University of Florida Gainesville, Florida, United States
Background: Pulmonary sarcoidosis is an inflammatory condition marked by the accumulation of noncaseating granulomas. While oral methotrexate (MTX) is a standard treatment option, the factors underlying variability in MTX response remain unclear. The aim of this study was to identify genetic determinants associated with interindividual response to MTX. Methods: We conducted a candidate gene association analysis and an exploratory genome-wide association study (GWAS) in a cohort of pulmonary sarcoidosis patients recruited from the University of Florida Health system. Sixteen candidate genes regulating MTX transport, the folate cycle, and the methionine cycle were selected a priori. The primary measure of MTX response was percent change in forced vital capacity (FVC). Genotype data underwent quality control, subsequently imputed and phased with the TOPMed Imputation Server. The base regression model was adjusted for age, sex, race (PCs 1-3), and MTX duration, with a more comprehensive model including smoking status. For candidate genes, coding variants with minor allele frequencies (MAF) five percent or greater were analyzed and p-values were adjusted using a Bonferroni correction (Padj=0.001). GWAS was conducted using PLINK v1.9 with a genome-wide significance threshold of 5x10-8. Results: Data from 47 patients were included in the analyses, with a median MTX treatment duration of 24 months (IQR 13-46). Of the 64 candidate SNPs tested, several were associated with FVC change, including rs1045642 in ABCB1 using the base model (P=0.018) and the more comprehensive model (P=0.044). However, none remained significant after adjustment for multiple comparisons. The top GWAS signal in the base model was rs61538846 in protein-coding gene ABTB3 on chromosome 12 (P=4.14×10-8) but was just below genome-wide significance in the comprehensive model (P=5.75×10-8). Conclusion: GWAS findings suggest ABTB3 might play some role in MTX response. The complex relationship between genetics, smoking, and MTX responses in pulmonary sarcoidosis patients warrants further investigation, perhaps utilizing interaction analyses in a larger patient population.
