Systemic lupus erythematosus (SLE) is a chronic heterogeneous systemic autoimmune disease that can, in principle, affect any kind of body organ or cell, primarily in young women [1]. In SLE, altered immune responses may stimulate the production of autoantibodies and immune complex deposits in body organs, resulting in organ damage [2]. Like other autoimmune diseases, SLE has a complex pathogenesis, and the disease mechanism is still unclear; however, it is widely accepted that genetic factors could be important contributors to SLE [2,3]. Accordingly, several lines of evidence have supported that SLE may be explained by genetic factors. For instance, the concordance rate of SLE in monozygotic twins (24% to 58%) is higher than the rate in dizygotic twins (2% to 5%), and also, the disease heritability is high (>66%) [4,5,6].

A number of genome-wide association studies (GWASs) have identified novel single-nucleotide polymorphisms (SNPs) associated with the risk of SLE, such as HLA, PTPN22, STAT4, IRF5, TNFAIP3, BLK, and BANK1, in various ethnic groups, but most of the GWASs have been performed in Caucasians [1,7,8,9,10,11,12,13]. In Korea, most of the previously reported SNPs were validated by GWASs, and potentially East Asian-specific SNPs, such as the SNPs in ETS1, IKZF1, and SLC15A4, were also identified [14,15,16]. Recently, Bentham et al. [12] performed a large-scale GWAS with 7,219 cases and 15,991 controls in Europeans and defined 43 SLE loci, including 10 new loci.

Among the SLE-associated loci in Bentham et al. [12], some of them have not been replicated in the Korean population, and others were replicated but not concluded to be associated due to a limited sample size. In this study, we aimed to replicate five SNPs that were not replicated or concluded to be association in Koreans.

SLE is a complex autoimmune disease caused by complex interactions between genetic and environmental components [4,20]. Its high heritability and relatively higher risks in siblings suggest a genetic contribution to the risk of SLE [21,22]. In this study, we aimed to replicate five SNPs that were discovered in Caucasians [12] but not replicated in Koreans (rs2286672 in PLD2 locus, rs887369 in CXorf21 locus, rs9782955 in LYST, and rs3794060 in NADSYN1) or replicated in Koreans (rs1801274 in FCGR2A locus) with insufficient sample size to conclude any association. Through a replication study with 656 cases and 622 controls, rs1801274 in FCGR2A was found to be significantly associated with SLE in Koreans. However, the other four candidate SNPs were not replicated in Koreans.

The risk allele (G) of rs1801274 in FCGR2A is a missense variant that changes a histidine to arginine [23]. The human Fcγ receptor (FCGR) gene family (FCGR2A, FCGR2B, and FCGR2C) is located on chromosome 1q23, and it is considered to be associated with the susceptibility to SLE [23,24]. Functionally, human Fcγ receptor is involved in anti-inflammatory regulation of immune responses. Another important role of human Fcγ receptor is the clearance of immune complexes [25]. Indeed, FCGR polymorphisms have been reported to be associated with the susceptibility to autoimmune diseases, including SLE [26,27,28]. A well-known polymorphism is the missense variant at amino acid 131 in FCGR2A, which decreases binding affinity to human immunoglobulin G [23,28,29]. The homozygosity for R131, being regarded as the low-binding allele of FCGR2A, is known to be associated with a 1.30-fold greater risk for the development of SLE compared with both of the other genotypes combined [30,31]. Thus, FCGR2A-R131 may have potential roles in causing defective immune complex clearance and increased tissue deposition, thereby leading to accelerated organ damage [30,32]. FCGR2A on phagocytic cells is a receptor for C-reactive protein (CRP) and the serum amyloid P (SAP) component, both acting as opsonins for nuclear antigens [33,34], and the binding between receptor and CRP or SAP might be influenced by polymorphisms [30,35], because there is a dose-response characteristic between FCGR-2A-R/H131 and the risk of SLE, with an escalation of SLE risk between RR homozygotes and RH heterozygotes [30,31,32]. Vigato-Ferreira et al. [27] examined the allelic distribution of FCGR2A in a Brazilian population (157 SLEs and 160 controls). They found that two polymorphisms of FCGR2A were associated with SLE (FCGR2A-R-131 and RR-131), noting that the FCGR2A-H-131 allele was associated with the susceptibility to arthritis and anti-DNA antibodies [27]. In the meta-analysis performed by Li et al. [28], the FCGR2A-R/H131 variant was associated with the development of SLE in Asians both at the allele and genotype level. Low copy number of FCGR genes, including FCGR2A-RR-131, FCGR3B, and the 2B.4 haplotype of FCGR2B, has also been reported to be associated with the susceptibility to SLE [26]. Other studies also reported the association between FCGR2A and SLE nephritis in the Korean population [36,37,38,39], demonstrating that the FCGR2A H131R missense variation is presented as a risk allele of SLE and SLE nephritis. However, the association was hard to conclude because of the lack of power due to the limited small sample size (73 to 300 patients).

In conclusion, in this study, we performed a replication study of five SNPs, previously known to be associated with SLE but not replicated in Koreans, with a relatively large amount of samples, demonstrating that rs1801274 in FCGR2A shows a nominally significant association with SLE, but the other four SNPs appear to have no association in the Korean population. Our result is supportive that FCGR polymorphisms may play important roles in the susceptibility to SLE in diverse populations, including Koreans.