Genetic Association and Expression Correlation between Colony-Stimulating Factor 1 Gene Encoding M-CSF and Adult-Onset Still’s Disease

Abstract

Adult-onset Still’s disease (AOSD) is a rare and inflammatory disorder characterized by spiking fever, rash, arthritis, and multisystemic involvement. HLA has been shown to be associated with AOSD; however, it could not explain the innate immunity and autoinflammatory characteristics of AOSD. To assess the genetic susceptibility of AOSD, we conducted a genome-wide association study (GWAS) on a cohort of 70 AOSD cases and 688 controls following a replication study of 36 cases and 200 controls and meta-analysis. The plasma concentrations of associated gene product were determined. The GWAS, replication, and combined sample analysis confirmed that SNP rs11102024 on 5′-upstream of CSF1 encoding macrophage colony-stimulating factor (M-CSF) was associated with AOSD (P=1.20×10-8, OR (95% CI): 3.28 (2.25~4.79)). Plasma levels of M-CSF increased in AOSD patients (n=82, median: 9.31 pg/mL), particularly in the cases with activity score≥6 (n=42, 10.94 pg/mL), compared to the healthy donors (n=68, 5.31 pg/mL) (P<0.0001). Patients carrying rs11102024TT genotype had higher M-CSF levels (median: 20.28 pg/mL) than those with AA genotype (6.82 pg/mL) (P<0.0001) or AT genotype (11.61 pg/mL) (P=0.027). Patients with systemic pattern outcome were associated with elevated M-CSF and frequently observed in TT carriers. Our data suggest that genetic variants near CSF1 are associated with AOSD and the rs11102024 T allele links to higher M-CSF levels and systemic outcome. These results provide a promising initiative for the early intervention and therapeutic target of AOSD. Further investigation is needed to have better understandings and the clinical implementation of genetic variants nearby CSF1 in AOSD.

Diagnosis and treatment of adult-onset Still’s disease: a concise summary of the German society of rheumatology S2 guideline

“…Furthermore, multiple biomarkers other than ferritin or IL-18 have been assessed [16, 19, 30, 32-38, 38-41, 43, 45, 68, 74-76, 79, 88, 95, 101, 102, 104, 108, 135, 160, 161, 186, 188, 197], but validation studies are largely lacking. In certain cases, genetic studies may be useful to exclude hereditary autoinflammatory diseases, but do not show sufficient diagnostic precision to be routinely recommended in AOSD work-up [12,31,42,97,189,211]. From a diagnostic perspective, it is noteworthy that flares or primary manifestations of AOSD have been noted in temporal relation to COVID vaccinations during the course of the current pandemic [99,123,145,159,172,212].…”

Adult-Onset Still’s Disease (AOSD): Advances in Understanding Pathophysiology, Genetics and Emerging Treatment Options

“…These results are of remarkable interest, especially in the perspective of early intervention and treatment of specific disease manifestations [ 33 ]. If genetic susceptibility demonstrates a relevant influence in AOSD pathogenesis, it is well known that infectious triggers, including viruses (Parvovirus B19, Epstein-Barr virus, Cytomegalovirus) and bacteria ( Yersinia and Mycoplasma spp.…”

“…Indeed, plasma levels of leukocyte immunoglobulin-like receptor A3 (LIR-A3), encoded by LILRA3 gene, were found to be higher in patients with AOSD compared with healthy controls; LIR-A3 is able to interfere with certain inhibitory mechanisms and in turn amplify the NETosis process and promote inflammation in AOSD [32]. These results are of remarkable interest, especially in the perspective of early intervention and treatment of specific disease manifestations [33]. If genetic susceptibility demonstrates a relevant influence in AOSD pathogenesis, it is well known that infectious triggers, including viruses (Parvovirus B19, Epstein-Barr virus, Cytomegalovirus) and bacteria (Yersinia and Mycoplasma spp.…”

Macrophage colony-stimulating factor and its role in the tumor microenvironment: novel therapeutic avenues and mechanistic insights

“…For instance, hypoxic conditions can promote M2-like phenotype polarization by activating the ERK signaling pathway, thereby facilitating tumorigenesis (45). Additionally, factors such as the acidic conditions in the tumor microenvironment, factors secreted by tumor cells, and interactions with other immune cells are crucial determinants influencing TAM polarization (11,13,14,33,38,(46)(47)(48)(49). These factors collectively form a complex regulatory network that dictates the multifaceted roles of TAMs in tumor development and immune evasion.…”