odds ratios and p values were calculated for covariates in all familial aggregation models [
      • Rybicki B.A.
      • Iannuzzi M.C.
      • Frederick M.M.
      • Thompson B.W.
      • Rossman M.D.
      • Bresnitz E.A.
      • Terrin M.L.
      • Moller D.R.
      • Barnard J.
      • Baughman R.P.
      • DePalo L.
      • Hunninghake G.
      • Johns C.
      • Judson M.A.
      • Knatterud G.L.
      • McLennan G.
      • Newman L.S.
      • Rabin D.L.
      • Rose C.
      • Teirstein A.S.
      • Weinberger S.E.
      • Yeager H.
      • Cherniack R.
      ACCESS Research Group
      Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS).
      ]. The results are presented in Table 3. In the combined ACCESS study sample of both European American and African American case control pairs, it was found that the relative risk in both avuncular relationships (OR 5.7; CI 1.6–20.7) and grandparents (OR 5.2; CI 1.5–18.0) may be higher than in parents (OR 3.8; CI 1.2–11.3) [
      • Rybicki B.A.
      • Iannuzzi M.C.
      • Frederick M.M.
      • Thompson B.W.
      • Rossman M.D.
      • Bresnitz E.A.
      • Terrin M.L.
      • Moller D.R.
      • Barnard J.
      • Baughman R.P.
      • DePalo L.
      • Hunninghake G.
      • Johns C.
      • Judson M.A.
      • Knatterud G.L.
      • McLennan G.
      • Newman L.S.
      • Rabin D.L.
      • Rose C.
      • Teirstein A.S.
      • Weinberger S.E.
      • Yeager H.
      • Cherniack R.
      ACCESS Research Group
      Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS).
      ]. Relative risks, calculated for first degree familial relationships sibs and parents combined were higher in European American subjects with an OR of 16.6 (CI 2.2–126.1) compared to African American subjects with an OR of 3.1 (CI 1.4–7.1). In another study in 179 African American families, a familial risk ratio (λ) was calculated [
      • Rybicki B.A.
      • Kirkey K.L.
      • Major M.
      • Maliarik M.J.
      • Popovich Jr., J.
      • Chase G.A.
      • Iannuzzi M.C.
      Familial risk ratio of sarcoidosis in African-American sibs and parents.
      ], between 1970 and 1999. The familial risk ratios in family members were more or less similar to the relative risks of African American subjects from the ACCESS study: λ 2.24 (CI 1.16–3.92) versus OR 5.1 (CI 1.6–16.4) for sibs and λ 2.82 (CI 1.41–5.05) versus OR 1.8 (CI 0.5–6.0) for parents. The familial risk ratio for parents and sibs combined was λ 2.49 (CI 1.58–3.73) versus OR 3.1 (CI 1.4–7.1). The extremely high λ of 36–73 in the London cohort [
      • McGrath D.S.
      • Daniil Z.
      • Foley P.
      • du Bois J.L.
      • Lympany P.A.
      • Cullinan P.
      • du Bois R.M.
      Epidemiology of familial sarcoidosis in the UK.
      ] was calculated in a different way and the size may be due to bias in comparing the prevalence of familial sarcoidosis with population prevalence estimates [
      • Rybicki B.A.
      • Iannuzzi M.C.
      • Frederick M.M.
      • Thompson B.W.
      • Rossman M.D.
      • Bresnitz E.A.
      • Terrin M.L.
      • Moller D.R.
      • Barnard J.
      • Baughman R.P.
      • DePalo L.
      • Hunninghake G.
      • Johns C.
      • Judson M.A.
      • Knatterud G.L.
      • McLennan G.
      • Newman L.S.
      • Rabin D.L.
      • Rose C.
      • Teirstein A.S.
      • Weinberger S.E.
      • Yeager H.
      • Cherniack R.
      ACCESS Research Group
      Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS).
      ]. The results primarily show that the subject deserves further investigation, because the high familial relative risk for disease in family members of specific groups of patients with sarcoidosis may be clinically useful.
      Table 3Measures of familial aggregation of sarcoidosis for various relative types.
      Familial relative risks and familial risk ratios (λ) in various relative typesStudy populationStudy ref (nr)
      Sibs: λ 2.24 (1.16, 3.9327 siblings

      Parents: λ 2.82 (1.41, 5.05) 161 parents
      Family study with 179 African American families ascertained through index sarcoidosis cases diagnosed at Henry Ford Hospital in Detroit, Michigan, between 1970 and 1999.[
      • Rybicki B.A.
      • Kirkey K.L.
      • Major M.
      • Maliarik M.J.
      • Popovich Jr., J.
      • Chase G.A.
      • Iannuzzi M.C.
      Familial risk ratio of sarcoidosis in African-American sibs and parents.
      ]
      Sibs: λ 36-73 38 siblings of 15 index patients with an affected siblingSurvey among 406 index patients with sarcoidosis, from a hospital in London (62.2% Caucasian, 37.4% Afro-Caribbean and 11.8% Asian), attending the Royal Brompton Hospital between the years 1990 and 1995[
      • McGrath D.S.
      • Daniil Z.
      • Foley P.
      • du Bois J.L.
      • Lympany P.A.
      • Cullinan P.
      • du Bois R.M.
      Epidemiology of familial sarcoidosis in the UK.
      ]
      Sibs OR
      In the ACCESS study (ACCESS), the method of Liang was used to calculate odds ratios and p values for covariates in all familial aggregation models.
      5.8 (2.1–15.9) 2722 cases/2587 controls

      Avuncular OR 5.7 (1.6–20.7) 5884 cases/5435 controls

      Grandparents OR 5.2 (1.5–18.0) 2936 cases/2792 controls

      Parents OR 3.8 (1.2–11.3) 1468 cases/1396 controls

      Children OR 3.3 (0.3–32.2) 1335 cases/1354 controls

      Spouses OR 0.2 (0.04–1.1) 702 cases/700 controls
      355 European American and 291 African American case-control pairs, who participated in the multicenter ACCESS (A Case–Control Etiology Study of Sarcoidosis) study from 1996 to 1999.[
      • Rybicki B.A.
      • Iannuzzi M.C.
      • Frederick M.M.
      • Thompson B.W.
      • Rossman M.D.
      • Bresnitz E.A.
      • Terrin M.L.
      • Moller D.R.
      • Barnard J.
      • Baughman R.P.
      • DePalo L.
      • Hunninghake G.
      • Johns C.
      • Judson M.A.
      • Knatterud G.L.
      • McLennan G.
      • Newman L.S.
      • Rabin D.L.
      • Rose C.
      • Teirstein A.S.
      • Weinberger S.E.
      • Yeager H.
      • Cherniack R.
      ACCESS Research Group
      Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS).
      ]
      *Numbers between brackets represent 95% confidence intervals. In italic the number of individuals used for the calculations.
      a In the ACCESS study (ACCESS), the method of Liang was used to calculate odds ratios and p values for covariates in all familial aggregation models.

      3.7 Heterogeneity of sarcoidosis familial risk

      Studies have shown that African Americans are more commonly and severely affected by sarcoidosis compared with European Americans and that prevalence of a family history of sarcoidosis is also higher in African Americans [
      • Rybicki B.A.
      • Harrington D.
      • Major M.
      • Simoff M.
      • Popovich Jr., J.
      • Maliarik M.
      • Iannuzzi M.C.
      Heterogeneity of familial risk in sarcoidosis.
      ]. Therefore, etiologic heterogeneity has been suspected [
      • Rybicki B.A.
      • Harrington D.
      • Major M.
      • Simoff M.
      • Popovich Jr., J.
      • Maliarik M.
      • Iannuzzi M.C.
      Heterogeneity of familial risk in sarcoidosis.
      ]. Rybicki and colleagues assessed heterogeneity among sarcoidosis families by means of a non-parametric statistical method, in a study population of 361 African American and 197 European American families(14). The results confirmed heterogeneity in disease risk, more pronounced in African American families compared to European American families. Characteristics of the index sarcoidosis patients that were found to be associated with high-risk families were: African American race (OR 3.24; CI 1.71–6.14) and having an affected offspring or second-degree relative with sarcoidosis (OR 6.21; CI 2.85–13.45) [
      • Rybicki B.A.
      • Harrington D.
      • Major M.
      • Simoff M.
      • Popovich Jr., J.
      • Maliarik M.
      • Iannuzzi M.C.
      Heterogeneity of familial risk in sarcoidosis.
      ]. It was thought that in African American families there may be a greater sharing of transmissible disease risk factors among family members [
      • Rybicki B.A.
      • Harrington D.
      • Major M.
      • Simoff M.
      • Popovich Jr., J.
      • Maliarik M.
      • Iannuzzi M.C.
      Heterogeneity of familial risk in sarcoidosis.
      ].
      In the ACCESS study [
      • Rybicki B.A.
      • Iannuzzi M.C.
      • Frederick M.M.
      • Thompson B.W.
      • Rossman M.D.
      • Bresnitz E.A.
      • Terrin M.L.
      • Moller D.R.
      • Barnard J.
      • Baughman R.P.
      • DePalo L.
      • Hunninghake G.
      • Johns C.
      • Judson M.A.
      • Knatterud G.L.
      • McLennan G.
      • Newman L.S.
      • Rabin D.L.
      • Rose C.
      • Teirstein A.S.
      • Weinberger S.E.
      • Yeager H.
      • Cherniack R.
      ACCESS Research Group
      Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS).
      ], sibs and parents of European American patients (OR16.6; CI 2.2–126.1) had a markedly higher familial relative risk compared with those of African-American patients (OR3.1; CI 1.4–7.1). The authors concluded that the disproportionately higher familial relative risk found in European Americans compared with African-Americans suggests genetic factors may exert a more detectable effect in European American families with sarcoidosis [
      • Rybicki B.A.
      • Iannuzzi M.C.
      • Frederick M.M.
      • Thompson B.W.
      • Rossman M.D.
      • Bresnitz E.A.
      • Terrin M.L.
      • Moller D.R.
      • Barnard J.
      • Baughman R.P.
      • DePalo L.
      • Hunninghake G.
      • Johns C.
      • Judson M.A.
      • Knatterud G.L.
      • McLennan G.
      • Newman L.S.
      • Rabin D.L.
      • Rose C.
      • Teirstein A.S.
      • Weinberger S.E.
      • Yeager H.
      • Cherniack R.
      ACCESS Research Group
      Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS).
      ]. With respect to these findings it should be noted that the variable race or ethnicity is difficult to measure and use in research, because it is composed of various characteristics (such as shared origins or social background; shared culture or tradition; and a common language or religious tradition) that may change over time [
      • Agyemang C.
      • Bhopal R.
      • Bruijnzeels M.
      Negro, Black, Black African, African Caribbean, African American or what? Labelling African origin populations in the health arena in the 21st century.
      ]. Thus, further stratification in future studies, especially of the African American cohort, might be informative with respect to the familial variation in disease risks.

      3.8 Clinical findings in familial sarcoidosis

      Perhaps most in line with the aim of our review, that is to support in clinical decision making and providing information to patients, we searched for clinical findings in the included studies. Pietinalho and colleagues [
      • Pietinalho A.
      • Ohmichi M.
      • Hirasawa M.
      • Hiraga Y.
      • Lofroos A.B.
      • Selroos O.
      Familial sarcoidosis in Finland and Hokkaido, Japan--a comparative study.
      ] were the first to make a clinical comparison between sporadic and familial cases of sarcoidosis in Finnish (56 familial/544 non-familial cases) and Japanese (40 familial/646 non-familial cases) patients with sarcoidosis. They found no statistically significant differences between familial and sporadic sarcoidosis in either sarcoidosis patients from Finland or Japan. However, familial patients in both areas had a slightly less favourable prognosis compared with sporadic patients, based on normalization of chest radiography during five-year follow-up. There was no trend over time, but the differences were larger for the Japanese patients [
      • Pietinalho A.
      • Ohmichi M.
      • Hirasawa M.
      • Hiraga Y.
      • Lofroos A.B.
      • Selroos O.
      Familial sarcoidosis in Finland and Hokkaido, Japan--a comparative study.
      ]. In Spain [
      • Fite E.
      • Alsina J.M.
      • Anto J.M.
      • Morera J.
      Sarcoidosis: family contact study.
      ], Löfgren syndrome was observed frequently and also occurred more often in the familial cases of sarcoidosis. Notably, most sarcoidosis cases in that study were female [
      • Fite E.
      • Alsina J.M.
      • Anto J.M.
      • Morera J.
      Sarcoidosis: family contact study.
      ]. Others reported rare clinical presentations in familial sarcoidosis, including neuro-ophthalmic sarcoidosis occurring in a woman, whose paternal-uncle also had sarcoidosis [
      • Turner R.G.
      • James D.G.
      • Friedmann A.I.
      • Vijendram M.
      • Davies J.P.
      Neuro-ophthalmic sarcoidosis.
      ], and sarcoidosis of the lacrimal gland in two sisters [
      • Nowinski T.
      • Flanagan J.
      • Ruchman M.
      Lacrimal gland enlargement in familial sarcoidosis.
      ]. By means of phenotypic expression modeling in African American sibling pairs using logistic regression, increased risks for ocular (OR 3; CI 1.7–5.4) and liver involvement (OR 3.3; CI 1.5–7.4) were found in the affected sibs [
      • Judson M.A.
      • Hirst K.
      • Iyengar S.K.
      • Rybicki B.A.
      • El-Ghormli L.
      • Baughman R.P.
      • Donohue J.F.
      • Elston R.C.
      • Kavuru M.S.
      • Moller D.R.
      • Newman L.S.
      • Rabin D.L.
      • Rossman M.D.
      • Teirstein A.S.
      • Iannuzzi M.C.
      SAGA Study Consortium
      Comparison of sarcoidosis phenotypes among affected African-American siblings.
      ]. Recently, Pacheco and colleagues [
      • Pacheco Y.
      • Calender A.
      • Israel-Biet D.
      • Roy P.
      • Lebecque S.
      • Cottin V.
      • Bouvry D.
      • Nunes H.
      • Seve P.
      • Perard L.
      • Devouassoux G.
      • Freymond N.
      • Khouatra C.
      • Wallaert B.
      • Lamy R.
      • Elsensohn M.H.
      • Bardel C.
      • Valeyre D.
      GSF group
      Familial vs. sporadic sarcoidosis: BTNL2 polymorphisms, clinical presentations, and outcomes in a French cohort.
      ] did a more extensive comparison between patients with familial (207 cases) and sporadic sarcoidosis (256 cases) from France. In this study, the combination of lung and skin involvement at diagnosis [
      • Pacheco Y.
      • Calender A.
      • Israel-Biet D.
      • Roy P.
      • Lebecque S.
      • Cottin V.
      • Bouvry D.
      • Nunes H.
      • Seve P.
      • Perard L.
      • Devouassoux G.
      • Freymond N.
      • Khouatra C.
      • Wallaert B.
      • Lamy R.
      • Elsensohn M.H.
      • Bardel C.
      • Valeyre D.
      GSF group
      Familial vs. sporadic sarcoidosis: BTNL2 polymorphisms, clinical presentations, and outcomes in a French cohort.
      ] and a younger age at diagnosis were more frequently observed in familial sarcoidosis [
      • Pacheco Y.
      • Calender A.
      • Israel-Biet D.
      • Roy P.
      • Lebecque S.
      • Cottin V.
      • Bouvry D.
      • Nunes H.
      • Seve P.
      • Perard L.
      • Devouassoux G.
      • Freymond N.
      • Khouatra C.
      • Wallaert B.
      • Lamy R.
      • Elsensohn M.H.
      • Bardel C.
      • Valeyre D.
      GSF group
      Familial vs. sporadic sarcoidosis: BTNL2 polymorphisms, clinical presentations, and outcomes in a French cohort.
      ]. Because others had not reported differences in age at diagnosis between familial and sporadic patients, it was thought that the observation of a younger age at diagnosis in familial sarcoidosis patients, could reflect earlier establishment of the diagnosis. Furthermore, differences in disease outcome were found by means of the Sarcoid Clinical Activity Classification (SCAC) [
      • Prasse A.
      • Katic C.
      • Germann M.
      • Buchwald A.
      • Zissel G.
      • Muller-Quernheim J.
      Phenotyping sarcoidosis from a pulmonary perspective.
      ], that is composed of six progression patterns and, whenever possible, a classification of outcome in four categories: 1) recovery within 3 years; 2) recovery between 3 and 5 years; 3) no recovery at 5 years; 4) death [
      • Pacheco Y.
      • Calender A.
      • Israel-Biet D.
      • Roy P.
      • Lebecque S.
      • Cottin V.
      • Bouvry D.
      • Nunes H.
      • Seve P.
      • Perard L.
      • Devouassoux G.
      • Freymond N.
      • Khouatra C.
      • Wallaert B.
      • Lamy R.
      • Elsensohn M.H.
      • Bardel C.
      • Valeyre D.
      GSF group
      Familial vs. sporadic sarcoidosis: BTNL2 polymorphisms, clinical presentations, and outcomes in a French cohort.
      ]. The authors consider a lack of power regarding the classification of outcome. However, familial sarcoidosis patients appeared to receive less treatment and to recover less often between 3 and 5 years [
      • Pacheco Y.
      • Calender A.
      • Israel-Biet D.
      • Roy P.
      • Lebecque S.
      • Cottin V.
      • Bouvry D.
      • Nunes H.
      • Seve P.
      • Perard L.
      • Devouassoux G.
      • Freymond N.
      • Khouatra C.
      • Wallaert B.
      • Lamy R.
      • Elsensohn M.H.
      • Bardel C.
      • Valeyre D.
      GSF group
      Familial vs. sporadic sarcoidosis: BTNL2 polymorphisms, clinical presentations, and outcomes in a French cohort.
      ]. We conclude that limited studies describe clinical findings in familial sarcoidosis and that scarce results show little overlap. Also, there was no standardized assessment of organ involvement across the different studies included in this review, such standardized assessment is currently available and would aid comparison between studies [
      • Judson M.A.
      • Costabel U.
      • Drent M.
      • Wells A.
      • Maier L.
      • Koth L.
      • Shigemitsu H.
      • Culver D.A.
      • Gelfand J.
      • Valeyre D.
      • Sweiss N.
      • Crouser E.
      • Morgenthau A.S.
      • Lower E.E.
      • Azuma A.
      • Ishihara M.
      • Morimoto S.
      • Tetsuo Yamaguchi T.
      • Shijubo N.
      • Grutters J.C.
      • Rosenbach M.
      • Li H.P.
      • Rottoli P.
      • Inoue Y.
      • Prasse A.
      • Baughman R.P.
      Organ assessment instrument investigators TW. The WASOG sarcoidosis organ assessment instrument: an update of a previous clinical tool.
      ]. Even so, several studies described more severe disease and multi-organ involvements in familial patients, which deserves further investigation.

      4. Conclusions

      Prevalence of familial sarcoidosis is high in specific study populations from countries worldwide. The estimated heritability of 60–70%, suggests a shared determinant, and the heterogeneous familial risk, associated with both genetic and environmental factors. Familial relative risks and clinical phenotypes may differ between ethnic groups and relative types, but require further study. These findings are potentially important in patient care and deserve investigation in the future.

      Declarations of interest

      None.

      Acknowledgements

      The authors thank Ms Carla Sloof, librarian at St. Antonius hospital, Nieuwegein, for her effort in setting up a systematic PubMed search; Ms Ellen Tromp, epidemiologist at St. Antonius hospital, Nieuwegein, for her consultation in statistical analyses. This study is part of the TopZorg Lung grant funded by ZonMw (nr 842002001).

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