Familial vs. sporadic sarcoidosis: BTNL2 polymorphisms, clinical presentations, and outcomes in a French cohort

Abstract

BackgroundThe occurrence of familial forms of sarcoidosis (OMIM 181100) suggests a genetic predisposition. The involvement of butyrophilin-like 2 (BTNL2) gene (rs2076530 variant) has to be investigated.ResultsThe study performed independent analyses of BTNL2 polymorphism, clinical phenotypes, and outcomes in familial vs. sporadic presentations in 256 sporadic and 207 familial cases from 140 families. The logistic multivariate model showed that a young age at diagnosis and the combination of lung and skin involvement at diagnosis may distinguish sporadic from familial sarcoidosis (p = 0.016 and p = 0.041). We observed also that Sarcoid Clinical Activity Classification (SCAC) profiles were significantly different between familial and sporadic cases (p = 0.0497).Variant rs2076530 was more frequent in patients than in controls (OR = 2.02; 95% CI: [1.32–3.09]) but showed no difference between sporadic and familial cases and no difference according to the clinical phenotype or the outcome.ConclusionDespite a significant difference in BTNL2 polymorphism between sarcoid patients and controls, there was no such difference between familial and sporadic sarcoidosis cases and no correlation between BTNL2 polymorphism and disease severity or outcome. Thus, BTNL2 difference cannot be considered as a key marker for disease classification or patient management.

Familial aggregation and heritability of sarcoidosis: a Swedish nested case−control study

“…Despite small numbers, analyses using information on sarcoidosis phenotype from our clinical cohort at Karolinska University Hospital indicated stronger familial associations for disease manifesting as Löfgren's compared to non-Löfgren's disease. This is in line with previous investigations describing Löfgren-like disease being somewhat more prevalent in familial than nonfamilial disease [13,30]. While this finding needs more exploration and replication by other studies, it may be suggestive of a stronger genetic association in Löfgren's compared to non-Löfgren's disease [7], providing also a reasonable, albeit partial, explanation for the differences between the two manifestations of sarcoidosis in terms of phenotype and prognosis [18][19][20].…”

Whole exome sequencing in three families segregating a pediatric case of sarcoidosis

“…Two sets of observations indicate a strong genetic heterogeneity. First, the rate of familial sarcoidosis remains low (3 to 5%) with most of the cases being a priori sporadic cases [ 7 ]. Second, a wide range of genetic variants have been previously identified by association studies in genes that may play a role in the pathogenesis of sarcoidosis, such as HLA-DP, BTNL2, Annexin A11, Toll-like receptors, CCDC88B (coiled-coil domain containing protein 88B), Ataxin/SH2B adapter protein 3, IL12B and NF-kappa-B p105 subunit [ 9 , 29 , 30 ].…”

“…The pedigree analysis suggests an autosomal dominant mode with incomplete penetrance. The French National SARCFAM study, based on a clinical network including 29 clinical centers, allowed the collection of clinical data and DNA samples of a cohort of 140 families with at least two first-degree relatives affected by sarcoidosis and rare situations of nuclear families with pediatric cases [ 7 ]. We gave priority consideration to the analysis of pediatric clinical situations in which the child with sarcoidosis has healthy parents, ie trios, expecting that new mutations and /or gene variants transmitted on a recessive pattern may highlight specific genetic pathways involved in the disease.…”

“…Initially the genetic studies were focused on the genes previously identified by GWAS as putative pathogenic determinants in the risk of sarcoidosis. One of candidate gene, BTNL2, codes a cofactor of CD86, a regulator of T-cell activation, and a BTNL2 rs2076530 SNP splicing variant has been shown to induce an ≈ 2.0 fold increase in risk of occurrence of the disease [ 7 , 8 ]. However, we have previously shown that this variant did not discriminate the sporadic and familial forms of the disease, thus suggesting BTNL2 is not a major gene predisposing to sarcoidosis [ 7 ].…”

“…One of candidate gene, BTNL2, codes a cofactor of CD86, a regulator of T-cell activation, and a BTNL2 rs2076530 SNP splicing variant has been shown to induce an ≈ 2.0 fold increase in risk of occurrence of the disease [ 7 , 8 ]. However, we have previously shown that this variant did not discriminate the sporadic and familial forms of the disease, thus suggesting BTNL2 is not a major gene predisposing to sarcoidosis [ 7 ]. GWAS studies in several series have identified SNP’s directly or indirectly implicated in innate immunity, such as HLADRB, CCDC88B, ANNEXINA11 (ANXA11), XAF1 and other candidate loci [ 9 ].…”