BTNL2 gene SNPs as a contributing factor to sarcoidosis pathogenesis in a cohort of Greek patients

Abstract

Sarcoidosis is a multisystemic granulomatous disease of unknown etiology that primarily affects adults between the ages of 20 and 40 years old. It is characterized by the activation of Th1 lymphocytes resulting in the production of inflammatory cytokines and the formation of noncaseating epithelioid cell granulomas in affected tissues. The lungs and lymphatic system are the ones most frequently affected. The disease usually presents spontaneous remission in the first two years and, in a few patients, the disease progresses to pulmonary fibrosis or other fatal complications depending on the affected organ. The pathogenesis of sarcoidosis is still not clearly defined, and is considered an interaction between the environment and risk alleles in many genes.The present case control study consisted of 146 Greek patients with sarcoidosis and 90 healthy volunteers from the same ethnic group. The coding and neighboring intronic regions of the BTNL2 gene were sequenced and risk alleles were compared amongst the two groups. Thirty-seven different variants were detected from which 12 were synonymous substitutions and 25 non-synonymous. With the help of in silico tools (SIFT, PolyPhen, PROVEAN, PMut and EX_SKIP), 13 variants were classified as possible pathological risk variants including 4 novel ones. The most common risk variants contributing to phenotypic modulation of sarcoidosis were p.S360G and p.S334L, with the latter contributing to a more severe disease stage with extra-pulmonary manifestations such as skin granulomas and relapses being more common.

BTNL2 germline variants may be involved in the pathogenesis of renal granuloma

“…The BTNL2 missense variant (c.1078A>G) was reported to contribute to the risk of sarcoidosis . In addition, the BTNL2 nonsense variant (c.1360G>T) was described as a possible pathological risk variant of sarcoidosis . A lack of BTNL2 expression in the left kidney in the present case was confirmed on western blotting, in concordance with genetic analysis (Fig.…”

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

“…Also, the multivariate analysis showed a significant difference between familial and sporadic cases regarding lungs and skin combination. According to Delaveri et al [20] such an observation may be in relation with the genetic predisposing background. Finally, as also reported by Sharma et al [16], familial and sporadic cases did not differ in terms of drugs used (corticosteroids alone vs. immunosuppressive drugs).…”

Granuloma genes in sarcoidosis

“…The genetic association of the BTNL2 variant with sarcoidosis has been confirmed in various populations, including African Americans and Japanese 17, 35-41 . Most recently, the association was confirmed in a Greek population of 146 sarcoidosis patients and 90 controls 42 . Sequencing of the coding and neighboring intronic regions of the BTNL2 gene in these individuals revealed the existence of 37 different variants, of which 12 were synonymous and 25 non-synonymous substitutions.…”