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

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 (Lofgren'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 x 10(-3)), non-LS (OR = 0.66, p = 2.71 x 10(-4)) and CXR stages 2-4 (OR = 0.62, p = 7.48 x 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 x 10(-8)), TNFA rs1800629 (OR = 1.56, p = 6.65 x 10(-4)), ATF6B rs3130288 (OR = 2.75, p = 1.06 x 10(-9)) and HLA-DQA1 rs2187668 (OR = 1.74, p = 8.83 x 10(-4)) with sarcoidosis compared to controls. For sub -phenotypes compared to controls, risk variants C6orf10 rs3129927 (OR = 5.35, p = 1.07 x 10(-12)), TNFA rs1800629 (OR = 2.66, p = 5.94 x 10(-7)), ATF6B rs3130288 (OR = 5.24, p = 5.21 x 10(-13)), LRRC16A rs9295661 (OR = 2.97, p = 4.29 x 10(-4)), HLA-DQA1 rs2187668 (OR = 3.14, p = 1.09 x 10(-6)) and HLA-DRA rs3135394 (OR = 5.23, p = 8.25 x 10(-13)) were associated with LS while C6orf10 rs3129927 (OR = 1.96, p = 4.27 x 10(-4)) and ATF6B rs3130288 (OR = 2.15, p = 3.36 x 10(-5)) were associated with non-LS. For CXR stages compared to controls, C6orf10 rs3129927 (OR = 3.67, p = 3.63 x 10(-11)), TNFA rs1800629 (OR = 1.84, p = 1.32 x 10(-4)), ATF6B rs3129927 (OR = 3.63, p = 1.82 x 10(-11)), HLA-DQA1 rs2187668 (OR = 2.13, p = 9.59 x 10(-5)) and HLA-DRA rs3135394 (OR = 3.42, p = 3.45 x 10(-10)) were risk variants for early CXR stages 0-1 while C6orf10 rs3129927 (OR = 1.99, p = 5.51 x 10(-4)), ATF6B rs3129927 (OR = 2.23, p = 3.52 x 10(-5)) and HLA-DRA rs3135394 (OR = 1.85, p = 2.00 x 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.

Automated summary

This study confirms the association of ANXA11 rs1049550 with sarcoidosis and extends its impact on different clinical manifestations. It also validates the association of several other gene variants with sarcoidosis. These findings contribute to the understanding of genotype-phenotype relationships in sarcoidosis.