FcγRIIa/IIIa polymorphism and its association with clinical manifestations in Korean lupus patients

Abstract

The aim of this study was to determine the distribution of the FcgammaRlla and FcgammaRIIIa polymorphisms and their association with clinical manifestations in Korean lupus patients. Three hundred SLE (systemic lupus erythematosus) patients (48 male, 252 female) meeting 1982 ACR criteria and 197 Korean disease-free controls were enrolled. Genotyping for FcgammaRlla 131 R/H and FcgammaRIIIa 176 F/V was performed by PCR of genomic DNA using allele-specific primers and the FcgammaRIIIa genotype was confirmed by direct sequencing of PCR product in some cases. There was significant skewing in the distribution of the three FcgammaRIIa genotypes between the SLE and the controls (P=0.002 for R/R131 vs R/H131 and H/H131, OR 2.5 (95% Cl 1.4-4.5), but not in FcgammaRIIIa genotypes. FcgammaRIIa-R allele was a significant predictor of lupus nephritis, as compared with SLE patients without nephritis (P=0.034 for R131 vs H131, OR 1.4 (95% Cl 1.03-1.9)), but proliferative nephritis (WHO class III and IV) was less common in patients with FcgammaRlla-R/R131 and in FcgammaRIIa-R allele. In 300 SLE patients, high binding allele combination H131/V176 was less common in SLE with nephritis than in SLE without nephritis. Hemolytic anemia was less common in R131/F176 allele combination among four FcgammaRIIa/FcgammaRIIIa allelic combinations. Male SLE patients showed a higher frequency of renal involvement, serositis, thrombocytopenia, malar rash and discoid rash than female SLE, and male SLE had a higher frequency of FcgammaRIIa-R/R131 or R131-allele than male controls, but FcgammaRIIa or FcgammaRIIIa genotypes had no association with renal involvement in male SLE patients. FcgammaRIIa-H/H131 showed a higher frequency of hemolytic anemia and less pulmonary complications in male SLE. Female SLE patients showed higher frequency of any hematologic abnormality, lymphopenia, anticardiolipin antibody (+) and anti-Ro antibody (+) than male SLE, and had earlier onset of first symptoms. There was no skewing in FcgammaRIIa or FcgammaRIIIa genotypes between female SLE and female controls, but FcgammaRIIa-R131 allele showed skewing between female SLE with nephritis and female SLE without nephritis. The age at onset of thrombocytopenia was earlier in FcgammaRIIa R/R131 among three FcgammaRIIa genotypes, and serositis in FcgammaRIIIa-F/F176 among three FcgammaRIIIa genotypes. FcgammaRIIa-R131 homozygote was a major predisposing factor to the development of SLE and FcgammaRIIa-RI31 homozygote and R131 allele were a predisposing factor, and H131/V176 was a protective allele combination in lupus nephritis. In contrast to other ethnic patients, in our study cohort, clinical manifestation was different between male and female, and FcgammaRIIa and FcgammaRIIIa showed somewhat different clinical associations between the genders.

Fcγ receptor IIa, IIIa, and IIIb polymorphisms in German patients with systemic lupus erythematosus: association with clinical symptoms

“…45 Yun et al described an earlier occurrence of photosensitivity and oral ulcers in Korean patients with the IIA-R/R131 genotype, which is in accordance with our findings. 46 This trend was also found for patients with the genotype FcγRIIIA-F/F158 (earlier occurrence of symptoms: p<0.05 in 22% of the tested variables; higher frequency: p<0.05 in 12.5% of the tested variables) and FcγRIIIB-NA2/2 (p<0.05 in 9% and 5% respectively). In the double negative genotypes we observed an accumulation of effects with even higher incidence and earlier onset of various symptoms (earlier occurrence of symptoms: p<0.05% in 42% of the tested variables; higher incidence: p<0.05 in 14%).…”

<i>FcγRIIB </i>Gene Polymorphisms Are Associated with Disease Risk and Clinical Manifestations of Systemic Lupus Erythematosus in Koreans

“…Yun et al (2001) identified that FCGRIIA R131 homozygote was a major predisposing factor for SLE and LN, and H131/V176 was a protective allele combination in LN. However, FCGRIIA was not associated with Chinese (Yap et al 1999) and Japanese SLE (Hatta et al 1999;Sato et al 2001).…”

“…Association of FcγR genes with various diseases in Korean populations have been previously reported, such as (Song et al 1998;Yun et al 2001;Lee et al 2002;Lee et al 2003), adult onset Still's disease (FCGRIIA H/R131, FCGRIIIA F/ V176, and FCGRIIIB NA1/NA2) (Oh et al 2002;Woo et al 2009), and ischemic stroke (FCGRIIA rs7511868, rs6427595, rs7512140, and rs6696854) (Kim et al 2009b). …”

Activating and inhibitory FcγRs in autoimmune disorders

“…For example, studies in African-American, Brazilian, German, and Thai populations have found significant associations between the FcγRIIA 131R allele and SLE disease susceptibility or severity of nephritis [71,126,128,129,131,133,136,137,144]. Moreover, several studies in Caucasian, Dutch, and Korean populations have found associations between the FcγRIIIA 158F allele and disease susceptibility and severity [127,130,134,145].…”

“…In the majority of studies, however, the low-affinity alleles have been identified as risk factors for the development or severity of autoimmune disease. Several studies have found an association of the low-affinity FcγRIIIA 158F and the FcγRIIA 131R alleles with the incidence and severity of lupus nephritis and arthritis [71,[125][126][127][128][129][130][131][132][133][134][135][136][137]. In addition, the low-affinity allele of human FcγRIIIB (FcγRIIIB-NA2) has been associated with SLE [71,138,139].…”