Familial risk and phenotypic variation of sarcoidosis in the Icelandic population

Abstract

Background: The familial risk of sarcoidosis is heterogeneous, and previous studies demonstrate conflicting results. The present study maps the pattern of familial distribution of all known, biopsy-verified sarcoidosis in the Icelandic population (1981-2021).

Methods: All cases were re-confirmed and categorised into one of the five phenotypic groups described by Schupp et al., and in different groups based on disease severity. Distant relationships were accurately traced for relatives of sarcoidosis patients and their mates using the nationwide Icelandic Genealogy Database. This allows creation of matched control groups for the calculation of relative risk and kinship coefficient (KC).

Results: 462 patients with biopsy-proven diagnoses of sarcoidosis were included. We identified 282 extended families and seven sibling pairs with sarcoidosis. 20 families had five or more affected individuals. Relative risk (RR) was 3.7 (95% CI 1.54-8.55) in 1st-degree relatives (p=0.003), 1.65 (1.05-1.92) in 4th-degree relatives (p=0.014) and 1.57 (1.08-1.70) in 5th-degree relatives (p=0.003). RRs among 1st-5th degree relatives of the patients' mates were not significant. KC for sarcoidosis was only significant for the first two meioses (KC=1.06, p<0.008 and KC=1.01, p=0.011, respectively). The most common sarcoidosis phenotypes were pulmonary-lymphonodal (47.6%), ocular-cardiac-cutaneous and central nervous system (21.6%), and musculoskeletal cutaneous (20.9%). There seems to be no clustering of a single phenotype or resistant sarcoidosis in the extended sarcoidosis families.

Conclusion: Our study does not consider heritability a strong risk factor for sarcoidosis. The risk is highest for 1st-degree relatives of patients with sarcoidosis. Single phenotypes and resistant sarcoidosis do not cluster in distinct families.

FIGURE 1

Overview of the data collection.

FIGURE 2

Ancestral pedigree of sarcoidosis patients. This ancestral pedigree was created by using the nationwide Icelandic Genealogy Database and shows patients with sarcoidosis extended over seven generations. Disease status is only known for the later generations. To protect the anonymity of the families, some of the unaffected relatives in the pedigree are not shown. The circles denote female family members and the squares male family members. The colour-coded circles represent the dominant phenotypes of the disease: musculoskeletal cutaneous phenotype; pulmonary and intrathoracic phenotype; ocular, cardiac, cutaneous and central nervous system (OCCC) phenotype.

FIGURE 3

Ancestral pedigree of sarcoidosis patients, with a sibling pair. A sibling pair in one of the 20 families having more than five individuals diagnosed with sarcoidosis found in the nationwide Icelandic Genealogy Database. The sibling pair had different phenotypes: musculoskeletal cutaneous and pulmonary. OCCC: ocular, cardiac, cutaneous and central nervous system.

FIGURE 4

Kinship coefficient (KC) for developing sarcoidosis. Mean KC value of sarcoidosis patients is compared to mean KC of 1000 matched control groups. The KC value declares the likelihood that two randomly picked alleles from two individuals were inherited from the same ancestor.

FIGURE 5

Overview of the phenotypic distribution of the Icelandic sarcoidosis population. Histogram showing how the phenotypic groups described by Schupp et al. [25] are distributed across the Icelandic sarcoidosis population. Of the five groups, the largest phenotypes were the pulmonary and intrathoracic group (pulmonary) (n=220), ocular–cardiac–cutaneous–central nervous system (OCCC) group (n=100) and musculoskeletal cutaneous (MSC) group (n=97). The extrapulmonary (n=8) and abdominal group (n=12) had the smallest patient number. There were 25 sarcoidosis patients in which complete information regarding the phenotype could not be found (no info).