Polymorphisms of MFGE8 are associated with susceptibility and clinical manifestations through gene expression modulation in Koreans with systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is characterized by impaired clearance of apoptotic cells. Milk fat globule epidermal growth factor 8 (MFGE8) is a protein that connects αvβ3 integrin on phagocytic macrophages with phosphatidylserine on apoptotic cells. We investigated whether genetic variation of the MFGE8 gene and serum MFGE8 concentration are associated with SLE. Single nucleotide polymorphisms (SNPs) were genotyped and serum concentrations were analyzed. The rs2271715 C allele and rs3743388 G allele showed higher frequency in SLE than in healthy subjects (HSs). Three haplotypes were found among 4 SNPs (rs4945, rs1878327, rs2271715, and rs3743388): AACG, CGCG, and CGTC. CGCG haplotype was significantly more common in SLE than in HSs. rs4945 was associated with the erythrocyte sedimentation rate and rs1878327 was associated with alopecia, C-reactive protein, complement 3, anti-dsDNA antibody, and high disease activity. rs2271715 and rs3743388 were associated with renal disease, cumulative glucocorticoid dose, and cyclophosphamide and mycophenolate mofetil use. Serum MFGE8 concentrations were significantly higher in SLE than in HSs. Furthermore, the levels of MFGE8 were significantly higher in SLE than HSs of the rs2271715 CC genotype. In conclusion, MFGE8 genetic polymorphisms are associated not only with susceptibility to SLE but also with disease activity through modulation of gene expression.

Milk Fat Globule Epidermal Growth Factor 8 (MFGE8) Gene Variants in Rheumatoid Arthritis and Sjögren’s Syndrome

“…To our knowledge, this is the first time that the CACG MFGE8 haplotype was found to confer reduced risk for RA and SS development, with MFGE8 protein levels being reduced in SS patients with evidence of carotid arterial wall thickening. Previous studies conducted in Korean and Taiwanese SLE cohorts have reported that SLE patients carrying the MFGE8 rs2271715 and rs3743388 variants display higher MFGE8 serum levels [ 1 ] and increased risk for SLE compared to HC [ 1 , 7 ] (findings not confirmed in the present cohort). Additionally, we observed that the CA genotype of the rs4945 variant exhibits a protective effect against RA development, a finding that was not observed in SS and SLE cohorts.…”

“…Additionally, we observed that the CA genotype of the rs4945 variant exhibits a protective effect against RA development, a finding that was not observed in SS and SLE cohorts. A recent study conducted in a Korean SLE cohort revealed that SLE patients carrying the A allele of the rs4945 variant a display higher erythrocyte sedimentation rate (ESR) compared to non-carriers [ 1 ]. However, no association with any clinical disease manifestation was observed in our disease cohorts.…”

“…Physiologically, MFGE8 binds to phosphatidylserine at the surface of apoptotic cells and enables their recognition by ανβ3/β5 integrins, promoting the phagocytosis of apoptotic cells by macrophages and the development of subsequent tolerogenic immune responses. Of interest, MFGE8 deficiency in mice delays the clearance of apoptotic lymphocytes, leading to enhanced self-antigen presentation and generation of a disease reminiscent of human systemic lupus erythematosus (SLE) [ 1 ].…”

“…Additionally, MFGE8 gene polymorphisms have been associated with autoimmunity development in humans. A Korean study reported that SLE patients carrying the MFGE8 rs2271715 CC and rs4945 CA or AA genotypes display higher MFGE8 serum levels, while the rs2271715 and rs3743388 polymorphism a associated with increased risk for SLE development [ 1 ].…”

Toll-like Receptor Signaling Inhibitory Peptide Improves Inflammation in Animal Model and Human Systemic Lupus Erythematosus

“…To date, genome-wide association studies, in vitro studies, experimental mouse models, and clinical sample analysis have provided relevant evidence on the involvement of TLRs, including TLR7/9, in SLE onset. Therefore, targeting TLRs and regulating TLR signaling have emerged as important strategies for the treatment of SLE [ 32 , 43 , 44 ]. The innate immune system recognizes damage-associated molecular patterns (DAMPs), which are nucleic acid-containing debris released from dead cells.…”