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Genetic polymorphism in milk fat globule-EGF factor 8 (MFG-E8) is associated with systemic lupus erythematosus in human

Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan

CS Wu

Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, Far Eastern Memorial Hospital, Taipei, Taiwan

HF Tsai

Department of Internal Medicine, Taipei Medical University Shuang Ho Hospital, Taipei, Taiwan

SK Chang

Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan

WI Tsai

Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

PN Hsu

Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwanphsu8635{at}ntu.edu.tw

Milk fat globule-EGF factor 8 (MFG-E8) is a molecule implicated in phagocytic clearance of apoptotic cells by bridging between macrophages and apoptotic cells. Defects in MFG-E8 cause lupus-like disease in murine models. The aim of our study is to determine whether genetic variation in MFG-E8 predisposes human to systemic lupus erythematosus (SLE). A case-control study of MFG-E8 genetic polymorphism was performed on 147 SLE patients and 146 non-lupus control subjects. Single nucleotide polymorphisms (SNPs) in the coding sequence of human MFG-E8 gene were investigated. SNPs on MFG-E8 residues 3 (3^{Arg or Ser}) and 76 (76^{Leu or Met}) did not show genetic linkage. Genetic polymorphism on MFG-E8 residue 76 correlated significantly to SLE. The MFG-E8-76^Met allele predisposed subjects to SLE in a recessive mode (odds ratio: 2.1, P = 0.020), while carriage of MFG-E8-76^Leu were negatively associated with SLE. The MFG-E8 genotypic combinations with 3^Ser and 76^Leu showed the most pronounced protective effect on SLE when compared to the most predisposing genotype 3^Arg/Arg-76^Met/Met (OR: 0.29, P = 0.007). According to our result, MFG-E8 is associated with SLE predisposition in Taiwanese. Our study implicates that the impairment of phagocytic clearance of apoptotic cells through phosphotidylserine-dependent MFG-E8 system may lead to the development of human SLE.

Key Words: apoptosis • genetic polymorphism • milk fat globule-EGF factor 8 (MFG-E8) • single nucleotide polymorphisms • systemic lupus erythematosus

Lupus, Vol. 18, No. 8, 676-681 (2009)
DOI: 10.1177/0961203309103027


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