Genetic Studies of Systemic Lupus Erythematosus in Asia: Where Are We Now?

ORIGINAL ARTICLE Genetic studies of systemic lupus erythematosus in Asia: where are we now?

I Kim1, YJ Kim1, K Kim2, C Kang2, C-B Choi1, Y-K Sung1, H-S Lee1 and S-C Bae1 1Department of Rheumatology, The Hospital for Rheumatic Diseases, Hanyang University, Seoul, Korea and 2Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea

There have been many genetic studies of systemic lupus erythematosus (SLE) in Asia, but the status of SLE in Asia remains unclear. Genes that have been associated with SLE in Caucasians have shown both consistent and inconsistent results in Asians. This prompted us to review studies of SLE-associated genes and compare the degree of consistency according to ethnicity in Asia. We searched PubMed and the national databases in Korea and Japan for SLE genetic studies. A total of 755 articles were found and after applying various exclusion criteria, 442 studies including 17 linkage studies, 2 genome-wide association studies and 423 candidate-gene analyses were reviewed. Nine linkage loci were confirmed to be associated with SLE susceptibility in non-Asians, but the risk locus (16q12) has been identified in only one Asian study. A total of 156 candidate genes were analyzed, of which 92 were studied in Asians. Although there were allelic (HLA-DRB1 and IRF5) or genetic heterogeneity (FCGR gene family), HLA-DRB1, the FCGR gene family, IRF5, STAT4 and MECP2 showed consistent associations with SLE susceptibility across ethnicities. In conclusion, genetic associations often vary with ethnicity, requiring validation in different ethnic groups, and hence future SLE genetic studies will require strong worldwide collaborations. Genes and Immunity (2009) 10, 421–432; doi:10.1038/gene.2009.24; published online 9 April 2009

Keywords: systemic lupus erythematosus; genetics; Asia

Introduction complex traits of SLE characterized by non-Mendelian inheritance.1 Systemic lupus erythematosus (SLE) is an autoimmune More than 700 genetic studies on SLE have been disease in which organs and cells are damaged by tissue- published. Although there have been many genetic binding autoantibodies and immune complexes. Genetic studies of SLE in Asia, their precise number and types factors including the environment and hormones influ- and the consistency of their findings remain unclear. ence the pathogenesis of SLE through abnormal immune Therefore, we searched the genes studied in Asia and responses. Numerous genetic studies on SLE have been compared the results with those obtained in non-Asian performed, and two main approaches have been used to populations. identify genetic loci associated with SLE: (1) linkage studies using multiplex families and (2) candidate-gene studies using unrelated affected and unaffected indivi- Results and discussion duals from a population. Genome-wide association Linkage studies studies (GWASs) have recently attempted to discover A total of 17 family-based linkage studies were identi- novel genes. Despite enormous efforts, the results of SLE fied, including 9 genome-wide linkage (GWL) studies genetic studies have been not very satisfactory. For and 8 fine-mapping linkage analyses. To date, the example, the finding of a significant genetic association following nine linkage loci have been identified as being in one study is all too often not replicable in another or associated with SLE susceptibility and replicated in the same independent population. Researchers have independent populations: 1q23, 1q31-32, 1q41-43, 2q37, attributed the variable associations and poor replication 4p16, 6p11-21, 10q22-23, 12q24 and 16q12-13.2 Only one rates to small samples producing a low statistical power, fine-mapping linkage study has been performed in Asia, the use of different methodological approaches to detect which involved chromosome 16 and 157 SLE families of genetic variants, imprecisely defined phenotypes, genetic a Chinese SLE cohort. That study showed that 16q12 was heterogeneity, differences in allele frequencies and associated with SLE, and the authors suggested that OAZ (OLF1/EBF-associated zinc-finger protein) is a risk locus for SLE.3 Correspondence: Dr S-C Bae, Department of Rheumatology, The Hospital for Rheumatic Diseases, Hanyang University, Seoul Candidate gene studies 133-792, Korea. E-mail: [email protected] A total of 423 candidate-gene studies were found and 156 Received 30 December 2008; revised and accepted 13 March 2009; genes have been investigated worldwide, with 92 genes published online 9 April 2009 being studied in Asia (Supplementary Table 1). Most Genetic studies of SLE in Asia IKimet al 422 (94%) of the Asian candidate-gene studies involved East positive result in a Colombian population.40 We found 11 Asian populations, with the other studies involving Thai, genetic studies on À308G/A variant in TNF-a in non- Malaysian, Vietnamese and other populations (Table 1). Asian and 9 in Asian populations. The association of TNF-a genetic variant with SLE susceptibility was found MHC class II region (6p21). As many as 70 published in Caucasians,7,8,44 African Americans,45 Hispanics46 and studies (25 in Asia) related to the major histocompat- Asians (including Chinese17 and Thai47 populations), but ibility complex (MHC) class II region have attempted to the result was not consistently demonstrated. Meta- find genetic associations of SLE susceptibility. MHC class analysis has shown that À308G/A was significantly II molecules influence antigen presentation by interact- associated with SLE in Caucasians, but not in Asians.48 ing with T-cell receptors, and mutations in MHC class II TNF-b, also known as lymphotoxin-a, was associated genes would contribute to abnormal responses to self- with SLE in German,49 Korean,21,22 Japanese50 and antigens. Human leukocyte antigen (HLA)-DRB1*1501 Chinese14,15,51,52 populations. Genes within MHC regions and HLA-DRB1*0301 are known to be associated with tend to be transmitted together in linkage disequilibrium SLE susceptibility in Caucasian.4–12 An association (for example, between À308G/A of TNF-a and the HLA- between SLE susceptibility and DR2 (or HLA- B8-C4A*Q0-DR3 haplotype), and this should be consid- DRB1*1501 or HLA-DRB1*16) was found in all 10 Asian ered as a confounding factor when interpreting the studies, which have included Korean, Chinese and results of association studies of complements, TNF-a and Malaysian populations.13–22 HLA-DR3 (or HLA- TNF-b. DRB1*0301 or HLA-DR17) also showed associations with SLE in four Asian studies (one Korean and three Other MHC-associated genes. The MHC class I chain- Chinese).14,15,22,23 Unlike HLA-DR2 and HLA-DR3, the related peptide A (MICA) gene, located at 6p21.3 near results for the other HLA regions varied with ethnicity. HLA-B, encodes the protein expressed on the cell surface An association between HLA-DR5 (or HLA-DRB1*1101) of fibroblasts and epithelial cells, and functions as a and SLE susceptibility was found in Mexican and stress-induced antigen recognized by intestinal epithelial Chinese14,24 populations, but not in Caucasian.8,25,26 In gamma delta T cells.53,54 There have been three associa- Koreans and Chinese, HLA-DR9 (or HLA-DRB1*0901) tion studies of MICA, with positive results in Italian55 was found to be associated with SLE,19,23 but not in and Spanish56 populations (although in the Spanish Caucasian.8,12,25,26 We recently found that HLA- study, the association of MICA with SLE susceptibility DRB1*1501 was most significantly associated with SLE was thought to come from linkage disequilibrium of and that HLA-DRB1*0803 and HLA-DRB1*0901 also HLA-B*08) and a negative result in a Chinese popula- showed significant associations in a Korean population tion.57 (unpublished data). The MHC class II transactivator (MHC2TA) gene is located at 16p13 and considered to regulate MHC class II MHC class III region. The MHC class III region contains expression.58 Associations of MHC2TA single-nucleotide genes encoding complement components, transporters of polymorphisms (SNPs) with susceptibility to rheumatoid antigen processing (TAP), tumor necrosis factor-a (TNF- arthritis (RA), multiple sclerosis and myocardial infarc- a) and TNF-b. Genes encoding complement components tion in a Nordic population have been reported.59 The such as complement 2 (C2), complement 4 (C4) and À168G/A (rs3087456) SNP of MHC2TA showed an factor B fall within the MHC class III region, and association with SLE in Japanese60 but not in Swedish deficiency of C2 and C4 increases the risk of developing and Spanish61,62 populations. SLE. The C4 gene consists of C4A and C4B, and complete deletion of C4 is reportedly associated with severe SLE.27 FCGR gene family (1q23-24). The Fc-g receptor (FCGR) An association between the C4A null allele (C4A*Q0) gene family, located at 1q23, comprises FCGR2A, and SLE susceptibility has been demonstrated in a FCGR2B, FCGR3A and FCGR3B, and is involved in Caucasian population.28–34 C4A*Q0 is also associated immune complex clearance and antibody-dependent with SLE susceptibility in multiethnic Asian populations, cellular cytotoxicity.63,64 The genetic association of including Japanese and Chinese.35 This result has been FCGR2A with SLE has been reported in non-Asian and replicated in Korean,19 Japanese36 and Chinese,37 but also Asian populations, but with inconsistent results. A total not in Chinese16 and Malaysian.38 However, C4A*Q0 is of 36 genetic association studies of FCGR2A have been known to be in linkage disequilibrium with HLA-DR3.39 performed worldwide: 17 with positive and 19 with Most studies of TAP genes have produced negative negative associations. In Asia, the association of the results in Colombians, Australians and Asians including 131H/R SNP with the development of SLE and lupus Japanese and Chinese,7,40–43 but the TAP-2 gene showed a nephritis was demonstrated in Korean,20,65,66 Japanese,67

Table 1 Numbers of SLE genetic studies included in our study

Total Non-Asian Asian Korean Japanese Chinese Other

Linkage study (GWL) 17 (9) 16 (9) 1 (0) — — 1 (0) — Genome-wide association studies 2 2 — — — — Candidate-gene studies 423 247 176 49 52 66 9

Total 442 265 (60.0%) 177 (40.0%) 49 (11.1%) 52 (11.8%) 67 (15.2%) 9 (2.0%)

GWL, genome-wide linkage study.

Genes and Immunity Genetic studies of SLE in Asia IKimet al 423 Thai68 and Vietnamese69 populations, but negative multiethnic populations including European Americans results have also been seen in Korean,70 Chinese,71 and African Americans.103 Three genetic studies that Japanese72,73 and Thai74 populations. There have been investigated the genetic association of PDCD1 with SLE 23 genetic studies on FCGR3A worldwide, and they have susceptibility in Chinese populations found that the also produced inconsistent results (12 with positive and þ 7146G/A SNP of PDCD1 was not associated with 11 with negative results), similar to the situation for SLE,104,105 whereas that of þ 7209C/T was associated FCGR2A. The association between the 176F/V SNP of with SLE susceptibility.105 FCGR3A and SLE susceptibility has also varied, with positive results in Korean,70 Japanese73 and Chinese75 OAZ (16q12). OAZ was identified in a fine-mapping populations, but also negative results in Korean,20,65,76 linkage study of Chinese SLE families as being associated Japanese,72 Chinese71 and Thai74 populations. Meta- with lupus nephritis,106 but this result has not been analyses have been performed to identify associations replicated. of FCGR2A and FCGR3A with SLE. The FCGR2A 131R allele was found to dose dependently increase the risk of IRF5. Interferon regulatory factor 5 (IRF5) is a tran- SLE,77,78 and the FCGR3A 176F allele increased the risk of scriptional mediator of the interferon-induced signaling lupus nephritis but not SLE susceptibility.77,79 Genetic pathway. Several SLE-associated SNPs of IRF5 (for studies on FCGR2B showed more consistent associations, example, rs2004640, rs752637 and rs729302) have been especially in Asian populations. FCGR2B polymorph- identified in Caucasians.107–112 Several new SLE-asso- isms showed consistently positive results in Japanese,73 ciated genetic variants of IRF5 (exon 1B splice-site Chinese75,80–82 and Thai74 populations, but in Caucasians variant, ins/del variant of exon 6, polyA þ signal variant there have been two studies with positive results83,84 and and CGGGGindel) were recently discovered in Cauca- four with negative results for the association with SLE sians,113,114 and risky haplotype that consisted of susceptibility.85–88 These observations suggest the pre- rs2004640, rs3807306, rs10488631 and rs2280714 was sence of genetic heterogeneity, with genetic variants of associated with higher level of serum interferon-a in FCGR2B increasing the risk of SLE more in Asians than Europeans and Hispanics.115 in Caucasians. It was found that SNPs identified in Caucasians The Fc receptor-like 3 (FCRL3) gene, located at (rs2004640, rs752637 and rs729302) were associated with 1q21-22, encodes a protein member of the Ig receptor the development of SLE in a Korean population.116 family that contains an immunoreceptor-tyrosine activa- rs10954213 and exon 6 indel were not associated with tion motif and an immunoreceptor-tyrosine inhibitory SLE in a Japanese study, but rs2004640 was significantly motif. Its function is not known well, but it might have a associated with SLE when combined with data from a regulatory function in signal transduction.89 The À169C/ Korean study.117 Associations between SLE and SNPs in T variant of the FCRL3 gene showed an association with intron 1 (À4001C/A, rs6953165 and rs41298401) were SLE in Japanese89 but not in Korean90 and Spanish91 also noted. rs2004640 and rs10954213 were not associated populations. Instead, the FCRL haplotype (Fcr3/4/6) with SLE susceptibility in a Chinese population, and showed a weak association with SLE (OR ¼ 1.32; rs2070197 was found to be monomorphic.118 A recent P ¼ 0.04) in a Spanish population.91 comparison of the allele frequencies of IRF5 polymorphisms with ethnicity revealed that SNPs strongly asso- PARP (1q41). Poly-ADP-ribose polymerase (PARP) is a ciated with SLE in Caucasians (IRF5-15-1, rs2070197 and zinc-finger DNA-binding protein induced by DNA rs10488631) were monomorphic in a Korean popula- strand breaks, and the gene encoding PARP is located tion,119 which, together with the Chinese study, suggest at 1q41. PARP has a function in DNA repair, apoptosis the presence of allelic heterogeneity, with alleles of IRF5 and transcription regulation.92 A family-based study related to the risk of SLE differing with ethnicity. found that a polymorphic CA repeat allele was associated with SLE susceptibility in a multiethnic popula- STAT4. STAT4 encodes a transcription factor that tion,93 but the result was not replicated in a French transmits signals induced by several cytokines. STAT4 population.94 PARP polymorphisms were not signifi- mediates signals produced by interleukin-12 (IL-12), type cantly associated with SLE in Korean and Chinese I interferon and IL-23,120 and stimulates IL-12-induced populations.95,96 However, the À1963A/G, þ 28077G/A interferon-g production.121 The rs7574865 SNP of STAT4 and þ 40329T/C SNPs of PARP were associated with was associated with the development of both SLE and the development of lupus nephritis and arthritis in RA in Caucasians,122 and association with SLE was Koreans.95 confirmed in two recent GWASs123,124 and in a Japanese population.125 A total of 9923 SLE cases and controls in a PDCD1 (2q37). The gene encoding programmed cell multiethnic population comprising Europeans, Koreans, death 1 (PDCD1) is located at 2q37. PDCD1 is a member Gullahs, African Americans and Hispanics were recently of the CD28/CTLA-4 (cytotoxic T-lymphocyte antigen investigated to identify the association between STAT4 4)/ICOS receptor family containing a tyrosine-based and SLE. rs10168266 showed the strongest association inhibitory motif.97 The þ 7146G/A SNP (PD1.3G/A; (P ¼ 1.38 Â 10–15) with SLE in Europeans, followed by rs11568821) of PDCD1 showed associations with SLE several other SNPs (rs7568275, rs7582694, rs10181656, susceptibility in Caucasians and Mexican,98,99 and this rs3024886, rs10174238 and rs3821236), and these strong genetic variant affects a binding site for RUNX1, associations with the same SNPs were also observed in suggesting that it contributes to the development of Koreans. rs7568275, in strong linkage disequilibrium SLE.98 However, þ 7146G/A showed a protective asso- with rs7574865 (r2 ¼ 1) that was previously identified as ciation with SLE in a Spanish population100 and no being associated with SLE, showed strong associations association in Swedish,101 independent Caucasian102 and with SLE in Europeans and Koreans (P ¼ 4.26 Â 10–15 and

Genes and Immunity Genetic studies of SLE in Asia IKimet al 424 1.27 Â 10–8, respectively). Three haplotypes (AAAG, DNase I performed in a Spanish population found that CATTTAAA and GGCGAGCG) related to the risk of þ 2035C/G, which is in strong linkage disequilibrium SLE have been detected in Europeans, of which with þ 2373A/G, was significantly associated with CATTTAAA was also highly significant in Koreans and SLE.145,146 Studies of DNase II, III and IV in Korean Hispanics, and additional conditional analysis revealed populations have found that none of these DNase that the associations of this haplotype are attributable to subtypes were associated with SLE susceptibility.147–149 rs10168266.126 However, genetic variants of DNase II (rs4804209, rs11085823 and rs2293682) were weakly associated with PTPN22. The protein tyrosine phosphatase 22 lupus nephritis,147 and DNase III (Trex-1 and Trex-2) and (PTPN22) gene encodes lymphoid tyrosine phosphatase IV showed associations with the development of SLE- that—interacting with C-terminal Src tyrosine kinase— associated autoantibodies.148,149 downregulates the T-cell receptor that mediates signaling.127 The association of the rs2476601 ( þ 1858C/T; CTLA-4. The CTLA-4 gene, located at 2q33, encodes a R620W) SNP of PTPN22 with SLE has been shown in protein that downregulates T-cell function,150 and differ- Caucasians128,129 and Hispanics,128,130 but not in African ent genetic variants of CTLA-4 have been found within Americans128 or Norwegians.131 We found no genetic the promoter region (À1722T/C, À1661A/G and À319C/ study of PTPN22 in Asians. In RA studies, rs2476601, T) and exon 1 ( þ 49A/G) in Caucasian,151–154 Span- which was RA-associated SNP in Caucasians,132 was ish,155,156 Korean,157,158 Japanese159–161 and Chinese162,163 monomorphic in Japanese,133 and a recent Korean study populations. However, analyses of associations between also revealed that this SNP was monomorphic and that CTLA-4 SNPs and SLE have produced inconsistent other RA-associated genes in Caucasians (TRAF1/C5, results. A meta-analysis showed that þ 49A/G was CD40, CCL21, 4q27 and 6q23) were not associated with significantly associated with SLE susceptibility, espe- RA in Koreans (only PADI4 showed a significant cially in Asians.164 association), suggesting the presence of genetic heterogeneity, with the genes contributing to the development MBL. Mannose-binding lectin (MBL) is structurally of RA differing between Caucasians and Asians.134 similar to C1q, which is involved in complement activation through a lectin pathway.64 The MBL gene is DNA methylation. DNA methylation influences the located at 10q11, and genetic polymorphisms have been transcriptional inhibition of gene expression, genomic found within exon 1 (rs1800450 (codon 54 G/A; allele B), imprinting and silencing of an inactive X chromosome, rs1800451 (codon 57 G/A; allele C) and rs5030737 (codon and is essential for mammalian development.135 DNA 52 C/T; allele D)) and the promoter region (rs11003125 methyltransferase 1 (DNMT1) is a major member of the (–550G/C; allele L) and rs7096206 (–221C/G; allele X)) in DNMT family that has a function in maintaining Caucasian,165–170 African American,166,167 Spanish,171 methylation patterns.136 The gene encoding DNMT1 is Japanese172–174 and Chinese175,176 populations. Although located at 19p13.3-13.2. An investigation of DNMT1 genetic studies investigating associations of MBL muta- polymorphisms with SLE susceptibility in a Korean tions with SLE have produced inconsistent results, a population found no SLE-associated SNPs, but meta-analysis found that rs1800450, rs11003125 and þ 14463G/C (V120L) showed a weak association with rs7096206 were significantly associated with SLE in the development of anti-La antibody.137 Caucasians, Asians and Africans.169 Methyl-CpG-binding protein 2 (MECP2) binds to methylated DNA and represses the transcription of MCP-1. Monocyte chemoattractant protein-1 (MCP-1; methylated genes.135 The MECP2 gene is located at CCL2) is a chemokine that recruits monocytes, and the chromosome Xq28, and an association between MECP2 MCP-1 gene is located at 17q11.2-q12. Proteinuria was genetic variants and SLE was recently identified.138 Eight reduced and survival was prolonged in an MCP-1- SNPs (including rs17435, rs1734787, rs1734791 and deficient MRL-lpr mouse model, suggesting that this rs1734792) were associated with SLE in Koreans, and gene has an important function in lupus nephritis.177 all SLE-associated SNPs in Koreans were replicated in The rs1024611 (À2518A/G) SNP of MCP-1 was positively Caucasians. associated with SLE susceptibility in Caucasians178,179 and Mexicans180 but not in Spaniards,181,182 African DNase. Deoxyribonuclease (DNase) is involved in DNA Americans,178 Koreans,183,184 Japanese185 and Chinese.186,187 metabolism and clearance of DNA fragments, and DNase activity is reportedly decreased in patients with Genome-wide association studies SLE.139 The associations of four subtypes of DNase with Two GWASs were recently performed in Caucasian.123,124 SLE have been investigated. A nonsense mutation at In the SLEGEN study, Harley et al.123 investigated 2566 exon 2 of DNase I was associated with decreased Caucasian patients with SLE and 4162 controls, and enzymatic activity in Japanese patients,140 but this found that after excluding the HLA region and IRF5, mutation was absent in Caucasians141 and Africans.142 novel genes such as ITGAM (integrin a M), KIAA1542 In addition to the absence of the exon 2 mutation, no and PXK (phox homology domain containing serine/ SLE-associated SNPs of DNase I were found in a Korean threonine kinase) showed significant associations with population, but rs1053874 ( þ 2373A/G; Gln244Arg) was SLE susceptibility. Another GWAS, performed by Hom associated with the production of anti-dsDNA antibody et al., investigated 545 080 SNPs in 1435 patients with SLE in this population.143 Although no association between and 3583 controls.5 After excluding the HLA region, two rs1053874 and SLE susceptibility was found in a Chinese novel loci near B lymphoid tyrosine kinase (BLK) population, a haplotype including rs1053874 was asso- (rs13277113) and ITGAM-ITGAX (rs1574637) were dis- ciated with SLE.144 Two SLE genetic studies related to covered to be significantly associated with SLE, and the

Genes and Immunity Genetic studies of SLE in Asia IKimet al 425 results were replicated in an independent Swedish was monomorphic, in contrast to the results of previous population. These two GWASs have revealed that the Caucasian studies.194 HLA region was most significantly associated with SLE susceptibility and that other previously reported PXK. PXK encodes the phox homology domain regions (for example, IRF5, STAT4, FCGR2A and containing serine/threonine kinase that binds to PTPN22) also showed associations. Genes encoding and modulates Na- and K-ATPase activity, and ITGAM, BLK, PXK and KIAA1542 were identified as has five splice isoforms that are widely expressed novel risk loci for SLE. in human tissues.195 PXK was significantly associated with SLE in a GWAS,123 with rs6445975 and rs10798269 SNPs of PXK (excluding the HLA region) showing Novel genes discovered from GWASs strong associations with SLE in Caucasians. However, BLK. BLK is a member of the Src kinase family involved the rs6445975 SNP of PXK was found to have no in B-cell receptor signaling,188 and might be important association with SLE susceptibility in 793 Korean for the development of the B-cell repertoire. Two patients with SLE (OR ¼ 1.06; P ¼ 0.57) (unpublished recent GWASs revealed BLK to be a novel risk locus data). for SLE. The SLEGEN study showed that rs2248932 and rs10903340 were associated with SLE in Caucasians.123 Hom et al.124 reported that rs13277113 of BLK was Conclusions associated with SLE susceptibility in Caucasians, and this result was replicated in a Swedish population. In There has been considerable progress in genetic studies addition, the expression of BLK in transformed B cells of SLE, thanks partly to technological advances in decreased dose dependently with the presence of the A genotyping SNPs, and recent GWASs have contributed allele of rs13277113. A recent multiethnic study including to the discovery of novel candidate genes and to 2583 Caucasians and 913 Koreans found that rs1564267 confirming previously reported genes. However, the was strongly associated with SLE in Koreans results of the numerous genetic studies have not been (P ¼ 5.16 Â 10–9), but the association was only moderate very satisfactory, with low rates of replicating initial in Caucasians (P ¼ 0.03) (unpublished data). findings and genetic associations often varying with ethnicity. The present review reveals that genetic BANK1. B-cell scaffold protein with ankyrin repeats 1 associations differ between Caucasians and Asians, and (BANK1) is an adapter protein that leads to B-cell- even within different Asian populations. SLE-associated receptor-induced calcium mobilization in association genes with or without consistent results between with tyrosine kinase Lyn.189 The association of BANK1 Caucasians and Asians are listed in Table 2. However, with SLE susceptibility was first demonstrated in a HLA-DRB1 and the FCGR gene family show consistent Swedish population and subsequently replicated in an independent Caucasian population that included Argen- tineans, Germans, Italians and Spaniards.190 rs10516485, Table 2 Genes associated with SLE susceptibility in Caucasians rs17266594 and rs3733197 SNPs of BANK1 were sig- and Asians nificantly associated with SLE in Caucasians. rs17266594 was localized to a branch point site of two isoforms (full Genes with consistent results both Genes without consistent results length and D2), and a homozygote for C allele induced in Caucasians and Asians between Caucasians and Asians the D2 isoform lacking exon 2, which is a domain for a IP3R binding.190 An investigation of BANK1 in 913 HLA-DRB1*0301 and TNF-a (C) HLA-DRB1*1501 Korean patients with SLE revealed that rs12498977 FCGR2A and FCGR3Ab FCGR2B (A) was significantly associated with SLE susceptibility IRF5 FCRL3 (Japanese only) (OR ¼ 1.28; P ¼ 4.3 Â 10–3) (unpublished data). STAT4 PTPN22 (C) MECP2 CTLA-4 (A) ITGAM. The ITGAM gene encodes integrin a M [also MBL a a known as complement receptor (CR) type 3], which is (C4A and TNF-b ) involved in adhesion between leukocytes and endothelia Novel genes discovered from GWASs and has been reported to be elevated in active SLE.191 SLE with immune vasculitis was found in the patient BLKc ITGAMd (C) with CR3 deficiency and impaired phagocytosis was also BANK1c PXKd (C) noted.192 Two GWASs found that rs11574637 and rs9888739 C indicated genes that had more consistent results in Caucasians, 123,124 SNPs of ITGAM were strongly associated with SLE. and A in Asians. 193 Nath et al. found that 11 of 22 SNPs of ITGAM were aThey are in strong linkage disequilibrium with HLA-DRB1. associated with SLE in Caucasians. Replication of the bFCGR3A 176F allele was associated with the risk of lupus association of rs1143679 with SLE susceptibility in an nephritis. independent Caucasian population and in African cAlthough associations of BLK and BANK1 were reinforced by Americans and Gullahs lead to the hypothesis that the recent unpublished work, further confirmation needed. A allele at rs1143679 that converts an arginine to a dThe rs1143679 SNP of ITGAM was monomorphic in Korean and histidine at amino-acid position 77 is a risk SNP for Japanese populations as well as no association of the rs6445975 SNP ITGAM, but this amino-acid change did not influence of PXK in Koreans, but these studies were limited to SNP analysis, C3bi binding site.193 A study of ITGAM in 661 Korean therefore further fine-mapping analysis of ITGAM and PXK and 176 Japanese patients with SLE found that rs1143679 needed.

Genes and Immunity Genetic studies of SLE in Asia IKimet al 426 associations across ethnicities. IRF5 and STAT4 were wide networking and collaboration will therefore be recently shown to be strongly associated with SLE, and required to find true-positive genetic associations in these results have been supported by replication studies future SLE studies. and GWASs. However, allelic heterogeneity in HLA- DRB1 and IRF5, and genetic heterogeneity in FCGR gene family have been seen. MECP2 showed the same genetic Materials and methods associations in Caucasians and Koreans, but confirmation in an independent population is needed. Although a GWAS is in progress in a few countries (including Web search tools and search terms Korea), GWL studies and GWASs have not been We searched PubMed using following keywords: ‘lupus performed with Asian populations, and a systematic erythematosus, systemic/genetics’[Mesh] and (‘genetic approach—such as finding novel susceptible genetic loci, predisposition to disease/genetics’[Mesh] or ‘genetic confirming them and then identifying their functions—is markers/genetics’[Mesh] or ‘linkage (genetics)/genetics’ lacking. Also, many Asian studies have been limited to [Mesh] or ‘polymorphism, genetic’[Mesh]). To obtain evaluate association of SNP without resequencing, which further information on Asian studies, we searched have been proved to be associated with SLE previously, national databases in Korea and Japan for SLE genetic and studies using tag SNP were lacking. In addition, studies using the above search terms. The Chinese collaboration between centers needs to be improved so national database was not searched because it was not that sufficient numbers of patients are available. World- available at our institute.

Inclusion/exclusion criteria for relevant SLE genetic studies A total of 755 articles were found, including 46 and 16 from the Korean and Japanese national databases, respectively. After reviewing the discovered articles, 313 articles were excluded for the following reasons: SLE susceptibility was not studied (n ¼ 107), review article (n ¼ 60), animal or in vitro studies (n ¼ 48), duplication (n ¼ 43), unknown ethnicity (n ¼ 16), uni- dentified content (n ¼ 15), meta-analysis (n ¼ 12) and no information on SNPs (n ¼ 12). After applying these exclusion criteria, 442 studies—including 17 linkage studies, 2 GWASs and 423 candidate-gene analysis studies—were reviewed (Figure 1). Among them, 177 (40.0%) studies involved Asian populations, with more than 90% of the Asian studies involving East Asian populations (that is, Korean, Japanese and Chinese) (Table 1). SLE-susceptible genes and their chromosome Figure 1 Flow chart of inclusion/exclusion criteria for relevant loci were summarized in Figure 2 and Supplementary systemic lupus erythematosus (SLE) genetic studies. Table 2.

1 2 3 4 5 6 7 8 9 10 11 12 BLK 8p23-22

HLA-DRB1, 6p21.3 DNase3 3p21.31 TAP-1/-2, (Trex1) TNF-α/-β, C2, C4, MICA MBL 10q11.2-21 11q12 PXK 3p14.3 DNase4 PTPN22 1p13.1-13.3 BANK1 4q24

FCRL3 1q21-22 IRF5 7q32 FCGR 1q23 gene STAT4 2q32.2-32.3 family CTLA-4 2q33 PARP 1q41 PDCD1 2q37.3

13 14 15 16 17 18 19 20 21 22 Y X MHC2TA 16p13 DNMT1 DNase1 19p13.2-13.3 16p13.3 DNase2 19p13.2 ITGAM 16p11.2 MCP-1 17q11.2-12 OAZ 16q12.1

MECP2 Xq28 DNase3 (TREX2) Figure 2 The SLE-susceptibility gene map. The map includes SLE-susceptibility genes and their loci summarized in this article.

Genes and Immunity Genetic studies of SLE in Asia IKimet al 427 Conflict of interest 14 Zhang J, Ai R, Chow F. The polymorphisms of HLA-DR and TNF B loci in northern Chinese Han nationality and The authors declare no conflict of interest. susceptibility to systemic lupus erythematosus. Chin Med Sci J 1997; 12: 107–110. 15 Zhang J, Zhou F, Ai R. [Study on some susceptible genes of systemic lupus erythematosus in Han nationality of China]. Acknowledgements Zhonghua Nei Ke Za Zhi 1996; 35: 19–22. 16 Doherty DG, Ireland R, Demaine AG, Wang F, Veerapan K, This study was supported by a grant of the Korea Welsh KI et al. Major histocompatibility complex genes and Healthcare technology R&D project, Ministry for Health, susceptibility to systemic lupus erythematosus in southern Welfare and Family Affairs, Republic of Korea (no. Chinese. Arthritis Rheum 1992; 35: 641–646. A010252 and A080588) and the Research Program for 17 Wang M, Dong Y, Huang S. 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