Evaluation of genetic risk, its clinical manifestation and disease management based on 18 susceptibility gene markers among West-Slavonic patients with sarcoidosis

Abstract

Sarcoidosis is a heterogenous, multisystemic inflammatory disease that primarily affects lungs. In this study, we multiplex genotyped 18 single-nucleotide polymorphisms (SNPs) to replicate the findings from previous genome-wide association studies (GWAS) and candidate gene studies, and extended analyses to different clinical manifestations (Löfgren’s syndrome and chest X-ray [CXR] stages) including treatment response among West-Slavonic subjects (564 sarcoidosis patients and 301 healthy controls). We confirm the replication (with Bonferroni's correction) of ANXA11 rs1049550 as protective variant for sarcoidosis (odds ratio [OR] = 0.71, p = 1.33 × 10−3), non-LS (OR = 0.66, p = 2.71 × 10−4) and CXR stages 2–4 (OR = 0.62, p = 7.48 × 10−5) compared to controls in West-Slavonic population. We also validate the association of risk variants C6orf10 rs3129927 (OR = 2.61, p = 2.60 × 10−8), TNFA rs1800629 (OR = 1.56, p = 6.65 × 10−4), ATF6B rs3130288 (OR = 2.75, p = 1.06 × 10−9) and HLA-DQA1 rs2187668 (OR = 1.74, p = 8.83 × 10−4) with sarcoidosis compared to controls. For sub-phenotypes compared to controls, risk variants C6orf10 rs3129927 (OR = 5.35, p = 1.07 × 10−12), TNFA rs1800629 (OR = 2.66, p = 5.94 × 10−7), ATF6B rs3130288 (OR = 5.24, p = 5.21 × 10−13), LRRC16A rs9295661 (OR = 2.97, p = 4.29 × 10−4), HLA-DQA1 rs2187668 (OR = 3.14, p = 1.09 × 10−6) and HLA-DRA rs3135394 (OR = 5.23, p = 8.25 × 10−13) were associated with LS while C6orf10 rs3129927 (OR = 1.96, p = 4.27 × 10−4) and ATF6B rs3130288 (OR = 2.15, p = 3.36 × 10−5) were associated with non-LS. For CXR stages compared to controls, C6orf10 rs3129927 (OR = 3.67, p = 3.63 × 10−11), TNFA rs1800629 (OR = 1.84, p = 1.32 × 10−4), ATF6B rs3129927 (OR = 3.63, p = 1.82 × 10−11), HLA-DQA1 rs2187668 (OR = 2.13, p = 9.59 × 10−5) and HLA-DRA rs3135394 (OR = 3.42, p = 3.45 × 10−10) were risk variants for early CXR stages 0–1 while C6orf10 rs3129927 (OR = 1.99, p = 5.51 × 10−4), ATF6B rs3129927 (OR = 2.23, p = 3.52 × 10−5) and HLA-DRA rs3135394 (OR = 1.85, p = 2.00 × 10−3) were risk variants for advanced CXR stages 2–4. The present findings nominate gene variants as plausible prognostic markers for clinical phenotypes, treatment response and disease resolution/progression and may form the basis for establishing genotype–phenotype relationships in patients with sarcoidosis among West-Slavonic population.