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Objective: Systemic lupus erythematosus (SLE) is a highly heritable complex disorder with heterogeneous clinical manifestations. In this study, we aimed to identify the genetic risk load using clinical and serological manifestations in SLE patients. Methods: We genotyped a total of 1,655 Korean patients with SLE (n = 1,243 as a discovery set and n = 412 as a replication set) using a customized genome‐wide single‐nucleotide polymorphism (SNP) array, KoreanChip. A weighted genetic risk score (wGRS) for an individual was calculated from 112 well‐validated non‐HLA SNPs and HLA haplotypes of SLE‐risk loci. We analyzed associations between individual wGRS and clinical SLE subphenotypes and autoantibodies using multivariable linear or logistic regression adjusted by onset age, sex, and disease duration. Results: Childhood‐onset SLE (<16 years) conferred the highest genetic risk compared with adult‐onset (16–50 years) or late‐onset (>50 years) SLE (P = 6.8 × 10−6). High wGRS significantly increased associations with SLE manifestations, regardless of onset age, sex, and disease duration. Individual wGRS significantly correlated positively with more clinical American College of Rheumatology criteria (β = 0.143, P = 1.8 × 10−6). Subphenotype analysis revealed significant associations between the highest and lowest wGRS quartile with risk of renal disorder (hazard ratio [HR] 1.74, P = 2.2 × 10−8) and anti–Sm antibody production (HR 1.85, P = 2.8 × 10−5). Higher wGRS markedly modulated the pathogenesis of proliferative and membranous lupus nephritis class III or IV (HR 1.98, P = 1.6 × 10−5) and class V (HR 2.79, P = 1.0 × 10−3), but especially lupus nephritis class V in anti–Sm‐positive SLE (area under the curve 0.68, P = 1.8 × 10−4). Conclusion: Patients with SLE and high wGRS tended to have earlier age of SLE onset, higher anti–Sm antibody positivity, and more diverse clinical phenotypes. Genetic profiling may predict high risk for lupus nephritis and a diverse clinical course in SLE patients. [ABSTRACT FROM AUTHOR]

Human leukocyte antigen (HLA) is a key genetic factor conferring risk of systemic lupus erythematosus (SLE), but precise independent localization of HLA effects is extremely challenging. As a result, the contribution of specific HLA alleles and amino-acid residues to the overall risk of SLE and to risk of specific autoantibodies are far from completely understood. Here, we dissected (a) overall SLE association signals across HLA, (b) HLA-peptide interaction, and (c) residue-autoantibody association. Classical alleles, SNPs, and amino-acid residues of eight HLA genes were imputed across 4,915 SLE cases and 13,513 controls from Eastern Asia. We performed association followed by conditional analysis across HLA, assessing both overall SLE risk and risk of autoantibody production. DR15 alleles HLA-DRB1*15:01 (P = 1.4x10-27, odds ratio (OR) = 1.57) and HLA-DQB1*06:02 (P = 7.4x10-23, OR = 1.55) formed the most significant haplotype (OR = 2.33). Conditioned protein-residue signals were stronger than allele signals and mapped predominantly to HLA-DRB1 residue 13 (P = 2.2x10-75) and its proxy position 11 (P = 1.1x10-67), followed by HLA-DRB1-37 (P = 4.5x10-24). After conditioning on HLA-DRB1, novel associations at HLA-A-70 (P = 1.4x10-8), HLA-DPB1-35 (P = 9.0x10-16), HLA-DQB1-37 (P = 2.7x10-14), and HLA-B-9 (P = 6.5x10-15) emerged. Together, these seven residues increased the proportion of explained heritability due to HLA to 2.6%. Risk residues for both overall disease and hallmark autoantibodies (i.e., nRNP: DRB1-11, P = 2.0x10-14; DRB1-13, P = 2.9x10-13; DRB1-30, P = 3.9x10-14) localized to the peptide-binding groove of HLA-DRB1. Enrichment for specific amino-acid characteristics in the peptide-binding groove correlated with overall SLE risk and with autoantibody presence. Risk residues were in primarily negatively charged side-chains, in contrast with rheumatoid arthritis. We identified novel SLE signals in HLA Class I loci (HLA-A, HLA-B), and localized primary Class II signals to five residues in HLA-DRB1, HLA-DPB1, and HLA-DQB1. These findings provide insights about the mechanisms by which the risk residues interact with each other to produce autoantibodies and are involved in SLE pathophysiology. [ABSTRACT FROM AUTHOR]

Objective Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder whose etiology is incompletely understood, but likely involves environmental triggers in genetically susceptible individuals. Using an unbiased genome-wide association (GWA) scan and replication analysis, we sought to identify the genetic loci associated with SLE in a Korean population. Methods A total of 1,174 SLE cases and 4,246 population controls from Korea were genotyped and analyzed with a GWA scan to identify single-nucleotide polymorphisms (SNPs) significantly associated with SLE, after strict quality control measures were applied. For select variants, replication of SLE risk loci was tested in an independent data set of 1,416 SLE cases and 1,145 population controls from Korea and China. Results Eleven regions outside the HLA exceeded the genome-wide significance level ( P = 5 × 10−8). A novel SNP-SLE association was identified between FCHSD2 and P2RY2, peaking at rs11235667 ( P = 1.03 × 10−8, odds ratio [OR] 0.59) on a 33-kb haplotype upstream of ATG16L2. In the independent replication data set, the SNP rs11235667 continued to show a significant association with SLE (replication meta-analysis P = 0.001, overall meta-analysis P = 6.67 × 10−11; OR 0.63). Within the HLA region, the SNP-SLE association peaked in the class II region at rs116727542, with multiple independent effects observed in this region. Classic HLA allele imputation analysis identified HLA-DRB1*1501 and HLA-DQB1*0602, each highly correlated with one another, as most strongly associated with SLE. Ten previously established SLE risk loci were replicated: STAT1- STAT4, TNFSF4, TNFAIP3, IKZF1, HIP1, IRF5, BLK, WDFY4, ETS1, and IRAK1- MECP2. Of these loci, previously unreported, independent second risk effects of SNPs in TNFAIP3 and TNFSF4, as well as differences in the association with a putative causal variant in the WDFY4 region, were identified. Conclusion Further studies are needed to identify true SLE risk effects in other loci suggestive of a significant association, and to identify the causal variants in the regions of ATG16L2, FCHSD2, and P2RY2. [ABSTRACT FROM AUTHOR]

Objective To investigate the association between HLA-DRB1 alleles and systemic lupus erythematosus (SLE) susceptibility and features of SLE, such as clinical manifestations and autoantibody profiles, in a Korean population. Methods We tested the genetic associations between HLA-DRB1 alleles and SLE susceptibility and clinical subphenotypes in 1,089 patients with SLE and 2,161 control subjects, including a discovery set (475 patients and 1,119 controls) and a replication set (614 patients and 1,042 controls). We used a relative predispositional effects (RPEs) method to examine the independent effect of each allele associated with SLE or its subphenotypes. Results We identified 4 HLA-DRB1 alleles that were associated with increased susceptibility to SLE, 2 of which had been detected previously (*15:01; P for RPE = 1.11 × 10−13, odds ratio [OR] 1.88) and *09:01 ( P for RPE = 1.59 × 10−5, OR 1.46), and 2 of which were novel alleles (*08:03 [ P for RPE = 8.80 × 10−8, OR 1.62]) and *07:01 ( P for RPE = 1.14 × 10−6, OR 1.57)]. In addition, protective effects on the development of SLE were observed for 2 novel alleles (HLA-DRB1*12:02 [ P for RPE = 6.35 × 10−4, OR 0.49]) and *11:01 [ P for RPE = 1.24 × 10−3, OR 0.59]). The SLE risk alleles had an additive genetic effect, as demonstrated by the finding that double copies of these alleles (OR 3.38) had larger risk effects size compared with single copies (OR 1.95) and no copy (OR 1 [reference]). In a subphenotype analysis, various HLA-DRB1 alleles (including SLE risk alleles) were observed to have significant predispositional effects on diverse clinical manifestations. In particular, HLA-DRB1*15:01 (OR 2.30), *09:01 (OR 2.46), *07:01 (OR 2.61), and *08:03 (OR 2.97) were strongly associated with the risk of anti-Sm antibody production. Conclusion We detected 6 HLA-DRB1 alleles that were associated with SLE in Koreans. The SLE risk alleles promoted the production of autoantibodies, including anti-Sm, and diverse clinical manifestations. [ABSTRACT FROM AUTHOR]

The genetic association of HLA-DRB1 with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) is well documented, but association with other HLA-DR beta genes (HLA-DRB3, HLA-DRB4 and HLA-DRB5) has not been thoroughly studied, despite their similar functions and chromosomal positions. We examined variants in all functional HLA-DR beta genes in RA and SLE patients and controls, down to the amino-acid level, to better understand disease association with the HLA-DR locus. To this end, we improved an existing HLA reference panel to impute variants in all protein-coding HLA-DR beta genes. Using the reference panel, HLA variants were inferred from high-density SNP data of 9,271 RA-control subjects and 5,342 SLE-control subjects. Disease association tests were performed by logistic regression and log-likelihood ratio tests. After imputation using the newly constructed HLA reference panel and statistical analysis, we observed that HLA-DRB1 variants better accounted for the association between MHC and susceptibility to RA and SLE than did the other three HLA-DRB variants. Moreover, there were no secondary effects in HLA-DRB3, HLA-DRB4, or HLA-DRB5 in RA or SLE. Of all the HLA-DR beta chain paralogs, those encoded by HLA-DRB1 solely or dominantly influence susceptibility to RA and SLE. [ABSTRACT FROM AUTHOR]

Recent advances in systemic lupus erythematosus (SLE) genetics in Asian populations have been achieved by genome- wide association studies (GWASs) and following replication studies, which expanded the genetic information about shared or population-specific risk genes between ethnic groups. Meta-analyses and multi-ethnic replication studies may be possible approaches that could demonstrate stronger or more suggestive evidence for multiple variants for SLE. In addition to the susceptibility of SLE itself, several genotype-phenotype analyses have shown that the specific phenotypes of SLE can also be influenced by genetic factors. Almost all SLE genetic loci are involved in the potential pathways of SLE pathogenesis, such as Toll-like receptor/type I interferon signaling, nuclear factor jB signaling, immune complex clearing mechanism, immune cell (B, T cell, neutrophil and monocyte) function and signaling, cell-cycle regulation, DNA methylation and autophagy. Further studies, including the next generation sequencing technology and the systematic strategy using bioinformatics, in addition to international collaboration among SLE genetic researchers, will give us better understanding of the genetic basis of SLE. [ABSTRACT FROM AUTHOR]

Objective Several copy number variations (CNVs) have been found to be associated with systemic lupus erythematosus (SLE) through the target gene approach. However, genome-wide features of CNVs and their role in the risk of SLE remain unknown. The aim of this study was to identify SLE-associated CNVs in Korean women. Methods Genome-wide assessments of CNVs were performed in 382 SLE patients and 191 control subjects, using an Illumina HumanHap610 BeadChip genotyping platform. SLE-associated CNV regions that were identified by genome-wide association study (GWAS) were replicated in quantitative polymerase chain reaction (PCR) and deletion-typing PCR analyses in an independent sample set comprising 564 SLE patients and 511 control subjects. Results Of 144 common CNV regions, 3 deletion-type CNV regions in 1q25.1, 8q23.3, and 10q21.3 were found to be significantly associated with SLE by GWAS analysis. In the independent replication, the CNV regions in 1q25.1 ( RABGAP1L) and 10q21.3 were successfully replicated (odds ratio [OR] 1.30, P = 0.038 and OR 1.90, P = 3.6 × 10−5, respectively), and the associations were confirmed again by deletion-typing PCR. The CNV region in the C4 gene, which showed a potential association in the discovery stage, was included in the replication analysis and was found to be significantly associated with the risk of SLE (OR 1.88, P = 0.01). Through deletion-typing PCR, the exact sizes and breakpoint sequences of the deletions were defined. Individuals with the deletions in all 3 loci ( RABGAP1L, 10q21.3, and C4) had a much higher risk of SLE than did those without any deletions in the 3 loci (OR 5.52, P = 3.9 × 10−4). Conclusion These CNV regions can be useful to identify the pathogenic mechanisms of SLE, and might be used to more accurately predict the risk of SLE by taking into consideration their synergistic effects on disease susceptibility. [ABSTRACT FROM AUTHOR]

DNase II is an important enzyme for DNA fragmentation and degradation during programmed cell death and, consequently, a potential candidate gene for genetic study of systemic lupus erythematosus (SLE). Genetic associations of DNase II with SLE and related phenotypes were examined in Korean patients with SLE. A total of 350 Korean SLE patients and 330 healthy subjects were enrolled. Direct DNA sequencing and TaqMan were employed. Logistic regression analyses were performed to examine the genetic association with SLE and related phenotypes. Through direct sequencing in 24 Korean individuals, six sequence variants were identified: one in the 5' flanking region, four in exons (including one nonsynonymous), and one in the 3' flanking region. Four of these polymorphisms were selected for a larger-scale genotyping (350 SLE patients and 330 normal controls). No significant associations with the risk of SLE were detected. However, further analyses of association with the risk of renal disorder among SLE patients revealed several positive associations. One promoter SNP (-1066G>C), +2630T>C(Ser145Ser), +6235G>Cand one haplotype showed weak associations with the risk of nephritis among SLE patients. [ABSTRACT FROM AUTHOR]

Background: Rheumatoid arthritis is a chronic inflammatory disease with a substantial genetic component. Susceptibility to disease has been linked with a region on chromosome 2q. Methods: We tested single-nucleotide polymorphisms (SNPs) in and around 13 candidate genes within the previously linked chromosome 2q region for association with rheumatoid arthritis. We then performed fine mapping of the STAT1–STAT4 region in a total of 1620 case patients with established rheumatoid arthritis and 2635 controls, all from North America. Implicated SNPs were further tested in an independent case–control series of 1529 patients with early rheumatoid arthritis and 881 controls, all from Sweden, and in a total of 1039 case patients and 1248 controls from three series of patients with systemic lupus erythematosus. Results: A SNP haplotype in the third intron of STAT4 was associated with susceptibility to both rheumatoid arthritis and systemic lupus erythematosus. The minor alleles of the haplotype-defining SNPs were present in 27% of chromosomes of patients with established rheumatoid arthritis, as compared with 22% of those of controls (for the SNP rs7574865, P=2.81×10−7; odds ratio for having the risk allele in chromosomes of patients vs. those of controls, 1.32). The association was replicated in Swedish patients with recent-onset rheumatoid arthritis (P=0.02) and matched controls. The haplotype marked by rs7574865 was strongly associated with lupus, being present on 31% of chromosomes of case patients and 22% of those of controls (P=1.87×10−9; odds ratio for having the risk allele in chromosomes of patients vs. those of controls, 1.55). Homozygosity of the risk allele, as compared with absence of the allele, was associated with a more than doubled risk for lupus and a 60% increased risk for rheumatoid arthritis. Conclusions: A haplotype of STAT4 is associated with increased risk for both rheumatoid arthritis and systemic lupus erythematosus, suggesting a shared pathway for these illnesses. N Engl J Med 2007;357:977-86. [ABSTRACT FROM AUTHOR]