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

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Genetic Studies of Systemic Lupus Erythematosus in Asia: Where Are We Now? Genes and Immunity (2009) 10, 421–432 & 2009 Macmillan Publishers Limited All rights reserved 1466-4879/09 $32.00 www.nature.com/gene 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
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